Development and evaluation of a novel drug delivery: Soluplus®/TPGS mixed micelles loaded with piperine in vitro and in vivo

Background: Although piperine can inhibit cells of tumors, the poor water solubility restricted its clinical application. This paper aimed to develop mixed micelles based on Soluplus^® and D-α-tocopherol polyethylene glycol succinate (TPGS) to improve the aqueous solubility and anti-cancer effect.

Methods: Piperine-loaded mixed micelles were prepared using a thin-film hydration method, and their physicochemical properties were characterized. The cellular uptake of the micelles was confirmed by confocal laser scanning microscopy in A549 lung cancer cells and HepG₂ liver cancer cells. In addition, cytotoxicity of the piperine mixed micelles was studied in A549 lung cancer cells and HepG₂ liver cancer cells. Free piperine or piperine-loaded Soluplus^®/TPGS mixed micelles were administered at an equivalent dose of piperine at 3.2?mg/kg via a single intravenous injection in the tail vain for the pharmacokinetic study in vivo.

Results: The diameter of piperine-loaded Soluplus^®/TPGS (4:1) mixed micelles was about 61.9?nm and the zeta potential –1.16?±?1.06?mV with 90.9% of drug encapsulation efficiency and 4.67% of drug-loading efficiency. Differential scanning calorimetry (DSC) studies confirmed that piperine is encapsulated by the Soluplus^®/TPGS. The release results in vitro showed that the piperine-loaded Soluplus^®/TPGS mixed micelles presented sustained release behavior compared to the free piperine. The mixed micelles exhibited better antitumor efficacy compared to free piperine and physical mixture against in A549 and HepG₂ cells by MTT assay. The pharmacokinetic study revealed that the AUC of piperine-loaded mixed micelles was 2.56 times higher than that of piperine and the MRT for piperine-loaded mixed micelles was 1.2-fold higher than piperine (p?Conclusion: The results of the study suggested that the piperine-loaded mixed micelles developed might be a potential nano-drug delivery system for cancer chemotherapy. These results demonstrated that piperine-loaded Soluplus^®/TPGS mixed micelles are an effective strategy to deliver piperine for cancer therapy.     

Polysialic acid and pluronic F127 mixed polymeric micelles of docetaxel as new approach for enhanced antitumor efficacy

In our previous study, polysialic acid-octadecyl dimethyl betaine (PSA-BS18) was synthesized and modified to liposomal EPI. Preliminary experiments revealed that the PSA-BS18 was a potential material for targeting tumor site with superior curative effects. In this study, PSA-BS18 and Pluronic F127 (F127) mixed polymeric micelles encapsulated docetaxel (DTX) (FP/DTX) were prepared by a self-assembly method. The FP/DTX was found to have a diameter of 34.83?±?0.50?nm with a narrow polydispersity, the entrapment efficiency was 99.12?±?1.17%, and the drug loading efficiency of 1.40?±?0.01%. The storage and dilution stability of FP/DTX was fine. In vitro release studies demonstrated that FP/DTX had delayed the drug release from the micelles. In vitro cytotoxicity assay on B16 cells presented that FP/DTX led to a stronger cytotoxic activity in comparison to F127 micelles based DTX (F127/DTX) and Tween80-based DTX (Taxotere^®). The in vivo imaging study showed that the accumulation of FP/DTX at tumor sites was more than F127/DTX. The in vivo antitumor activity of FP/DTX against B16 tumor xenograft model showed a significant higher inhibition and a lower toxicity compared with F127/DTX and Taxotere^®. Taken together, the results obtained above showed that PSA-BS18 and F127 mixed polymeric micelles may be a promising strategy for antitumor delivery of DTX.     

A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis,characterization, cytotoxicity,and pharmacokinetic evaluation

In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague-Dawley rats and compared with Stragen^® (PTX in Cremophor EL^®). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6–223.5?nm and ?5.3 to ?9.6?mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034–0.042?mg/mL) than 0:10 (0.124?mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4?±?9.3%, 61.3?±?0.5%, and 78.7?±?1.66%, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The V_d and t_1/2ß of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen^®. Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects.     

