99mTc Radiolabeled HA/TPGS-Based Curcumin-Loaded Nanoparticle for Breast Cancer Synergistic Theranostics: Design, in vitro and in vivo Evaluation.

BACKGROUND: Emerging cancer therapy requires highly sensitive diagnosis in combination with cancer-targeting therapy. In this study, a self-assembled pH-sensitive curcumin (Cur)-loaded nanoparticle of 99mTc radiolabeled hyaluronan-cholesteryl hemisuccinate conjugates (HA-CHEMS) and D-a-tocopheryl polyethylene glycol succinate (TPGS) was prepared for breast cancer synergistic theranostics. MATERIALS AND METHODS: The synthesized amphiphilic HA-CHEMS conjugates and TPGS self-assembled into Cur-loaded nanoparticles (HA-CHEMS-Cur-TPGS NPs) in an aqueous environment. The physicochemical properties of HA-CHEMS-Cur-TPGS NPs were characterized by transmission electron microscopy (TEM) and dynamic lighter scattering (DLS). The in vitro cytotoxicity of HA-CHEMS-Cur-TPGS NPs against breast cancer cells was evaluated by using the methyl thiazolyl tetrazolium (MTT) assay. Moreover, the in vivo animal experiments of HA-CHEMS-Cur-TPGS NPs including SPECT/CT imaging biodistribution and antitumor efficiency were investigated in 4T1 tumor-bearing BALB/c mice; furthermore, pharmacokinetics were investigated in healthy mice. RESULTS: HA-CHEMS-Cur-TPGS NPs exhibited high curcumin loading, uniform particle size distribution, and excellent stability in vitro. In the cytotoxicity assay, HA-CHEMS-Cur-TPGS NPs showed remarkably higher cytotoxicity to 4T1 cells with an IC50 value at 38 µg/mL, compared with free curcumin (77 µg/mL). Moreover, HA-CHEMS-Cur-TPGS NPs could be effectively and stably radiolabeled with 99mTc. The SPECT images showed that 99mTc-HA-CHEMS-Cur-TPGS NPs could target the 4T1 tumor up to 4.85±0.24%ID/g at 4 h post-injection in BALB/c mice. More importantly, the in vivo antitumor efficacy studies showed that HA-CHEMS-Cur-TPGS NPs greatly inhibited the tumor growth without resulting in obvious toxicities to major organs. CONCLUSION: The results indicated that HA-CHEMS-Cur-TPGS NPs with stable 99mTc labeling and high curcumin-loading capacity hold great potential for breast cancer synergistic theranostics.

Nanostructured lipid carrier-based pH and temperature dual-responsive hydrogel composed of carboxymethyl chitosan and poloxamer for drug delivery.

The aim of this study was to develop a novel nanostructured lipid carrier (NLC) based dual-responsive hydrogel for ocular drug delivery of quercetin (QN). NLC loaded with quercetin (QN-NLC) was prepared using melt-emulsification combined with ultra-sonication technique. A three-factor five-level central composite design (CCD) was employed to optimize the formulation of QN-NLC. The optimized QN-NLC presented a particle size of 75.54nm with narrow size distribution and high encapsulation efficiency (97.14%).QN-NLC was characterized by TEM and DSC. In addition, a pH and temperature dual-responsive hydrogel composed of carboxymethyl chitosan (CMCS) and poloxamer 407(F127) was constructed by a cross-linking reaction with a naturally occurring nontoxic crosslinking agent genipin (GP). FT-IR was employed to demonstrate that F127/CMCS hydrogel was successfully synthesized. The results of SEM analysis and swelling experiments indicated that F127/CMCS hydrogel was both temperature-responsive and pH-responsive. From the results of In vitro release studies, dual temperature and pH responsiveness of the hydrogel was demonstrated, and 80.52% of total quercetin was released from the QN-NLC based hydrogel (QN-NLC-Gel) within 3days, revealing QN-NLC-Gel released drug sustainably. Taken together, the developed NLC-based hydrogel is a promising drug delivery system for the ophthalmic application.

Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time-Controlled Release Etodolac Pellets.

The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

A time-adjustable pulsatile release system for ketoprofen: In vitro and in vivo investigation in a pharmacokinetic study and an IVIVC evaluation.

