International Journal of Pharmaceutics (v.439, #1-2)

Surfactant choice and the physical stability of nanosuspensions as a function of pH by Maria D. Donoso; Roy J. Haskell; Richard R. Schartman (1-7).
Nanosuspensions of the example compounds ketoconazole and itraconazole were shown to aggregate upon reducing the pH to levels comparable to that known to exist in the stomach. Manipulation of the surfactant/polymer ratio in the suspension vehicle did not elucidate the cause of the aggregation. X-ray diffraction on ketoconazole solids failed to identify a form change as causative. Ultimately, ketoconazole intrinsic dissolution rate experiments implicated surface salt formation between ketoconazole and the vehicle surfactant as the cause of the aggregation. The generality of the phenomenon is discussed.
Keywords: Nanoparticle; Suspension; Aggregation; Salt; Amorphous; Surfactant;

The current work examines the role of Fcγ-receptors on the elimination and tissue distribution of 8C2, a model murine IgG1 monoclonal antibody. The plasma pharmacokinetics of 125Iodine-labeled 8C2 were investigated in C57BL/6 control mice, FcγRI/RIII knockout mice, and FcγRIIb knockout mice, following intravenous doses of 0.04, 0.1 and 0.4 mg/kg. Plasma samples were collected and radioactivity was counted. Concentration data were analyzed with a population pharmacokinetic model. Additionally, the tissue disposition of 8C2 was investigated using whole body autoradioluminography (WBAL) and via counting excised tissues. Areas under the plasma concentration vs. time curves AUC0–10 days  ± SD (nM × days) were: 12.3 ± 0.3, 12.5 ± 1.3 and 15.1 ± 1.2 at 0.04 mg/kg; 39.3 ± 2.0, 28.9 ± 2.7 and 42.0 ± 9.4 at 0.1 mg/kg; and 225 ± 19, 158 ± 19 and 204 ± 26 at 0.4 mg/kg in C57BL/6, FcγRI/RIII(−/−) and FcγRIIb(−/−) mice. Strain was not a statistically significant predictor for any of the parameters of the population model. 8C2 plasma clearance, distribution clearance, and central compartment volume were 0.00543 L/days/kg, 0.0598 L/days/kg, and 0.057 L/kg. No substantial differences in 8C2 tissue uptake were identified by analysis of excised tissues or by WBAL. In conclusion, FcγR knockout is associated with only minor effects on the plasma and tissue disposition of 8C2, a model murine IgG1 mAb.
Keywords: Antibody; IgG; Fcγ-receptors; Pharmacokinetics; Tissue disposition; Whole body autoradiography;

Drug release modification by interpolymer interaction between countercharged types of Eudragit® RL 30D and FS 30D in double-layer films by Rouslan I. Moustafine; Andrey V. Bodrov; Vera A. Kemenova; Patrick Rombaut; Guy Van den Mooter (17-21).
Interpolymer interactions between the countercharged methacrylate copolymers Eudragit® RL 30D (polycation) and Eudragit® FS 30D (polyanion), were investigated in conditions mimicking the gastrointestinal environment. The formation of inter-macromolecular ionic bonds between Eudragit® RL 30D and Eudragit® FS 30D was investigated using FT-IR spectroscopy and modulated DSC. The FT-IR spectra of the tested polymeric matrices are characterized by visible changes in the observed IR region indicating the interaction between chains of two oppositely charged copolymers. A new band at 1570 cm−1 appeared which was assigned to the absorption of the carboxylate groups that form the ionic bonds with the quaternary ammonium groups. Moreover, while increasing the pH values from pH 5.8 to 7.4, a decrease of the intensity of the band at 960 cm−1 (quaternary ammonium group vibration) was observed. All binary mixtures were characterized by the presence of only one and narrow Tg, pointing to sample homogeneity, because of the compatibility of components. As a result of electrostatic interaction between the copolymer chains during swelling, the resulting Tg is decreased significantly and was dependent on the quantity of copolymers present in the structure of polycomplexes formed. Overall, the interaction between countercharged copolymers during passage in gastrointestinal tract can strongly modify the release profile of the model drug diclofenac sodium.
Keywords: Interpolyelectrolyte complexes; Eudragit® RL 30D; Eudragit® FS 30D; FT-IR; Glass transition; Diclofenac sodium;

Formation of a physical stable delivery system by simply autoclaving nanostructured lipid carriers (NLC) by Jana Pardeike; Sabrina Weber; Nadejda Matsko; Andreas Zimmer (22-27).
A unique long term stable carrier system for poorly soluble drugs was obtained by simply autoclaving nanostructured lipid carriers (NLC). NLC composed of Precirol ATO, oleic acid, glycerol 85%, Eumulgin SML 20 and water as well as NLC loaded with the poorly soluble drug Itraconazole formed a special organized matrix containing lamellar bilayers similar to biological membranes after the sterilization process. The tendency to expel the poorly soluble drug from the matrix was thereby avoided.
Keywords: Autoclaving; Cryo-TEM; Lamellar bilayer; Nanostructured lipid carriers; Poorly solubles;

