International Journal of Pharmaceutics (v.478, #2)

Display OmittedIn order to customise treatment for patients, topical formulations are often diluted with drug-free cream bases to adjust the drug dose and thereby the formulations' activity to the patients' needs. However, the process of dilution influences properties of the formulations. Stability can be reduced as well as the microbial stability and most importantly, efficacy and skin penetration behaviour can be severely and unpredictably changed.The present study investigates the effects of production parameters on creams, namely incorporation of an API (active pharmaceutical ingredients) into an OW cream with prior mixing with propylene glycol or without and subsequent automated or manual dilution of the resulting creams with three different cream bases. Effects were measured by influence on microscopic appearance, measurement of chemical stability, skin penetration and rheological behaviour.suggest strong influence of the cream bases used for dilution of the formulations. Mixture of equal amounts of the employed OW and WO cream proved unfavourable due to inferior penetration behaviour and less appealing microscopic and macroscopic appearance. Prior mixing with PG was of negligible importance for the characteristics of the dilutions, however, the type of API and manner of dilution had an influence on the viscosity of the formulations.
Keywords: Manual mixing; Microscopic characterisation; Rheological characterisation; Chemical stability;

Display OmittedThe feasibility of a novel reverse-phase wet granulation process has been established previously highlighting several potential advantages over the conventional wet granulation process and making recommendations for further development of the approach. The feasibility study showed that in the reverse-phase process granule formation proceeds via a controlled breakage mechanism. Consequently, the aim of the present study was to investigate the effect of impeller speeds and binder liquid viscosity on the size distribution and intragranular porosity of granules using this novel process. Impeller tip speed was found to have different effects on the granules produced by a conventional as opposed to a reverse-phase granulation process. For the conventional process, an increase in impeller speed from 1.57 to 3.14 m s−1 had minimal effect on granule size distribution. However, a further increase in impeller tip speed to 3.93 and 4.71 m s−1 resulted in a decrease in intragranular porosity and a corresponding increase in mean granule size. In contrast when the reverse-phase process was used, an increase in impeller speed from 1.57 to 4.71 m s−1 resulted in increased granule breakage and a decrease in the mean granule size. This was postulated to be due to the fact that the granulation process begins with fully saturated pores. Under these conditions further consolidation of granules at increased impeller tip speeds is limited and rebound or breakage occurs. Based on these results and analysis of the modified capillary number the conventional process appears to be driven by viscous forces whereas the reverse-phase process appears to be driven by capillary forces. Additionally, in the reverse-phase process a critical impeller speed, represented by the equilibrium between centrifugal and gravitational forces, appears to represent the point above which breakage of large wet agglomerates and mechanical dispersion of binder liquid take place. In contrast the conventional process appears to be difficult to control due to variations in granule consolidation, which depends upon experimental variables. Such variations meant increased impeller tip speed both decreased and increased granule size. The reverse-phase process appears to offer simple control over granule porosity and size through manipulation of the impeller speed and further evaluation of the approach is warranted.
Keywords: Wet granulation; Reverse-phase granulation; Intragranular porosity; GeoPyc; Impeller speed; Modified capillary number;

Improved blend and tablet properties of fine pharmaceutical powders via dry particle coating by Zhonghui Huang; James V. Scicolone; Xi Han; Rajesh N. Davé (447-455).
Dry coating of micronized APAP (∼11 μm) leads to improved flow as well as tablet tensile strength at 60% (w/w) API loading. Tensile strength with fine excipients is much higher and well within the proposed range (shaded region) for direct compression tableting.Display OmittedThe improvements in the flow and packing of fine pharmaceutical powder blends due to dry coating of micronized acetaminophen (mAPAP, ∼11 μm), a model poorly flowing drug, are quantified. Poor flow and packing density of fine excipients (∼20 μm) allowed testing the hypothesis that dry coating of cohesive API may counteract poor flow and packing of fine pharmaceutical powder blends. Further, fine excipients could improve compaction and reduce segregation tendency. It was found that flow function coefficient (FFC) and bulk density enhancements for 10%, 30%, and 60% (w/w), API loading blends with dry coated API are significantly higher than those without coated silica. At the highest API loading, for which coarser excipients were also used as reference, the flow and packing of dry coated mAPAP blends were significantly increased regardless of the excipient particle size, exceeding those of a well compacting excipient, Avicel 102. In addition, tensile strength of tablets with fine excipients was significantly higher, indicating improved compactibility. These results show for the first time that dry coating of fine, cohesive API powder leads to significantly improved flow and packing of high API loading blends consisting of fine excipients, while achieving improved tablet compactibility, suggesting suitability for direct compaction.
Keywords: Dry coating; Fine cohesive API powder; Fine excipients; Flow improvement; Pharmaceutical blends; Tablet hardness;

Vaginal inserts based on chitosan and carboxymethylcellulose complexes for local delivery of chlorhexidine: Preparation, characterization and antimicrobial activity by Federica Bigucci; Angela Abruzzo; Beatrice Vitali; Bruno Saladini; Teresa Cerchiara; Maria Caterina Gallucci; Barbara Luppi (456-463).
Display OmittedThe aim of this work was to prepare vaginal inserts based on chitosan/carboxymethylcellulose polyelectrolyte complexes for local delivery of chlorhexidine digluconate. Complexes were prepared with different chitosan/carboxymethylcellulose molar ratios at a pH value close to pK a interval of the polymers and were characterized in terms of physico-chemical properties, complexation yield and drug loading. Then complexes were used to prepare inserts as vaginal dosage forms and their physical handling, morphology, water-uptake ability and drug release properties as well as antimicrobial activity toward Candida albicans and Escherichia coli were evaluated. Results confirmed the ionic interaction between chitosan and carboxymethylcellulose and the influence of the charge amount on the complexation yield. Complexes were characterized by high values of drug loading and showed increasing water-uptake ability with the increase of carboxymethylcellulose amount. The selection of appropriate chitosan/carboxymethylcellulose molar ratios allowed to obtain cone-like shaped solid inserts, easy to handle and able to hydrate releasing the drug over time. Finally, the formulated inserts showed antimicrobial activity against common pathogens responsible for vaginal infections.
Keywords: Chitosan; Carboxymethylcellulose; Polyelectrolyte complexes; Chlorhexidine digluconate; Vaginal inserts; Antimicrobial activity;

Display OmittedNew drug formulations are sought for poorly water-soluble substances because there is a risk of compromised bioavailability if such substances are administered orally. Such active pharmaceutical ingredients can be reformulated as solid dispersions with suitable water-soluble polymers. In this contribution, formulation of a novel and physically stable dispersion of Simvastatin in poly(2-hydroxypropyl) methacrylamide (pHPMA) is demonstrated. Due to the limited water sorption of pHPMA and a high T g, the prepared dispersion is more suited for oral administration and storage compared with neat amorphous Simvastatin. Surprisingly, the rate of global reorientation and the internal motion of Simvastatin molecules were enhanced and exhibited dynamical heterogeneities when incorporated into the pHPMA matrix. As revealed by solid-state nuclear magnetic resonance combined with Raman spectroscopy exploiting the fluorescence phenomenon the mobility of the ester and lactone components increased considerably, whereas the naphthalene ring remained rigid. Furthermore, the solid dispersion was found to be nano-heterogeneous with nanometer-sized Simvastatin domains. The presence of these clusters had no impact on the dynamics of the rigid pHPMA chains. Thus, the diffusion of Simvastatin molecules through the glassy pHPMA walls and the subsequent transformation of the clusters into larger crystallites were prevented. No crystallization was detected for more than two years.
Keywords: Solid dispersions; Simvastatin; Pharmaceuticals; Solid-state NMR; Raman spectroscopy; Fluorescence;

