慢性搔癢症為導致病患生活品質下降的一個因素。研究指出鴉片類受體對於誘發及緩解搔癢有其作用，且許多混合型鴉片類受體促效及抑制劑被發現可有效緩解搔癢症。Nalbuphine (NA) 有 μ 受體拮抗及 κ 受體促效之作用，並且有研究指出其具有緩解鴉片導致的搔癢副作用之功能。NCKU125 為一個 NA 的前驅藥物，其高脂溶性及高分子量使其劑型設計以及經皮藥物遞送有所困難。研究指出奈米脂質顆粒遞藥系統可增加高脂溶性藥物的溶解度並增加藥物的皮膚穿透量，其中的奈米結構脂質載體 (nanostructured lipid carrier, NLC)由於其高物理安定性、藥物保護作用、以及其多種皮膚穿透途徑及易於製備等優點被選擇用於製備NCKU125 的遞藥系統。本研究之目的為研發包載 NCKU125 的 NLC 處方，並藉處方設計以解決 NCKU125 在水性環境中的安定性問題以及藉 NLC 之特性增加皮膚穿透速率，且該處方需有延長藥物釋出的特性以及適當的止癢效果。
本研究首先藉NCKU125 之溶解度篩選賦形劑，並評估 NCKU125 於液態油賦形劑中之安定性。利用熱均質法製備NCKU125-NLC 處方，並評估其粒徑、界面電位、酸鹼度、包覆率，以及28 天的室溫儲存之安定性，同時使用穿透式電子顯微鏡 (TEM) 觀察 NLC 之形態。體外 NCKU125 之藥物釋出試驗以及小鼠皮膚穿透試驗使用經皮吸收儀 (flow-through diffusion cell) 進行，製備包覆尼羅紅 (Nile red, NR) 的 NLC 以觀察 NLC 在皮膚中之分佈情形。建立 Substance P 誘導的小鼠抓癢模式，用於評估 NCKU125-NLC 之止癢效果。
經溶解度篩選結果，本研究選擇以 Geleol 和 Precirol ATO5 為固態油，以 oleic acid、oleyl alcohol、和 capyrol 90 為液態油，以水和 5 mM Na2HPO4 為水相，開發出 8 種包載 0.5% NCKU125 的 NLC 處方，其中以 capryol 90 液態油之處方— PCS (Precirol ATO5/ capryol 90/ 5 mM Na2HPO4) 及 GCS (Geleol/ capryol 90/ 5 mM Na2HPO4) 具有 NCKU125 在 NLC 處方中的室溫儲存安定性。各個含有 0.5% NCKU125 之處方粒徑在 200~400 nm 之間且 PDI 小於 0.3，ζ 電位及 pH 值分別為 -25~-50 mV 以及 4.9~7.0，而在 liquid cell-TEM 觀察下呈現分散之顆粒形態。所有 NLC 處方皆有超過 97% 的 NCKU125 包覆率，而體外藥物釋出試驗顯示各處方皆具有延長釋出的特性，且以 oleyl alcohol 和 capryol 90 為液態油處方的藥物釋出量大於含 oleic acid 的處方。體外皮膚穿透試驗顯示 PCS 及 GCS 分別在有限劑量及無限劑量之試驗中有最高的藥物穿透量，且NR-NLC 相較於NR 油溶液有較強的NR螢光分佈至毛囊中。皮膚投予 GCS 和 PCS 處方於 substance P 誘導之小鼠抓癢模式相較於 NLC 控制組均可降低抓癢次數，但未達到顯著性差異，且止癢效果隨時間延長而降低。
綜合上述，本研究成功開發出可包覆 NCKU125 之 NLC 處方，其中以 PCS 及 GCS 處方具有最佳的 NCKU125 化學安定性，並且有延長釋出的特性及較高之 NCKU125 釋出量與皮膚穿透量，同時在 substance P 誘導搔癢小鼠模式中具些許止癢效果。如何更有效的延長止癢之時間以及效果，為未來進一步研究的方向。

Summary

Nalbuphine is one of the opioid analgesics that possess mixed agonist/ antagonist effects. It is clinically used to manage moderate to severe pain and off-label used in the management of opioid-induced pruritus. NCKU125 is a nalbuphine prodrug synthesized to overcome its short elimination half-life and to prolong its action duration. The objective of this study was to develop NCKU125-loaded nanostructured lipid carrier (NLC) formulations with good stability, sustained drug release characteristics, and sufficient antipruritic effect. NLC formulations loaded with NCKU125 were developed with good entrapment efficiencies using Geleol/ Precirol ATO5 as solid lipids, oleic acid/ oleyl alcohol/ capryol 90 as oils, poloxamer 188 as surfactant, and water/ 5 mM Na2HPO4 as aqueous phase. The particle size, ζ-potential, and pH of these formulations were characterized. TEM images revealed spherical and dispersed particles of NLCs. Excipients were shown to influence the stability of NCKU125, with capryol 90 being the most suitable oil for NCKU125’s stability. The in vitro release study demonstrated the sustained drug release characteristics of the NLC formulations. Skin penetration study has shown NCKU125 and nalbuphine penetrated through the skin, and delivery of Nile red from NLC into hair follicles was observed under fluorescence microscope. Topical application of two NCKU125-NLC formulations reduced scratching numbers in substance P-induced scratching mouse model, but was not significantly different from NLC control. In conclusion, topical NCKU125-NLC formulations were successfully developed with good NCKU125 stability, sustained release characteristics, and some antipruritic effect.

