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Journal of Controlled Release 61 (1999) 1–8 Preparation and evaluation of double-phased mucoadhesive suppositories of lidocaine utilizing Carbopol and white Beeswax Reiko Yahagi, Hiraku Onishi, Yoshiharu Machida* Department of Clinical Pharmacy, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 1428501, Japan 指導老師: 林 鴻 儒 博士 學生: 曾 昭 智 日期: 97/12/19 Introduction • 栓劑為供放於肛門或 陰道的一種製劑，其 形狀或重量因使用部 位不同而異。通常於 體溫時即能溶解或熔 化，使藥物發揮療效。 • 栓劑給藥後經直腸黏 膜細胞吸收之後，一 條通過直腸上靜脈進 入肝臟代謝，代謝後 再進入體循環；另一 條則經直腸下靜脈直 接進入體循環。 http://www.innerbody.com/image/digeov.html Introduction •一般栓劑給藥後會移動到上端直腸同時溶解或熔 化，因此藥物容易經由直腸上靜脈進入肝臟造成 首過效應(first-pass effect)。 •本實驗為了避免首過效應(first-pass effect)，而製 備雙層黏附栓劑來增加栓劑在末端直腸的滯留時 間。 Materials • Lidocaine (LID) 做為模型藥物，因為它單獨服 用時有明顯的首過效應。 • Witepsol H-15 (H-15) 脂肪酸，做為栓劑的基質。 • Carbopol 934P (CP) 聚丙烯酸，提升栓劑基質的 黏附性。 • White beeswax 維持栓劑的形狀。 雙層栓劑的製備 Methods H-15和WAX混合加熱至 60℃ 加入CP超音波震盪 10 min 含藥層 H-15加熱至60℃ 加入CP超音波震盪 10 min 加入LID混合 灌入模具 室溫冷卻後脫模；切取栓體 前20 mm再塞入模具 將60℃的含藥層灌入模具 內，室溫冷卻後脫模即得 雙層栓劑。 Results and discussion Table 1 Effect of white beeswax content on suppository base hardness Each value represents the mean ± SD of five experiments. Results and discussion △H Fig. 1. Endothermic curve for Witepsol H-15 containing 10% Carbopol and white beeswax in the differential scanning calorimeter. Heating rate is 3℃/min. Results and discussion Fig. 2. Movement of suppositories containing white beeswax in the recta of rats. ●: CP 10%, ○: CP 10%–WAX 10%, △: CP 10%–WAX 20%, □: CP 10% – WAX 30% (*P＜0.05, **P ＜ 0.01 vs. CP 10%). Each point represents the mean±SE of four rats. Results and discussion Fig. 3. Structure of double-phased suppository. Results and discussion Fig. 4. Release profiles of lidocaine from suppositories in second fluid of JP XIII at 37℃. ●: H-15 alone, ○: CP 2%, △: CP 5%, □: CP10%. Each point represents the mean±SE of three experiments. Results and discussion Fig. 5. Plasma concentration profiles of lidocaine (a), monoethylglycine xylidide (b), and glycine xylidide (c) after rectal administration of suppositories to rabbits. ● : H-15 alone, ○: CP 2%, △: CP 5%, □: CP 10%(*P ＜ 0.05, **P ＜ 0.01, ***P ＜ 0.001 vs. H-15 alone). Each point represents the mean±SE of three to five rabbits. Results and discussion Fig. 6. Comparisons of AUCs of lidocaine and metabolites after rectal administration of suppositories to rabbits (*P＜0.05, ***P＜0.001 vs. H-15 alone). Each point represents the mean±SE of three to five experiments. Results and discussion Fig. 7. Effect of CP content on MRT values for lidocaine and metabolites after rectal administration of suppositories to rabbits. ○: LID (single-phased), △: MEGX (single-phased), □: GX (single-phased), ●: LID (double-phased), ▲: MEGX (double-phased), ■: GX (double-phased). Each point represents the mean±SE of three to five experiments. Conclusions •結果顯示以H-15﹢CP10% ﹢WAX20%當固定層和 H-15﹢CP5% ﹢LID當藥物釋放層為雙層栓劑的最 佳比例。 • 雙層栓劑能在末端直腸滯留和適當的藥物釋放特 性，有助於藥物在末端直腸的吸收。而且能提升 藥物的生物可利用度和避免首過效應(first-pass effect)。 Thanks for your attention !! 首過效應（first-pass effect ）: 藥物在尚未進入體循環前，先被腸胃或肝臟 代謝，而使進入體循環的原形藥量減少的現象。 首過效應會使藥物的生物利用度降低，而影響藥 物的療效。 生物利用度: 藥物被吸收進入體循環的相對量和速率。