Pharmaceutical properties of supramolecular assembly of co-loaded cardanol/triazole-halloysite systems by Marina Massaro; Carmelo G. Colletti; Renato Noto; Serena Riela; Paola Poma; Susanna Guernelli; Filippo Parisi; Stefana Milioto; Giuseppe Lazzara (476-485).
Display OmittedHalloysite nanotubes were explored as drug carrier for cardanol, which is considered as a promising natural anticancer active species. To this aim, besides the pristine nanoclay, a chemical modification of the nanocarrier was performed by attaching triazolium salts with different hydrophobicity at the outer surface of the hollow nanotubes. The interaction between cardanol and nanotubes was highlighted in solution by HPLC. This method proved the loading of the drug into the nanotubes. The solid dried complexes formed by pristine and modified halloysite with the cardanol were characterized by IR spectroscopy, thermogravimetric analysis as well as water contact angle to evidence the structure, thermal properties and wettability of the obtained materials. The kinetics of cardanol release as well as cell viability experiments provided promising results that put forward a new strategy for potential applications of cardanol as active antiproliferative molecule and clay nanotubes as drug carrier.
Keywords: Hepatocellular carcinoma; Cardanol; Drug carrier; Halloysite; HPLC;

A monolithic drug-in-adhesive patch of methoxyflavones from Kaempferia parviflora: In vitro and in vivo evaluation by Sarunya Tuntiyasawasdikul; Ekapol Limpongsa; Napaphak Jaipakdee; Bungorn Sripanidkulchai (486-495).
Display OmittedThe aim of this study was to design and develop a suitable monolithic drug-in-adhesive type patch of methoxyflavones from Kaempferia parviflora (K. parviflora) using acrylic polymer Durotak® 87-2852. The absence of interaction between components in K. parviflora extract and the adhesive polymer was confirmed by attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR). Thirteen K. parviflora patches with different extract loading and permeation enhancers were prepared by the solvent evaporation technique. All formulations showed good physicochemical properties, good stability and satisfactory adhesive properties. The effect of K. parviflora loading and permeation enhancers on methoxyflavones transport across porcine ear skin was also evaluated. The permeation of methoxyflavones increased with the amount of K. parviflora. Among the permeation enhancers investigated, oleic acid increased permeation flux of total methoxyflavones by 1.25 fold compared to the control; whereas menthol shortened the lag time. When oleic acid and menthol were combined, the maximum flux of methoxyflavones and shortest lag time were observed, suggesting a synergistic effect of menthol with oleic acid. The optimal patch formulation contained 15% K. parviflora, 3% oleic acid and 3% of menthol, and this was evaluated via an in vivo pharmacokinetic study using rats. The maximum plasma drug concentration (C max) of total methoxyflavones was 218.08 ng/ml with T max at 8 h. The concentrations of methoxyflavones in plasma continued to increase until the end of the experiment, indicating a sustained release into the systemic circulation.
Keywords: Methoxyflavones; Transdermal patch; Pharmacokinetic study;

Display OmittedHydrogels synthesized from poly(l-lysine isophthalamide) (PLP) crosslinked with l-lysine methyl ester were investigated as drug delivery systems for a wide size range of molecules (0.3–2000 kDa). PLP is an anionic, pseudo-peptidic polymer that is an ideal hydrogel backbone due to its pH-responsiveness and amphiphilicity. Drug loading and release were evaluated for various model drugs: hydrophobic fluorescein (Mw = 332 Da) and hydrophilic fluorescein isothiocyanate–dextran (FITC–Dex Mw = 10 kDa, 150 kDa, 500 kDa, and 2000 kDa). Weight incorporation was high, up to 22.8 ± 3.1%. Release after 24 h in pH 7.4 was in the range from 70.4 ± 1.2% to 91.6 ± 0.8% for all model drugs. In contrast, drug release after 24 h in pH 3.0 was significantly lower, less than 8% for fluorescein, 500 kDa, and 2000 kDa FITC–Dex. Thus, the adaptability of these novel hydrogels to both hydrophobic and hydrophilic molecules, spanning a wide size range, suggests their use as a platform delivery system. This is also the first known hydrogel system for the oral delivery of payloads larger than 70 kDa, which, combined with triggered release in response to pH changes along the gastrointestinal tract, indicates that these hydrogels have promising applications in oral drug delivery.
Keywords: Hydrogels; Oral drug delivery; pH-responsive; Controlled release; Amphiphilic;

Multi-modal detection of colon malignancy by NIR-tagged recognition polymers and ultrasound contrast agents by Meital Bloch; Lauren Jablonowski; Eylon Yavin; Dorit Moradov; Irena Djavsarov; Abraham Nyska; Margaret Wheatley; Abraham Rubinstein (504-516).
Display OmittedTo increase colonoscopy capability to discriminate benign from malignant polyps, we suggest combining two imaging approaches based on targeted polymeric platforms. Water-soluble cationized polyacrylamide (CPAA) was tagged with the near infrared (NIR) dye IR-783-S-Ph-COOH to form Flu–CPAA. The recognition peptide VRPMPLQ (reported to bind specifically to CRC tissues) was then conjugated with the Flu–CPAA to form Flu–CPAA–Pep which was then incorporated into echogenic microbubbles (MBs) made of polylactic acid (PLA) that are highly responsive to ultrasound. The ultimate design includes intravenous administration combined with local ultrasound and intra-colon inspection at the NIR range. In this proof of principle study PLA MBs were prepared by the double emulsion technique and loaded with several types of Flu–CPAA–Pep polymers. After insonation the submicron PLA fragments (SPF)-containing Flu–CPAA–Pep were examined in vitro for their ability to attach to colon cancer cells and in vivo (DMH induced rat model) for their ability to attach to colon malignant tissues and compared to the specific attachment of the free Flu–CPAA–Pep.The generation of SPF-containing Flu–CPAA–Pep resulted in a tissue attachment similar to that of the free, unloaded Flu–CPAA–Pep. The addition of VRPMPLQ to the polymeric backbone of the Flu–CPAA reduced cytotoxicity and improved the specific binding.
Keywords: Colon cancer; Real time diagnosis; Cationized polyacrylamide; Recognition peptide; Ultrasound; Microbubbles;

Pulmonary drug delivery systems for tuberculosis treatment by Dinh-Duy Pham; Elias Fattal; Nicolas Tsapis (517-529).
Formulations for inhalation in the treatment of tuberculosis.Dinh-Duy Pham, Elias Fattal, Nicolas Tsapis.Display OmittedTuberculosis (TB) remains a major global health problem as it is the second leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Conventional treatments fail either because of poor patient compliance to the drug regimen or due to the emergence of multidrug-resistant tuberculosis. The aim of this review is to give an update on the information available on tuberculosis, its pathogenesis and current antitubercular chemotherapies. Direct lung delivery of anti-TB drugs using pulmonary delivery systems is then reviewed since it appears as an interesting strategy to improve first and second line drugs. A particular focus is place on research performed on inhalable dry powder formulations of antitubercular drugs to target alveolar macrophages where the bacteria develop. Numerous studies show that anti-TB drugs can be incorporated into liposomes, microparticles or nanoparticles which can be delivered as dry powders to the deep lungs for instantaneous, targeted and/or controlled release. Treatments of infected animals show a significant reduction of the number of viable bacteria as well as a decrease in tissue damage. These new formulations appear as interesting alternatives to deliver directly drugs to the lungs and favor efficient TB treatment.
Keywords: Tuberculosis; Lung delivery; Dry powders; Liposomes; Nanoparticles;