Key words: nanostructured lipid carrier, topical delivery, nalbuphine, prodrug, antipruritus

Introduction
Chronic pruritus is a factor that influences patients’ quality of life. Studies have suggested that opioid receptors have a role in the induction and alleviation of pruritus. Many opioid receptor mixed agonist/ antagonists were shown to be effective in alleviating pruritus, and one of them is nalbuphine. Nalbuphine is a μ receptor antagonist and κ receptor agonist, which is clinically used to manage moderate to severe pain and off-label used in the management of opioid-induced pruritus. Its application for alleviating chronic pruritus such as uremic pruritus is under development. With its short elimination half-life (2~3 hours), several prodrugs were synthesized to prolong its duration of action. NCKU125 is one of the prodrugs that were synthesized. With its large molecular weight and high lipophilicity, formulating it will be difficult and poor skin permeation can be expected. The main drug delivery routes across the skin include intercellular permeation and hair follicle penetration. Nano-sized formulations, however, may help enhancing solubility of highly lipophilic drugs and facilitating drug penetration through hair follicles. Lipid-based nanoparticles were considered to be a choice for topical formulation due to their lipophilic characteristics. Nanostructured lipid carrier (NLC) is one of the lipid-based nanoparticles widely investigated for topical drug delivery systems. It is a colloidal dispersion system that uses lipid and oil mixture as nanoparticle matrix and disperses in aqueous phase. It has the advantages of high drug loading capacity, good physicochemical stability, and ease of preparation. Studies have shown that NLCs facilitate intercellular permeation as well as hair follicle transport, and thus enhancing drug permeation efficiency. NLC can be a potential delivery system which not only make formulating NCKU125 possible, but drug permeation enhancement can also be expected. The objective of this study was to develop NCKU125-loaded NLC formulations which would present good NCKU125 stability, sustained release characteristics, and sufficient antipruritic effect.

Methods
Various excipients including lipids, oils, and surfactants were screened for NCKU125’s solubility. The stability of NCKU125 in oils was assessed. HPLC was employed to quantify amounts of NCKU125 and NA. NLC formulations were prepared by melting and mixing of lipid components containing NCKU125 with aqueous phase containing poloxamer 188, followed by homogenization and sonification. The prepared NLCs were evaluated for their particle characteristics, drug entrapment efficiency and stability in NLCs, and their morphology under TEM. The in vitro drug release and drug penetration through mouse skin were evaluated using Franz diffusion cell. Skin distribution of NLCs was examined under fluorescence microscopy following application of Nile red (NR) -NLC onto mouse skin. Antipruritic effect of NCKU125-NLCs was assessed in substance P-induced scratching mouse model.

Results
NLCs containing 0.5% NCKU125 were prepared using Geleol (G)/ Precirol ATO5 (P) as solid lipids, oleic acid (A)/ oleyl alcohol (L)/ capryol 90 (C) as oils, poloxamer 188 as surfactant, and water (W)/ 5 mM Na2HPO4 (S) as aqueous phase. Excipients were shown to influence the stability of NCKU125, with capryol 90 being the most suitable oil for NCKU125 stability. Particle size of NLC formulations ranged from 200~400 nm. ζ-potential and pH ranged from -25~-50 mV and 4.9~7.0, respectively. The entrapment efficiencies of all the formulations were greater than 97%. GCS (Geleol/ capryol 90/ 5 mM Na2¬HPO4) and PCS (Precirol ATO5/ capryol 90/ 5 mM Na2HPO4) were shown to be the most stable formulations for NCKU125, with drug content approximating 100% after 28 days of storage. Under liquid cell-TEM, PCS was shown as a dispersed, spherical particulate system. GCS, PCS, GLS, and PLS formulations released more drug in 24 hours than GAW, PAW, GAS, and PAS formulations. All of them demonstrated sustained drug release characteristics. Moreover, the highest skin penetration efficiency was shown with PCS and GCS when dosed with different amount of formulations. Fluorescence microscope revealed more intensive NR fluorescence in the hair follicles from NR-NLC than NR oil solution. Topical application of PCS- and GCS-NCKU125 reduced scratching numbers in substance P-induced scratching mouse model, but was not significantly different from NLC control. The antipruritic effects of these formulations gradually diminished with prolonged time after application.

Conclusion
NCKU125-NLC formulations were developed, and GCS as well as PCS have been shown with good NCKU125 stability, highest amount of sustained drug release and skin penetration efficiency, and also some antipruritic effect. Further investigation may be required to optimize NCKU125-NLC formulations to achieve sufficient antipruritic effect in the future.

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