school

UM E-Theses Collection (澳門大學電子學位論文庫)

check Full Text
Title

利用噴霧冷凍乾燥和溶劑-蒸發法製備黃芩素固體分散體以提高其溶出度和口服生物利用度的研究

English Abstract

Spray freeze drying (SFD) has been successfully developed to prepare solid dispersions at ambient temperature, which was developed in the 1990s. SFD technology involves the atomization of a feed liquid containing poorly water-soluble or insoluble APIs and excipients directly into a cryogenic liquid at ambient temperature to produce a frozen micronized powder that is subsequently dried. This process offers a variety of advantages compared to traditional technologies for solid dispersions, including amorphous structure and high surface area. Baicalein (5, 6, 7-trihydroxyflavone), one of the major flavones isolated from the root of Scutellaria baicalensis, has been demonstrated to have numerous pharmacological activities including anti-inflammatory, antioxidative, anticancer, antiallergic, and antiviral effects. It is a Class II (i.e., poorly water-soluble and highly permeable, with Papp = 1.7×10-5 cm·s -1 ) API according to the Biopharmaceutics Classification System. Its poor water solubility (~0.13 mg·mL-1 ), inadequate dissolution, and extensive first-pass metabolism result in its low oral bioavailability and limit its use in the pharmaceutical field. The objective of this study was to prepare solid dispersions consisting of baicalein and a carrier with a low glass transition/melting point (Pluronic F68) by SFD technology. We compared these powders to those produced from the conventional solvent-evaporation method. In the SFD process, a feeding solution was atomized above the surface of liquid nitrogen following lyophilization, which resulted in instantaneously frozen microparticles. However, solid dispersions prepared by the solvent-evaporation method formed a sticky layer on the glass flask with crystalline baicalein separated out from the carrier. The powder samples were characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), surface area measurement, differential scanning calorimetry (DSC), and Fourier transform infrared spectrometry (FTIR). SEM and PXRD results suggested that the majority of baicalein in the SFD processed solid dispersion was in the amorphous state, which has a higher specific surface area than bulk baicalein. However, the majority of baicalein was recrystallized in the solid dispersion at the same composition prepared by the solvent-evaporation method, which showed a similar dissolution rate to the physical mixture. SFD product was physically and chemically stable after being stored at 40ºC with low humidity for six months. After enzyme hydrolysis, baicalein in the SFD product displayed a significantly shorter Tmax and higher Cmax than bulk baicalein after oral dosing. The relative bioavailability of the SFD product vs. bulk baicalein determined by comparing the AUC0-12 was 233%, which demonstrated the significantly improved oral bioavailability of baicalein produced by the SFD technique. Keywords: Solid dispersion; Baicalein; Pluronic F68; Spray freeze drying (SFD); Solvent evaporation; Dissolution; Bioavailability.

Chinese Abstract

噴霧冷凍乾燥技術是一種于九十年代發展起來的製備固體分散體的新技術, 這種製備方法因避免了加熱過程,特別適合將熱敏性藥物製備成固體分散體。噴 霧冷凍乾燥技術的製備過程大致為將溶有輔料和水難溶性藥物的溶液通過蠕動 泵輸送至噴嘴,在液氮上方噴霧而使霧滴在液氮中迅速被凍結成固態顆粒,隨後 將這些顆粒轉移至冷凍乾燥機中進行乾燥,得到固體分散體。這種製備方法與傳 統製備方法相比,更易得到具有無定形狀態、高比表面積的固體分散體。 黄芩素是一種從黃芩藥材中提取得到的黃酮類化合物,为黄芩的有效成分之 一,在临床上主要用于抗炎和抗菌,此外还具有抗氧化、抗肿瘤、抗血栓形成以 及保护肝脏、心脑血管、神经元等多种药理作用。黃芩素屬於生物藥劑學分類系 統中的 II 類藥物,即難溶於水(25℃時,其溶解度為 0.13 mg·mL-1 )、易透過 (Papp=1.7×10-5 cm·s -1 ) 的藥物。研究數據顯示,由於其難溶於水、溶出不完全、 首過效應嚴重,黃芩素的口服生物利用度很低,限制了其在醫藥學上的應用。因 此本實驗旨在擬通過將黃芩素製備成固體分散體改變其溶出性能,使黃芩素在水中的溶出速度增加,從而提高其口服生物利用度。 本實驗以一種低玻璃轉化溫度和低熔點的輔料 (Pluronic F68)為載體,採用 噴霧冷凍乾燥法製備黃芩素固體分散體,并將所制得的樣品與傳統的溶劑-蒸發 法製備的樣品相比較。在採用噴霧冷凍乾燥法製備固體分散體的過程中,料液被 凍結成固態細小顆粒,凍乾后形成蓬鬆粉末狀顆粒。然而,採用溶劑-蒸發法時, 樣品粘附於玻璃燒瓶內壁上,而且可見到黃芩素晶體析出。採用掃描電鏡法、粉 末 X-衍射法、比表面積測定法、差示掃描量熱法和傅利葉紅外光譜法對製備的 樣品進行表徵。掃描電鏡和粉末 X-衍射結果顯示,採用噴霧冷凍乾燥法製備的 黃芩素固體分散體為無定形狀態,其比表面積大於黃芩素原藥的。然而,當採用 溶劑-蒸發法製備藥物/載體比相同的黃芩素固體分散體時,大部份黃芩素在蒸發 溶劑時析出晶體,其體外溶出速度與同比例的物理混合物相同。噴霧冷凍乾燥法 製備的樣品在低濕、40℃條件下保存 6 個月,其物理穩定性和化學穩定性都較好。 對噴霧冷凍乾燥法製備的樣品進行大鼠體內藥物動力學評價,經大鼠口服給 藥后,以酶解后的黃芩素總量為指標,其 Tmax 快于黃芩素原藥,而 Cmax 高於黃 芩素原藥。由 AUC0-12計算黃芩素固體分散體相對於黃芩素原藥的相對生物利用 度為 233%,說明噴霧冷凍乾燥技術能有效地提高黃芩素的口服生物利用度。 關鍵詞:固體分散體;黃芩素;Pluronic F68;噴霧冷凍乾燥法;溶劑-蒸發法; 溶出度;生物利用度。

Issue date

2010

Author

何秀瓊

Faculty

Institute of Chinese Medical Sciences

Degree

M.Sc.

Subject

Chinese Medicinal Science -- Institute of Chinese Medical Sciences

Freeze-drying

冷凍式乾燥化

Pharmaceutical technology

藥劑科技

Supervisor

Zheng, Ying

Files In This Item

Full-text (Intranet)

Full-text (Intranet)

Location
1/F Zone C
Library URL
991006589379706306