Fine granules showing sustained drug release prepared by high-shear melt granulation using triglycerin full behenate and milled microcrystalline cellulose by Hajime Aoki; Yasunori Iwao; Takeaki Uchimoto; Shuji Noguchi; Ryusuke Kajihara; Kana Takahashi; Masayuki Ishida; Yasuko Terada; Yoshio Suzuki; Shigeru Itai (530-539).
Display OmittedThis study aimed to prepare fine granules with a diameter less than 200 μm and sustained drug release properties by melt granulation. Triglycerin full behenate (TR-FB) was examined as a new meltable binder (MB) by comparison of its properties with those of glycerin monostearate (GM), widely used as MB. The effect of milling microcrystalline cellulose (MCC), an excipient for melt granulation, on the granule properties was also investigated. TR-FB was more stable during heating and storage than GM, and produced smaller granules with narrower particle size distribution, larger yield in the 106–200 μm range, uniform roundness and better sustained drug release profile than those prepared with GM. Granules prepared with milled MCC had almost the same physicochemical properties as those produced with intact MCC. However, milled MCC produced granules with a more rigid structure and smaller void space than intact MCC. Consequently, the granules produced with milled MCC showed better sustained drug release behavior than those prepared with intact MCC. We successfully prepared fine granules with sustained drug release properties and diameter of less than 200 μm using TR-FB and milled MCC.
Keywords: High-shear melt granulation; Computed tomography; Synchrotron X-ray radiation; Milling process; Internal structure; Triglycerin full behenate;

Formulation, optimization and in vitroin vivo evaluation of febuxostat nanosuspension by Bhupesh K. Ahuja; Sunil K. Jena; Sharan K. Paidi; Surbhi Bagri; Sarasija Suresh (540-552).
Display OmittedThe purpose of the present study was to develop febuxostat nanosuspension and investigate its effect on febuxostat solubility, dissolution rate and oral bioavailability. The wet media milling technique was adopted with a combination of hydroxypropyl methylcellulose (HPMC E3) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as surface stabilizers for the generation of nanocrystals. Rotatable central composite design (CCD) was selected for nanosuspension optimization. The critical parameters were bead volume, milling time, polymer and surfactant concentrations; whereas particle size, polydispersity index (PDI) and zeta potential were taken as responses. The presence of crystallinity was confirmed by differential scanning calorimetry and powder X-ray diffraction. Scanning electron microscopy and transmission electron microscopy revealed small and uniform plate like morphology. A significant increase was observed in saturation solubility and dissolution rate of the optimized nanosuspension in all the pH conditions tested. Oral bioavailability of FXT and optimized FNC was evaluated in SD rats. The nanosuspension exhibited enhanced C max (26.48 ± 2.71 vs. 19.85 ± 2.96 μg/mL) and AUC0−∞ (222.29 ± 9.81 vs. 100.32 ± 9.36 μg h/mL) with a 221.6% increase in relative bioavailability. Thus, FNC is a viable approach to enhance the bioavailability of FXT, a BCS Class II drug.
Keywords: Febuxostat; Wet media milling; Nanosuspension; Saturation solubility; Stability; Oral bioavailability;

Hepatocellular carcinoma dually-targeted nanoparticles for reduction triggered intracellular delivery of doxorubicin by Omar Mezghrani; Yue Tang; Xue Ke; Yi Chen; Danrong Hu; Jiasheng Tu; Li Zhao; Nadia Bourkaib (553-568).
Display OmittedHepatocellular carcinoma (HCC) dual targeted stimuli responsive nanoparticles (NPs) for intracellular delivery of doxorubicin (DOX) were developed based on a reduction cleavable hyaluronic acid–glycyrrhetinic acid conjugate (HA-Cyst-GA). HA-Cyst-GA conjugate readily formed NPs in aqueous milieu and exhibited a high drug loading capacity (33.9%). The NPs redox responsiveness evaluation showed a tendency to lose their structural integrity in response to a reductive stimulus while remaining stable at physiological conditions, and that drug release was dramatically accelerated in presence of an intracellular level of glutathione. Moreover, cellular uptake studies highlighted the affinity of hepatoma cells (HepG2) toward the NPs as compared to breast cancer cells (MDA-MB-231). HA-Cyst-GA DOX-NPs displayed an increased cytotoxic potency over their non-responsive counterparts and free DOX with IC50 of 5.75, 9.33 and 10.23 μg/mL, respectively. CLSM observations showed that HA-Cyst-GA DOX-NPs mediated a faster intracellular release and nuclear delivery of DOX as compared to the insensitive control. In vivo imaging study performed on H22 tumor bearing mice revealed a selective accumulation of DiR labeled NPs in the tumor and liver upon systemic administration. The antitumor efficacy was evaluated in HepG2 tumor xenograft model. Overall HA-Cyst-GA NPs appear as a potential HCC targeted intracellular delivery platform for DOX.
Keywords: Hepatocellular carcinoma targeting; Dual ligand targeting; Hyaluronic acid; Glycyrrhetinic acid; Redox responsive; Antitumor efficacy;

Display OmittedDuring the last few decades, both scientific and applied research communities have shown increased attention to self-assembled lyotropic liquid crystalline phases of polar lipids, due to their remarkable structural complexity and usefulness in diverse applications.Amphiphilic properties of polar lipids in relation to water are the driving force for self-assemblies following an extraordinary polymorphism. This polymorphism is an interesting phenomenon in which lipids combine short-range disorder and long-range order. The most widely investigated liquid crystalline phases are the lamellar, the cubic and the hexagonal.Such phases have high solubilization capacity for hydrophilic, lipophilic and amphiphilic guest molecules and the ability to protect molecules against hydrolysis or oxidation. So, they can be used as an interesting drug delivery matrix for drugs, amino acids, peptides, proteins and vitamins in various food, pharmaceutical and biotechnical applications.This review presents recent progress in glycerol monooleate liquid crystalline phases used as drug delivery vehicles.
Keywords: Glycerol monooleate; Liquid crystalline phase; Cubic phase; Hexagonal phase; Drug delivery;

Properties of polidocanol foam in view of its use in sclerotherapy by V. Nastasa; K. Samaras; Ch. Ampatzidis; T.D. Karapantsios; M.A. Trelles; J. Moreno-Moraga; A. Smarandache; M.L. Pascu (588-596).
Display OmittedFoam sclerotherapy is a widely used method to treat varicose veins disease. It is easy to use and apply, affordable, and has high efficiency that depends on foam stability upon injection. Since sclerotherapy is usually applied in a medical doctor’s office, one of the most employed methods to generate foam is based on the Tessari technique which uses pumping cycles of liquid and air in-and-out of a double syringe system. Finally, the produced foam exits through a small orifice (∼2 mm) at the output of a three-way valve. The present work shows results regarding the factors that may influence foam stability (liquid to air ratio, type of connector, syringe diameter, number of pumping cycles, etc.) of a commonly used sclerosing agent (polidocanol). Furthermore, an effort is made to evaluate the effect of adding different substances on the stability of polidocanol foams (0.5% w/w) by altering the surface tension or/and the bulk and interfacial rheological properties of the fluids. It is shown that adding small concentrations of nonionic surfactants can increase foam stability with just a very small variation of the mean bubbles size.
Keywords: Sclerotherapy; Foam stability; Polidocanol; Surfactant; Rheology;