Preparation and evaluation of self-assembly Soluplus®-sodium cholate-phospholipid ternary mixed micelles of docetaxel

Abstract

Ternary mixed micelles constituted of Soluplus^®, sodium cholate, and phospholipid were prepared as nano-delivery system of the anticancer drug, docetaxel. The formulation of docetaxel-loaded ternary mixed micelles (DTX-TMMs) with an optimized composition (Soluplus^®/sodium cholate/phospholipid= 3:2:1 by weight) were obtained. The main particle size of DTX-TMMs was 76.36?±?2.45?nm, polydispersity index (PDI) was 0.138?±?0.039, and the zeta potential was ?8.46?±?0.55?mv. The encapsulation efficiency was 94.24?±?4.30% and the drug loading was 1.25%. The critical micelle concentration value was used to assess the ability of carrier materials to form micelles. The results indicated that the addition of Soluplus^® to sodium cholate-phospholipid mixed micelles could reduce the critical micelle concentration and improve the stability. In vitro release studies demonstrated that compared with DTX-Injection group, the DTX-TMMs presented a controlled release property of drugs. In vivo pharmacodynamics results suggested that DTX-TMMs had the most effective inhibitory effect on tumor proliferation and had good biosafety. In addition, the relative bioavailability of mixed micelles was increased by 1.36 times compared with the DTX-Injection in vivo pharmacokinetic study indicated that a better therapeutic effect could be achieved. In summary, the ternary mixed micelles prepared in this study are considered to be promising anticancer drug delivery systems.     

Synthesis and characterization of amphiphilic star-shaped copolymers based on β-cyclodextrin for micelles drug delivery

Purpose: A series of β-CD amphiphilic star-shaped copolymers with exceptional characteristics were synthesized and their potential as carriers for micelles drug delivery was investigated.

Methods: A series of amphiphilic copolymers based on β-CD were synthesized by introducing poly (acrylic acid)-co-poly(methyl methacrylate)-poly (vinyl pyrrolidone) or poly (acrylic acid)-co-poly(methyl methacrylate)-co-poly(monoacylated-β-CD)-poly (vinyl pyrrolidone) blocks to the primary hydroxyl group positions of β-CD. The micellization behavior of the copolymers, the synthesis conditions, characteristics, drug release in vitro and tissue distribution of vinpocetine (VP) micelles in vivo were investigated.

Results: Around 60 types of β-CD amphiphilic star-shaped copolymers were successfully synthesized and the critical micelle concentration ranged from 9.80?×?10^?4 to 5.24?×?10^?2g/L. The particle size, drug loading and entrapment efficiency of VP-loaded β-CD-P₄ micelles prepared with optimal formulation were about 65?nm, 21.44?±?0.14%, and 49.05?±?0.36%, respectively. The particles had good sphericity. The cumulative release rates at 72?h of VP-loaded β-CD-P₄ micelles in pH 1.0, pH 4.5, pH 6.5, or pH 7.4 media were 93%, 69%, 49%, and 43%, respectively. And, the lung targeting efficiency of VP-loaded β-CD-P₄ micelles was 8.98 times higher than that of VP injection.

Conclusion: The VP-loaded β-CD-P₄ micelles exhibited controlled-release property, pH-induced feature and lung targeting capacity compared with VP injection, suggesting that the β-CD-P₄ copolymers are an excellent candidate for micelles drug delivery.     

Synthesis,in vitro characterization,and anti-tumor effects of novel polystyrene-poly(amide-ether-ester-imide) co-polymeric micelles for delivery of docetaxel in breast cancer in Balb/C mice

Objective: The goal of the present work was to make novel co-polymeric micellar carriers for the delivery of docetaxel (DTX).

Significance: Co-polymeric micelles can not only solubilize DTX and eliminate the need for toxic surfactants to dissolve it, but also cause passive targeting of the drug to the tumor and reduce its toxic side effects.

