International Journal of Pharmaceutics (v.446, #1-2)
Editorial Board (iii).
Reduction in the volume of water for ingesting orally disintegrating tablets of solifenacin (Vesicare® OD), and the clinical disintegration time of Vesicare® OD after unit-dose packaging by Shinya Uchida; Tomohiro Yoshita; Noriyuki Namiki (1-5).
This study aimed to determine the amount of water required for ingesting an orally disintegrating tablet (ODT) of solifenacin (Vesicare®, VES) and VES conventional tablets (VES-CT). We measured the disintegration time of VES-ODT in the oral cavity (clinical disintegration time) before and after unit-dose packaging. Thirty healthy volunteers participated in this randomized crossover trial. The participants were asked to drink water during the intake placebos of VES and after the disintegration of placebos of VES-ODT in their oral cavity. The amounts of water required for ingesting placebos of VES-CT and of VES-ODT were 42.8 ± 27.0 mL and 20.0 ± 23.7 mL, respectively, which indicated that the amount of water required for ingesting ODTs was significantly lesser than that for ingesting CTs. Furthermore, 5 (16.7%) participants did not require water for ingesting the ODTs. Clinical disintegration time of VES-ODT was 21.4 s in 10 healthy volunteers. This clinical disintegration time did not change significantly after unit-dose packaging or subsequent storage for 56 days. This study showed that the amount of water required for ingesting VES-ODT is lower than that for ingesting VES-CT.
Keywords: Orally disintegrating tablet; Solifenacin; Water intake; Clinical trial; Unit-dose packaging;
Deformation properties of pharmaceutical excipients determined using an in-die and out-die method by Ilija Ilić; Biljana Govedarica; Rok Šibanc; Rok Dreu; Stane Srčič (6-15).
This study investigated deformation mechanisms of some commonly used pharmaceutical fillers, such as microcrystalline cellulose, lactose, dicalcium phosphate, isomalt and cornstarch, using a combination of the in-die and out-die method with the Heckel and Walker models. The tableting mixtures contained of 98.5% (w/w) filler, the rest consisted of dry binder and an antiadhesive agent. Our results showed that plasticity and elasticity may be considered independent deformation properties as highly plastic materials (microcrystalline cellulose, cornstarch) also exhibited high elasticity. Particular emphasis was placed on explaining the differences observed between the in-die and out-die method—comparison revealed that the differences are a consequence of the material's elastic properties. Larger error of in-die results can be expected for more elastic materials, and thus in-die Heckel should be used with some considerations. In contrast, the Walker model was found to be more robust and smaller differences were observed between the two methods. We consider the most correct results to have been obtained by the out-die approach, which excludes the elastic properties of the material evaluated. An excellent correlation between elastic determination at the single-particle level and multiple-particle scale was demonstrated, suggesting a great potential of nanoscale determination of a material's mechanical properties for better elucidation of deformation mechanisms.
Keywords: Heckel; Walker; In-die; Out-die; Deformation; Nanoindentation;
Comparative in vitro and in vivo evaluation of lipid based nanocarriers of Huperzine A by Pratikkumar A. Patel; Sushant C. Patil; Dhaval R. Kalaria; Yogeshwar N. Kalia; Vandana B. Patravale (16-23).
The purpose of the present investigation was to explore feasibility of nanocarrier based transdermal delivery of Huperzine A (HupA) for the treatment of Alzheimer's disease. For this investigation, microemulsion (ME), solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs) were formulated and characterized for physicochemical parameters. The pseudo-ternary phase diagrams for microemulsion region were developed using generally recognized as safe (GRAS) excipients. The SLNs and NLCs were prepared by microemulsion template technique. These nanodispersions were formulated into gels for transdermal application and evaluated for various physicochemical parameters. In vitro permeation profiles in rat skin exhibited zero-order kinetics. HupA loaded ME exhibited superior permeation than NLCs followed by SLNs and cumulative amount permeated after 24 h was found to be 147.68 ± 9.42 μg/cm2, 129.11 ± 32.76 μg/cm2 and 10.74 ± 0.68 μg/cm2, respectively. Furthermore, optimized gels were subjected to primary skin irritation testing over a period of 48 h and were found to be safe for skin application. In vivo efficacy tested in scopolamine induced amnesia model indicated significant improvement in cognitive function in mice group treated with developed nanocarrier based formulations as compared to the control group.
Keywords: Huperzine A; Solid lipid nanoparticles; Nanostructured lipid carriers; Transdermal delivery system; Alzheimer's disease; Elevated plus maze;
Controlled preparation and antitumor efficacy of vitamin E TPGS-functionalized PLGA nanoparticles for delivery of paclitaxel by Guoying Wang; Bo Yu; Yuequn Wu; Baolin Huang; Yuan Yuan; Chang Sheng Liu (24-33).