Long-term investigation on the phase stability, magnetic behavior, toxicity, and MRI characteristics of superparamagnetic Fe/Fe-oxide core/shell nanoparticles by Afshin Masoudi; Hamid Reza Madaah Hosseini; Seyed Morteza Seyed Reyhani; Mohammad Ali Shokrgozar; Mohammad Ali Oghabian; Reza Ahmadi (28-40).
To efficiently enhance the contrast obtaining from magnetic resonance imaging (MRI), pharmaceutical grade colloidal dispersions of PEG coated iron-based nanoparticles were prepared and compared to conventional pure iron oxide contrast agent. In this study, we synthesized ∼14 nm iron nanoparticles via NaBH4 reduction of iron(III) chloride in an aqueous medium. The resulting nanoparticles were further oxidized by two different methods via (CH3)3NO oxygen transferring agent and exposure to oxygen flow. XRD and electron microscopy analyses confirmed the formation of a second layer on the surface of α-Fe core. As magnetic measurements and Mössbauer spectra of 4-months post prepared nanoparticles showed, 2.3 ± 0.5 nm amorphous oxide shell produced in oxygen flow could not protect the inner metallic iron from oxidation and resulting sample suffered from drastic change in its characteristics. However, (CH3)3NO yielded nanoparticles with 3.6 ± 0.4 and 4.5 ± 0.7 nm crystalline oxide shells that retained their key properties even in long-term examinations. In addition, no significant difference was detected in cytotoxicity results of MTT assay test up to 4-months for core/shell nanoparticles, in comparison with pure iron oxide sample, and all fall below 50% viability in the iron concentration of 400 μg. In vitro MR signal reduction and corresponding relaxometry parameters, especially r 2/r 1  > 2, assure that all nanoparticles can be administrated for negative contrast enhancement. Accumulation of core/shell nanoparticles in axillary and brachial lymph nodes of examined rats and minimum contrast enhancement of 20% regarding to pure iron oxide implies the efficiency of these materials as potential contrast agent.
Keywords: Iron/iron oxide core/shell; Chemical stability; Magnetic behavior; MRI contrast enhancement; Cytotoxicity;

NMR techniques in drug delivery: Application to zein protein complexes by F.F.O. Sousa; Asteria Luzardo-Álvarez; José Blanco-Méndez; Manuel Martín-Pastor (41-48).
Zein is a protein containing a large amount of nonpolar amino acids, which has shown the ability to form aggregates and entrap solutes, such as drugs and amino acids. NMR techniques were used to detect binding interactions and measure affinity between zein and three different drugs: tetracycline, amoxicillin and indomethacin. The release study of zein microparticle formulations containing any of these drugs was confronted with the affinity results, showing a remarkable correlation. The feasible methodology employed, focused in the functionality of the protein–drug interaction, can be very promising for the rational design of appropriate drug vehicles for drug delivery.
Keywords: Saturation transfer difference; Drug delivery; Zein; NMR; Biomaterials;

Brain delivery of camptothecin by means of solid lipid nanoparticles: Formulation design, in vitro and in vivo studies by Susana Martins; Ingunn Tho; Isolde Reimold; Gert Fricker; Eliana Souto; Domingos Ferreira; Martin Brandl (49-62).
For the purpose of brain delivery upon intravenous injection, formulations of camptothecin-loaded solid lipid nanoparticles (SLN), prepared by hot high pressure homogenisation, were designed. Incorporation of camptothecin in the hydrophobic and acidic environment of SLN matrix was chosen to stabilise the lactone ring, which is essential for its antitumour activity, and for avoiding premature loss of drug on the way to target camptothecin to the brain.A multivariate approach was used to assess the influence of the qualitative and quantitative composition on the physicochemical properties of camptothecin-loaded SLN in comparison to plain SLN. Mean particle sizes of ≤200 nm, homogenous size distributions and high encapsulation efficiencies (>90%) were achieved for the most suitable formulations. In vitro release studies in plasma, showed a prolonged release profile of camptothecin from SLN, confirming the physical stability of the particles under physiological pH. A higher affinity of the SLN to the porcine brain capillary endothelial cells (BCEC) was shown in comparison to macrophages. MTT studies in BCEC revealed a moderate decrease in the cell viability of camptothecin, when incorporated in SLN compared to free camptothecin in solution. In vivo studies in rats showed that fluorescently labelled SLN were detected in the brain after i.v. administration. This study indicates that the camptothecin-loaded SLN are a promising drug brain delivery system worth to explore further for brain tumour therapy.
Keywords: Solid lipid nanoparticles (SLN); Camptothecin; Multivariate analysis; Surfactants; Brain capillary endothelial cells (BCEC); Brain delivery;

Fast dissolving eutectic compositions of curcumin by N. Rajesh Goud; Kuthuru Suresh; Palash Sanphui; Ashwini Nangia (63-72).
The bioactive herbal ingredient curcumin was screened with pharmaceutically acceptable coformers to discover solid-state forms of high solubility. Mechano-chemical grinding of curcumin with cocrystal formers in a fixed stoichiometry ratio resulted in binary eutectic compositions of curcumin–coformer with nicotinamide (1:2), ferulic acid (1:1), hydroquinone (1:1), p-hydroxybenzoic acid (1:1), and l-tartaric acid (1:1). The eutectic nature of the product crystalline solids was established by differential scanning calorimetry, and the absence of hydrogen-bonded crystalline phases such as cocrystals/salts was ascertained by powder X-ray diffraction, IR-Raman, and solid-state NMR spectroscopy. The best case of CUR–NAM eutectic exhibits 10-fold faster IDR and 6-times higher AUC compared to crystalline curcumin.
Keywords: Dissolution; Eutectic; Nicotinamide; Solubility; Thermal analysis;

Preparation and evaluation of nanoparticles for directed tissue engineering by Annasara Hansson; Tiziana Di Francesco; Françoise Falson; Patricia Rousselle; Olivier Jordan; Gerrit Borchard (73-80).
Herein we describe the preparation of a nanoparticulate system formed from an RGD-functionalized chitosan derivative by complexation with chondroitin sulfate. These bioactive complexes were developed to promote wound healing by inducing adhesion and subsequently migration of skin cells. The particles were characterized for their size, surface charge, stability and shape. Briefly, the nanoparticles were found to be stable up to 7 days in water at a diameter of 150–200 nm and a positive charge of 20 mV. In physiological media the particles swell significantly but remain intact. Tested in an in vitro cell model of human dermal fibroblasts, the particles were shown to promote cell adhesion and induce spreading in human dermal fibroblasts. The mean surface area per cell was found to be increased by three-fold (n  = 3 assays, p  < 0.01), for the cells plated on particles exposing RGD-peptides when compared to cells on control particles. This indicates a stimulation of the cells due to the exposure of the bioactive RGD-moieties and an enhanced cell–biomaterial interaction. Using nanoparticles is a novel approach to direct cellular behavior with numerous possible applications in tissue engineering such as substrate for dermal and epithelial cells, injectable suspensions or as building blocks to form scaffolds.
Keywords: Cell adhesion; Chitosan derivative; Human dermal fibroblast; Nanoparticle; RGD peptide; Wound healing;

