Improved solubility and oral bioavailability of apigenin via Soluplus/Pluronic F127 binary mixed micelles system

The aim of this study was to develop a novel mix micelles system composing of two biocompatible copolymers of Soluplus^® and Pluronic F127 to improve the solubility, oral bioavailability of insoluble drug apigenin (AP) as model drug. The AP-loaded mixed micelles (AP-M) were prepared by ethanol thin-film hydration method. The formed optimal formulation of AP-M were provided with small size (178.5?nm) and spherical shape at ratio of 4:1 (Soluplus^®:Pluronic F127), as well as increasing solubility of to 5.61?mg/mL in water which was about 3442-fold compared to that of free AP. The entrapment efficiency and drug loading of AP-M were 95.72 and 5.32%, respectively, and a sustained release of AP-M was obtained as in vitro release study indicated. Transcellular transport study showed that the cell uptake of AP was increased in Caco-2 cell transport models. The oral bioavailability of AP-M was 4.03-fold of free AP in SD rats, indicating the mixed micelles of Soluplus^® and Pluronic F127 is an industrially feasible drug delivery system to promote insoluble drug oral absorption in the gastrointestinal tract.     

Improved oral bioavailability and therapeutic efficacy of dabigatran etexilate via Soluplus-TPGS binary mixed micelles system

The clinical use of dabigatran etexilate (DABE) is limited by its poor absorption and relatively low bioavailability. Our study aimed to explore the potential of a mixed micelle system composed of Soluplus^® and D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral absorption and bioavailability of DBAE. DBAE was first encapsulated into Soluplus/TPGS mixed micelles by a simple thin film hydration method. The DBAE loaded micelles displayed an average size distribution of around 83.13?nm. The cellular uptake of DBAE loaded micelles in Caco-2 cell monolayer was significantly enhanced by 2–2.6 fold over time as compared with DBAE suspension. Both lipid raft/caveolae and macropinocytosis-mediated the cell uptake of DBAE loaded micelles through P-glycoprotein (P-gp)-independent pathway. Compared with the DBAE suspension, the intestinal absorption of DBAE from DBAE mixed micelles in rats was significantly improved by 8 and 5-fold in ileum at 2?h and 4?h, respectively. Moreover, DBAE mixed micelles were absorbed into systemic circulation via both portal vein and lymphatic pathway. The oral bioavailability of DBAE mixed micelles in rats was 3.37 fold higher than that of DBAE suspension. DBAE mixed micelles exhibited a comparable anti-thrombolytic activity with a thrombosis inhibition rate of 63.18% compared with DBAE suspension in vivo. Thus, our study provides a promising drug delivery system to enhance the oral bioavailability and therapeutic efficacy of DBAE.     

Harmine-loaded galactosylated pluronic F68-gelucire 44/14 mixed micelles for liver targeting

Harmine (HM), a phytoconstituent has wide range of pharmacological activities including antimicrobial, antifungal, antioxidative, and anticancer. HM has shown promising anticancer activity against liver cancer cells. However, poor aqueous solubility, multidrug pump P-gp efflux, extensive in vivo metabolism, and rapid elimination due to glucuronidation/sulfation limit clinical utility of HM. In order to overcome the drawbacks of HM, the current work reports preparation of HM-loaded galactosylated pluronic F-68 (PF68)-Gelucire^® 44/14 (GL44) mixed micelles (HM-MM). 3² factorial design was used to investigate the effect of formulation variables on formation HM-loaded mixed micelles. Solvent evaporation method was used for preparation of HM-MM. The optimized HM-MM was evaluated for size, percent drug entrapped (EE), in vitro HM release, oral bioavailability, and biodistribution in rats. HM-MM with an average size 277.5?±?3.24?nm had an EE of 86.5?±?1.51% w/w. HM-MM released HM in a controlled manner. Additionally, HM-MM showed significant enhancement in oral bioavailability (around six-folds) of HM when compared to HM alone. Further, HM-MM showed around sevenfold higher amount of HM in the liver when compared to HM alone revealing efficient drug targeting capability. Such significant improvement in oral bioavailability of HM when formulated into mixed micelles could be attributed to solubilization of hydrophobic HM into micellar core along with P-gp inhibition effect of both galactosylated PF68 and GL44. Thus, the present work highlights galactosylated PF68 and GL44 mixed micelles as an efficient carrier system having drug targeting capability and potential to enhance bioavailability of BCS class II drugs.     