Mechanistic study of carvacrol processing and stabilization as glassy solid solution and microcapsule by Markus W. Tackenberg; Carola Geisthövel; Andreas Marmann; Heike P. Schuchmann; Peter Kleinebudde; Markus Thommes (597-605).
Display OmittedEssential oils and other liquid active pharmaceutical ingredients (APIs) are frequently microencapsulated to improve shelf life, handling, and for tailoring release. A glassy solid solution (GSS), a single-phase system, where the excipient is plasticized by the API, could be an alternative formulation system. Thus this study focuses on the investigation of two formulation strategies using carvacrol as a model compound, namely a microcapsule (MC) and a glassy solid solution (GSS). Applying the solubility parameter approach, polyvinylpyrrolidone (PVP) was chosen as a suitable matrix material for a GSS system, whereas maltodextrin and sucrose served as excipients for a microcapsule (MC) system. Differential scanning calorimetry (DSC) measurements of the excipients’ glass transition temperatures and the melting point of carvacrol verified plasticizing properties of carvacrol on PVP. Batch mixing processes, as preliminary experiments for future extrusion processes, were performed to prepare GSSs and MCs with various amounts of carvacrol, followed by crushing and sieving. Maximally 4.5% carvacrol was encapsulated in the carbohydrate material, whereas up to 16.3% were stabilized as GSS, which is an outstanding amount. However, grinding of the samples led to a loss of up to 30% of carvacrol.
Keywords: Carvacrol; Microencapsulation; Plasticization; Glassy solid solution; Carbohydrates; PVP;

Display OmittedThis work discusses the scientific aspects of the definition of dose as the ‘highest single oral IR dose’ recommended for administration in the SmPC (summary of product characteristics) in the current European Medicines Agency (EMA) 2010 Guideline, for the purpose of biopharmaceutics classification system (BCS)-based biowaiver decision making. Analysis of theoretical and experimental data dealing with drug dissolution and biopharmaceutic drug classification reveals that the drug dose is an important parameter for both drug dissolution and biopharmaceutic classification. The relevant implications for the dose considerations in bioequivalence studies are also discussed briefly. It is suggested that the concept of “the highest single dose oral IR dose recommended for administration in the SmPC” of the EMA 2010 Guideline be abolished. It is advisable, each dose strength be considered separately i.e., whether or not it meets the solubility–dissolution regulatory criteria.
Keywords: Dose; BCS; EMA; Guideline; Bioequivalence;

AOT reversed micelleDisplay OmittedPresented paper is a continuation of our studies on morin interaction with AOT (sodium bis(2-ethylhexyl) sulfosuccinate) reversed micelles solutions in two solvents: ethanol and n-decanol. Now we focused on morin influence on size and diffusion phenomena in the system morin/solvent/AOT/water. In this paper precise measurements of dynamic light scattering (DLS) of the effects of temperature, solvents (alcohols), water on the size and diffusion of AOT reversed micelles in the morin/AOT/alcohol/water system are reported. The concentrations of AOT were varied from 0.51 to 0.78 mol/L. Morin concentration in during auto-correlation function registration was not the same in each solvent because of its different solubility depending on the solvent. Water concentration in the studied systems was defined by R parameter according to relation: R  = (H2O)/(AOT) and was equal 0 and 30 in ethanol, and 0 in n-decanol. DLS measurements were done at 298.15 and 308.15 K.DLS experiment involved on detection two relaxation modes (fast and slow) in the systems containing AOT reversed micelles, water, morin and solvents (ethanol and n-decanol). The DLS data clearly show the solvent influence as well as morin presence on AOT reversed micelles size and consequently their diffusion coefficients. Contrary to n-decanol strong competition between morin and ethanol molecules in AOT reversed micelles palisade layer has been found. It suggests that morin molecules replaced ethanol in AOT reversed micelles and locate in their palisade layer strongly increasing AOT reversed micelles size. Furthermore, it was found a sharp increase in correlation radii of slow modes of AOT reversed micelles containing morin molecules and their diffusion coefficients diminishing.
Keywords: Morin; Ethanol; n-Decanol; Surfactant; Hydrodynamic radius; DLS;

Display OmittedPaclitaxel (PTX) has been used in the treatment of wide range of cancers but its entry into cancer cell is restricted by p-glycoprotein (p-gp). Also, it was reported that verapamil (VP) could inhibit p-gp efflux. Hence, three kinds of solid lipid nanoparticles (SLN) such as PVS (PTX and VP co-loaded SLN), PSV (PTX loaded SLN, later added VP) and PVSV (PTX and VP co-loaded SLN, later added VP) were prepared to overcome MDR by combination of PTX and VP. PVS was the SLN loaded with both PTX and VP at the same time. PSV was the SLN loaded with PTX and then modified with VP – complexed hydroxypropyl-β-cylcodextrin (HPCD). Finally, PVSV was the SLN loaded with PTX and half of VP at the same time subsequently, modified with half of VP - complexed HPCD. The physicochemical characterizations of PVS, PSV or PVSV such as particle size, zeta potential, encapsulation efficiency or in vitro PTX release were examined. PVSV showed that release of VP was higher than PTX solution in first 15 h and sustained release of both VP and PTX. PVSV showed significantly higher cytotoxicity and cellular uptake than that of the PTX solution in MCF-7/ADR resistant cells. Furthermore, PVSV significantly down regulated the expression of p-gp than the PTX solution in MCF-7/ADR resistant cells. Based on these findings, this study indicated that the PVSV exhibited great potential for breast cancer therapy
Keywords: Paclitaxel; Verapamil; Co-encapsulation; Solid lipid nanoparticle; Multidrug resistance;

Display OmittedSublingual drug delivery is an interesting route for drug having significant hepatic first-pass metabolism or requiring rapid pharmacological effect as for patients suffering from swallowing difficulties, nausea or vomiting. Sublingual absorption could however be limited by the kinetic of drug dissolution. This study evaluated influences of cyclodextrins (β-CD or HP-β-CD) and their different inclusion process (spray-drying or freeze-drying) on the drug dissolution kinetic of solid dispersions in poly(ethylene glycol) (PEG, Mw 6000 Da) of piroxicam, used as poor hydrosoluble drug model. A secondary objective was to determine influences of drug dispersion process in PEG (evaporation or melting methods) on the drug dissolution kinetic of piroxicam. Piroxicam solid dispersions containing or not cyclodextrins were characterized by different scanning calorimetry (DSC), Thermogravometry analyser (TGA) and Fourier transform-infrared spectroscopy (FT-IR) spectroscopy. In vitro drug dissolution study of these solid dispersions was then performed. The results demonstrated the high potential and interest of solid dispersions of drug previously included in cyclodextrins for sublingual delivery of hydrophobic drugs. This study also showed the advantages of evaporation method on the melting ones during drug dispersion in PEG. Indeed, drug complexation with cyclodextrins as dispersion by melting prevented the presence in solid dispersions of drug in crystalline form which can represent up to 63%. Moreover, dispersion in PEG by evaporation method gave more porous drug delivery system than with melting methods. This allowed complete (limited at most at 80–90% with melting methods) and quick drug dissolution without rebound effect like with melting ones.