Successfully tailoring the pore size of mesoporous silica nanoparticles: Exploitation of delivery systems for poorly water-soluble drugs by Lejiao Jia; Jingyi Shen; Zhenyu Li; Dianrui Zhang; Qiang Zhang; Cunxian Duan; Guangpu Liu; Dandan Zheng; Yue Liu; Xiaona Tian (81-91).
A novel approach was applied to fabricate mesoporous silica nanoparticles (MSNs) with different pore size in this study. The pore size of MSNs can be modulated conveniently from 3 nm to 10 nm by controlling the etching time of MSNs with the NaBH4 solution. The as-synthesized MSNs were investigated as carriers for loading and delivery of the model drug paclitaxel (PTX). The characteristics, drug loading capacity, in vitro drug release behavior, anti-tumor activity and the mechanism of cell uptake were systematically studies. The resultant MSNs showed uniform and mono-dispersed sphere with high drug loading capacity (12–21%). The in vitro drug release exhibited that the released rate of PTX from MSNs could be controlled by the pore size and the larger the pore size, the faster the release rate of PTX. The in vitro anti-tumor studies demonstrated that PTX-loaded MSNs produced higher cytotoxicity than free PTX. Besides, the PTX-loaded MSNs with largest pore size showed the highest anti-tumor activity. These results indicated that these MSNs could provide a promising platform for delivering water-insoluble drugs, controlling the release rate of drugs and increasing the anti-tumor activity.
Keywords: Mesoporous silica nanoparticles; Pore sizes; Paclitaxel; Poor water solubility; In vitro anti-tumor;

Poor water solubility of drugs can complicate their commercialisation because of reduced drug oral bioavailability. Formulation strategies such as increasing the drug surface area are frequently employed in an attempt to increase dissolution rate and hence, improve oral bioavailability. Maximising the drug surface area exposed to the dissolution medium can be achieved by loading drug onto a high surface area carrier like mesoporous silica (SBA-15). The aim of this work was to investigate the impact of altering supercritical carbon dioxide (SC-CO2) processing conditions, in an attempt to enhance drug loading onto SBA-15 and increase the drug's dissolution rate. Other formulation variables such as the mass ratio of drug to SBA-15 and the procedure for combining the drug and SBA-15 were also investigated. A model drug with poor water solubility, fenofibrate, was selected for this study. High drug loading efficiencies were obtained using SC-CO2, which were influenced by the processing conditions employed. Fenofibrate release rate was enhanced greatly after loading onto mesoporous silica. The results highlighted the potential of this SC-CO2 drug loading approach to improve the oral bioavailability of poorly water soluble drugs.
Keywords: Supercritical carbon dioxide; Mesoporous silica; Dissolution enhancement; Fenofibrate; Drug-loading; Poorly-water soluble; SBA-15;

A systematic study of captopril-loaded polyester fiber mats prepared by electrospinning by Hua Zhang; Shaofeng Lou; Gareth R. Williams; Christopher Branford-White; Huali Nie; Jing Quan; Li-Min Zhu (100-108).
In this study, drug-loaded nanofibers were prepared by electrospinning captopril (CPL) with aliphatic biodegradable polyesters. Poly(l-lactic acid) (PLLA), poly(lactic-co-glycolic acid) (PLGA), and poly(lactic-co-ɛ-caprolactone) (PLCL) were used as filament-forming matrix polymers, and the concentration of CPL in each fiber type was varied. Scanning electron microscopy indicated that the morphology and diameters of the fibers were influenced by the concentration of polymer in the spinning solution and the drug loading. CPL was found to be distributed in the polymer fibers in an amorphous manner using differential scanning calorimetry and X-ray diffraction. FTIR indicated that hydrogen bonding existed between the drug molecules and the carrier polymers. In vitro dissolution tests showed that drug release from the fibers was highly dependent on the release medium, temperature, and on the polymer used. A range of kinetic models were fitted to the drug-release data obtained, and indicated that release was diffusion controlled in all cases. The different polymer fibers have application in diverse areas of drug delivery, for instance as sub-lingual or sustained release systems. Furthermore, by combining different CPL-loaded fibers, it would be possible to produce a bespoke formulation with tailored drug-release properties.
Keywords: Aliphatic biodegradable polyesters; Electrospinning; in vitro drug release;

Acoustic emission (AE) which has been successfully applied for monitoring a rather wide variety of solids elaboration processes was almost never evaluated in the field of industrial pharmaceutical crystallization. Few papers reported that solution crystallization processes give rise to acoustic emission signals that could be related to the development of the basic crystallization phenomena. This study is intended to demonstrate new perspectives opened up by the possible use of acoustic emission (AE) as a non-intrusive and non destructive sensor for monitoring solution crystallization with a particular focus being put on the presence of impurities in real industrial processes. The wealth of acquired AE information is highlighted and it is suggested that such information could allow the design of innovative multipurpose sensing strategies. It is shown notably that AE provides a very early detection of nucleation events, much before the onset of the so-called “nucleation burst”. It is also shown that AE brings new insight into the effect of impurities on both the development of the crystallization process and the quality of the crystallized product.
Keywords: Acoustic emission; Crystallization; In situ sensors; Impurities; Nucleation; Monitoring;