A time-adjustable pulsatile release system (TAPS) containing ketoprofen (KF) as an active pharmaceutical agent was developed having been designed for bedtime dosing and releasing drug in the early morning to control the symptoms of rheumatoid arthritis (RA). The formulation involved a tablet core (KF) and a control-release layer, and the coating membrane was composed of EC and Eudragit L100. A single-factor study, a central composite design and a response surface method were selected to optimize the formula and the optimum prescription was as follows: tablet core (KF 50mg, MCC 70mg, lactose 40mg, L-HPC 38mg), and film (EC 7.8g, Eudragit L100 4.2g, PEG 6000 1.8g in 95% alcohol each 200ml). The in vivo release behavior of the tablets was evaluated in Beagle dogs after a parallel oral administration of KF TAPS tablets and commercial KF capsules, when it was found that the KF TAPS tablets released the drug after a lag-time of 3.458h and the Tmax was 5.833h. The relative bioavailability was 85.01%, and the two formulations were bioequivalent in terms of Cmax and AUC0-t and the in vitro- in vivo correlations indicated that test formulation had a good in vivo-in vitro correlation (r=0.9703). These results show that the novel drug delivery system (TAPS) has the potential to be used as a KF preparation with chronophamacokinetics characteristics.

Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate.

The aim of this study was to develop and characterize a novel colloidal system, namely, timolol maleate chitosan coated liposomes (TM-CHL) to enhance the ocular permeation, precorneal residence time and bioavailability. The resulting TM-CHL was the most promising formulation with a mean particle size of 150.7nm and an EE% of 75.83±1.61%. In vitro release of the TM-CHL showed an extended drug release profile. The TM-CHL exhibited significant mucin adhesion and compared with commercial eye drops, TM-CHL produced a 3.18-fold increase in the apparent permeability coefficient (Papp), resulting in a significant enhancement of corneal permeation. In addition, the gamma scintigraphic study and the pharmacokinetic study showed that TM-CHL could be retained at the corneal surface for longer time compared with eye drops. The ocular irritation study indicated that the developed liposomes produced no significant irritant effects. Furthermore, pharmacodynamics results showed that the maximum intraocular pressure(IOP) produced by TM-CHL was (19.67±1.14) mmHg compared with the (23.80±1.49) mmHg for TM eye drops, revealing that TM-CHL was more effective in reducing the IOP. These results demonstrate that CHL is a potentially useful carrier for ocular drug delivery, which could improve the efficacy of TM.

Design and evaluation of a novel potential carrier for a hydrophilic antitumor drug: Auricularia auricular polysaccharide-chitosan nanoparticles as a delivery system for doxorubicin hydrochloride.

To improve the low loading content of hydrophilic drugs in nanodrug delivery systems, a natural watersoluble polysaccharide, Auricularia auricular polysaccharide (AAP), was extracted and purified as a vehicle for the hydrophilic drug doxorubicin hydrochloride (Dox·HCl). This involved the preparation of polyelectrolyte complexes nanoparticles (PEC NPs) using the electrostatic interaction between cationic chitosan (CS) and anionic AAP. The formation of AAP-CS-NPs was confirmed by FT-IR and TEM. It was found that Dox-loaded AAP-CS-NPs possessed a spherical morphology with average diameters of 237.6nm and 74.1% Dox·HCl encapsulation efficiency. The stability of Dox AAP-CS-NPs was examined by suspending the nanoparticles in PBS (pH 7.4) at room temperature. The particle size of the nanoparticle samples remained stable and exhibited no obvious variations in drug content after half a month. In addition, in vitro cytotoxicity studies showed that blank AAP-CS-NPs did not exhibit any cytotoxic effects, while Dox AAP-CS-NPs increased the Dox·HCl cytotoxicity against MCF-7 cells as the result of significantly increased cellular uptake, compared with free Dox·HCl. Hence, the overall results obtained suggest that AAP-CS-NPs are very effective in entrapping Dox·HCl and to penetrate into tumor cells, rendering them promising carriers for hydrophilic antitumor drugs.

Recent Aspects of Osmotic Pump Systems: Functionalization, Clinical use and Advanced Imaging Technology.