Methods: Poly(styrene-maleic acid) (SMA) was conjugated to poly (amide-ether-ester-imide)-poly ethylene glycol (PAEEI-PEG). Copolymer synthesis was proven by Fourier transform infrared (FTIR) and ¹H-nuclear magnetic resonance (¹H-NMR). The SMA-PAEEI-PEG micelles loaded with DTX were prepared and their critical micelle concentration (CMC), zeta potential, particle size, entrapment efficiency, and their release efficiency were studied. MCF-7 and MDA-MB231 breast cancer cells were used to evaluate the cellular uptake and cytotoxicity of the micelles. The antitumor activity of the DTX-loaded nanomicelles was measured in Balb/c mice.

Results: The FTIR and HNMR spectroscopy confirmed successful conjugation of SMA and PAEEI-PEG. The drug loading efficiency was in the range of 34.01–72.75% and drug release lasted for 120?h. The CMC value of the micelles was affected by the SMA/PAEEI-PEG ratio and was in the range of 29.85–14.28?µg/ml. The DTX-loaded micelles showed five times more cytotoxicity than the free drug. The DTX loaded micelles were more effective in tumor growth suppression in vivo and the animals showed an enhanced rate of survival.

Conclusion: The results show that the SMA-PAEEI-PEG micelles of DTX could potentially provide a suitable parenteral formulation with more stability, higher cytotoxicity, and improved antitumor activity.     

Powder form and stability of Pluronic mixed micelle dispersions for drug delivery applications

The aim of this work was to optimize a formulation of the Pluronic® F127/L121 mixed micelle system and evaluate it in terms of stability upon dilution in biologically relevant media and to explore the possibility of preparing F127/L121 micelles in a powder form that can be simply reconstituted to an initial freshly made mixed micelle formulation. The mixed F127/L121 micelles were prepared at a relatively high concentration of Pluronics (1% w/w for both Pluronics) using two different methods (direct dissolution and film rehydration) with an external input of energy. The optimal preparation of the mixed F127/L121 micelles (hydrodynamic diameter (d_h)?=?75?nm, polydispersity index (PDI)?=?0.287) was achieved using the film rehydration method followed by ultrasonication. Stability studies of the F127/L121 micelle system were performed at 25?°C and 37?°C and upon dilution in different biologically relevant media. The F127/L121 micelles were stable in phosphate buffered saline (PBS) upon 100-fold dilution for at least 10?d and in PBS containing bovine serum albumin upon 10 and 50-fold dilution for at least 48 and 12?h, respectively. A dry powdered form of the mixed micelles was prepared by freeze-drying after slow or fast freezing process. The influence of the type and amount of cryoprotectant on the prevention of F127/L121 micelles aggregation during the freeze-drying and reconstitution processes were evaluated. The use of trehalose (5%, w/w) and sucrose (2.5%, w/w) with slow and fast freezing process, respectively, resulted in a reconstituted product with mostly similar d_h and PDI values of the fresh micelle formulation.     

Soluplus/TPGS mixed micelles for dioscin delivery in cancer therapy

Background: Dioscin has shown cytotoxicity against cancer cells, but its poor solubility and stability have limited its clinical application. In this study, we designed mixed micelles composed of TPGS and Soluplus^® copolymers entrapping the poorly soluble anticancer drug dioscin.

Method: In order to improve the aqueous solubility and bioactivity of dioscin, TPGS/Soluplus^® mixed micelles with an optimal ratio were prepared using a thin-film hydration method, and their physicochemical properties were characterized. Cellular cytotoxicity and uptake of the dioscin-loaded TPGS/Soluplus^® mixed micelles were studied in MCF-7 breast cancer cells and A2780s ovarian cancer cells. The pharmacokinetics of free dioscin and dioscin-loaded TPGS/Soluplus^® mixed micelles was studied in vivo in male Sprague-Dawley rats via a single intravenous injection in the tail vein.