FLT3-specific curcumin micelles enhance activity of curcumin on FLT3-ITD overexpressing MV4-11 leukemic cells

Curcumin, a major active compound in the turmeric rhizome, has many biological properties, especially anti-leukemia activity. The overexpression of FMS-like tyrosine kinase 3 protein with internal tandem duplication (FLT3-ITD) mutation protein was related to the poor prognosis and disease progression of leukemia. In this study, the cytotoxicity and inhibitory effect of curcumin on cell cycle of FLT3-ITD overexpressing MV4-11 leukemic cells were evaluated. Moreover, curcumin polymeric micelles conjugated with FLT3-specific peptide (FLT3-Cur-micelles) were prepared using a film hydration method to increase curcumin solubility and the inhibitory effect on MV4-11 cells was evaluated. Cytotoxicity and cell cycle analysis were performed using an MTT assay and flow cytometry, respectively. Physical properties of FLT3-Cur-micelles, including particle size, size distribution, morphology, and entrapment efficiency (EE), were evaluated. Cellular uptake of the micelles on MV4-11 cells was determined by flow cytometry and fluorescence microscopy. FLT3-Cur-micelles were observed with size less than 50?nm and high EE of >75%. In addition, FLT3-Cur-micelles demonstrated excellent internalization and increased curcumin accumulation in leukemic cells when compared to free curcumin. Furthermore, FLT3-Cur-micelles exhibited a strong cytotoxic effect on MV4-11 cells with IC₅₀ value of 1.1?µM, whereas the blank micelles showed no effect. Furthermore, FLT3-Cur-micelles showed no significant effect on normal human PBMCs with IC₅₀ value >25?µM. In summary, FLT3-Cur-micelles are a promising nanocarrier system for enhancing anti-leukemic activity of curcumin and suitable for further preclinical studies.     

Chrysin-loaded folate conjugated PF127-F68 mixed micelles with enhanced oral bioavailability and anticancer activity against human breast cancer cells

Chrysin (CH), a phytoconstituent has numerous pharmacological activities including anticancer activity. However, CH suffers from a drawback of poor aqueous solubility and in turn poor bioavailability limiting its clinical utility. In this work CH loaded folate-conjugated pluronic PF127-pluronic F68 mixed micelles were prepared with an objective to augment oral bioavailability and cytotoxicity of CH in human breast cancer cell line MCF-7 by active targeting mechanism. Folate-conjugated PF127 was synthesized and used for preparation of CH-MM. Optimized batch (using factorial design) of CH-MM was characterized by Fourier-transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), atomic force microscopy (AFM), in vitro CH release, in vivo study, and in vitro cell line study. FTIR study suggested encapsulation of CH into the micelle core. CH-MM showed controlled release of CH releasing higher amount (2.5 fold) in 24?h when compared to CH alone (A-CH). Further significant increase in C_max (2 fold) and AUC_0–∞ (3 fold) for CH-MM when compared to A-CH suggested significant improvement in oral bioavailability of CH. Additionally, CH-MM showed 5 fold reduction in GI₅₀ value of CH when tested in MCF-7 cells reducing GI₅₀ value of CH significantly. CH-MM can serve as a platform carrier system for active targeting of BCS class II molecules with potential anticancer activity.     

Preparation,characterization, and pharmacokinetics study of a novel genistein-loaded mixed micelles system

Genistein (GEN), is a natural dietary isoflavone, has been reported to show anticancer activities. However, its poor aqueous solubility and oral bioavailability limit its clinical application. We designed a novel genistein-loaded mixed micelles (GEN-M) system composed of Soluplus^® and Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were prepared by organic solvent evaporation aimed to overcome the challenges of GEN’s poor solubility and then further improve its oral bioavailability. The optimized, spherical-shaped GEN-M was obtained at a ratio of 10:1 (Soluplus^®:TPGS). The mean particle size of GEN-M was 184.7?±?2.8?nm, with a narrow polydispersity index (PDI) of 0.162?±?0.002. The zeta potential value of GEN-M was ?2.92?±?0.01?mV. The micelles solutions was transparent with blue opalescence has high the entrapment efficiency (EE) and drug loading (DL) of 97.12?±?2.11 and 3.87?±?1.26%, respectively. GEN-M was demonstrated a sustained release behavior when formed micelles shown in drug release in vitro. The solubility of GEN in water increased to 1.53?±?0.04?mg/mL after encapsulation. The permeability of GEN across a Caco-2 cell monolayer was enhanced, and the pharmacokinetics study of GEN-M showed a 2.42-fold increase in relative oral bioavailability compared with free GEN. Based on these findings, we conclude that this novel nanomicelles drug delivery system could be leveraged to deliver GEN and other hydrophobic drugs.     