Development and evaluation of diclofenac sodium thermorevesible subcutaneous drug delivery system by Fazli Nasir; Zafar Iqbal; Jamshaid A. Khan; Abad Khan; Fazli Khuda; Lateef Ahmad; Amirzada Khan; Abbas Khan; Abdullah Dayoo; Roohullah (120-126).
Plasma concentration (μg/ml) of diclofenac sodium at various time intervals after subcutaneous injection of commercial diclofenac sodium injection and DS in situ gels.The objective of current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for diclofenac sodium. The poloxamer 407, methyl cellulose, hydroxypropyl methyl cellulose and polyethylene glycol were used alone and in combination in different ratios to design the delivery system. The physical properties like Tsol–gel, viscosity, clarity of solution and gel were evaluated. The in vitro release of the drug delivery system was evaluated using membrane less method and the drug release kinetics and mechanism was predicted by applying various mathematical models to the in vitro dissolution data. Rabbits were used as in vivo model following subcutaneous injection to predict various pharmacokinetics parameters by applying Pk-Summit software. The in vitro and in vivo data revealed that the system consisting of the poloxamer 407 in concentration of 20% (DP20) was the most capable formulation for extending the drug release and maintaining therapeutic blood level of DS for longer duration (144 h). The data obtained for drug content after autoclaving the solutions indicate that autoclaving results in 6% degradation of DS. The data also suggested that the studied polymers poloxamer, MC and PG are good candidate to extend the drug release possessing a unique thermoreversible property.
Keywords: Thermoreversible in situ gels; Pluronics; Methyl cellulose; Diclofenac sodium; Subcutaneous;

Lyophilisomes as a new generation of drug delivery capsules by Etienne van Bracht; René Raavé; Wouter P.R. Verdurmen; Ronnie G. Wismans; Paul J. Geutjes; Roland E. Brock; Egbert Oosterwijk; Toin H. van Kuppevelt; Willeke F. Daamen (127-135).
Nanoparticulate drug delivery systems are currently explored to overcome critical challenges associated with classical administration forms. In this study, we present a drug delivery system based on a novel class of proteinaceous biodegradable nano/micro capsules, lyophilisomes. Lyophilisomes can be prepared from biomolecules without the need for amphiphilicity. Albumin-based lyophilisomes were prepared by freezing, annealing and lyophilizing, resulting in capsules ranging from 100 to 3000 nm. Lyophilisomes were loaded with the anti-tumor drugs doxorubicin and curcumin using different concentrations and time/temperature regimes. Incubation in 0.1 mg/ml doxorubicin or 1.0 mg/ml curcumin resulted in an entrapment efficiency of 95 ± 1% and 4 ± 1%, respectively. This corresponds to a drug loading of 0.24 mg doxorubicin per milligram albumin and 0.10 mg curcumin per milligram albumin. Drug release profiles from doxorubicin and curcumin-loaded lyophilisomes were studied in culture medium and showed slow release for doxorubicin (2.7% after 72 h), and rapid release for curcumin (55% after 72 h). When applied to cells, non-loaded lyophilisomes did not influence cell viability, even at high concentrations (1 mg/ml). Lyophilisomes were internalized by cells. When loaded with doxorubicin and curcumin, lyophilisomes strongly reduced cell proliferation and viability of SKOV-3 and HeLa cells, respectively, to a level similar or better compared to an equal amount of free drugs. In conclusion, albumin lyophilisomes show potential as (nano)carriers of drugs for tumor cell elimination.
Keywords: Albumin; Cancer; Curcumin; Doxorubicin; Drug delivery; Nano/micro particles;

Development and in vitro characterization of insulin loaded whey protein and alginate microparticles by Emmanuelle Déat-Lainé; Valérie Hoffart; Jean-Michel Cardot; Muriel Subirade; Eric Beyssac (136-144).
Insulin was encapsulated into microparticles (MP) made of denaturized whey proteins (WP) and alginate (ALG) using an extrusion/cold gelation process with calcium ions. High encapsulation efficiency of 85% was obtained. Influence of insulin on polymeric viscosity and on microparticle behavior was evaluated. Insulin seemed to interact with WP chains by non covalent binding and steric hindrance. This influence was balanced by ALG addition. Nevertheless, insulin was released rapidly by diffusion at both acidic and intestinal dissolution media. Despite this fast in vitro release, WP/ALG MP showed an important enzymatic inhibition effect on trypsin and alpha-chymotrypsin. Thus, WP/ALG MP contributed to an effective insulin protection towards enzymatic degradation. The aforementioned results suggested that WP based microparticles are a promising carrier for improving oral delivery of insulin.
Keywords: Whey protein; Alginate; Insulin; Microparticle; Oral administration;

Hot-melt extrusion was applied to improve the solubility of the poorly water-soluble drug oxeglitazar. Various polymers and their blends were used as carriers: copovidone (COP), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol copolymer (PVCL–PVAc–PEG) and hypromellose 2910/5 (HPMC). After extrusion, the extrudate was pelletized. The physical state of the drug was assessed using X-ray diffraction and differential scanning calorimetry. The dissolution performance of the extrudates was compared to the physical mixture and pure oxeglitazar. The stability under long-term storage conditions (25 °C/60%rH) was investigated.The solubility of oxeglitazar was improved with all hot-melt extruded formulations: 26–66% of the drug was dissolved and a 1.9–5.0-fold supersaturation was reached with the pelletized extrudates. All extrudates which were assessed for their storage stability showed sufficient product stability. A super-additive effect of COP and HPMC as a polymeric blend was successfully demonstrated as a higher supersaturation and longer time of supersaturation were shown for the ternary blend. Through variations of the ratio COP:HPMC, it was shown that the shape of the dissolution curve is dominated by the polymer with the higher amount in the polymeric blend. If PVCL–PVAc–PEG is applied as single or additional carrier, the initial release rate is drastically reduced.
Keywords: Solid dispersion; Hot-melt extrusion; Dissolution; Oral drug delivery; Solubility; Polymeric drug carrier; Oxeglitazar;