Results: The average size of the optimized mixed micelle was 67.15?nm, with 92.59% drug encapsulation efficiency and 4.63% drug loading efficiency. The in vitro release profile showed that the mixed micelles presented sustained release behavior compared to the anhydrous ethanol solution of dioscin. In vitro cytotoxicity assays were conducted on human cancer cell lines including A2780s ovarian cancer cells and MCF-7 breast cancer cells. The mixed micelles exhibited better antitumor activity compared to free dioscin against all cell lines, which may benefit from the significant increase in the cellular uptake of dioscin from mixed micelles compared to free dioscin. The pharmacokinetic study showed that the mixed micelle formulation achieved a 1.3 times longer mean residual time (MRT) in circulation and a 2.16 times larger area under the plasma concentration–time curve (AUC) than the free dioscin solution.

Conclusion: Our results suggest that the dioscin-loaded mixed micelles developed in this study might be a potential nano drug-delivery system for cancer chemotherapy.     

Co-delivery of hydrophilic and hydrophobic drugs by micelles: a new approach using drug conjugated PEG–PCLNanoparticles

Co-delivery strategy has been proposed to minimize the amount of each drug and to achieve the synergistic effect for cancer therapies. A conjugate of the antitumor drug, doxorubicin, with diblock methoxy poly (ethylene glycol)-poly caprolactone (mPEG-PCL) copolymer was synthesized by the reaction of mPEG–PCL copolymer with doxorubicin in the presence of p-nitrophenylchloroformate. The conjugated copolymer was characterized in vitro by ¹H-NMR, FTIR, DSC and GPC techniques. Then, the doxorubicin conjugated mPEG–PCL(DOX–mPEG-PCL) was self-assembled into micelles in the presence of curcumin in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM).The encapsulation efficiency of doxorubicin and curcumin were 82.31?±?3.32 and 78.15?±?3.14%, respectively. The results revealed that the micelles formed by the DOX–mPEG-PCL with and without curcumin have spherical structure with average size of 116 and 134?nm respectively. The release behavior of curcumin and doxorubicin loaded to micelles were investigated in a different media. The release rate of micelles consisted of the conjugated copolymer was pH dependent as it was higher at lower pH than in neutral condition. Another feature of the conjugated micelles was a sustained release profile. The cytotoxicity of micelles were evaluated by MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, atetrazole) assay on lung cancer A549 cell lines. In vitro cytotoxicity assay showed that the mPEG–PCL copolymer did not affect the growth of A549 cells. The cytotoxic activity of the micelles against A549 cells was greater than free doxorubicin and free curcumin.     

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.     

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.     

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.     

In vitro and in vivo evaluation of paclitaxel–lapatinib-loaded F127 pluronic micelles

The aim of this study was to evaluate the in vitro and in vivo efficacy of paclitaxel–lapatinib-loaded Pluronic micelles. Lapatinib and pluronic sensitize the cancerous cells to paclitaxel via efflux pump inhibition. In addition, pluronic polymers can trigger intrinsic apoptosis pathways. Furthermore, micellar system can passively target the chemotherapeutic agents by enhanced permeability and retention effect. The paclitaxel–lapatinib-loaded micelles were characterized in means of encapsulation efficacy and size. The in vitro analyses were performed by MTT assay and uptake studies. Real-time imaging and in vivo anti-tumor efficacy studies were also performed. The prepared micelles have acceptable encapsulation ratio and size. Hemolysis assay confirmed that the micelles are hemo-compatible. MTT assay demonstrated that drug-loaded micelles have superior cytotoxicity compared with the naked drugs. The confocal microscopy and flowcytometry analyses showed that micelles are mainly internalized by endocytosis. According to the results of the in vivo imaging, the micelles are accumulated within liver. In vivo anti-tumor efficacy studies confirmed that tumor inhibition of drug-loaded micelles was significant compared to Intaxel^®.     