Enhanced oral bioavailability and sustained delivery of glimepiride via niosomal encapsulation: in-vitro characterization and in-vivo evaluation

This study was designed to investigate the potency of niosomes, for glimepiride (GLM) encapsulation, aiming at enhancing its oral bioavailability and hypoglycemic efficacy. Niosomes containing nonionic surfactants (NIS) were prepared by thin film hydration technique and characterized. In-vitro release study was performed using a dialysis technique. In-vivo pharmacodynamic studies, as well as pharmacokinetic evaluation were performed on alloxan-induced diabetic rats. GLM niosomes exhibited high-entrapment efficiency percentages (E.E. %) up to 98.70% and a particle size diameter ranging from 186.8?±?18.69 to 797.7?±?12.45?nm, with negatively charged zeta potential (ZP). Different GLM niosomal formulation showed retarded in vitro release, compared to free drug. In-vivo studies revealed the superiority of GLM niosomes in lowering blood glucose level (BGL) and in maintaining a therapeutic level of GLM for a longer period of time, as compared to free drug and market product. There was no significant difference between mean plasma AUC_0-48?hr of GLM-loaded niosomes and that of market product. GLM-loaded niosomes exhibited seven-fold enhancement in relative bioavailability in comparison with free drug. These findings reinforce the potential use of niosomes for enhancing the oral bioavailability and prolonged delivery of GLM via oral administration.     

Preparation and evaluation of curcumin-loaded self-assembled micelles

Objective: Curcumin being used to treat various chronic diseases while its poor bioavailability issue limited its wide clinical application as a therapeutic agent. The aim of this work was to prepare curcumin-loaded self-assembled micelles using soluplus and solutol^®HS15 (SSCMs) to enhance curcumin’s solubility and thus oral bioavailability.

Methods: Optimum formulation was investigated and the optimized ratio of drugs and excipients was obtained and the SSCMs were prepared via ethanol solvent evaporation method. The optimal SSCMs were characterized by transmission electron microscopy, drug content analysis including loading efficiency (LE%) and entrapment efficiency (EE%), and the cumulative amount of curcumin released from the micelles were all calculated using HPLC method. The in vitro cytotoxicity and the permeability of SSCMs were measured by Caco-2 cell monolayers and the oral bioavailability was evaluated by SD rats.

Key findings: The solubility of curcumin in self-assembled micelles was dramatically increased by 4200 times as compared to free curcumin. Caco-2 cells transport experiment exhibited that while soluplus and solutol^®HS15 were self-assembled into micelles, it could not only promote the permeability of curcumin across membrane for better absorption, but also could restrain the curcumin pumped outside due to the role of P-gp efflux mechanism of soluplus and solutol^®HS15. Furthermore, the prepared SSCMs formulation was almost nontoxic and had safety performance on Caco-2 cells model. Moreover, curcumin’s oral bioavailability of SSCMs formulation in SD rats had doubled than that of free curcumin.

Conclusions: The prepared SSCMs were characterized by PS, PDI, LE%, EE% data analysis. After the soluplus and solutol^®HS15 were self assembled into micelles, both the solubility and membrane permeability of curcumin were evaluated to have been enhanced, as well as the effect of efflux pump of curcumin was inhibited, hence to promote oral absorption and generate an increased bioavailability.     

