Novel cremochylomicrons for improved oral bioavailability of the antineoplastic phytomedicine berberine chloride: Optimization and pharmacokinetics.

Berberine chloride (BER) is an antineoplastic phytomedicine that combat non-Hodgkin lymphoma. BER suffers from low oral bioavailability due to p-glycoprotein efflux and first-pass metabolism. Lymphatic drug targeting recently gained a profound attention due to circumventing hepatic first-pass metabolism and targeting lymph diseases. Therefore, novel BER-loaded cremochylomicrons were elaborated to mitigate BER drawbacks and enhance its lymphatic targeting and bioavailability. Optimized cremochylomicron was prepared with 2.5%w/v Cremophor El and 12.5% w/w berberine content. Promising in vitro characteristics (particle size = 175.6 nm and entrapment efficiency = 95.5%) were obtained. Lyophilized system showed high colloidal stability over 6 months. In addition in vivo pharmacokinetics study demonstrated significant enhancement (>2fold) in the rate and extent of absorption in cremochylomicron over free BER. Moreover, cremochylomicrons demonstrated in significant increase in mean residence time and volume of distribution with decreased intestinal drug clearance as a result of efflux inhibition. In another avenue, a significant reduction in BER absorption (43%) in presence of cycloheximide inhibitor was obtained confirming the lymphatic targeting ability of cremochylomicrons. In conclusion, berberine-loaded cremochylomicron could be considered as a promising nanoplatform for targeting lymphatic system and improving BER oral bioavailability with lower dose and side effects.

Elsheikh MA ，Elnaggar YSR ，Hamdy DA ，Abdallah OY ... -  《-》

Bioactive-Chylomicrons for Oral Lymphatic Targeting of Berberine Chloride: Novel Flow-Blockage Assay in Tissue-Based and Caco-2 Cell Line Models.

Elsheikh MA ，Elnaggar YSR ，Otify DY ，Abdallah OY ... -  《-》

Solid dispersion of berberine-phospholipid complex/TPGS 1000/SiO₂: preparation, characterization and in vivo studies.

Berberine (Ber), an isoquinoline alkaloid, arouses wide interests in many researchers in recent years because of its numerous new pharmacological actions. However Ber's low oral bioavailability restricts its wide application. In this study, a solid dispersion (BPTS-SD) composed of berberine-phospholipid complex (BPC), D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS 1000) and SiO₂ was prepared by simple solvent evaporation technique. BPC was employed to improve the liposolubility of Ber, and SiO₂ was used to improve the flowability of BPTS-SD, while TPGS 1000 played a dual role: firstly, as a solid dispersion carrier to improve the dissolution rate of BPC and secondly, as a P-glycoprotein (P-gp) inhibitor to enhance the intestinal absorption of Ber. FTIR, DSC and SEM analysis proved the formation of BPC and BPTS-SD. Po/w of BPC successfully increased from 0.25 to 8.75. In vitro dissolution study showed that the cumulative dissolution percentages of BPTS-SDs were nearly 2.67-4.78-folds of BPC. Single-pass intestinal perfusion studies showed that the absorption of Ber in BPC was increased nearly 1.4-2.0-folds compared to that of Ber which was mainly due to the improved liposolubility, and further increased by BPTS-SD around 0.1-1.3-folds compared to that of BPC through the P-gp inhibition of TPGS 1000. Significant improvements in Cmax and AUC₀→t of BPC and BPTS-SD were obtained in pharmacokinetic study (the highest improvement in oral relative bioavailability of BPTS-SD-1 was 322.66% of Ber). All these results indicated that BPTS-SD can be a promising drug delivery system to improve their oral bioavailability for the Ber's analogues. In particular this solid dispersion can be prepared just by a simple method and has a strong feasibility for industrialization.

Zhang Z ，Chen Y ，Deng J ，Jia X ，Zhou J ，Lv H ... -  《-》

Preparation of an anhydrous reverse micelle delivery system to enhance oral bioavailability and anti-diabetic efficacy of berberine.

To enhance oral bioavailability and anti-diabetic efficacy of berberine (BER), an anhydrous reverse micelle (ARM) delivery system was prepared through lyophilization of water-in-oil (W/O) emulsions. Using soy phosphatidylcholine as emulsifiers, BER-containing W/O emulsions were prepared and then lyophilized to form dry products which, upon addition of oil, formed clear ARMs containing amorphous BER nanoparticles. BER-loaded ARMs or free BER solutions were administered to streptozocin-induced diabetic mice. In vivo measurements demonstrated that the blood glucose levels (BGLs) of diabetic mice reduced on average to 22% of the initial values 4h after intravenous injection of BER solution at the dose of 2.5mg/kg body weight, while the average BGL reduction was 57% in the group gavaged with ARMs at the dose of 100mg/kg body weight. No significant BGL reduction was noticed in mice orally received BER solutions. Compared to BER solutions, the oral bioavailability of BER-loaded ARMs was enhanced 2.4-fold, and the maximum blood concentration of BER was enhanced 2.1-fold with a 2-h time lag leading to a prolonged efficacy. Thus, this novel ARM delivery system provides a valid method to improve oral bioavailability and anti-diabetic efficacy of BER, offering a promising product alternative to other hypoglycemic drugs for diabetes therapy.

Wang T ，Wang N ，Song H ，Xi X ，Wang J ，Hao A ，Li T ... -  《-》

Monodisperse microparticles loaded with the self-assembled berberine-phospholipid complex-based phytosomes for improving oral bioavailability and enhancing hypoglycemic efficiency.

Berberine (BER), possessing a variety of pharmacological functions, has caused a growing interest in recent years. More importantly, BER is a potential natural alternative to other synthetic antidiabetic drugs. However, poor gastrointestinal absorption and low oral bioavailability have limited its development for further clinical application. In this study, for the first time, the phytosomes loaded with berberine-phospholipid complex (P-BER) were prepared by a rapid solvent evaporation method followed by a self-assembly technique for developing a more efficient BER drug delivery system. The P-BER showed a nanoscale particle size, a negative surface charge, and excellent drug entrapment efficiency (∼85%). Compared to the orally administrated BER in previous pharmacokinetic studies, the oral bioavailability of the P-BER was significantly improved by 3-fold. More importantly, the oral administration of P-BER could suppress the fasting glucose levels and improve the ability of systematic hyperlipidemia metabolism of db/db diabetic mice. All results have demonstrated that the P-BER could be a promising oral drug delivery system.

Yu F ，Li Y ，Chen Q ，He Y ，Wang H ，Yang L ，Guo S ，Meng Z ，Cui J ，Xue M ，Chen XD ... -  《-》