Formation of monetite nanoparticles and nanofibers in reverse micelles

Reverse micelles solution of water and cyclohexane containing either cetyltrimethylammonium bromide (CTAB) or polyoxyethylene-8-dodecyl ether (C₁₂E₈) surfactants and n-pentanol as co-surfactant have been used as organized reaction microenvironments for monetite (dicalcium phosphate anhydrous, DCPA) precipitation. Well-crystallized monetite nanoparticles with various morphologies such as spheres, nanofibers and bundles of nanowires were obtained in CTAB reverse micelles solution. The molar ratio of water and surfactant (W _o) and the molar ratio of co-surfactant and surfactant (P _o) have great influence on the structure and morphology of the final products. A generalized mechanism for the growth of monetite in reverse micelles is proposed, in which the interaction between the surfactant molecules and PO₄³⁻ ions leads to the formation of a surfactant/CaHPO₄ complex. It is because of this central complex that the further fusion with reactant ions containing reverse micelles will occur only in one direction. Changing the content of water and co-surfactant has great influence on the morphology of reverse micelles and on the interaction between the surfactant/CaHPO₄ complex leading to a fine tuning of the morphology of products. By contrast, lacking of this interaction in the C₁₂E₈ system only tablet amorphous calcium phosphate can be formed.     

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.     

N-octyl-N-arginine-chitosan (OACS) micelles for gambogic acid oral delivery: preparation,characterization and its study on in situ intestinal perfusion

Context: Gambogic acid (GA) can inhibit the growth of various cancer cells. However, the low bioavailability caused by insolubility, limits its clinical application. L-arginine is always used with GA to form a complex to obtain the higher solubility. Moreover, guanidyl group from arginine, which can facilitate the cellular uptake, was identified.

Objective: In this study, L-arginine and chitosan (CS) were used for the first time to prepare N-octyl-N-arginine CS (OACS), a novel amphiphilic carrier for GA with solubility- and absorption-enhancing functions; the characterization of the GA loaded OACS micelles (GA-OACS) and its absorption-enhancing effect were also investigated.

Materials and methods: GA-OACS were prepared by the dialysis method. The formed micelles were characterized and evaluated by atomic force microscope (AFM), dynamic light scattering, differential scanning calorimeter (DSC), solubility test, in vitro release and in situ intestinal perfusion.

Results: The GA-OACS micelles were successfully prepared attaining a 35.3% drug loading and 82.2% entrapment efficiency. GA-OACS had a homogeneous particle size of 160.3?nm; +21.8?mv zeta potential with smooth continuous surface was observed by using AFM. DSC diagram suggested that GA was encapsulated in the micelles. Meanwhile, GA encapsulated in micelles exhibited a desirable slow release in vitro experiment. The solubility of GA in OACS micelles was increased up to 3.16?±?0.13?mg/mL, 2320 times than that of free GA. The single pass perfusion showed that the absorption of GA-OACS micelles was enhanced 3.6-fold, 2.1-fold and 2.2-fold for jejunum, ileum and colon, respectively.

Discussion and conclusion: OACS provided excellent ability of drug loading, increasing solubility and enhanced absorption for GA, which indicated that OACS micelles as an oral drug delivery carrier may have potential research and application values.     

YAG:Ce3+, Gd3+ nano-phosphor for white light emitting diodes

YAG:Ce³⁺, Gd³⁺ nano-phosphors were synthesised by the glycothermal method. The X-ray diffraction measurements showed that the samples can be well-crystallised at 600°C. The transition electron microscope showed that the particles have sizes mostly in the range between 35 and 100?nm. The YAG:Ce nano-phosphor had a wide emission band ranging from blue to yellow with a peak at 532?nm, due to the transition from the lowest 5d band to ²F_7/2, ²F_5/2 states of the Ce³⁺ ion. Red-shift of emission peak wavelength from 532 to 568?nm was achieved doping Gd³⁺ ions into the YAG:Ce³⁺ to substitute some Y³⁺ ions. White light emitting diodes (LEDs) were obtained by combining blue LED chip (InGaN-based 460?nm emitting) with (Y_{2.94? x} Ce_0.06Gd _x )Al₅O₁₂ phosphor. As x has the value of 0.8, an intense white LED with good colour rendering of 86 was obtained.     