Paclitaxel-loaded TPGS-functionalized PLGA nanoparticles (PTPNs) with controllable and nearly uniform size of 130–150 nm and EE% of over 80% were successfully synthesized by a modified inverse-phase nanoprecipitation method. Compared to Taxol® and the lipid-containing PTPNs, the PTPNs prepared showed stronger antitumor efficacy in vitro and in vivo.Vitamin E TPGS-functionalized polymeric nanoparticles have been developed as a promising drug delivery platform in recent years. Obtaining reproducible monodisperse TPGS/polymeric nanoparticles with high encapsulation efficiency (EE%) still remains a big challenge. In this study, an inverse-phase nanoprecipitation method was developed to synthesize TPGS-functionalized PLGA nanoparticles (TPNs) for controlled release of paclitaxel (PTX). To take advantages of lipids, a part of TPGS in the TPNs was replaced by lipids. The results showed that with weight ratio of TPGS-to-PLGA of 2–3 and a molar replacement of lecithin ratio of 30%, the PTX-loaded TPNs (PTPNs) and PTX-loaded lipid-containing TPNs (PLTPNs) exhibited controllable and nearly uniform size of 130–150 nm and EE% of over 80%. Compared to Taxol®, both the PTPNs and PLTPNs significantly increased the intracellular uptake and exerted strong inhibitory effect on human lung cancer A549 model cells. Furthermore, a selective accumulation to tumor site and significant antitumor efficacy of TPNs in the A549 lung cancer xenografted nude mice were observed by intravenous administration, especially for the PTPNs group. Our data suggested that the inverse-phase nanoprecipitation method holds great potential for the fabrication of the paclitaxel-loaded TPNs and the TPNs prepared here is a promising controllable delivery system for paclitaxel.
Keywords: Paclitaxel; TPGS-functionalized PLGA nanoparticles; Controllable preparation; Drug delivery; Antitumor efficacy;
The crystal engineering of salbutamol sulphate via simulated pulmonary surfactant monolayers by Michael J. Davies; Thomas D. Kerry; Linda Seton; Mark F. Murphy; Paul Gibbons; Jiyi Khoo; Majid Naderi (34-45).
This study aims to crystallise salbutamol sulphate beneath simulated pulmonary surfactant monolayers. Such ensembles serve as heterogeneous nucleating sites to direct crystallisation. This contribution builds upon previous work to confirm the suitability of Langmuir monolayers in supporting the rational generation of respirable therapeutic material.Langmuir monolayers (i.e. DPPC or a ‘mixed’ system) were supported on a subphase containing the extremely water soluble model drug (2.5 g/ml) and compressed to 5 mN m−1 or 35 mN m−1 whilst experiencing a temperature reduction and positioned within a humid environment. Control samples were produced via batch crystallisation. Analysis involved scanning electron microscopy (SEM), atomic force microscopy (AFM), powder X-ray diffraction (PXRD) and inverse gas chromatography (IGC).Expanded Langmuir isotherms confirmed drug–surfactant interaction; crystal growth was inhibited at high surface pressure. Resultant crystals exhibited a range of morphologies, dependent upon the crystallisation route. AFM analysis highlighted nanoscale surface undulations. IGC data confirmed sample surface energy profiles were variable and influenced by crystallisation route.Principal modes of drug–surfactant interaction are proposed as hydrogen bond and ion–dipole associations. A range of pharmaceutical approaches have been applied to understand drug–surfactant complementarity. The results strengthen the argument for the use of Langmuir monolayers in drug particle engineering.
Keywords: Inhaled drug delivery; Langmuir monolayers; Salbutamol sulphate; Atomic force microscopy (AFM); Inverse gas chromatography (IGC);
Application of Positron Emission Particle Tracking (PEPT) to validate a Discrete Element Method (DEM) model of granular flow and mixing in the Turbula mixer by M. Marigo; M. Davies; T. Leadbeater; D.L. Cairns; A. Ingram; E.H. Stitt (46-58).
Positron Emission Particle Tracking (PEPT) experimental measurement technique was employed to compare and validate the Discrete Element Method (DEM) simulation prediction for the motion of particles within the Turbula laboratory scale mixer.The laboratory-scale Turbula mixer comprises a simple cylindrical vessel that moves with a complex, yet periodic 3D motion comprising of rotation, translation and inversion. Arising from this complexity, relatively few studies to obtain fundamental understanding of particle motion and mixing mechanisms have been reported. Particle motion within a cylindrical vessel of a Turbula mixer has been measured for 2 mm glass spheres using Positron Emission Particle Tracking (PEPT) in a 2 l blending mixing vessel at 50% fill level. These data are compared to results from Discrete Element Method (DEM) simulations previously published by the authors. PEPT mixing experiments, using a single particle tracer, gave qualitatively similar trends to the DEM predictions for axial and radial dispersion as well as for the axial displacement statistics at different operational speeds. Both experimental and simulation results indicate a minimum mixing efficiency at ca. 46 rpm. The occupancy plots also show a non-linear relationship with the operating speed. These results add further evidence to a transition between two flow and mixing regimes. Despite the similarity in overall flow and mixing behaviour measured and predicted, including the mixing speed at which the flow behaviour transition occurs, a systematic offset between measured and predicted result is observed.
Keywords: Turbula mixer; Particle mixing; PEPT; DEM;
Influence of membrane structure on the preparation of colloidal lipid dispersions by premix membrane emulsification by Sonja Joseph; Heike Bunjes (59-62).
Since premix membrane emulsification was developed as alternative technique for the preparation of emulsions and solid lipid particles as carrier systems for lipophilic drugs, many types of membranes have been used in this preparation process. The purpose of this study was to evaluate the influence of different types of membranes on the processability of colloidal lipid dispersions using the premix membrane emulsification technique. Polycarbonate, polyester, nylon, polyvinylidene fluoride, polysulfone and polyethersulfone membranes with a pore size of 200 nm were used in a small- and a large-volume extrusion process to yield dispersions of highly concentrated (20%) nonpolar lipids (medium chain triglycerides, trimyristin) stabilized by sodium dodecyl sulfate (15%) in aqueous solution. The structure of the different membranes was characterized by scanning electron microscopy. Similar mean particle sizes and size distributions were observed for all solid lipid nanoparticles obtained from both extrusion processes after 11 or 21 extrusion cycles. Smaller mean particle sizes were observed for emulsions prepared with track-etched membranes (polycarbonate, polyester). The use of a stack of four polycarbonate membranes in the large-volume extrusion process led to small particle sizes with monomodal size distributions already after one membrane passage.