Improved oral bioavailability of valsartan using proliposomes: design,characterization and in vivo pharmacokinetics

Abstract

The objective of our investigational work was to develop a proliposomal formulation to improve the oral bioavailability of valsartan. Proliposomes were formulated by thin film hydration technique using different ratios of phospholipids:drug:cholesterol. The prepared proliposomes were evaluated for vesicle size, encapsulation efficiency, morphological properties, in vitro drug release, in vitro permeability and in vivo pharmacokinetics. In vitro drug-release studies were performed in simulated gastric fluid (pH 1.2) and purified water using dialysis bag method. In vitro drug permeation was studied using parallel artificial membrane permeation assay (PAMPA), Caco-2 monolayer and everted rat intestinal perfusion techniques. In vivo pharmacokinetic studies were conducted in male Sprague Dawley (SD) rats. Among the proliposomal formulations, F-V was found to have the highest encapsulation efficiency of 95.6?±?2.9% with a vesicle size of 364.1?±?14.9?nm. The in vitro dissolution studies indicated an improved drug release from proliposomal formulation, F-V in comparison to pure drug suspension in both, purified water and pH 1.2 dissolution media after 12?h. Permeability across PAMPA, Caco-2 cell and everted rat intestinal perfusion studies were higher with F-V formulation as compared to pure drug. Following single oral administration of F-V formulation, a relative bioavailability of 202.36% was achieved as compared to pure valsartan.     

PVP and surfactant combined carrier as an effective absorption enhancer of poorly soluble astilbin in vitro and in vivo

Context: Astilbin is considered to be a new and promising immunosuppressant for immune related diseases, but limited in clinical application due to its poor water solubility, difficult oral absorption and low bioavailability.

Objective: The present work studied the effect of PVP and surfactant combined carrier on its capability to improve drug absorption.

Materials and methods: PVP K30-Tween 80 combined carries was applied into the astilbin solid dispersions, tested both in vivo in beagle dogs and in vitro in transport experiments across Caco-2 cell monolayers.

Results and discussion: In the animal studies a many fold increase in plasma AUC was observed for the solid dispersions of drug in PVP K30-Tween 80 combined carries compared to active pharmaceutical ingredient (API). The applicability of Caco-2 monolayers as a tool for predicting the in vivo transport behavior of Astilbin in combination with a solubility enhancing carries was shown. In vitro transport studies confirmed the effect of combined carries on the absorption behavior of the astilbin. MTT studies showed the cell viability gradually decreased with the increase of the drug concentration in a dose dependent manner for astilbin and that in solid dispersions. The permeability and apparent permeability coefficients (P_app) increased with drug in the Caco-2 cell.

Conclusion: In this study, it was found that PVP K30 and Tween 80 promoted the permeability of drugs best within a certain amount. For astilbin PVP K30 and surfactant combined carrier had a strong potential to improve oral bioavailability.     

Enhanced oral bioavailability of paclitaxel by solid dispersion granulation

The main objective of this study was to develop novel orally administrable tablets containing solid dispersion granules (SDG) of amorphous paclitaxel (PTX) prepared by fluid bed technology, and to evaluate its in vitro dissolution and in vivo pharmacokinetics (PK) in beagle dogs. The SDG were prepared using optimized composition by fluid bed technology, and characterized for solid-state properties. The release study of SDG tablet (SDG-T) in simulated gastric fluid showed a rapid release of PTX, reaching maximum dissolution within 20?min. Finally, the PK profile of SDG-T and a reference formulation Oraxol? (oral solution formulation used in Phase I clinical study) at a dose of 60?mg orally with co-administration of P-gp inhibitor HM38101, and Taxol® at a dose of 10?mg intravenously (i.v.) was investigated in beagle dogs. The mean absolute BA% of PTX following SDG-T and Oraxol? solution was 8.23 and 6.22% in comparison to i.v. administration of Taxol®. The relative BA% of PTX from SDG-T in comparison to Oraxol? solution was 132.25% at a dose of 60?mg following oral administration. In conclusion, we have successfully prepared PTX tablets with solid dispersion granules (SDG) of amorphous PTX using fluid bed technology that could provide plasma PTX concentration in the range of 10–150?ng/mL for a period of 24?h following oral administration in dogs with a P-gp inhibitor. Hence, this could be a promising formulation for PTX oral delivery and could be used in our intended clinical studies following pre-clinical efficacy studies.     