BACKGROUND: Osmotic pump drug delivery systems are one of the most promising and widely developed systems. They are based on the principle of osmosis and are characterized by a zero-order release pattern independent of the physicochemical properties of the drug involved and some physiological factors. In the past 30 years, a series of difficulties, such as the very wide solubility range of different drugs, have been resolved accompanied by the development of various types of osmotic pumps. Furthermore, more advanced designs have been proposed according to practical requirements. METHODS: We started a systematic references collection on osmotic pump systems through different available databases. Then these information were analyzed and divided according to different subjects. Finally, we made clear our thought and begun to write it in a logical way. RESULTS: This review mainly concentrates on five kinds of functional osmotic pumps including technology combined, targeted, chronotherapy- based, ascending and compound osmotic pumps, involving ways to improve bioavailability and reduce side effects. Special attention is paid to the application of advanced imaging technologies to study osmotic pumps including the coating process, processing steps, polymer hydration and changes in the internal structure. CONCLUSIONS: Present-day osmotic pumps not only produce a constant release, but also have the ability to produce adjustable release according to practical requirements. Hence, technology combined, targeted, chronotherapy-based, ascending and compound osmotic pumps are a positive development. These latest advances offer various advantages compared with the classic osmotic pump, and enable them to meet the new needs for clinical use with fewer side effects and improved safety. In addition, following the improvements in the versatility and complexity of the novel osmotic pump system, conventional assessing parameters may fail to meet the increasing demand for information. Hence, novel imaging and monitoring technologies have been employed to monitor osmotic pumps from the coating process, processing steps, and polymer hydration to the changes in polymeric internal structure, which are associated with the different performance offered by the in vivo action of similar products.

[Formulation optimization of ginkgo flavonoids matrix tablets by orthogonal design].

Sustained-release tablet has become one of the hottest research spots in the area of sustained release preparations with its unique advantages. At present, a series of shortcomings were exited in the ordinary ginkgo preparations, which were used for the treatment of cardiovascular and cerebrovascular diseases. In order to avoid these shortcomings, ginkgo flavonoids matrix tablets were prepared in this paper. Furthermore, the amount and varieties of matrix material, adhesives and fillers were investigated. Meanwhile, the formulation was optimized by using the method of orthogonal design, and Zero-order, First-order, Higuchi, Ritger-peppas equation were used for the model fitting and mechanism discussing of drug release.

Formulation of a stable and high-loaded quercetin injectable emulsion.

The purpose of this paper was to prepare a stable and high-loaded quercetin emulsion with the quercetin-phospholipid complex. The complex was analyzed by FT-IR and SEM. Quercetin and soybean lecithin were reacted in dichloromethane at a ratio of 1:2.5 for 2 h at 40°C to prepare the complex. The optimum quercetin emulsion formulation consisted of (according to quality percentage), the complex (quercetin 0.06% in the emulsion), miglyol 812 10%, soybean oil 2%, solutol HS 15 1.2%, cremophor ELP 0.4%, vitamin E 0.2%, oleic acid 0.5%, glycerol 2.5%. The quercetin emulsion was sterilized at 121°C for 15 min. The drug content and particle size distribution of the emulsion before and after sterilization were almost unchanged. The results of accelerate stability (stored at 40°C over one month) and short-time stability (stored at room temperature over six months) tests showed that the quercetin emulsion had enough physicochemical stability to undergo storage. The histopathological examination for rabbit ear vein irritation test indicated that the quercetin emulsion produced no more irritation than normal saline.

Optimized preparation of vinpocetine proliposomes by a novel method and in vivo evaluation of its pharmacokinetics in New Zealand rabbits.

Free-flowing proliposomes which contained vinpocetine were prepared successfully to increase the oral bioavailability of vinpocetine. In this study the proliposomes were prepared by a novel method which was reported for the first time and the formulation was optimized using the centre composite design (CCD). The optimized formulation was Soybean phosphatidylcholine: 860 mg; cholesterol: 95 mg and sorbitol: 8000 mg. After the proliposomes were contacted with water, the suspension of vinpocetine liposomes formed automatically and the entrapment efficiency was approximately 86.3% with an average particle size of about 300 nm. The physicochemical properties of the proliposomes including SEM, TEM, XRD and FTIR were also detected. HPLC system was applied to study the concentration of vinpocetine in the plasma of the New Zealand rabbits after oral administration of vinpocetine proliposomes and vinpocetine suspension. The pharmacokinetic parameters were calculated by the software program DAS2.0. The concentration-time curves of vinpocetine suspension and vinpocetine proliposomes were much more different. There were two absorption peaks on the concentration-time curves of the vinpocetine proliposomes. The pharmacokinetic parameters of vinpocetine and vinpocetine proliposomes in New Zealand rabbits were T(max) 1 h and 3 h (there was also an absorption peak at 1 h); C(max) 163.82+/-12.28 ng/ml and 166.43+/-21.04 ng/ml; AUC(0-infinity) 1479.70+/-68.51 ng/ml h and 420.70+/-35.86 ng/ml h, respectively. The bioavailability of vinpocetine in proliposomes was more than 3.5 times higher than the vinpocetine suspension. The optimized vinpocetine proliposomes did improve the oral bioavailability of vinpocetine in New Zealand rabbits and offer a new approach to enhance the gastrointestinal absorption of poorly water soluble drugs.