Lactosylated PLGA nanoparticles containing ϵ-polylysine for the sustained release and liver-targeted delivery of the negatively charged proteins by Ping Zhou; Tong An; Chuan Zhao; Yuan Li; Rongshan Li; Rui Yang; Yinsong Wang; Xiujun Gao (633-643).
Display OmittedThe acidic internal pH environment, initial burst release and lack of targeting property are main limitations of poly(lactide-co-glycolide) (PLGA) nanoparticles for carrying proteins. In this study, ϵ-polylysine (ϵ-PL) was used as an anti-acidic agent and a protein protectant to prepare PLGA nanoparticles for the protein delivery. To obtain the liver-targeting capability, lactosylated PLGA (Lac-PLGA) was synthesized by conjugation of lactose acid to PLGA at both ends, and then used to prepare nanoparticles containing ϵ-PL by the nanoprecipitation method. Bovine serumal bumin (BSA), a negatively charged protein, was efficiently loaded into Lac-PLGA/ϵ-PL nanoparticles and exhibited significant decreased burst release in vitro, sustained release in the blood and increased liver distribution in mice after intravenous injections. The enhanced stability of BSA was due to its electrical interaction with ϵ-PL and the neutralized internal environment of nanoparticles. In conclusion, Lac-PLGA/ϵ-PL nanoparticle system can be used as a promising carrier for the negatively charged proteins.
Keywords: Lactosylated PLGA; ϵ-Polylysine; Nanoparticle; Protein; Sustained release;

Targeted killing of cancer cells in vivo and in vitro with IGF-IR antibody-directed carbon nanohorns based drug delivery by Nannan Li; Qian Zhao; Chang Shu; Xiaona Ma; Ruixin Li; Hongjun Shen; Wenying Zhong (644-654).
Display OmittedOxidized single-wall carbon nanohorns (oxSWNHs) have shown great potential in drug delivery. The purpose of this study was to design an effective targeted drug delivery system (DDS) based on oxSWNHs, which could carry high dose of drug to tumor sites and improve the therapeutic efficacy with less adverse effects. OxSWNHs incorporated the anticancer drug vincristine (VCR) via physical adsorption, then wrapped DSPE-PEG-IGF-IR monoclonal antibody (mAb) through an amide liker to obtain the drug delivery system, VCR@oxSWNHs-PEG-mAb. The in vitro release behavior study indicated that the DDS had good sustained release and the cumulative release of VCR was 80% at 144 h. Compared with free VCR, the tumor targeting drug delivery efficiently enhanced the cytotoxicity in cultured MCF-7 cells in vitro, and afforded higher antitumor efficacy without obvious toxic effects to normal organs in tumor mice in vivo. In addition, the targeted DDS could reduce the toxicity of VCR to the living mice. This study demonstrated that VCR@oxSWNHs-PEG-mAb might be promising for high treatment efficacy with minimal side effects in future cancer therapy.
Keywords: Oxidized single-wall carbon nanohorn; Vincristine; IGF-IR monoclonal antibody; Drug delivery system; Antitumor efficiency;

Display OmittedThe main purpose of this study was to investigate the effect of gelatin as interior support on the physical stability of freeze-dried liposomes. Anticancer agent paclitaxel (PTX) was selected as a model drug. Freeze-dried liposomes containing interior gelatin support (GLs) were prepared by thin-film dispersion/freeze-drying method. Several properties of the GLs, including entrapment efficiency, particle size and gelation temperature, were extensively characterized. Encapsulation efficiency of conventional liposomes (CLs) and liposomes containing lyoprotectants as interior support dropped to lower than 20% after reconstitution, while GLs still maintained an entrapment efficiency of over 84%. Scanning electron microscopy revealed well preserved liposomal structure of GLs after reconstitution. Meanwhile, the particle size and entrapment efficiency of GLs were also well preserved after reconstitution. In contrary, deformation of CLs and recrystallization of PTX were observed, as well as significant changes in particle size and entrapment efficiency. Taken together, interior gelatin support obviously enhanced the physical stability of liposomes against the lyophilization stress.
Keywords: Liposomes; Gelliposomes; Freeze-drying; Gelatin; Stability; Paclitaxel;

In situ perfusion in rodents to explore intestinal drug absorption: Challenges and opportunities by Jef Stappaerts; Joachim Brouwers; Pieter Annaert; Patrick Augustijns (665-681).
Display OmittedThe in situ intestinal perfusion technique in rodents is a very important absorption model, not only because of its predictive value, but it is also very suitable to unravel the mechanisms underlying intestinal drug absorption. This literature overview covers a number of specific applications for which the in situ intestinal perfusion set-up can be applied in favor of established in vitro absorption tools, such as the Caco-2 cell model. Qualities including the expression of drug transporters and metabolizing enzymes relevant for human intestinal absorption and compatibility with complex solvent systems render the in situ technique the most designated absorption model to perform transporter-metabolism studies or to evaluate the intestinal absorption from biorelevant media.Over the years, the in situ intestinal perfusion model has exhibited an exceptional ability to adapt to the latest challenges in drug absorption profiling. For instance, the introduction of the mesenteric vein cannulation allows determining the appearance of compounds in the blood and is of great use, especially when evaluating the absorption of compounds undergoing intestinal metabolism. Moreover, the use of the closed loop intestinal perfusion set-up is interesting when compounds or perfusion media are scarce. Compatibility with emerging trends in pharmaceutical profiling, such as the use of knockout or transgenic animals, generates unparalleled possibilities to gain mechanistic insight into specific absorption processes.Notwithstanding the fact that the in situ experiments are technically challenging and relatively time-consuming, the model offers great opportunities to gain insight into the processes determining intestinal drug absorption.
Keywords: Transporter–metabolism interplay; Site dependent absorption; Knockout animals; Solubility–permeability interplay; Supersaturation; Intestinal perfusion;

Authors’ response to the letter from Kalleian Eserian et al by Diana A. van Riet-Nales; Myrthe E. Doeve; Agnes E. Nicia; Steven Teerenstra; Kim Notenboom; Yechiel A. Hekster; Bart J.F. van den Bemt (682-683).
Display OmittedThis letter is a response to the comments of Kalleian Eserian et al. on our study relating to the accuracy, precision and sustainability of six tablet splitters and a kitchen knife as an alternative to breaking paracetamol 500 mg tablets by hand. We would like to inform the readers of International Journal of Pharmaceutics that our study focused on splitting tablets with a mechanical tool rather than breaking tablets by hand. Although publications on hand breaking tablets were not cited for this reason, we are familiar with the conclusions of these publications. This is especially true for the publications that were written by direct colleagues from the department of the corresponding author e.g., Van Santen et al. and Van der Steen et al.
Keywords: Medication; Pharmaceutical development; Tablet splitting; Break mark; Weight uniformity;

In vivo absorption behaviour of theophylline from starch-methyl methacrylate matrix tablets in beagle dogs by F. Fernández-Campos; C. Ferrero; H. Colom; M.R. Jiménez-Castellanos (684-692).
Display OmittedThis study evaluates in vivo the drug absorption profiles from potato starch-methyl methacrylate matrices* using theophylline as a model drug. Healthy beagle dogs under fasting conditions were used for in vivo studies and plasma samples were analyzed by a fluorescence polarization immunoassay analysis (FPIA method). Non-compartmental and compartmental (population approach) analysis was performed to determine the pharmacokinetic parameters. The principle of superposition was applied to predict multiple dose plasma concentrations from experimental single dose data. An in vitroin vivo correlation (IVIVC) was also assessed. The sustained absorption kinetics of theophylline from these formulations was demonstrated by comparison with two commercially available oral sustained-release theophylline products (Theo-Dur® and Theolair®). A one-compartment model with first order kinetics without lag-time best describes the absorption/disposition of theophylline from the formulations. Results revealed a theophylline absorption rate in the order FD-HSMMA ≥ Theo-Dur®  ≥ OD-CSMMA > Theolair®  ≥ FD-CSMMA. On the basis of simulated plasma theophylline levels, a twice daily dosage (every 12 h) with the FD-CSMMA tablets should be recommended. A Level C IVIVC was found between the in vitro t 50% and the in vivo AUC/D, although further optimization of the in vitro dissolution test would be needed to adequately correlate with in vivo data.
Keywords: Potato starch-methyl methacrylate copolymers; Anhydrous theophylline; Sustained-release matrix tablet; Beagle dog; Pharmacokinetics; IVIVC;