Enhancement of the oral bioavailability of breviscapine by nanoemulsions drug delivery system

Aim to design an effective breviscapine nanoscale drug delivery system to realize the improvement of its oral bioavailability. Based on the investigations of the stabilities in the gastrointestinal tract (GIT), permeation and efflux across the cell membrane, the breviscapine nanoemulsion (NE) was formulated and evaluated in vitro and in vivo. The globule size and polydispersity index of the NE was 45.6?nm and 0.105, and the efficient encapsulation was 95.2%. In vitro, the drug release from NEs in pH 6.8 PBS fit to the first-order kinetics. The Caco-2 cell transport experiments showed that the breviscapine NE facilitated the improvement of the apparent permeability coefficient (P_app) from the apical side to basilar side compared with the free drug. In vivo, the relative bioavailability of breviscapine NE reached to 249.7%. All the studies implicated that the NE carrier contributed to the enhancement of the oral absorption of breviscapine due to the improved stability and permeation in the GIT. The nanoemulsions technology is better for the poor permeable and unstable active agents in GIT as well as helps the industrial scale process.     

Development and evaluation of hollow mesoporous silica microspheres bearing on enhanced oral delivery of curcumin

The aim of this work is to develop curcumin-loaded hollow mesoporous silica microspheres (HMSMs@curcumin) to improve the poor oral bioavailability of curcumin. Hollow mesoporous silica microspheres (HMSMs) were synthesized in facile route using a hard template. HMSMs and HMSMs@curcumin were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption/desorption measurements, differential scanning calorimetry (DSC), Fourier transform infrared (FTIR), and X-ray diffraction (XRD). In addition, to demonstrate the potential application of the HMSMs@curcumin, cytotoxicity, in vitro release behavior and in vivo pharmacokinetics of curcumin loaded in these HMSMs were investigated by using of Caco-2 cells and Sprague-Dawley (SD) rats, respectively. These mono-dispersed HMSMs exhibited high drug loading ratio and encapsulation efficiency due to the mesoporous shell and hollow core. The excellent characteristics of HMSMs such as mono-dispersed morphology, smooth surface, uniform, ordered and size-narrowing mesopores resulted in a good in vitro release profile of curcumin from HMSMs@curcumin. Moreover, an impressive improvement in the oral absorption of curcumin and prolonged systemic circulation time were achieved in the in vivo animal studies. In addition, the good biocompatibility of developed HMSMs with Caco-2 cells was confirmed based on the in vitro cytotoxicity assay. In conclusion, this system demonstrated a great potential for efficient delivery of curcumin in vitro and in vivo, suggesting a good prospect for its application in clinic for therapeutic drug delivery in future.     

A combination of complexation and self-nanoemulsifying drug delivery system for enhancing oral bioavailability and anticancer efficacy of curcumin

Abstract

Objective: Curcumin, the golden spice from Indian saffron, has shown chemoprotective action against many types of cancer including breast cancer. However, poor oral bioavailability is the major hurdle in its clinical application. In the recent years, self-nanoemulsifying drug delivery system (SNEDDS) has emerged as a promising tool to improve the oral absorption and enhancing the bioavailability of poorly water-soluble drugs. In this context, complexation with lipid carriers like phospholipid has also shown the tremendous potential to improve the solubility and therapeutic efficacy of certain drugs with poor oral bioavailability.

Methods: In the present investigation, a systematic combination of both the approaches is utilized to prepare the phospholipid complex of curcumin and facilitate its incorporation into SNEDDS. The combined use of both the approaches has been explored for the first time to enhance the oral bioavailability and in turn increase the anticancer activity of curcumin.

Results: As evident from the pharmacokinetic studies and in situ single pass intestinal perfusion studies in Sprague–Dawley rats, the optimized SNEDDS of curcumin–phospholipid complex has shown enhanced oral absorption and bioavailability of curcumin. The cytotoxicity study in metastatic breast carcinoma cell line has shown the enhancement of cytotoxic action by 38.7%. The primary tumor growth reduction by 58.9% as compared with the control group in 4T1 tumor-bearing BALB/c mice further supported the theory of enhancement of anticancer activity of curcumin in SNEDDS.

Conclusion: The developed formulation can be a potential and safe carrier for the oral delivery of curcumin.     