Keywords: Solid lipid nanoparticles; Nanoemulsions; Premix membrane emulsification; Extrusion; Polycarbonate membrane; Polyester membrane;
Caprolactam-silica network, a strong potentiator of the antimicrobial activity of kanamycin against Gram-positive and Gram-negative bacterial strains by Georgeta Voicu; Valentina Grumezescu; Ecaterina Andronescu; Alexandru Mihai Grumezescu; Anton Ficai; Denisa Ficai; Cristina Daniela Ghitulica; Irina Gheorghe; Mariana Carmen Chifiriuc (63-69).
Here, we report the fabrication of a novel ɛ-caprolactam-silica (ɛ-SiO2) network and assessed its biocompatibility and ability to improve the antimicrobial activity of kanamycin. The results of the quantitative antimicrobial assay demonstrate that the obtained ɛ-SiO2 network has efficiently improved the kanamycin activity on Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 strains, with a significant decrease of the minimum inhibitory concentration. The ɛ-SiO2 network could be feasibly obtained and represents an alternative for the design of new antibiotic drug carriers or delivery systems to control bacterial infections.
Keywords: MIC; Kanamycin sulfate; Silica; Antimicrobial therapy; Caprolactam;
Proposal of stability categories for nano-dispersions obtained from pharmaceutical self-emulsifying formulations by Andreas Niederquell; Martin Kuentz (70-80).
Lipid-based formulations that disperse in water as nano-droplets are of considerable pharmaceutical interest. However, there is a recent debate on which systems form stable swollen micelles rather than other thermodynamically unstable nano-emulsions. This study introduces stability categories for nano-dispersions by considering theoretical arguments of particle size and polydispersity. In a second step, 20 pharmaceutical nano-emulsifying formulations were investigated with respect to the physical stability of the aqueous dispersions. Thermo-reversibility was studied using dynamic laser light scattering, ultrasonic resonator technology and near-infrared (NIR) analytical centrifugation. As a result, the majority of the dispersions were indeed nano-emulsions that exhibited only kinetic stability. Dispersions that were stable following the heat stress test were then further evaluated with respect to an alternative compounding other than dilution from a preconcentrate. Seven dispersions were hereafter deemed to be stable in the thermodynamic sense because they exhibited the same light scattering results independent of their compounding method. In conclusion, the proposed stability categories were shown to successfully assign dispersions. This has a general importance and can, for example, be applied when nano-dispersions are used as pre-clinical formulations.
Keywords: Self-emulsifying; Lipid-based formulations; Nano-emulsions; Microemulsions; Stability;
Paclitaxel-loaded hydroxyapatite/collagen hybrid gels as drug delivery systems for metastatic cancer cells by Kenji Watanabe; Yuki Nishio; Rie Makiura; Atsushi Nakahira; Chie Kojima (81-86).
Hydroxyapatite (HA) is a biocompatible and porous inorganic material that can behave as an effective drug carrier. In this study, HA nanoparticles were prepared according to the hydrothermal method and used as a drug carrier for a water-insoluble anticancer drug, paclitaxel (Tax). The absorption of Tax onto the HA was dependent on the solvent composition. The Tax-loaded HA (Tax/HA) exhibited a lower level of activity than the free Tax because the HA material was not stably dispersed in aqueous media. The Tax/HA was therefore embedded in a collagen gel to give the Tax/HA-embedded collagen gel (Tax/HA/Col), which exhibited a higher level of activity than the Tax-containing collagen gel (Tax/Col). Interestingly, the highly metastatic MDA-MB-231 cells were more sensitive to the Tax/HA/Col than the poorly metastatic MCF-7 cells. Tax/HA/Col is therefore useful for the drug delivery into metastatic cancer cells.
Keywords: Hydroxyapatite; Collagen; Paclitaxel; Hydrogel; Cancer chemotherapy;
Gene delivery into human cancer cells by cationic lipid-mediated magnetofection by Srinath Govindarajan; Kumiko Kitaura; Makoto Takafuji; Hirotaka Ihara; K.S. Varadarajan; Anant B. Patel; Vijaya Gopal (87-99).
In this study, a combination of magnetic nanoparticles (MNPs) together with cationic lipid N,N-di-n-hexadecyl-N,N-dihydroxyethylammonium chloride formulated with colipid cholesterol, upon magnetofection, enhanced DNA uptake into human glioblastoma-astrocytoma, epithelial-like cell line U-87 MG, hepatocellular carcinoma Hep G2, cervical cancer HeLa and breast cancer MDA-MB-231 cells. Having confirmed this, we monitored uptake of plasmid DNA mediated by ternary magnetoplexes by fluorescence microscopy, flow cytometry and reporter gene expression assays in the presence and absence of a magnetic field. Our observations clearly indicate enhanced transfection efficiency in vitro, upon magnetofection, in the presence of serum as seen from β-Gal reporter gene expression. The observed activity in serum suggests the suitability of MNPs for in vivo applications. Further, we measured the transverse relaxation time (T 2) and obtained T 2-weighted MRI images of treated U-87 MG cells. T 2 determined for MNP-VP-Me22 and MNP-VP-Et22 corresponds to 22.6 ± 0.8 ms and 36.0 ± 2.1 ms, respectively, as compared to 47 ± 1.7 ms for control, suggesting their applicability in molecular imaging. Our results collectively highlight the potential of lipid-based approach to augment magnetic-field guided-gene delivery using MNPs and additionally towards developing intracellular molecular probes for magnetic resonance imaging.
