Self-microemulsifying Drug Delivery System Improved Oral Bioavailability of 20(<i>S</i>)-Protopanaxadiol: From Preparation to Evaluation

Abstract

20(S)-Protopanaxadiol (20(S)-PPD)is one type of sapogenin of protopanaxadiols and has a variety of pharmacological activities. In order to improve the dissolution of 20(S)-PPD as well as its oral bioavailability, a self-microemulsifying drug delivery system (SMEDDS) was utilized for 20(S)-PPD preparation. Following the preparation of the 20(S)-PPD SMEDDS, its dissolution, stability, and intestinal absorption in rats were studied, and the pharmacokinetics and optimal dosage after oral administration were evaluated. The dissolution tendency of the SMEDDS in phosphate buffered saline (PBS), 0.1 M HCl and distilled water was consistent. SMEDDS was stable under a condition of high temperature (40°C), high humidity or with strong light irradiation, or within 6 h in artificial digestive tracts. 20(S)-PPD SMEDDS was well-absorbed in all intestinal segments in rats. When the drug concentration was higher than 200 µg/mL or the perfusion flow was faster than 0.5 mL/min, passive diffusion of drug in the duodenum reached a saturated level. In addition, Pglycoprotein inhibitor did not affect the intestinal absorption of 20(S)-PPD SMEDDS. Pharmacokinetic study showed that T max in male rats was shortened significantly, while C max and area under the curve (AUC (0-t) ) were remarkably increased. The relative oral bioavailability of 20(S)-PPD SMEDDS was increased approximately three fold compared with the 20(S)-PPD carboxy methyl cellulose (CMC). 20(S)-PPD SMEDDS (100 mg/mL) was administered by gastric infusion to both mice and rats for 14 d. SMEDDS improved the oral bioavailability of 20(S)-PPD and reduced the necessary drug dosage. 20(S)-PPD SMEDDS could become a promising clinical alternative as an anti-tumor or antidepressant drug.Key words 20(S)-protopanaxadiol; self-microemulsifying drug delivery system; preparation; bioavailability; intestinal absorption; pharmacokinetics Panax ginseng is documented to tonify internal organs, benefit the spirit, suppress the fright as well as improve eyesight and intelligence.1) The long term application also facilitates relaxation and increases life span.2) Various chemical components were distinguished in Panax ginseng, including saponins, volatile oil, polysaccharides, amino acid and polypeptide, and microelements, of which ginsenosides are the main active ingredients, including oleanolic acid (OA), protopanaxadiol (PPD) and protopanaxatriol type (PPT).3) 20(S)-PPD ( Fig. 1) is one of aglycones of ginsenosides and has a wide range of pharmacological activities, especially in antitumor and neurological function recovery. [4][5][6][7][8] However, the low bioavailability of ginsenosides (1% for Rb 1 , 3.4% for Rb 2 , 1.9% for Rg 1 ) after oral administration restricts their clinical applications. 9-11)Importantly, PPD is the final active component after the absorption of ginsenosides in intestine. 12,13)

Cytochromes P450 Inhibitory Excipient-Based Self-Microemulsions for the Improved Bioavailability of Protopanaxatriol and Protopanaxadiol: Preparation and Evaluation

“…Previously, an SME of PPD resulted in an increase of bioavailability by 3-fold [16]. The underlying mechanisms were attributable to the facilitation of lymphatic transport and the improvement in intestinal absorption, as documented previously [16,[26][27][28]. In the present study, both SME-1 and SME-2 could increase the bioavailability of PPT and PPD, but SME-1 resulted in significantly higher increases than SME-2.…”

“…Previously, an SME of PPD resulted in an increase of bioavailability by 3-fold [16]. The underlying mechanisms were attributable to the facilitation of lymphatic transport and the improvement in intestinal absorption, as documented previously [16,[26][27][28].…”

“…The dependence of the absolute bioavailability of PPD in rats on solubility was reported in several studies, which showed that the oral bioavailability varied from 20.7 % to 48.1 % as a function of solubilizing excipients [2,7,8]. In order to improve the bioavailability of PPD, a number of studies have paid special attention to increase the solubility and dissolution by utilizing different formulation strategies such as nanocrystals [13][14][15], SME [16], and micelles [17]. However, few studies have focused on the first-pass metabolism.…”

Simultaneous determination of ten compounds in two main medicinal plant parts of Tibetan herb, <i>Pterocephalus hookeri</i> (CB Clarke) Höeck, by ultra-high performance liquid chromatography-photodiode array

“…GraphPad Prism software (version 5.0, GraphPad Software Inc, San Diego, CA, USA) was used to generate graphs and perform one-way analysis of variance (ANOVA) [22]. Differences were considered significant at p < 0.05.…”

Characterization and evaluation of a self-microemulsifying drug delivery system containing tectorigenin, an isoflavone with low aqueous solubility and poor permeability

“…However, it is not clear whether the dosage form can promote transmembrane absorption. Self-microemulsifying drug delivery system (SMEDDS) possesses the ability to simultaneously improve drug solubility and permeability, which has been increasingly employed to enhance the oral bioavailability of drugs (Bing Wang et al, 2015;Ding et al, 2016). SMEDDS is a mixture of oil, emulsifier, and co-emulsifier.…”