There is a requirement to deliver accurate amounts of broad spectrum antimicrobial compounds locally to exuding wounds. Varying amounts of exudate complicates this process by limiting the residence and therefore efficacy of active substances. Minimum bactericidal concentrations (MBC) of antimicrobials are necessary to suppress infection and lessen the chances of resistant strains of potentially pathogenic bacteria from prevailing. Polysaccharide wafers can adhere to exudating wound beds, absorbing fluids and forming highly viscous gels that remain in situ for prolonged periods of time to release sustained amounts of antimicrobial. In this study, five different formulations were produced containing the antimicrobial, chlorhexidine digluconate (CHD). Absorption of simulated wound fluid, resultant rheological properties of gels and efficacy against plated cultures of Pseudomonas aeruginosa were measured and compared. CHD reduced the ‘water uptake’ of wafers by 11–50% (w/w) and decreased the rheological consistency of non-SA containing gels by 10–65%. Release studies indicated that karaya wafers gave the highest sustained release of CHD, >60 μg/mL in 24 h, well in excess of the MBC for P. aeruginosa. Release kinetics indicated an anomalous diffusion mechanism according to Korsmeyer–Peppas, with diffusion exponents varying from 0.31 to 0.41 for most wafers except xanthan (0.65).
Keywords: Antimicrobial wafers; Chlorhexidine digluconate; Rheology; Disc diffusion; Diffusion cell; Pseudomonas aeruginosa;

In vitro simulation of drug intestinal absorption by Gaetano Lamberti; Sara Cascone; Margherita Iannaccone; Giuseppe Titomanlio (165-168).
In this work, a simple set-up was designed, realized and tested to evaluate the effect of intestinal absorption on the in vitro drug release studies. The conventional USP-approved dissolution apparatus 2 was equipped with an hollow fibers filter, along with the necessary tubing and pumps, to simulate the two-fluids real behavior (the gastro intestinal lumen and the gastro intestinal circulatory system). The realized set-up was characterized in term of mass exchange characteristic, using the theophylline as the model drug, also with the aid of a simple mathematical model; then the release kinetics of a controlled release tablet was evaluated in the conventional test as well as in the novel simulator. The concentration of drug in the release compartment (which simulates the gastric lumen) was found lower in the novel simulator than in the traditional one.
Keywords: Theophylline; Intestinal absorption; Oral administration; Mass balance; Controlled drug release;

Response to Comment on Blasi et al. (2011) “Lipid nanoparticles for brain targeting I. Formulation optimization” by Paolo Blasi; Stefano Giovagnoli; Aurélie Schoubben; Maurizio Ricci (171-174).

Silk sericin has been recently reported for its advantageous biological properties to promote wound healing. In this study, we established that the ethyl alcohol (EtOH) could be used to precipitate sericin and form the stable sericin/polyvinyl alcohol (PVA) scaffolds without the crosslinking. The sericin/PVA scaffolds were fabricated via freeze-drying and subsequently precipitating in various concentrations of EtOH. The EtOH-precipitated sericin/PVA scaffolds showed denser structure, higher compressive modulus, but lower water swelling ability than the non-precipitated scaffolds. Sericin could be released from the EtOH-precipitated sericin/PVA scaffolds in a sustained manner. After cultured with L929 mouse fibroblasts, the 70 vol% EtOH-precipitated sericin/PVA scaffolds showed the highest potential to promote cell proliferation. After applied to the full-thickness wounds of rats, the 70 vol% EtOH-precipitated sericin/PVA scaffolds showed significantly higher percentage of wound size reduction and higher extent of type III collagen formation and epithelialization, compared with the control scaffolds without sericin. The accelerated wound healing by the 70 vol% EtOH-precipitated sericin/PVA scaffolds was possibly due to (1) the bioactivity of sericin itself to promote wound healing, (2) the sustained release of precipitated sericin from the scaffolds, and (3) the activation and recruitment of wound healing-macrophages by sericin to the wounds. This finding suggested that the EtOH-precipitated sericin/PVA scaffolds were more effective for the wound healing, comparing with the EtOH-precipitated PVA scaffolds without sericin.
Keywords: Sericin; Ethyl alcohol; Precipitation; Scaffold; Wound healing; Epithelialization;

Adjuvants to prolong the local anesthetic effects of coated microneedle products by Ying Zhang; Kris Siebenaler; Ken Brown; Daniel Dohmeier; Kris Hansen (187-192).
Clonidine prolongs the local residence of lidocaine delivered via sMTS (a coated microneedle system)The objective of this study was to identify an adjuvant for anesthetics coated on microneedles to provide rapid onset and prolonged analgesic action with minimal skin tissue reaction. Aqueous lidocaine or prilocaine formulations with or without clonidine or the related analogs, guanfacine and apraclonidine, were dip-coated onto polymeric microneedles. The amount of lidocaine or prilocaine coated onto the microneedles was assessed by high performance liquid chromatography (HPLC). Delivery efficiency and dermal pharmacokinetics associated with lidocaine or prilocaine delivered via the microneedles were characterized in vivo using domestic swine. Skin punch biopsies were collected and analyzed to determine the anesthetic concentrations in the skin using HPLC–mass spectrometry (LC–MS). Addition of clonidine to the formulations decreased the systemic absorption rate of the anesthetics from the patch application site without impacting the coating performance or the rapid onset of anesthesia. Formulations with 0.3 wt.% clonidine, identified as the optimal dose for lidocaine-delivery via microneedles, maintained the lidocaine skin concentration above the estimated therapeutic level (100 ng/mg) for 1 h without causing any skin irritation or color change. The other two clonidine analogs, guanfacine and apraclonidine, also led to delayed systemic absorption of lidocaine from the skin, indicating utility in providing prolonged analgesia.
Keywords: Microneedles, Transdermal drug delivery, Pharmacokinetics, Clonidine, Lidocaine, Prilocaine;