Keywords: Liposomal magnetofection; Magnetic nanoparticles; Magnetic resonance imaging; Gene delivery; Cationic liposomes;
Effect of drug–polymer interactions on the aqueous solubility of milled solid dispersions by Hisham Al-Obaidi; M. Jayne Lawrence; Sonal Shah; Henna Moghul; Noor Al-Saden; Fiza Bari (100-105).
The role of molecular interactions in ball milled solid dispersions in determining the aqueous solubility of the poorly water-soluble drug, griseofulvin (GF) has been examined. Ball milled solid dispersions of GF and hydroxypropylmethylcellulose acetate succinate (HPMCAS) and GF and polyvinylpyrrolidone (PVP) were prepared and characterized by laser diffraction, scanning electron microscopy and X-ray powder diffraction and the aqueous saturation solubility measured and analyzed using one way ANOVA. The results showed that solid dispersions of GF and HPMCAS possessed an aqueous GF saturation solubility of about ten times higher than the GF solubility achieved from PVP-based solid dispersions. Furthermore, although the aqueous solubility of GF did not vary with the milling conditions used to prepare the solid dispersions with PVP, significant changes in solubility were observed upon changing the milling conditions for preparation of the GF/HPMCAS solid dispersions. Surprisingly, the GF/HPMCAS solid dispersion prepared using spray drying exhibited a significantly lower aqueous solubility than those prepared by bead milling despite their smaller particle size and GF being fully in its amorphous form. It is thought that the higher surface energy of the spray-dried solid dispersions negatively affected the aqueous solubility of GF. In conclusion, the results suggest that the molecular interactions occurring between GF and HPMCAS affect the aqueous solubility of GF and that the molecular interactions appear to remain in the liquid state. In contrast no molecular interactions were evident in the GF/PVP solid dispersions.
Keywords: Saturation solubility; Solid dispersions; Drug–polymer interactions; Particle size; Crystallization;
Encapsulation of Rifampicin in a solid lipid nanoparticulate system to limit its degradation and interaction with Isoniazid at acidic pH by Harinder Singh; Rohit Bhandari; Indu Pal Kaur (106-111).
Rifampicin (RIF), a vital constituent of antitubercular therapy, hydrolyzes at the acidic pH of the stomach. The degradation is further enhanced by its interaction with Isoniazid (INH). Extent of RIF decomposition, in the presence and absence of INH, was determined at pH 1.2 (pH of empty stomach) at 37 °C for 4 h (maximum stomach residence time). Both the drugs decomposed at gastric pH (26.5% and 1.43% for RIF and INH respectively).Considering that solid lipid nanoparticles (SLNs) avert drug–drug interaction and also drug degradation, we incorporated RIF into SLNs. Latter reduced its degradation to ∼9% (from 26.50% when present alone) and to ∼20% (from 48.81% when INH was also present).Subsequent to this, we also incorporated INH into SLNs and the percent degradation of RIF in this combination (RIF SLNs + INH SLNs) further reduced to 12.35%. Furthermore, the degradation of INH in combination with RIF also reduced significantly from 13.2% to 2.7% when both the drugs were encapsulated individually within SLNs.Study therefore highlights the need to develop combinations of antitubercular drugs (ATDs) with caution and also establishes the usefulness of nanoparticulate technology to avoid drug–drug interaction.
Keywords: Rifampicin; Isoniazid; Interaction; Decomposition; Bioavailability; Solid lipid nanoparticles;
Glutathione-mediated drug release from Tiopronin-conjugated gold nanoparticles for acute liver injury therapy by Quan-Ying Bao; Dong-Dong Geng; Jing-Wei Xue; Geng Zhou; Shen-Yang Gu; Ya Ding; Can Zhang (112-118).
Tiopronin-conjugated gold nanoparticles (TPN@GNPs), with glutathione (GSH)-responsive drug release property, were prepared by one-pot synthesis method for the therapeutic application to the acute liver injury in mice. It showed much better treatment on the acute liver injury compared with conventional TPN injection, which is due to the passive target TPN@GNPs to liver by the EPR effect of gold nanoparticles and GSH-mediated TPN release after the conjugates were uptake by liver cells. It demonstrates that gold nanoparticle-based drug delivery system allows smart functions and superior properties by taking advantages of the unique small size effects and surface chemical properties.Tiopronin-conjugated gold nanoparticles (TPN@GNPs), with glutathione (GSH)-responsive drug release property, were developed for acute liver injury therapy. The TPN@GNPs were prepared using a one-pot synthesis method and characterized by UV–vis and transmission electronic microscopy methods. The TPN@GNPs displayed typical surface plasmon resonance of nanogold with a narrow size distribution (ca. 2 nm). The in vitro drug release profiles of the conjugates indicated that TPN@GNPs were able to release TPN in a sustained fashion for 4 h at a simulated intracellular level of GSH. pH values or ionic strengths of the release media had no obvious influence on TPN release from the surface of nanoparticles. The pharmacokinetic studies in rats showed that the TPN@GNPs had longer MRT (7.71 h) than TPN (3.96 h), indicating sustained release pattern of TPN@GNPs in vivo. The sustained release of TPN at the relative high GSH concentration could ameliorate the instability of TPN and enable the drug release in the target cells. Although the IC50 value of TPN@GNPs with TPN/AuCl4 − of 3:1 (mol/mol) showed slight increase in comparison with that of the free TPN in HepG2 cells (1.26 ± 1.07 vs. 1.73 ± 1.16 mg/mL), the TPN@GNPs displayed better effects over TPN in the treatment of acute liver injury in vivo. In a liver injury mice model induced by CCl4, the histological analysis showed both the TPN@GNPs and free TPN group could repair the liver injury. In addition, the biochemical parameters showed TPN@GNPs could reduced the aminotransferase to a lower level compared with TPN, which might be due to the sustained drug release and passive liver targeting properties of TPN@GNPs. It demonstrated that gold nanoparticle-based drug delivery system allowed smart functions and superior properties by taking advantages of the unique small size effects and surface chemical properties.
