奈米結構脂質載體之研究及其經皮遞送之應用

Abstract

經皮藥物遞送系統是藉由藥物分子經由皮膚外側吸收進入血流和皮下各層組織的一種給藥方式。近年來其應用不斷地受到矚目，主要原因是它所提供的方便性及安全性。更值得一提的是，對於不同藥物的投予需求也可以發揮功能性的幫助，例如已被廣泛使用的局部用藥就是以經皮藥物遞送系統提供局部且控釋的療效，也可以避免傳統藥物投予途徑帶來的負作用（例如口服非固醇類消炎藥引起的腸胃道不適）；或者是具有酸鹼不穩定性的藥物，可以利用經皮藥物遞送系統提供一個新的藥物遞輸途徑，避免在口服給藥的過程中被消化道多變的酸鹼性環境所破壞。在本研究中，主要針對吲哚洒美辛與蘭索拉唑進行奈米脂質顆粒劑型的製備與應用的探討。 藉由混合不同類型的油脂質作油相，與不同的乳化系統為水相，製備出含藥固體脂質奈米粒與奈米結構脂質載體。並且對製劑成品進行基本的物性探討，例如不同賦型劑組合下的熱分析性質、其表面電位與粒徑以及製劑與藥物安定性分析。並且對不同的奈米脂質顆粒製劑，以直立式擴散槽與動物或人工皮膜，進行的體外穿透試驗；或以大鼠進行體內經皮吸收試驗，評估不同劑型與給藥方式下，藥物的體外穿透程度或體內藥物動力學性質。 實驗結果顯示，以示差掃描熱分析儀與光學顯微鏡觀察的結果，由Precirol ATO 5與castor oil組成的油相基質最符合吲哚美洒辛奈米結構脂質載體在熱力學與藥物性質上的製劑需求，並且在油相中使用結晶抑制劑可以進一步降低吲哚美洒辛的結晶性，有助於有助於維持製劑的存放安定性。製備完成的吲哚美洒辛奈米結構脂質載體的粒徑大約在200 nm，表面電位為-10 mV。吲哚美洒辛奈米結構脂質載體在小豬皮上具有兩段式的藥物穿透性質，相較於市售凝膠屬較為緩慢，適合應用於慢性疼或發炎等症狀。 蘭索拉唑奈米結構脂質載體，其粒徑、表面電位與熱性質受固體脂質的選擇與搭配比例，以及水相中乳化劑的選擇影響而有所不同。使用硬脂胺作為油相的材料有助於維持蘭索拉唑在製劑過程中的安定性。以無毛天竺鼠皮與大白鼠皮所進行的藥物體外穿透試驗中，藥物的穿透能力受配方組成改變有很大的影響，油相中的硬脂胺可以提高藥物穿透的能力，而不同種類穿透促進劑對於提供藥物穿透最大的效益上有不同的最適添加濃度。體內經皮吸收試驗的結果，顯示蘭索拉唑奈米結構脂質載體的親水凝膠製劑與靜脈注射及口服蘭索拉唑相比，提供了延長藥物體內滯留的特性，適合應用於產生慢性胃食道逆流症狀之消化道疾病。

The transdermal drug delivery system (TDDS) becomes more attractive in recent years by providing a convenient and safe drug administration route. For different drugs, it can further serve as functional roles in different purposes, for example, providing a localized and controlled drug delivery for NSAIDs without side effects on gastrointestinal tract; or a new way of acid-labile drugs’ administration to avoid from degradation in gastrointestinal tract or liver. The aim of this study is to develop dosage forms of indomethacin and lansoprazole with lipid nanoparticles and further discuss the application on TDDS. By using different lipid blends as the oil phase and various emulsification systems, we prepared different drug loaded solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC), and determined their physical properties, such as thermal behavior, particle size, zeta-potential, and storage stability. Finally, we also examined the in vitro drug permeation and in vivo pharmacokinetic study of different dosage forms. As the results from differential scanning calorimetry and light spectrometer, the oil phase with a blend of Precirol ATO 5 and castor oil provides suitable physical properties for carrying indomethacin., and the storage stability can be further improved by combination of a crystallization inhibitor in the oil phase. The size of indomethacin loaded NLCs is around 200 nm, and zeta-potential is about -10 mV. Indomethacin loaded NLC provides a two-stage permeation behavior, and its drug permeation ability is lower than a commercial gel, which is benefit for treating chronic pain and inflammation. Particle size , zeta-potential and thermal behavior of the lansoprazole loaded NLCs are related with the compositions in different ratio of lipids or surfactants. Stearylamine can protect lansoprazole from degradation during the hot-melt emulsification process. The in vitro drug permeation behavior of lansoprazole loaded NLC and NLC enriched hydrogel are affected by the formulation compositions. Stearylamine in oil phase helps drug permeation; different permeation enhancers in hydrogel provide the best improvement on drug permeation with different concentrations. The in vivo pharmacokinetic study shows that NLC enriched hydrogel applied in rats’ skin provides a prolonged drug delivery rather than either intravenous bolus or oral administration, which makes an improvement of treating chronic gastroesophageal reflux disease.