Diffusion coefficients of tetrazolium blue in homogeneous and micellar solutions

Diffusion coefficients of the electron acceptor dye tetrazolium blue were measured by the Taylor dispersion method, with an accuracy better than 4%, in two solvents: (i) a homogeneous one-aqueous phosphate buffer, 0.1 M, pH=7.0 (medium I); and (ii) a heterogeneous one-nonionic micelles of Triton X-100, 2.0 mM (where M stands for mol·dm^–3), in the same aqueous phosphate buffer (medium II). The values obtained were D ₁₂ ^I =3.64×10^–10m²·s^–1 and D ₁₂ ^II =3.01×10^–10m²·s^–1·D ₁₂ ^II has the meaning of a macroscopird or average diffusion coefficient, in which the partition coefficient of tetrazolium blue between micelles and water, as well as the diffusion coefficients of this dye and of the micelles in the aqueous phase, are involved.     

Development and validation of spectrophotometric and HPTLC methods for simultaneous determination of rosiglitazone maleate and metformin hydrochloride in the presence of interfering matrix excipients

Two simple methods have been developed and validated for the simultaneous determination of rosiglitazone maleate (ROS) and metformin hydrochloride (MET) in synthetic mixtures and coated tablets in a ratio of 1:250 (ROS:MET). The first method was a spectrophotometric one. The minor component, ROS was determined by measuring the values of absorbance at λ_max 312?nm and the D₁ amplitudes at 331?nm where MET shows no absorption contribution. However, absorbance interferences from tablet excipients were successfully corrected by D₁ at 331?nm zero-crossing technique. Study of spectral interference from tablet excipients was included in the text. Standard curves for A_max and D₁ methods were in the concentration range 20.0–80.0?μg?mL^?1. The major component, MET was determined both in binary mixtures and tablets by measuring its A_max at 236?nm. Extensive dilution eliminated any absorption contribution from the coexisting ROS or tablet matrix. Standard curves showed linearity in the concentration range 4.0–12.8?μg?mL^?1. The second method was based on high performance thin layer chromatography (HPTLC) separation of the two drugs followed by densitometric measurements of their spots at 230?nm. The separation was carried out on Merck HPTLC aluminium sheets of silica gel 60 F254 using methanol:water:NH₄Cl 1% w/v (5:4:1 v/v/v) as the mobile phase. Linear calibration graphs of peak area values were obtained versus concentrations in the range of 0.4–2.0?μg?band^?1 and 20.0–100.0?μg?band^?1 for ROS and MET, respectively. According to International Conference on Harmonisation (ICH) guidelines, different validation parameters were verified for the two methods and presented.     

Pluronic-poly (acrylic acid)-cysteine/Pluronic L121 mixed micelles improve the oral bioavailability of paclitaxel

The aim of the study is to synthesize a thiolated Pluronic copolymer, Pluronic-poly (acrylic acid)-cysteine copolymer, to construct a mixed micelle system with the Pluronic-poly (acrylic acid)-cysteine copolymer and Pluronic L121 (PL121) and to evaluate the potential of these mixed micelles as an oral drug delivery system for paclitaxel. Compared with Pluronic-poly (acrylic acid)-cysteine micelles, drug-loading capacity of Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles was increased from 0.4 to 2.87%. In vitro release test indicated that Pluronic-poly (acrylic acid)-cysteine/PL121 mixed micelles exhibited a pH sensitivity. The permeability of drug-loaded micelles in the intestinal tract was studied with an in situ perfusion method in rats. The presence of verapamil and Pluronic both improved the intestinal permeability of paclitaxel, which further certified the inhibition effect of thiolated Pluronic on P-gp. In pharmacokinetic study, the area under the plasma concentration-time curve (AUC_0→∞) of paclitaxel-loaded mixed micelles was four times greater than that of the paclitaxel solution (p?相似文献