Keywords: Gold conjugates; Tiopronin; Pharmacokinetics; Passive target; Acute liver injury; Drug delivery;
Post-modification of preformed liposomes with novel non-phospholipid poly(ethylene glycol)-conjugated hexadecylcarbamoylmethyl hexadecanoic acid for enhanced circulation persistence in vivo by Okhil K. Nag; Vivek R. Yadav; Andria Hedrick; Vibhudutta Awasthi (119-129).
We report synthesis and characterization of a novel PEG2000-conjugated hexadecylcarbamoylmethyl hexadecanoate (HDAS-PEG) as a PEG-phospholipid substitute for enhancing circulation persistence of liposomes. HDAS-PEG showed critical micelle concentration of 4.25 μM. We used post-insertion technique to introduce HDAS-PEG in outer lipid layer of the preformed liposomes. The presence of surface HDAS-PEG was confirmed by altered electrophoretic mobility, confocal microscopy and PEG estimation by ELISA. The post-inserted HDAS-PEG desorbed at approximately half the rate at which post-inserted DSPE-PEG desorbed from the liposome surface. HDAS-PEG significantly reduced liposome-induced complement activation (C4d, Bb and SC5b); HDAS-PEG was more effective than more commonly used DSPE-PEG in this capacity. For studying circulation persistence, the liposomes were labeled with 99mTc radionuclide and administered in rats. 99mTc-HDAS-PEG-liposomes showed prolonged persistence in blood as compared to that shown by 99mTc-plain liposomes. After 24 h of administration, <1% of 99mTc-plain liposomes remained in blood, whereas approximately 28% of injected 99mTc-HDAS-PEG-liposomes were present in blood. In comparison, only 4.8% of 99mTc-DSPE-PEG-liposomes were measured in blood after 24 h. As expected, the clearance route of the liposomes was through liver and spleen. These results demonstrate the potential of a novel non-phosphoryl HDAS-PEG for surface modification of preformed liposomes with a goal of prolonging their circulation persistence and more effective inhibition of complement activation.
Keywords: Liposomes; Poly(ethylene glycol); Circulation persistence; Post-insertion; Complement;
Rhamnolipids enhance epithelial permeability in Caco-2 monolayers by Lifang Jiang; Xuwei Long; Qin Meng (130-135).
Rhamnolipids effectively increased the paracellular/transcellular transport and inhibit the P-glycoprotein activity of Transwell®-cultured Caco-2 cells.This work aimed to evaluate the applicability of rhamnolipids as permeation enhancers for oral drugs. In this study, rhamnolipids were found to effectively increase the paracellular and transcellular transport of Transwell®-cultured Caco-2 cells, an in vitro model of the human small intestinal epithelium, in a concentration-dependent manner. Rhamnolipids at 150 mg/L increased the paracellular apparent permeability (P app) of phenol red almost 7- to 8-fold, the largest enhancement ever reported, while Tween-80 exhibited no such effect. Regarding the transcellular pathway, rhamnolipids at 150 mg/L enhanced the P app of propranolol 2-fold, similar to the performance of Tween-80 at 400 mg/L. Moreover, rhamnolipids like Tween-80, significantly inhibited P-glycoprotein (P-gp) activity reflected by the reduced efflux ratio (basolateral-to-apical/apical-to-basolateral) of rhodamine 123 (R123), a P-gp substrate, on Caco-2 cells. Inhibition of P-gp activity was confirmed on plate cultured Caco-2 monolayers by assaying accumulation/efflux of R123 and R110, a non-P-gp substrate. Finally, rhamnolipids were demonstrated to be safe by cell viability and hemolysis assays. In conclusion, rhamnolipids were highly effective regulators of all three transport pathways, suggesting their use as a safe absorption enhancer for oral drugs.
Keywords: Rhamnolipids; Tween-80; Absorption enhancer; Transporter; P-glycoprotein;
Formulation of lipid bearing pellets as a delivery system for poorly soluble drugs by Shruti Chopra; Natarajan Venkatesan; Guru V. Betageri (136-144).