Display OmittedLeachable materials that are released from infusion sets during their use can induce local and systemic toxic effects. We studied the mechanisms and kinetics of cell death induced by infusion sets leachates in vitro using L-929 and bEnd. 3 cells. Changes in cell morphology and metabolic activity were determined using light microscopy and the MTT test, respectively. Detailed analysis of the mechanisms of cell death was performed using membrane integrity and caspases 3 and 7 activity tests, annexin V-FITC/7-AAD analysis by FACS, and DAPI nuclear staining followed by confocal microscopy. Infusion sets released toxic leachables and induced toxic effects. Latex flashball was the most toxic part of the studied infusion sets, and it potently induced cell oncosis via increased permeability of the cell membrane. Latex-induced decrease in cells metabolic activity and cell death were not accompanied by activation of caspases 3 and 7, changes in nuclear morphology, or substantial annexin V-FITC cell staining. Leachables from the tube part of the infusion sets were less toxic, and induced some biochemical changes without altering the cells morphology. Further studies are needed to reveal the in vivo toxicity of infusion sets and its correlation with the results of in vitro toxicity studies.
Keywords: Disposable medical devices; Infusion sets; Natural rubber latex; In vitro toxicity; Oncosis;

Display OmittedCapping and lamination are two problems that are often faced during the industrial manufacturing of pharmaceutical tablets. Several reasons have been proposed to explain these phenomena. Among them, air entrapment is supposed to play a role in some cases. Nevertheless, no direct proof were given to prove that air entrapment can promote lamination or capping and various publications have questioned this hypothesis.In this article, using a model product compacted on a compression simulator, a direct proof of the implication of air entrapment during lamination was given. In fact, at the surface of the compact, defects with a spherical shape, clearly linked with an entrapped bubble of air, began to appear on the surface of the compact just below the pressure level to which lamination was observed. Moreover it was also observed that, when the compact thickness increased, the lamination pressure decreased, meaning that the compact thickness can promote lamination. As a conclusion, contrary to what is said in some publications, air entrapment can be involved when problems of lamination occur, and, in this case, powder desaeration should be considered.
Keywords: Compression; Tablet; Capping; Lamination;

Impact of microcrystalline cellulose material attributes: A case study on continuous twin screw granulation by Margot Fonteyne; Ana Correia; Sofie De Plecker; Jurgen Vercruysse; Ilija Ilić; Qi Zhou; Chris Vervaet; Jean Paul Remon; Fernanda Onofre; Vincent Bulone; Thomas De Beer (705-717).
Display OmittedThe International Conference on Harmonisation (ICH) states in its Q8 ‘Pharmaceutical Development’ guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of material attributes, manufacturing process options and process parameters. The present case study evaluates the effect of unspecified variability of raw material properties upon the quality attributes of granules; produced using a continuous from-powder-to-tablet wet granulation line (ConsiGma™ 25). The impact of different material attributes of six samples of microcrystalline cellulose (MCC) was investigated. During a blind study the different samples of MCC were used separately and the resulting granules were evaluated in order to identify the differences between the six samples. Variation in size distribution due to varying water binding capacity of the MCC samples was observed. The cause of this different water binding capacity was investigated and was caused by a different degree of crystallinity. Afterwards, an experimental design was conducted in order to evaluate the effect of both product and process variability upon the granule size distribution. This model was used in order to calculate the required process parameters to obtain a preset granule size distribution regardless of the type of MCC used. The difference in water binding capacity and its effect on granular properties was still present when combining the MCC grades with different binders.
Keywords: Twin screw granulation; Quality by design; Raw material variability; MCC; Water binding capacity;

Sylysia 350/Eudragit S100 solid nanomatrix as a promising system for oral delivery of cyclosporine A by Wenbing Dai; Yulan Guo; Hua Zhang; Xueqing Wang; Qiang Zhang (718-725).
Display OmittedCyclosporine A (CyA) is a poorly soluble peptide and the available preparation is the surfactant based Sandimmum Neoral®. In this study, we developed a novel pH-sensitive nanomatrix system of CyA with medical-grade nanoporous silica and Eudragit® to enhance the oral absorption of CyA as well as to improve the potential nephrotoxicity caused by the pronounced initial plasma peak of Neoral®. The nanomatrixs were prepared by an absolutely simple conventional process. The scanning electron microscopy (SEM), X-ray powder diffraction analysis (XRD), differential thermal analysis (DSC) and specific surface area and pore size analysis were used to analyze the physicochemical characterization of the nanomatrix. The nanomatrix, consisted of CyA, Eudragit® S100 and Sylysia 350 (1/5/5, w/w/w %), not only increased the dissolution of CyA in vitro but also exhibited excellent enteric behavior. The characterization of CyA nanomatrix showed the CyA was highly dispersed in the nanomatrix in a molecular or amorphous state and partly filled into the nanopores of Sylysia 350. The results of comparative pharmacokinetic study showed that the optimized nanomatrix had a relative bioavailability of 90.8% with Neoral® but a lower C max than that of Neoral®. In conclusion, the novel nanomatrix of CyA, composed of pharmaceutical excipients of biological safety and easily prepared, is expected to become a promising marketed product for the oral delivery of CyA.
Keywords: Bioavailability; Cyclosporine A; Poorly soluble drug; pH-sensitive delivery system; Nanomatrix;

Display OmittedNanostructured lipid carriers (NLC) are interesting delivery systems for enhancing the penetration of an active substance through the skin after topical administration. In the present study, lycopene was loaded into NLC, composed of Eumulgin® SG, orange wax and rice bran oil, using high pressure homogenization (HPH). Photon correlation spectroscopy analysis showed that the lycopene-loaded NLC had a size of 150–160 nm with a relatively small size distribution (PdI < 0.15). The entrapment efficiency of lycopene was found to be 100 ± 0% for all formulations. An in vitro release study of lycopene showed a biphasic release profile: a relatively fast release during the first 6 h followed by a sustained release during the next 18 h. An in vitro occlusion test showed that the occlusive properties of NLC increased with increasing lycopene loading. A free radical scavenging activity test of the NLC loaded with 50 mg% lycopene showed a Trolox equivalent antioxidant capacity value of 36.6 ± 0.4 μM Trolox/mg NLC which is higher than that of the NLC base (26.6 ± 0.1 μM Trolox/mg NLC). The concentration of 50% antioxidant activity (IC50) of the lycopene-loaded NLC was 14.1 ± 0.6 mg/mL, and lower than that of the formulation without lycopene (17.7 ± 0.4 mg/mL). The particle size, size distribution, and zeta potential of lycopene-loaded NLC stored at different temperatures of 4, 30, 40 °C for 120 days did not change in time, demonstrating an excellent colloidal stability of the systems. Chemical stability data indicated that the utilization of NLC increased the stability of lycopene and it was found that the degradation of lycopene was retarded when stored at low temperatures. In conclusion, NLC are attractive systems for the cutaneous delivery of lycopene.
Keywords: Nanostructured lipid carriers; Lycopene; Release; Stability; Occlusion;

Display OmittedThe Ussing chambers model is almost exclusively used in the presence of plain aqueous phosphate buffers as solvent system. In an attempt to further elucidate the effect of luminal ingredients and postprandial conditions on intestinal permeability, pooled fasted and fed state human intestinal fluids (FaHIFpool, FeHIFpool) were used. In addition, simulated intestinal fluids of both nutritional states (FaSSIF, FeSSIF) were evaluated as possible surrogate media for HIF. The use of FaHIFpool generated a broad range of P app values for a series of 16 model drugs, ranging from 0.03 × 10−6  cm/s (carvedilol) to 33.8 × 10−6  cm/s (naproxen). A linear correlation was observed between P app values using FaSSIF and FaHIFpool as solvent system (R  = 0.990), justifying the use of FaSSIF as surrogate medium for FaHIF in the Ussing chambers. In exclusion of the outlier carvedilol, a strong sigmoidal relationship was found between P app and fahuman of 15 model drugs, illustrated by correlation coefficients of 0.961 and 0.936 for FaHIFpool and FaSSIF, respectively. When addressing food effects on intestinal permeability, the use of FeHIFpool resulted in a significantly lower P app value for nine out of sixteen compounds compared to fasting conditions. FeSSIF as solvent system significantly overestimated P app values in FeHIFpool. To conclude, the optimized Ussing chambers model using biorelevant media as apical solvent system holds great potential to investigate food effects in a more integrative approach, taking into account drug solubilisation, supersaturation and formulation effects.
Keywords: Ussing chambers; Rat intestine; Permeability; Human intestinal fluid; Food effect;