Although polymers and surfactants are commonly used as stabilizers to impart physical stability to the suspensions produced by wet stirred media milling of poorly water-soluble drugs, scant information is available in pharmaceutical literature regarding their impact on the breakage kinetics. We present a combined microhydrodynamics–polymer adsorption analysis to elucidate the roles of stabilizers with a focus on the kinetics. Griseofulvin (GF), a model poorly water-soluble drug, was milled at various concentrations of hydroxypropyl cellulose (HPC) in the presence–absence of sodium dodecyl sulfate (SDS). Particle sizing, scanning electron microscopy, thermal analysis, and rheometry were used to determine the breakage kinetics, adsorption isotherm, and apparent viscosity, which were then used to analyze the aggregation state of the milled suspensions and the microhydrodynamics. In the absence of SDS, an increase in HPC concentration slowed the particle aggregation leading to faster apparent breakage. On the other hand, due to a synergistic stabilizing action of HPC with SDS, lower HPC concentration was needed to stabilize the suspensions, and an optimum HPC concentration for the fastest apparent breakage was identified. The microhydrodynamic analysis quantified, for the first time, the viscous dampening effect of polymers, while only the combined analysis could explain the observed optimum.
Keywords: Drug nanoparticles; Wet stirred media milling; Breakage kinetics; Adsorption; Rheology; Microhydrodynamics;

Insights into the multi-equilibrium, superstructure system based on β-cyclodextrin and a highly water soluble guest by Elgte Elmin B. De Paula; Frederico B. De Sousa; Júlio César C. Da Silva; Flaviana R. Fernandes; Maria Norma Melo; Frédéric Frézard; Richard M. Grazul; Rubén D. Sinisterra; Flávia C. Machado (207-215).
Pentamidine isethionate (PNT) is an antiprotozoal active in many cases of leishmaniasis, despite the present limitations including high toxicity and parenteral administration. In the present work, a PNT encapsulation strategy into β-cyclodextrin cavity at 1:1 and 2:1 (βCD:PNT) molar ratios was used in order to improve the drug's physical and chemical properties. Combining thermodynamic and structural approaches such as isothermal titration calorimetry (ITC), electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance (1H NMR, and ROESY) the inclusion process and the thermodynamics parameters were identified. ITC and ESI-MS experimental data suggest the simultaneous formation of different supramolecular complexes in solution. Moreover, NMR data are in accordance with these results, suggesting a deep inclusion of PNT into the βCD cavity, through correlations observed in 2D ROESY contour maps. The systems were also characterized by FTIR, TG/DTA and SEM. These techniques indicate the formation of inclusion complex in the solid state. In vivo PNT activity was evaluated orally in mice. The inclusion complex showed a significant reduction of parasite load compared to free PNT.
Keywords: Supramolecular complex; β-cyclodextrin; Pentamidine; Multi-equilibrium; Leishmaniasis; In vivo experiments;

A diverse range of diseases involving the reproductive system are treated with luteinizing hormone-releasing hormone (LHRH) agonists which must be administered daily. Currently, an efficient oral delivery system is not available. Here, we show the facile inclusion of lipoamino acids into the peptide sequence of LHRH, rendering it more stable towards enzymatic degradation, as well as enhancing permeability across Caco-2 cell monolayers. Selected LHRH derivatives were tested in vivo by daily oral administration to rats. The size and weight of the sex organs remained unchanged and the levels of LH were stable over the course of the experiment. However, some of the lipidic peptides (3, 8 and 9) were able to reduce serum levels of follicle-stimulating hormone (FSH), an important finding towards the development of orally available LHRH agonists.
Keywords: Luteinizing hormone-releasing hormone; Agonist; Oral peptide delivery; Lipoamino acid;

The aim of the present work was to evaluate drug release and quality of EVA/drug matrices at different PEO 7 M concentrations (5 and 15%), manufactured using two different hot-melt extruders: a lab-scale mini extruder and a pilot-scale extruder. The process parameters used on both extruders (temperature and screw speed) and drug release from the matrices were compared. On the lab-scale extruder all formulations were extruded at 90 °C, whereas on the pilot-scale extruder the temperature of the die was adjusted to 100 °C in order to achieve a constant pressure at the extrusion die, hence constant material flow through the die to yield smooth extrudates. Screw speed was also adjusted from 60 rpm (lab-scale extruder) to 90 rpm (pilot-scale extruder) in order to obtain a balance between feeding rate and screw speed. Drug release from the obtained matrices on both extruders was also assessed. Despite the differences in diameter (diameter of 2 and 3 mm for the lab-scale extruder and pilot-scale extruder, respectively), temperature and screw speed, drug release per surface area was similar. DSC analysis of a formulation [EVA40/MPT (50/50, w/w) with 5% PEO] indicated small changes in its solid state after extrusion on both extruders: drug crystallinity was reduced by max. 20%, PEO recrystallized after cooling and EVA remained semi-crystalline. Extrusion experiments on the pilot-scale extruder of EVA/MPT, 50/50 (w/w) formulations were also monitored in-line using Raman and NIR spectroscopy in order to evaluate the material behavior at a molecular level in the extrusion barrel as function of the process settings (extrusion temperature: 90, 110 and 140 °C; screw speed: 90 and 110 rpm). At 90 and 110 °C the crystallinity of the drug was reduced, but the majority of MPT remained in its crystalline state as specific peaks in the Raman spectra of the drug became broader. These differences were accentuated when extrusion was performed at 140 °C as the drug completely melted. Peak shifts to lower frequencies [(C―O) groups of the drug and (CH3COO) groups of EVA] were registered at all extrusion temperatures, with maximum effect at 140 °C indicating molecular interactions. Increasing the screw speed did not result in peak shifts of Raman spectra. NIR confirmed these observations and showed an additional peak in the spectra characteristic of (OH) bounds.
Keywords: Hot-melt extrusion; Ethylene vinyl acetate; Sustained-release; Raman spectroscopy; NIR;

