Diclofenac Diethylamine 皮膚製劑研發   全文下載

Developing an Efficacious Diclofenac Diethylamine Transdermal Formulation

本研究目的為研發一有效的diclofenac diethylamine (DDA)局部外用配方，作為局部使用的止痛乳液。以2% W/V DDA加入1、2、3或4% V/V濃度的油酸（滲透增強劑）及松節油混合物（1:1 V/V），製備一系列的乳液。測量每個乳液的外觀，粘稠度，延展性，pH值和長期穩定性後，以細胞擴散法量化每個乳液對矽膜和兔子皮膚的滲透。隨後，以三個不同的動物試驗模型評估每個乳液的抗發炎，鎮痛和刺激性。最後，由志願者做人體試驗，評估對每個乳液的主觀感覺以及短期使用後可能對皮膚產生的刺激。 4個含DDA乳液（L1，L2和L3和L4）都呈透明，無色，均勻及不結塊狀態，pH值約6.2，配方間無顯著性（P > 0.05）差異（數據未顯示）。增加配方中油酸濃度，會溫和地增加DDA對矽模的穿透，且大幅改善對兔子皮膚的穿透。兔子試驗模型中，每個含DDA製劑都顯著降低其組織發炎。本研究確認含4% V/V油酸的DDA乳液具最佳整體性能，應可作為進一步臨床試驗的基礎。

The aim of current study was to develop an efficacious topical formulation of diclofenac diethylamine (DDA), for eventual use as a locally applied analgesic lotion. A series of lotions were prepared that incorporated 2% w/v DDA but a variable (1, 2, 3 or 4% v/v) concen-tration of oleic acid (permeation enhancer)-turpentine oil binary mixture (1:1 v/v). After measurements of each lotion’s visual appearance, viscosity, spreadability, pH and long term stability, a diffusion cell method was employed to quantify DDA permeation from each lotion across both silicone membranes and rabbit skin. Subsequently, three distinct in vivo animal models were utilised to evaluate each lotion’s induced anti-inflammatory, antinociception and irritancy effects. Lastly, a panel of human volunteers assessed the subjective sensory feel of each lotion as well as its potential for cutaneous irritancy following a brief application. Upon preparation, all four DDA-containing lotions (L1, L2, L3 and L4) appeared as clear, colourless, homogenous and aggregate-free solutions. All the lotions exhibited a pH of ~6.2 with non-significant (p > 0.05) differences between each formulation (data not shown). Increasing the formulation’s oleic acid concentration yielded a general trend of mild enhancement of DDA transport across silicone membrane and dramatic improvements of DDA flux through rabbit skin. Application of each of the DDA-containing formulations significantly reduced tissue inflammation in the rabbit model. It was determined that the DDA lotion containing 4% v/v oleic acid exhibited the best performance overall and that this specific formulation should be the basis for further clinical investigation.