Display OmittedInhibitors against multidrug resistance (MDR) efflux transporters have failed in most clinical settings due to unfavorable pharmacokinetic interactions with co-administered anti-cancer drug and their inherent toxicities. Nanoparticles (NPs) have shown potential to overcome drug efflux by delivering and localizing therapeutic molecules within tumor mass. In this work, we investigated effect of nanocarrier surface charge and formulation parameters for a hydrophilic and lipophilic MDR inhibitor on their ability to reverse drug resistance. Active inhibition of efflux pumps was achieved by encapsulating first and third generation P-gp inhibitors- verapamil and elacridar respectively in non-ionic, anionic and cationic surfactant-based NPs. The ability of NPs to reverse P-glycoprotein (P-gp)-mediated MDR efflux was evaluated in sensitive (A2780) and resistant (A2780Adr) ovarian cancer cell lines by various in vitro accumulation and cytotoxicity assays. Uptake mechanism for NP appears to be caveolae-dependent with 20%-higher internalization in A2780Adr than A2780 cell lines which can be co-related to the biophysical membrane composition. Cationic- CTAB NPs showed highest reversal efficacy followed by PVA and SDS-NP (P + S NP) and PVA-NPs. As compared to doxorubicin treated drug resistant cells lines, blank-, verapamil- and elacridar-CTAB-NPs showed 2.6-, 20- and 193-fold lower IC50 values. This work highlights the importance of inhibitor-loaded charged particles to overcome cancer drug resistance.
Keywords: Cancer; P-gp; Multidrug resistance; Nanoparticle; Inhibitor;

Display OmittedThe purpose of this study was to better understand the preferential binding behavior of arginine to protein as well as the impact of arginine on the conformational and colloidal stability of protein solution. Physical stabilities of model proteins, bovine serum albumin (BSA) and ovalbumin (OVA), were investigated by fluorescence-based and dynamic light scattering techniques in the absence and presence of arginine. We investigated the interactions between arginine and tryptophan or tyrosine residues by conducting solubility and fluorescence studies of two amino acid derivatives, N-acetyl-l-tryptophanamide (NATA) and N-acetyl-l-tyrosinamide (NAYA), in arginine solutions. The result showed that arginine preferentially bond to the aromatic amino acids of proteins mainly through hydrogen bonds and Van der Waals’ forces, while the binding constant K of arginine with BSA and OVA at 298 K was 41.92 and 5.77 L/mol, respectively. The fluorescence quenching, the decreased fluorescence lifetime and the red-shifted ANS peak position revealed that arginine perturbed the local environment of tryptophan and tyrosine residues. We also found the attenuated electrostatic repulsion among BSA and OVA molecules after adding arginine. These findings provided strong evidence that arginine possessed negative effects on tertiary conformational and colloidal stability of BSA and OVA during the preferential binding process.
Keywords: Arginine; Bovine serum albumin; Ovalbumin; Tertiary conformational stability; Colloidal stability;

Shell-crosslinked hybrid nanoparticles for direct cytosolic delivery for tumor therapy by Wei He; Zhu Jin; Yaqi Lv; Hui Cao; Jing Yao; Jianping Zhou; Lifang Yin (762-772).
Display OmittedTo obtain efficient therapeutics, drug release into the cytosol is required because drug targets are often located in the cytosol or have active sites that require intracellular machinery in the cytosolic compartment. However, typical nanocarriers gain cellular entry by endocytic mechanisms, confining the internalized nanocarriers to the endosomal–lysosomal system, thus resulting in the rapid destruction of active drugs without release into the cytosol. Herein, hybrid nanoparticles (HNs) with a core–shell structure, which was based on nanoemulsion-templates stabilized by both β-lactoglobulin (β-LG) and lecithin, were developed. Additionally, its formation mechanism and structure were also studied. Importantly, the HNs could directly penetrate the cell membrane and enter the cytosol, without entrapment within the endosomal–lysosomal system via the lipid raft-like pathway, thus enhancing its antitumor activities. We therefore concluded that HNs are promising targeting delivery systems for drugs, especially for pharmaceutical proteins and gene-targeting drugs.
Keywords: Core–shell nanoparticles; Drug release; Direct cytosolic delivery; Cellular uptake; Inhibitors; Tumor therapy;

Aerosil as a novel co-crystal co-former for improving the dissolution rate of hydrochlorothiazide by Sanaa A. El-Gizawy; Mohamed A. Osman; Mona F. Arafa; Gamal M. El Maghraby (773-778).
Display OmittedCo-crystallization of drugs with benign co-formers is promising for enhancing dissolution rate of poorly soluble drugs. The selection of safe and pharmacologically inert co-formers is a critical step in this process. Accordingly, the objective of this work was to investigate aerosil 200 as a potential co-former for the preparation of hydrochlorothiazide co-crystal. Co-crystal formation involved acetone assisted co-grinding after mixing hydrochlorothiazide with increasing molar ratios of aerosil (1:1, 1:2 and 1:4). The prepared formulations were subjected to Fourier transform infrared spectroscopy, differential thermal analysis, and powder X-ray diffraction studies. These investigations provided evidence for co-crystal formation between the drug and aerosil. Complete co-crystallization was even achieved at the lowest tested concentration of aerosil suggesting that the stoichiometric ratio of co-crystal formation is 1:1 molar ratio. The dissolution studies revealed faster dissolution rate of the drug from co-crystals compared to the pure unprocessed drug or that which was subjected to wet grinding in absence of aerosil. Increasing the molar ratio of aerosil increased the amount dissolved in the first 5 min. This may be attributed to adsorption of the formed co-crystal on the surface of excess aerosil. In conclusion, aerosil can be considered as co-crystal co-former with potential future application.
Keywords: Hydrochlorothiazide crystals; Liquid assisted grinding; Dissolution efficiency; Colloidal silicon dioxide;

The effect of the drying temperature on the properties of wet-extruded calcium stearate pellets: Pellet microstructure, drug distribution, solid state and drug dissolution by S. Schrank; B. Kann; E. Saurugger; M. Hainschitz; M. Windbergs; B.J. Glasser; J. Khinast; E. Roblegg (779-787).
Display OmittedAlthough drying is widely applied during the manufacturing of solid dosage forms, its potential effect on the product’s (key) properties is often underestimated. Hence, the present study addresses drying related modifications of wet-extruded pellets comprising calcium stearate (CaSt, matrix former) and ibuprofen (model drug). After spheronization, the pellets were tray dried at different temperatures. The dried pellets were evaluated regarding their microstructure, the ibuprofen distribution, solid state modifications and the resulting in-vitro dissolution profiles. The ibuprofen distribution profiles along the pellets’ cross-sections varied for the different drying conditions. The profiles turned from inhomogeneous to uniform with increasing drying temperature. Temperatures above 20 °C yielded solid state modifications, including ibuprofen transition into the amorphous state and the formation of eutectic compositions. As none of the batches exhibited a high specific surface area associated with an open, well-interconnected pore system, the dissolution profiles were a function of the ibuprofen distribution. Differences in the solid state did not contribute to the dissolution behavior, since the CaSt matrix did not swell or dissolve in the dissolution medium. These findings show that drying may considerably affect the final product properties even for moderate drying conditions.
Keywords: Extrusion/spheronization; Ibuprofen; Differential scanning calorimetry; Infrared spectroscopy; Small and wide angle X-ray scattering; Raman imaging;