The aim of this study was to develop and characterize phospholipid bearing pellets for a poorly water-soluble drug, nisoldipine. Pellets were prepared using extrusion–spheronization technique containing microcrystalline cellulose, soy phosphatidylcholine (SPC), granulating fluid and lactose. Operational parameters such as extrusion speed, spheronization speed and residence time were evaluated. Optimal extrusion speed was found to be 50 rpm with a spheronization speed of 60 Hz and residence time of 2 min. Pellets were characterized for their size, shape, density, flow properties, friability, moisture content, surface morphology and thermal properties. Pellets were evaluated for their assay and in vitro drug release. Mathematical modeling was used to determine the release patterns of the pellets. Pellets were found to be spherical, 600–850 μm size with <0.01% friability and had >70% yield. Scanning electron microscopic (SEM) studies showed a smoother external surface and a porous internal matrix. SPC incorporated pellets resulted in improved dissolution of the drug. Pellets with SPC (20 and 30%) released >90% of the drug within 24 h. The dissolution profiles of the pellets were best fitted to Korsmeyer–Peppas kinetic model. In this study, we could successfully incorporate a lipid and a water-insoluble drug into a pellet formulation with improved dissolution profile.
Keywords: Soy phosphatidylcholine; Nisoldipine; Solubility; Extrusion; Spheronization; Pellets;
Template free synthesis of mesoporous hectorites: Efficient host for pH responsive drug delivery by Radheshyam R. Pawar; Bhavesh D. Kevadiya; Harshad Brahmbhatt; Hari C. Bajaj (145-152).
The organized mesoporous matrices with large surface area and large pore volumes are potential drug carriers and hence find good applications in the field of controlled and sustained drug delivery. Two novel mesoporous synthetic hectorite (MSH) materials, namely, MSH3 and MSH4 with diverse composition and pore performance have been synthesized by a template free route and studied for the controlled drug delivery applications. MSH3 with 0.14LiF:5.93 Mg(OH)2:8 SiO2 synthetic composition exhibited higher quinine adsorption than that by MSH4 (2.8LiF:4.6 Mg(OH)2:8SiO2). In vitro studies at 37 ± 0.5 °C temperature under sequential buffer conditions showed controlled drug release with respect to the variation in pH values while following Eudragit VR L100 coated gelatin capsules; however, dialysis bag technique do not show such pH controlled delivery. Kinetic data suggest the release of QUI from the nanocomposite follows dissolution diffusion model.
Keywords: Drug delivery; Eudragit VR L100; Mesoporous synthetic hectorites; Pore engineering; Quinine hydrochloride dihydrate; Template free synthesis;
A pH-responsive nano-carrier with mesoporous silica nanoparticles cores and poly(acrylic acid) shell-layers: Fabrication, characterization and properties for controlled release of salidroside by Hailong Peng; Ruichen Dong; Shenqi Wang; Zhong Zhang; Mei Luo; Chunqing Bai; Qiang Zhao; Jinhua Li; Lingxin Chen; Hua Xiong (153-159).
A novel pH-responsive nano-carrier MSNs–PAA, possessing mesoporous silica nanoparticles (MSNs) cores and poly(acrylic acid) (PAA) shell-layers, was developed for controlled release of salidroside. The vinyl double bonds modified MSNs were synthesized by using cetyltrimethylammonium bromide (CTAB) as templates, tetraethyl orthosilicate (TEOS) as silicon source, and 3-(trimethoxylsilyl) propyl methacrylate (MPS) as surface modification functionalities. The pH-responsive layers of PAA were grafted onto the vinyl double bonds of the MSNs via precipitation polymerization, producing the MSNs–PAA with a hollow cubic core and mesoporous shell with penetrating pore channels. The characteristic results also showed that PAA was successfully grafted onto the surface of the MSNs. The MSNs–PAA was investigated as carriers for loading and regulating the release of salidroside in different pH solutions for the first time. The results demonstrated that the PAA layers on the surface of MSNs–PAA exhibited opened and closed states at different pH values, and thus could regulate the uptake and release of salidroside. The application of such pH-responsive nano-carrier might offer a potential platform for controlled delivery and increasing the bioavailability of drugs.
Keywords: Mesoporous silica nanoparticles; Poly(acrylic acid); pH-responsive; Controlled release; Salidroside;
Preparation and evaluation of unpleasant taste-masked pioglitazone orally disintegrating tablets by Yoshinori Nakano; Arisa Maeda; Shinya Uchida; Noriyuki Namiki (160-165).
This study aimed to evaluate the taste and mouth feel of newly designed orally disintegrating tablets (ODTs) of pioglitazone, which is a typical type 2 diabetes medicine with an unpleasant taste, using a visual analog scale (VAS) analysis. The ODTs were subjected to either of these 2 taste-masking procedures: a physical masking procedure that included coating the inactive core granules with mixture of pioglitazone and Eudragit® E PO, followed by mixing the granules with aspartame and other excipients to form the tablet (physical masking ODT); or a gustatory masking procedure that involved blending pioglitazone with both sodium chloride and aspartame, followed by mixing the blend with other excipients to form the tablet (gustatory masking ODT). From the results of the VAS analysis, physical masking could suppress the bitterness but not the astringent; therefore, the overall palatability of the ODT was considered not improved. In contrast, gustatory masking significantly suppressed both the bitterness and astringent, and offered a slight sweetness; therefore, the overall palatability of the ODT was considered improved. In conclusion, VAS is a useful tool to evaluate the taste of ODTs and that gustatory masking can effectively mask the unpleasant taste of pioglitazone ODT.
Keywords: Orally disintegrating tablet; Pioglitazone; Visual analog scale; Taste-masking; Sodium chloride; Aspartame;
Solid lipid nanoparticle preparation by a warm microemulsion based process: Influence of microemulsion microstructure by P. Fadda; M. Monduzzi; F. Caboi; S. Piras; P. Lazzari (166-175).
