A novel folate-modified self-microemulsifying drug delivery system of curcumin for colon targeting

Lin Zhang1*, Weiwei Zhu2*, Chunfen Yang1, Hongxia Guo1, Aihua Yu1, Jianbo Ji3, Yan Gao1, Min Sun1, Guangxi Zhai11Department of Pharmaceutical Engineering, College of Pharmacy, Shandong University, Jinan; 2Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai; 3Department of Pharmacology, College of Pharmacy, Shandong University, Jinan, China*These authors contributed equally to the workBackground: The objective of this study was to prepare, characterize, and evaluate a folate-modified self-microemulsifying drug delivery system (FSMEDDS) with the aim to improve the solubility of curcumin and its delivery to the colon, facilitating endocytosis of FSMEDDS mediated by folate receptors on colon cancer cells.Methods: Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of curcumin-loaded SMEDDS was optimized by a simplex lattice experiment design. Then, three lipophilic folate derivatives (folate-polyethylene glycol-distearoylphosphatidylethanolamine, folate-polyethylene glycol-cholesteryl hemisuccinate, and folate-polyethylene glycol-cholesterol) used as a surfactant were added to curcumin-loaded SMEDDS formulations. An in situ colon perfusion method in rats was used to optimize the formulation of FSMEDDS. Curcumin-loaded FSMEDDS was then filled into colon-targeted capsules and the in vitro release was investigated. Cytotoxicity studies and cellular uptake studies was used in this research.Results: The optimal formulation of FSMEDDS obtained with the established in situ colon perfusion method in rats was comprised of 57.5% Cremophor® EL, 32.5% Transcutol® HP, 10% Capryol™ 90, and a small amount of folate-polyethylene glycol-cholesteryl hemisuccinate (the weight ratio of folate materials to Cremophor EL was 1:100). The in vitro release results indicated that the obtained formulation of curcumin could reach the colon efficiently and release the drug immediately. Cellular uptake studies analyzed with fluorescence microscopy and flow cytometry indicated that the FSMEDDS formulation could efficiently bind with the folate receptors on the surface of positive folate receptors cell lines. In addition, FSMEDDS showed greater cytotoxicity than SMEDDS in the above two cells.Conclusion: FSMEDDS-filled colon-targeted capsules are a potential carrier for colon delivery of curcumin.Keywords: curcumin, SMEDDS, folate receptor, colon targetin

Lipid nanocapsules for transdermal delivery of ropivacaine: in vitro and in vivo evaluation

The objective of this research was to develop novel ropivacaine-loaded lipid nanocapsules (RPV-LNCs) and evaluate the potential of RPV-LNCs as external preparation for transdermal delivery. RPV-LNCs were prepared by phase inversion technique and optimized by response surface design. The permeation ability of RPV-LNCs was characterized both in vitro and in vivo. The results showed that the optimized RPV-LNCs represented typical core-shell structure with the mean diameter of 62.1 +/- 1.7 nm. The entrapment efficiency and drug loading were 92.6 +/- 1.3% and 1.35 +/- 0.20%, respectively. Moreover, the cumulative amount of RPV penetrated through excised skin from LNCs was 2.17 folds than that of the propylene glycol. In vivo, RPV-LNCs contributed a higher RPV concentration in plasma (5.743 mu g/mL). The RPV retained within dermis was 27.9 +/- 5.2 mu g/mL for LNCs, obviously remarkable than that of the propylene glycol group (15.6 +/- 3.9 mu g/mL). The skin histopathology study and scanning electron microscope (SEM) showed that interaction between LNCs and skin surface changed the apparent morphology of stratum corneum and broke the close conjugation of corneocyte layers. All the detailed evidence showed that LNCs could provide a promising tuning as a transdermal delivery system of ropivacaine

Ropivacaine loaded microemulsion and microemulsion-based gel for transdermal delivery: Preparation, optimization, and evaluation

The objective of the present study was to prepare and evaluate a ropivacaine-loaded microemulsion (ME) formulation and microemulsion-based Carbopol gel (ME-gel) for transdermal delivery. Pseudo-ternary phase diagrams and a simplex lattice experiment design were utilized to screen and optimize the ME formulation. In the process, drug solubility and particle size were inspected as dependent variables whilst Capryol (R) 90 (X-1), Smix (X-2, Labrasol (R): absolute ethanol = 1:2 w/w), water (X-3) as independent variables. Following the optimization, the optimal ME formulation was comprised of 15% Capryol (R) 90, 53% Smix, and 32% water, respectively. Ropivacaine loaded ME appeared to be spherical under transmission electron microscope, and the average particle size was 58.79 nm. The results of ex vivo permeation study showed that ropivacaine had a significant higher cumulative amount from ME than that from ME-gel. Histopathology study elucidated that the microstructure of skin surface was significantly changed by the treatment of ME formulation. Skin irritation study indicated that neither ME nor ME-gel caused any irritation responses. Both ME and ME-gel presented a remarkable analgesic activity on acetic acid-induced writhing in mice. In conclusion, ME could be a promising formulation for ropivacaine transdermally administration