Curcumin encapsulated pH sensitive gelatin based interpenetrating polymeric network nanogels for anti cancer drug delivery by K. Madhusudana Rao; K.S.V. Krishna Rao; G. Ramanjaneyulu; Chang-Sik Ha (788-795).
Display OmittedInterpenetrating polymeric network nanogels (IPN-NGs) composed of natural gelatin biological protein macromolecules and poly(acrylamidoglycolic acid) were produced by simple free radical emulsion polymerization. The developed IPN-NGs were characterized by Fourier-transform infra-red spectroscopy to confirm the formation of NGs. The hydrophobic curcumin drug was loaded successfully into these NGs using an in-situ method. The curcumin-encapsulated NGs were well dispersed in aqueous solutions and showed good bioavailability. Curcumin was dispersed molecularly in the IPN-NGs, which was confirmed by differential scanning calorimetry and X-ray diffraction. The NGs exhibited pH sensitive properties according to dynamic light scattering and the zeta size potentials. Transmission electron microscopy revealed the NGs to be spherical, approximately 100 nm in size. The encapsulation efficiency of these IPN-NGs drug formulations ranged from 42 to 48%. In addition, the release of curcumin from the NGs was examined in phosphate buffer medium. The cytotoxicity of the IPN-NGs was studied using in vitro cultures of fibroblasts and a colorectal cancer cell line. The results suggest that the newly developed pH sensitive gelatin-poly(acrylamidoglycolic acid)-curcumin NGs can be applied for colorectal cancer drug delivery applications.
Keywords: Curcumin; Gelatin; Nanogels; pH sensitive; Bioavailability; Anticancer drug delivery;

Display OmittedThe primary objective of this paper is to compare the sorption characteristics of hydroxypropylmethylcellulose (HPMC) and hard gelatin (HG) capsules and their ability to protect capsule contents. Moisture sorption and desorption isotherms for empty HPMC and HG capsules have been investigated using dynamic vapour sorption (DVS) at 25 °C. All sorption studies were analysed using the Young–Nelson model equations which distinguishes three moisture sorption types: monolayer adsorption moisture, condensation and absorption. Water vapour diffusion coefficients (D), solubility (S) and permeability (P) parameters of the capsule shells were calculated. ANOVA was performed with the Tukey comparison test to analyse the effect of %RH and capsule type on S, P, and D parameters. The moisture uptake of HG capsules were higher than HPMC capsules at all %RH conditions studied. It was found that values of D and P across HPMC capsules were greater than for HG capsules at 0–40 %RH; whereas over the same %RH range S values were higher for HG than for HPMC capsules. S values decreased gradually as the %RH was increased up to 60% RH. To probe the effect of moisture ingress, spray dried lactose was loaded into capsules. Phase evolution was characterised by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and differential scanning calorimetry (DSC). The capsules under investigation are not capable of protecting spray dried lactose from induced solid state changes as a result of moisture uptake. For somewhat less moisture sensitive formulations, HPMC would appear to be a better choice than HG in terms of protection of moisture induced deterioration.
Keywords: Hard capsules; Gelatin; HPMC; DVS; Sorption–desorption; Diffusion; Permeability;

Measurement, analysis and prediction of topical UV filter bioavailability by L. Roussel; E. Gilbert; D. Salmon; C. Serre; B. Gabard; M. Haftek; H.I. Maibach; F. Pirot (804-810).
Display OmittedThe aim of the present study was to objectively quantify and predict bioavailability of three sunscreen agents (i.e., benzophenone-3, 2-ethylhexylsalicylate, and 2 ethylhexyl-4-methoxycinnamate) in epidermis treated by petrolatum and emulsion-based formulations for 7 and 30 min on four human volunteers. Profiles of sunscreen agents through stratum corneum (SC), derived from the assessment of chemical amounts in SC layers collected by successive adhesive tape-stripping, were successfully fitted to Fick’s second law of diffusion. Therefore, permeability coefficients of sunscreen agents were found lower with petrolatum than with emulsion based formulations confirming the crucial role of vehicle in topical delivery. Furthermore, the robustness of that methodology was confirmed by the linear relationship between the chemical absorption measured after 30 min and that predicted from the 7-min exposure experiment. Interestingly, in this dermatopharmacokinetic method, the deconvolution of permeability coefficients in their respective partition coefficients and absorption constants allowed a better understanding of vehicle effects upon topical bioavailability mechanisms and bioequivalence of skin products.
Keywords: Chemical UV filters; Topical bioavailability; Dermatopharmacokinetics; Bioequivalence;

Trichotomous gastric retention of amorphous capecitabine: An attempt to overcome pharmacokinetic gap by Yuvraj Singh; Meenakshi Singh; Jay Gopal Meher; Vivek K. Pawar; Manish K. Chourasia (811-821).
Display OmittedCapecitabine (CAP) is an oral drug of choice for treatment of colorectal cancer. But its short plasma half-life limits clinical utility and the usually prescribed dosing regimen results in significant periods of therapeutically irrelevant concentration. To overcome this pharmacokinetic void a trichotomous gastroretentive (TRGDDS) system made up of CAP housed in xanthan gum microparticles (CXGMP) has been developed for extending CAP's gastric residence time thereby prolonging the subsequent elimination. TRGDDS was evaluated for particle size (243 ± 25 μm), surface morphology (porous) entrapment efficiency (87.72 ± 7.31%), buoyancy (86.32 ± 2.3%), mucoadhesiveness (88 ± 4.3%), swelling index (80.37 ± 4.65). X-ray diffraction (XRD) and differential scanning calorimetry (DSC) of CXGMP suggested CAP had been rendered amorphous, a property which unconventionally slows its dissolution. Significant control was offered by CXGMP compared to crystalline CAP in terms of drug release. Pharmacokinetic studies in Wistar rat further revealed that CXGMP increased the MRT (three times), elimination half-life (roughly 4 fold) and AUC (1.44 folds) of CAP at a dose of 5 mg/kg in comparison to CAP solution of same strength. Conclusively the employment of TRGDDS had extended the duration for which CAP stayed in the rodent model, providing evidence for potentially obtaining a more efficacious dosing regimen in actual disease models.
Keywords: Colorectal cancer; Gastroretentive drug delivery system; Capecitabine; Mucoadhesion; Texture profile analysis;

Display OmittedThe aging population and the growing multimorbidity of the major patient population as well as the advanced (pharmaco)therapeutic treatment options are increasing the complexity of independent drug therapy management and administration. The increased complexity may have an impact on drug adherence (including any need for patients initiated coping strategies), and consequently on the safety and efficacy of the medicine. To overcome adherence issues caused by the design of the medicine, it is crucial that developers consider the age appropriateness of the medicine (route of administration, dosage form, excipients in the composition, frequency of dosing) in meeting patients’ needs to manage their therapy without the support of a care giver. In order to understand the scientific evidence on such age appropriately designed medicines for use by older adults, a literature search was performed in the Medline database (all languages included). The search produced 34 publications that met the inclusion and exclusion criteria for the patient population of 65 years an older. An in-depth analysis of the included publications with respect to the methodological quality (study design, data collection, endpoints chosen) and results showed that none of these publications had adequately investigated the age appropriateness of the medicine for use by older adults. The authors consider that the knowledge gap in this area requires attention of all stakeholders in the healthcare community.
Keywords: Formulation appropriateness; Patient centric drug delivery; Older adults; Scientific evidence; Drug administration;