Micro-computed tomography imaging of composite nanoparticle distribution in the lung by Moritz Beck-Broichsitter; Julia Gauss; Christoph Schweiger; Susanne Roesler; Thomas Schmehl; Marian Kampschulte; Alexander C. Langheinrich; Werner Seeger (230-233).
Nanomedicine comprises a significant potential to approach the therapy of severe diseases. Knowledge of nanoparticle behavior at the target site would contribute to the development of specialized tools for respiratory medicine. Here, we were interested in the potential of micro-computed tomography (μCT) imaging to monitor the pulmonary distribution of polymeric nanoparticles.Composite nanoparticles were analyzed for physicochemical properties, morphology and composition. μCT was employed to visualize the pulmonary distribution of composite nanoparticles in an ex vivo lung model.Employed composite nanoparticles were composed of poly(styrene) cores coated by a thin shell of colloidal iron oxide. Particles were mainly located in the interstitial space and associated with pulmonary cells, as observed by light microscopy. μCT detected enhanced X-ray opacities in the conducting (linear pattern) and respiratory airways (aciniform X-ray attenuations).In conclusion, multifunctional nanoparticles will prompt the development of novel therapeutic and diagnostic tools in respiratory medicine.
Keywords: Micro-computed tomography imaging; “Theranostic” nanoparticles; Aerosol; Lung; Targeting;

Immobilization of antifungal drugs to solid particles has been addressed in order to limit the skin penetration to the skin surface during topical administration. Antifungal drug griseofulvin has been immobilized at the surface of silica particles by formation of its inclusion complex with β-cyclodextrins grafted to silica. A simple and fast process for loading griseofulvin into the hydrophobic cavity of cyclodextrins at the surface of the solid particles in aqueous suspension has been designed. It allowed the formation of the griseofulvin:cyclodextrin inclusion complex of 1:1 stoichiometry to completion. Grafting β-cyclodextrins to silica surface has been performed in a two-step procedure. The coupling agent 3-amino-propylmethyldiethoxysilane was reacted onto fumed silica particles as a first step. The second step was the reaction of grafted primary amino groups with tosylated β-cyclodextrin that led to β-cyclodextrin grafted silica. Loading griseofulvin onto grafted silica particles have been investigated by IR spectroscopy and by tracking possible crystals of griseofulvin in aqueous suspension by optical and scanning electron microscopy and X-ray diffraction. Successful formation of the inclusion complex at the surface of grafted silica suggested a strong adsorption of griseofulvin by means of heterogeneous nucleation of crystals, followed by inclusion complexation taking place between the partners being in close proximity at the surface of silica particles. The high adsorption capacity of CD-grafted silica for griseofulvin compared to bare silica and amino-grafted silica supports this interpretation.
Keywords: Silica; β-cyclodextrin; Griseofulvin; Inclusion complexes;

Modification of concomitant drug release from oil vehicles using drug–prodrug combinations to achieve sustained balanced analgesia after joint installation by Mette Thing; Sabrine Smedegaard Jensen; Claus Larsen; Jesper Østergaard; Susan Weng Larsen (246-253).
Intra-articular injection of two drugs in a sustained drug delivery system combining the use of lipophilic solution with the prodrug approach may provide efficient and prolonged postoperative pain treatment after arthroscopic procedures. In the present study, the concomitant release of N,N-diethyl glycolamide ester of naproxen and ropivacaine from an oil vehicle consisting of medium-chain triglycerides were investigated in vitro. The release into both phosphate buffer and 80% (v/v) synovial fluid at pH 7.4 was examined in two dialysis membrane-based release models. The ester prodrug exhibited high solubility in medium-chain triglyceride, a high partition coefficient and was rapidly converted to naproxen in synovial fluid. Compared to naproxen, the release of the prodrug from the oil was sustained. In synovial fluid, the reconversion to naproxen resulted in faster release compared to that observed using buffer. In both release models, the use of ropivacaine–prodrug combination provided concomitant release from the oil into synovial fluid with ropivacaine being released faster than naproxen. The use of lipophilic prodrugs that are converted fast to the parent drug in synovial fluid seems to be a feasible approach to obtain prolonged joint residence time.
Keywords: Intra-articular administration; Lipophilic solution; In vitro release; Prodrug; Multimodal analgesia; Drug delivery;

Stability study and lyophilization of vitamin E-loaded nanocapsules prepared by membrane contactor by N. Khayata; W. Abdelwahed; M.F. Chehna; C. Charcosset; H. Fessi (254-259).
In this research, we studied the accelerated stability of vitamin E-loaded nanocapsules (NCs) prepared by the nanoprecipitation method. Vitamin E-loaded NCs were optimized firstly at the laboratory scale and then scaled up using the membrane contactor technique. The optimum conditions of the membrane contactor preparation (pilot scale) produced vitamin E-loaded NCs with an average size of 253 nm, polydispersity index 0.19 and a zeta potential −16 mV. The average size, polydispersity index and zeta potential values were 185 nm, 0.12 and −15 mV, respectively for the NCs prepared at laboratory scale. No significant changes were noticed in these values after 3 and 6 months of storage at high temperature (40 ± 2 °C) and relative humidity (75 ± 5%) in spite of vitamin E sensitivity to light, heat and oxygen. The entrapment efficiency of NCs prepared at pilot scale was 97% at the beginning of the stability study, and became (95%, 59%) after 3 and 6 months of storage, respectively. These values at lab-scale were (98%, 96%, and 89%) at time zero and after 3 and 6 months of storage, respectively. This confirms the ability of vitamin E encapsulation to preserve its stability, which is one major goal of our work.Lyophilization of the optimized formula at lab-scale was also performed. Four types of cryoprotectants were tested (poly(vinyl pyrrolidone), sucrose, mannitol, and glucose). Freeze-dried NCs prepared with sucrose were found acceptable. The other lyophilized NCs obtained at different conditions presented large aggregates.
Keywords: Nanocapsule; Nanoparticle; Vitamin E; Membrane contactor; Membrane emulsification; Stability study; Lyophilization;