[Study on ingredients of essential oils of Curcuma wenyujin extracted by supercritical-CO2 fluid extraction and steam distillation].

OBJECTIVE: To compare the ingredients of essential oils of Curcuma wenyujin extracted by supercritical-CO2 fluid extraction and by steam distillation. METHOD: GC-MS was applied in this experiment. RESULT: The ingredients and physical and chemical properties of essential oils of C. wenyujin extracted by supercritical-CO2 fluid extraction and by steam distillation are similar. CONCLUSION: Supercritical-CO2 fluid extraction is better than steam distillation in extraction time, power consumption, recovery and purity.

Design and evaluation of jingzhiguanxin monolithic osmotic pump tablet.

A monolithic osmotic pump tablet (MOPT) of Traditional Chinese Medicine Compound Recipe (TCMCR) was successfully prepared and active components of Jingzhiguanxin prescription which has been widely used in China and Japan was selected as model drug. Analysis methods of maker compound in vitro of danshensu, paeoniflorin and safflor yellow A were built, and different methods were compared by f2 factors. The results showed that there were fine correlation among them. Finally UV method of safflor yellow A was chosen to determine the release of the drugs, which was fast, convenient, met the need of determination and could represent other methods. During the research, single factor influence selection was studied emphatically. It showed that there were significant influence between different varieties and quantity of osmotic promoting agents, different kind of retardants, different varieties and quantity of PEG (polyethylene glycol) and membrane weight. However, no significant influence existed between different quantity of retardants and SDS, different membrane orifices and methods of dissolution. Based on the single factor influence selection, an optimal formulation was decided, and three maker compounds of Jingzhiguanxin MOPT could isochronous release and at the same time they had good zero order release characteristics to 8 h. Paeoniflorin release in vivo was estimated by deconvolution, the results shown that there were a good in-vitro in-vivo correlation (r=0.9571).

Studies of the pharmacokinetics of paeoniflorin in two Jing-Zhi-Guan-Xin formulations after oral administration to beagle dogs.

Paeoniflorin is the principal bioactive component of Paeoniae Radix. The traditional chinese medicine compound recipe (TCMCR) tablets of Jing-Zhi-Guan-Xin (JZGX), which is composed of Radix Salviae Miltiorrhizae, Radix Paeoniae Rubrae, Rhizoma Chuan-xiong, Flos Carthami and Lignum Dalbergiae Odorafera, have been widely used in China and Japan. The plasma concentrations of paeoniflorin in beagle dogs after oral administration of two Jing-Zhi-Guan-Xin formulations (the dose used in the two formulations were both 200 mg paeoniflorin) were measured using a simple and rapid HPLC method. The mean terminal half-lives (t1/2) of JZGX tablet and JZGX elementary osmotic pump tablet (EOPT) formulations of paeoniflorin were 147.52 +/- 28.98 and 276.60 +/- 24.24 min, the maximum plasma concentrations (Cmax) of paeoniflorin were 210.49 +/- 23.89 and 94.36 +/- 14.01 ng/ml, times to reach maximum concentrations (tmax) were 130.00 +/- 30.98 and 280.00 +/- 48.99 min, the area under the plasma concentration-time curves (AUC0-infinity) were 43066.50 +/- 10119.51 and 42266.87 +/- 2654.90 ng min/ml, the mean residence times (MRT) were 212.87 +/- 41.82 and 399.14 +/- 34.98 min, respectively, and the relative bioavailability (Fr) of JZGX EOPT compared with JZGX tablet was 101.8 +/- 18.8%. These results, compared with the pharmacokinetic parameters of paeoniflorin after oral administration of Paeoniae Radix extract alone, indicated that the absorption of paeoniflorin after oral administration of the two JZGX formulations was significantly greater than that after oral administration of Paeoniae Radix extract alone.