Warm microemulsions (WME) containing lipids are used as starting systems to obtain solid lipid nanoparticles (SLN) in alternative processes to those based on high pressure homogenization technique.SLN characteristics can be influenced by the microemulsion composition and the specific conditions adopted in the quenching process related to the transformation of WME into nanoparticles.To establish optimized conditions for the production of SLN starting from WME, in a first step of this work we have defined the microstructure of warm microemulsions highlighted in the lecithin (LCT)/water (W)/tripalmitin (TP)/1-butanol (B)/taurocholate sodium salt (ST) phase behavior at 70 °C. Moreover, we have further studied the LCT/W/TP/B system by evaluating the effect on the microemulsion area due to the LCT/B weight ratio, the replacement of 1-butanol with different alcohols (ROH), and the addition of taurocholate sodium salt (ST) at different LCT/ST weight ratios. The microstructure of the isotropic phase region obtained in the presence of ST has been characterized by both 1H NMR PGSE measurements and electrical conductivity.The characteristics of final nanoparticles are discussed taking into account both the microstructure of the parent WME and the conditions of the quenching process leading to SLN.The present results highlight the relevance of the microstructural characteristic of WME to assure the obtainment of SLN with average diameter in the order of 100–200 nm and narrow size distribution.
Keywords: Microemulsions; Glyceryl tripalmitate; Alcohols; Sodium taurocholate; Solid lipid nanoparticles;
Incorporation of carbon nanotubes into a gelatin–catechin conjugate: Innovative approach for the preparation of anticancer materials by Giuseppe Cirillo; Orazio Vittorio; Silke Hampel; Umile Gianfranco Spizzirri; Nevio Picci; Francesca Iemma (176-182).
A new hybrid material made of gelatin, catechin and carbon nanotubes was prepared by the non-covalent incorporation of carbon nanotubes (CNTs) into a gelatin–catechin covalent conjugate. The composite materials was tested by means of determination of the dispersion stability in water and the functionalization degree was assessed by the Folin–Ciocalteu method, finding a 0.9 mg of CT/g of protein conjugate. Subsequently, the complete retention of the antioxidant properties of the flavonoid after incorporation into the composite was proved by DPPH and ABTS assays and IC50 values of 5.74 mg mL−1 and 0.39 mg mL−1 were recorded. The presence of CNT into the materials did not interfere with the scavenging activities of the catechin. Finally, the anticancer activity on HeLa cancer cells was evaluated and a considerable increase in the therapeutic activity of the flavonoid was recorded moving from the free to the conjugated form in the presence of CNT, while in absence of CNT a reduction of the efficiency was observed.
Keywords: Anticancer activity; Carbon nanotubes; Catechin; Gelatin; Polymer composites;
Synthesis and characterization of magnetoliposomes for MRI contrast enhancement by M.R. Faria; M.M. Cruz; M.C. Gonçalves; A. Carvalho; G. Feio; M.B.F. Martins (183-190).
This work assesses the characteristics of magnetoliposomes of soybean phosphatidylcholine (SPC):cholesterol (Chol) loaded with superparamagnetic iron oxide nanoparticles (IONPs) stabilized with tetramethylammonium hydroxide (TMAOH) and their capacity to enhance magnetic resonance imaging (MRI) contrast. Magnetoliposomes of SPC were used for comparative studies. IONPs and magnetoliposomes were characterized using transmission electron microscopy, dynamic light scattering, SQUID magnetometry, FTIR and MRI. The saturation magnetization at 10 K was ∼0.06 Am2/kg for SPC:Chol magnetoliposomes with 7 g iron oxide/mol of lipid and ∼0.05 Am2/kg for SPC magnetoliposomes with 21 g iron oxide/mol of lipid. As these values are associated with the number of incorporated magnetic IONPs, the saturation magnetization is 1.2 times higher for magnetoliposomes of SPC:Chol as compared with magnetoliposomes of SPC alone. The behavior of temperature dependence in both cases is typical of superparamagnetic particles.FTIR spectra evidence the increase of magnetoliposome membrane ordering with the presence of Chol. Principal component analysis (PCA) applied to FTIR spectra evidenced a clear distinction between scores for SPC:Chol, and SPC magnetoliposomes and for SPC empty liposomes. PCA applied to FTIR data differentiate magnetoliposomes from empty liposomes. MR images of aqueous phantoms obtained with and without magnetoliposomes, clearly evidence their effect on T2 image weighting.
Keywords: Magnetoliposome; Superparamagnetic iron oxide nanoparticle; FTIR; PCA; MRI; Negative contrast agent;
Chitosan-graft-β-cyclodextrin nanoparticles as a carrier for controlled drug release by Zeting Yuan; Yajing Ye; Feng Gao; Huihui Yuan; Minbo Lan; Kaiyan Lou; Wei Wang (191-198).