Mechanism of enhanced oral absorption of akebia saponin D by a self-nanoemulsifying drug delivery system loaded with phospholipid complex

Akebia saponin D (ASD) exhibits a variety of pharmacological activities, such as anti-osteoporosis, neuroprotection, hepatoprotection, but has poor oral bioavailability. A self-nanoemulsifying drug delivery system loaded with akebia saponin D - phospholipid complex (APC-SNEDDS) (composition: Peceol: Cremophor^® EL: Transcutol HP: ASD: phospholipid; ratio: 10:45:45:51:12.3, w:w:w:w:w) was first developed to improve the oral absorption of saponins and it was found to significantly enhance ASD’s oral bioavailability by 4.3 - fold (p?<?.01). This study was conducted to elucidate the mechanism of enhanced oral absorption of ASD by the drug delivery system of APC-SNEDDS. The aggregation morphology and particle size of ASD and APC-SNEDDS prepared in aqueous solutions were determined by transmission electron microscope and particle size analyzer, respectively. Stability of ASD and APC-SNEDDS in gastrointestinal luminal contents and mucosa homogenates were also explored. The differences of in situ intestinal permeability of ASD and APC-SNEDDS were compared. APC-SNEDDS reduced the aggregation size from 389?±?7?nm (ASD) to 148?±?3?nm (APC-SNEDDS). APC-SNEDDS increased the remaining drug in large intestine luminal contents from 47?±?1% (ASD) to 83?±?1% (APC-SNEDDS) during 4?h incubation. APC-SNEDDS provided an 11-fold increase in Ka value and an 11-fold increase in P_eff value compared to ASD. In summary, APC-SNEDDS improved ASD’s oral bioavailability mainly by increasing membrane permeability, destroying self-micelles and inhibiting the intestinal metabolism.     

Fabrication of solid lipid nanoparticles of lurasidone HCl for oral delivery: optimization,in vitro characterization,cell line studies and in vivo efficacy in schizophrenia

Objective: The aim of the present investigation was to investigate the efficacy of solid lipid nanoparticles (SLNs) to enhance the absorption and bioavailability of lurasidone hydrochloride (LH) following oral administration.

Methods: The LH loaded SLNs (LH-SLNs) were prepared by high pressure homogenization (HPH) method, optimized using box Behnken design and evaluated for particle size (PS), entrapment efficiency (EE), morphology, FTIR, DSC, XRD, in vitro release, ex vivo permeation, transport studies across Caco-2 cell line and in vivo pharmacokinetic and pharmacodynamic studies.

Results: The LH-SLNs had PS of 139.8?±?5.5?nm, EE of 79.10?±?2.50% and zeta potential of ?30.8?±?3.5?mV. TEM images showed that LH-SLNs had a uniform size distribution and spherical shape. The in vitro release from LH-SLNs followed the Higuchi model. The ex vivo permeability study demonstrated enhanced drug permeation from LH-SLNs (>90%) through rat intestine as compared to LH-suspension. The SLNs were found to be taken up by energy dependent, endocytic mechanism which was mediated by clathrin/caveolae-mediated endocytosis across Caco-2 cell line. The pharmacokinetic results showed that oral bioavailability of LH was improved over 5.16-fold after incorporation into SLNs as compared to LH-suspension. The pharmacodynamic study proved the antipsychotic potential of LH-SLNs in the treatment of schizophrenia.

Conclusion: It was concluded that oral administration of LH-SLNs in rats improved the bioavailability of LH via lymphatic uptake along with improved therapeutic effect in MK-801 induced schizophrenia model in rats.     

Development and characterization of stabilized double loaded mPEG-PDLLA micelles for simultaneous delivery of paclitaxel and docetaxel

Objective: Double loaded micelles (DLM) in which paclitaxel (PTX) and docetaxel (DTX) were co-solubilized with monomethoxy poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PLA) copolymer were prepared and evaluated in an aim to investigate the effect of a combination of PTX and DTX on the stability of mPEG-PLA micelles compared to single drug-loaded micelles (SDM), especially that recent clinical anticancer formulations are limited by the existence of toxic excipients and stability issues.

Materials and methods: The SDM and DLM of PTX and DTX were prepared by a solvent evaporation method. Micellar size, size distribution, drug loading content and drug release were investigated. Transmission electron microscopy was used to investigate the stabilization mechanism.

Results: The drug loading efficiency of both PTX and DTX in DLM and SDM were 25% and 10%, respectively. ¹H NMR showed a successful encapsulation of both drugs in the polymeric micelle. DLM showed better physical stability at drug concentrations higher than 1?mg/mL compared to SDM. Moreover, DLM, SDM-PTX and SDM-DTX were stable for 24, 9 and 1?h, respectively. The stabilization mechanism of DLM was investigated, a network structure of DLM was observed in TEM graphs. Furthermore, DLM showed complete and faster drug release compared to SDM. mPEG-PLA double loaded micelles can deliver two poorly water soluble anticancer drugs at clinically relevant doses. The obtained results offer a promising alternative for double drug therapy without any formulation associated undesirable effects and encourage further in vivo development and optimization of the DLM as a drug delivery system for anticancer drugs.     