Development of redox-responsive theranostic nanoparticles for near-infrared fluorescence imaging-guided photodynamic/chemotherapy of tumor

The development of imaging-guided smart drug delivery systems for combinational photodynamic/chemotherapy of the tumor has become highly demanded in oncology. Herein, redox-responsive theranostic polymeric nanoparticles (NPs) were fabricated innovatively using low molecular weight heparin (LWMH) as the backbone. Chlorin e6 (Ce6) and alpha-tocopherol succinate (TOS) were conjugated to LMWH via cystamine as the redox-sensitive linker, forming amphiphilic Ce6-LMWH-TOS (CHT) polymer, which could self-assemble into NPs in water and encapsulate paclitaxel (PTX) inside the inner core (PTX/CHT NPs). The enhanced near-infrared (NIR) fluorescence intensity and reactive oxygen species (ROS) generation of Ce6 were observed in a reductive environment, suggesting the cystamine-switched “ON/OFF” of Ce6. Also, the in vitro release of PTX exhibited a redox-triggered profile. MCF-7 cells showed a dramatically higher uptake of Ce6 delivered by CHT NPs compared with free Ce6. The improved therapeutic effect of PTX/CHT NPs compared with mono-photodynamic or mono-chemotherapy was observed in vitro via MTT and apoptosis assays. Also, the PTX/CHT NPs exhibited a significantly better in anti-tumor efficiency upon NIR irradiation according to the results of in vivo combination therapy conducted on 4T1-tumor-bearing mice. The in vivo NIR fluorescence capacity of CHT NPs was also evaluated in tumor-bearing nude mice, implying that the CHT NPs could enhance the accumulation and retention of Ce6 in tumor foci compared with free Ce6. Interestingly, the anti-metastasis activity of CHT NPs was observed against MCF-7 cells by a wound healing assay, which was comparable to LMWH, suggesting LMWH was promising for construction of nanocarriers for cancer management

Design and evaluation of a self-microemulsifying drug delivery system for apigenin

Objective of this study was to prepare, characterize and evaluate a self-microemulsifying drug delivery system (SMEDDS) with the aim to improve the solubility and dissolution of apigenin. Ternary phase diagrams were constructed in order to obtain the most efficient self-emulsification region, and the formulation of apigenin loaded SMEDDS was optimized by a simplex lattice experiment design. The optimal formulation of SMEDDS obtained was comprised of 60% Cremophor(R)EL, 30% Transcutol(R)HP and 10% Capryol (TM) 90. The equilibrium solubility of apigenin in SMEDDS was about 15 mg/g, and it could increase the solubility of apigenin in water for about 7500 folds. Apigenin loaded SMEDDS could turn into microemulsion when diluted with distilled water and the droplets were spherical under transmission electron microscope (TEM), the average particle size was 17.1 nm and zeta potential -5.18 mV. In vitro dissolution studies showed about 95% of apigenin was released within 10 min. All of the results showed that SMEDDS could enhance the solubility and dissolution of apigenin, and would be a potential carrier to improve the oral absorption of apigenin, a poorly water soluble drug

Preparation, optimization, characterization and cytotoxicity in vitro of Baicalin-loaded mixed micelles

The aim of this study was to develop a Baicalin (BC)-loaded mixed micelle delivery system (BC-ST-P123-MMs) with sodium taurocholate (ST) and pluronic P123 block copolymer (P123) as carrier materials to improve the solubility of BC, a poorly soluble drug. In this study, the mixed micelle system was prepared using the method of thin-film dispersion and then optimized by the homogeneous design-response surface methodology with the entrapment efficiency and drug loading as indexes. The average size and the zeta potential of the BC-ST-P123-MMs were 15.60 nm and -5.26 mV, respectively. Drug loading (DL, 16.94%) and entrapment efficiency (EE, 90.67%) contributed to high solubility (10.20 mg/mL) of BC in water. The optimized BC-ST-P123-MMs appeared spherical with obvious core-shell structure and well dispersed without aggregation and adhesion under TEM. In addition, DSC result indicated that BC had been wrapped in BC-ST-P123-MMs and crystalline state of BC was changed. The release result in vitro showed that BC-ST-P123-MMs presented sustained release behavior compared to control group. The IC50 value of BC-ST-P123-MMs (46.18 mu g/mL) was lower than that of BC solution (67.14 mu g/mL) on Hep G2 cell lines. Cellular uptake tests illustrated that the ST-P123-MMs system as carrier could significantly enhance the uptake of drugs by tumor cells. The results demonstrated that the BC-loaded mixed micelles could improve solubility of BC and exhibited great potential for delivering drug into cancer cells