Chitosan (CS) grafted with β-cyclodextrin (CD-g-CS) nanoparticles as a new carrier for poorly water-soluble drugs has been developed. The CD-g-CS polymer is readily synthesized from chitosan and mono-6-deoxy-6-(p-toluenesulfonyl)-β-cyclodextrin. Three different degrees of substitution (DS) of β-cyclodextrin (β-CD) on CD-g-CS (9.6, 14.0 and 20.0%) are designed and evaluated by controlling the mole ratio of β-CD to chitosan. Then CD-g-CS nanoparticles are prepared by an ionic gelation method, with the controlled size of 202.0–589.0 nm. Stable colloidal dispersion of the nanoparticles has been formed with the zeta potential of +23.0 to +43.0 mV. In vitro stability test indicates that CD-g-CS nanoparticles are more stable in phosphate-buffered saline compared with CS nanoparticles. Finally, the poorly water-soluble drug, ketoprofen (KTP), is used as a model drug to evaluate the efficiency of the new drug delivery carrier. It is found that the encapsulation efficiency of KTP in the nanoparticles with 20% DS of CD is as high as 1.36-fold than that of CS nanoparticles. Moreover, notably KTP is released from the nanoparticles in a controlled-release manner and is pH-responsive on DS of CD. In summary, these results suggest that the CD-g-CS nanoparticles, as a general promising drug delivery system, can be used as a potential biodegradable nano-drug delivery system for controlled release of poorly water-soluble drugs with pH-responsive capability.
Keywords: Chitosan; Cyclodextrin; Ionic gelation; Nano-drug delivery system;
Impact of physical parameters on particle size and reaction yield when using the ionic gelation method to obtain cationic polymeric chitosan–tripolyphosphate nanoparticles by A. Fàbregas; M. Miñarro; E. García-Montoya; P. Pérez-Lozano; C. Carrillo; R. Sarrate; N. Sánchez; J.R. Ticó; J.M. Suñé-Negre (199-204).
Ionic gelation is the most frequently used method to obtain chitosan–tripolyphosphate nanoparticles due to its simplicity and because it does not generate waste solvents in the samples prepared.This paper presents a study of the physical factors involved in this method for obtaining nanoparticles in order to determine which of them significantly influences the particle size of polymeric nanoparticles made from low-molecular-weight chitosan, without any additional chemical treatment, with the aim of standardising and optimising the method conditions, in addition to establishing the reaction yield.The results indicate that stirring speed during ionic gelation reaction is decisive for the size of the nanoparticles obtained. Furthermore, it thus follows that the stirring speed during ionic gelation significantly affects reaction yield, and therefore, by manipulating this parameter a greater proportion of nanoparticles of a given size range can be obtained.
Keywords: Nanoparticles; Chitosan–tripolyphosphate; Cationic; Polymeric; Ionic gelation;
Peptide decorated calcium phosphate/carboxymethyl chitosan hybrid nanoparticles with improved drug delivery efficiency by Jun Wang; Bin Chen; Dong Zhao; Yan Peng; Ren-Xi Zhuo; Si-Xue Cheng (205-210).
In this study, a facile strategy to effectively improve the delivery efficiency of nano-sized drug delivery systems was developed. Calcium phosphate/carboxymethyl chitosan (Ca–P/CMC) hybrid nanoparticles were prepared by the precipitation of calcium phosphate in the aqueous solution containing CMC. The obtained Ca–P/CMC nanoparticles were characterized by SEM, XPS and TGA. Doxorubicin hydrochloride (DOX), a water-soluble anticancer drug, was loaded in the nanoparticles with high encapsulation efficiency. The in vitro drug release showed that the release of DOX from the nanoparticles could be effectively sustained. After drug loading, the nanoparticles were decorated by peptide KALA by self-assembly through the electrostatic interaction between the positively charged KALA and the negatively charged CMC chains to obtain drug loaded Ca–P/CMC/KALA nanoparticles. The size and size distribution of the nanoparticles were measured by a particle size analyzer. The KALA decorated nanoparticles exhibited a larger size and an increased zeta potential. The effect of KALA content on the HeLa cell inhibition was studied. The in vitro study showed that the cell inhibition effect could be significantly enhanced by the presence of KALA.
Keywords: Nanoparticles; Drug delivery; Calcium phosphate; Peptide; Self-assembly;
Compression-coated tablets of glipizide using hydroxypropylcellulose for zero-order release: In vitro and in vivo evaluation by Haiqin Huang; Zhenghong Wu; Xiaole Qi; Huiting Zhang; Qin Chen; Jiayu Xing; Haiyan Chen; Yao Rui (211-218).
Compression coating, which presents some advantages like short manufacturing process and non-solvent residue over liquid coating, has been introduced to the oral administration systems for decades. The purpose of this study was to design a zero-order release of compression-coated tablets using hydroxypropylcellulose (HPC) as the coating layer and glipizide which was solubilized by manufacturing the inclusion complex of β-cyclodextrin as a model drug. The effects of the weight ratio of drug and the viscosity of HPC on the release profile were investigated by “f 2” factor with Glucotrol XL®. The uptake and erosion study, the correlation coefficient (R) and the exponent (n) were used as indicators to justify drug release mechanism. Bioavailability in vivo was determined by administering the compression-coated tablets to rabbits in contrast with Glucotrol XL®. It was found that the formulation presented a well zero-order behavior at the weight ratio of drug 11:14 (core:layer) and the combination of HPC-L (8.0 mPa s) and HPC-M (350 mPa s) (8:9), with the “f 2” of 66.90. The mechanism for zero-order release of these compression-coated tablets was solvent penetration into the dosage form and drug dissolution from the erosion of the gelled HPC matrix. The parameter AUC0–∞ of the compression coated tablets and the market tablets were 37,255.93 ± 1474.08 h ng/ml and 43265.40 ± 1015.28 h ng/ml, while the relative bioavailability was 87.66 ± 1.56%. These studies demonstrate that the designed compression-coated tablets may be a promising strategy for peroral controlled release delivery system of water-insoluble drugs.
Keywords: Compression-coated tablet; Zero-order release; Hydroxypropylcellulose (HPC);