Development and optimization of self-nanoemulsifying drug delivery systems (SNEDDS) for curcumin transdermal delivery: an anti-inflammatory exposure

The purpose of this work is to develop novel lipid-based self-nanoemulsifying drug delivery systems (SNEDDS) as carriers for transdermal delivery of curcumin. SNEDDS containing black seed oil, medium chain mono- and diglycerides and surfactants, were prepared as curcumin delivery vehicles. Their formation spontaneity, morphology, droplet size, and drug loading were evaluated. Gel preparation containing two of the SNEDDS formulations were used in the carrageenan induced paw edema to evaluate the anti-inflammatory effect. Results showed droplet size as low as 71?nm. The highest drug loading was observed with SNEDDS-F6 of ～45?mg/g. In in-vivo investigation, SNEDDS-F6 exhibited significant anti-inflammatory activities in terms of 80% reduction in paw edema when compared with positive control. The prepared SNEDDS with the elevated entrapment efficiency, good transdermal penetration ability could be a suitable candidate for effective transdermal curcumin skin delivery.     

Low molecular weight chitosan-based conjugates for efficient Rhein oral delivery: synthesis,characterization, and pharmacokinetics

Objective: This article aims to design low molecular weight chitosan (LMWC)-based conjugates of Rhein (RH) by means of an amino acid linker (Alanine) for improved solubility and enhanced bioavailability.

Significance: Rhein is a potential candidate for the therapy of kidney disease. However, the poor solubility, inadequate bioavailability, and lack of proper formulation restrict its clinical applicability. LMWC-drug conjugates offer the potential to improve the water-solubility of RH, increase its oral absorption, and thereby enhance its bioavailability.

Methods: The conjugates were synthesized via a carbodiimide reaction and confirmed using UV-vis, FTIR, and ¹H-NMR spectroscopy. The water-solubility and in vitro release properties were evaluated. Free RH and RH-LMWC conjugates were administered at an equivalent oral gavage dose of RH at 35?mg/kg for pharmacokinetic studies in Sprague Dawley rats.

Results: The conjugates with RH content of 9.65% were successfully synthesized and featured a satisfactory water-solubility of 9.73?mg/mL, which exhibited a sustained release pattern over 72?h, and the enzymes present may promote the degradation of the conjugate to increase the release of Rhein. Oral administration of RH-LMWC conjugates to rats led to seven-folds and 3.1-folds increase in the T_1/2 and AUC_0–∞, respectively, as compared to RH suspension.

Conclusion: The present work demonstrated that the RH-LMWC conjugates exhibited sustained release properties with outstanding oral bioavailability enhancements compared to administration of RH itself. Potentially, RH-LMWC conjugates may serve as a promising lead for developing a new platform for RH oral delivery.     

Enhancement of oral bioavailability of fenofibrate by solid self-microemulsifying drug delivery systems

A solid form of self-microemulsifying drug delivery system (Solid SMEDDS) was developed by spray-drying with dextran as the inert solid carrier, to improve the oral bioavailability of a poorly water-soluble drug, fenofibrate. The optimized liquid SMEDDS, composed of Labrafil M 1944 CS/Labrasol/Capryol PGMC (15/75/10%v/v) with 10% w/v fenofibrate gave a z-average diameter of around 240?nm. There was no significant difference in the mean droplet size and size distribution of the emulsions obtained from the liquid and solid forms of SMEDDS. Solid state characterizations of solid SMEDDS showed that the crystal state of fenofibrate in solid SMEDDS was converted from crystalline to amorphous form. Solid SMEDDS had significantly higher dissolution rates than the drug powder, due to its fast self-emulsification in the dissolution media. Furthermore, the AUC value of solid SMEDDS was twofold greater than that of the powder, indicating this formulation greatly improved the oral bioavailability of drug in rats. Thus, these results suggest that solid SMEDDS could be used as an effective oral solid dosage form to improve dissolution and oral bioavailability of fenofibrate.