Influence of penetration enhancer on drug permeation from volatile formulations by P. Santos; A.C. Watkinson; J. Hadgraft; M.E. Lane (260-268).
Previously we have reported the influence of supersaturation on the permeation of fentanyl across model membranes and skin. The findings indicated that the vehicle and, specifically its residence time in skin, influence the ability of the formulation to enhance membrane drug permeation. The aim of the present study was to probe the role of vehicle components on (trans)dermal drug delivery in more detail. To this end, three commonly used chemical penetration enhancers were selected for investigation namely, propylene glycol (PG), octyl salicylate (OSAL) and isopropyl myristate (IPM). A further objective was to clarify the mechanism of action of OSAL. Model spray formulations were prepared consisting of 10% (v/v) of individual enhancers in ethanol. Saturated and supersaturated systems were evaluated for their ability to promote fentanyl transport across human skin in vitro. Mass balance studies and determination of the extent of uptake of enhancers by skin were also conducted. The results indicated that increasing the degree of drug saturation (DS) does not promote drug permeation for formulations in PG but increasing drug DS did promote drug permeation for IPM and some OSAL systems. This probably reflects faster depletion of PG compared with IPM and OSAL. Non-linear modelling of the permeation data indicated that PG and IPM act to promote drug solubility in the membrane whereas OSAL appears to act as a skin penetration enhancer by increasing drug diffusivity in the skin.
Keywords: Fentanyl; Saturation; Supersaturation; Propylene glycol; Octyl salicylate; Isopropyl myristate;

A single injection of liposomal asialo-erythropoietin improves motor function deficit caused by cerebral ischemia/reperfusion by Takayuki Ishii; Tomohiro Asai; Tatsuya Fukuta; Dai Oyama; Nodoka Yasuda; Yurika Agato; Kosuke Shimizu; Tetsuo Minamino; Naoto Oku (269-274).
Modification of the liposomal surface with a targeting molecule is a promising approach for the targeted delivery of therapeutics. Asialo-erythropoietin (AEPO) is a potent tool for targeting an ischemic region by binding to the EPO receptors on neuronal cells. Additionally, it shows a strong cytoprotective effect against programed cell death. Hence, AEPO-modified liposomes appear likely to have both a neuronal-targeting character and a neuroprotective effect on cerebral ischemic injury. In this study, we assessed the targeting ability of AEPO-modified PEGylated liposomes (AEPO-liposomes) to ischemic region and their improvement effect on neurological deficits induced by ischemia/reperfusion (I/R) in transient middle cerebral artery occlusion (t-MCAO) rats. Immunohistological analysis showed that the AEPO-liposomes given immediately after reperfusion extravasated into the ischemic region and attached strongly to neuronal cells. Also, neuronal nuclei (NeuN) staining was clearly visible only in the AEPO-liposome-treated group, suggesting that AEPO-liposomes protected neuronal cells from ischemia/reperfusion-induced damage. Moreover, a single administration of low-dose AEPO-liposomes significantly improved the neurological deficit compared to vehicle and free-AEPO treatment at 7 days after injection. In conclusion, AEPO-liposomes have clear potential as a neuroprotectant after stroke and as a DDS device targeting ischemic regions.
Keywords: Ischemic stroke; Middle cerebral artery occlusion; Asialo-erythropoietin; Liposomes; NeuN; Motor function deficits;

Characterization and molecular modeling of the inclusion complexes of 2-(2-nitrovinyl) furan (G-0) with cyclodextrines by Vivian Ruz; Mathy Froeyen; Roger Busson; Mirtha M. González; Luc Baudemprez; Guy Van den Mooter (275-285).
The objective of this study was to prepare and characterize complexes of 2-(2-nitrovinyl) furan (G-0) with 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and sulfobutyl ether-β-cyclodextrin (SBE-β-CD). The solid inclusion complexes were prepared using kneading and freeze-drying methods. Phase solubility profiles were used to obtain the apparent stability constants and the complexation efficiency. They were classified as AL type for both systems: the apparent stability constants K 1:1 of the complexes were 48.7 and 79.2 M−1 for HP-β-CD and SBE-β-CD respectively.The solid inclusion complexes were evaluated by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD) and nuclear magnetic resonance spectroscopy (NMR). Especially the use of the two-dimensional ROESY spectrum was useful to confirm the presence of an inclusion complex. The spatial configuration of the drug inside the cyclodextrin cavity was investigated using molecular modeling studies. The latter results were in agreement with the experimental data. Inclusion complexes of G-0 with HP-β-CD contributed to improve the chemical stability of the drug in the presence of other commonly used pharmaceutical excipients.
Keywords: 2-(2-nitrovinyl) furan; Cyclodextrin; Inclusion complexes; Molecular modeling;

Robot-assisted preparation of oncology drugs: The role of nurses by Elisabetta Palma; Celestino Bufarini (286-288).
Since 2007, the preparation of cancer drugs at the Pharmacy of the University Hospital of Ancona has been progressively robotized. Currently, the process of preparation of intravenous cancer drugs is almost totally automated (95%). At present, the Cytotoxic laboratory of Ancona is the sole, in Europe, that can count on two robots. The robots handle 56 oncology molecules, which correspond to more than 160 different vials. The production rate in 2011 exceeded 19,000 preparations. The quality of compounding and the sterility controls are satisfactory, every step of the process is traceable. The nursing staff played a fundamental role in the robot development process. The nursing staff and the pharmacists are still collaborating with the robotic engineers in order to increase efficiency, ergonomics and user-friendliness of the robots.
Keywords: Antineoplastic agents/administration & dosage; Drug compounding; Infusions; Intravenous/instrumentation; Quality control; Robotics;

A comparison of quality control methods for active coating processes by D. Brock; J.A. Zeitler; A. Funke; K. Knop; P. Kleinebudde (289-295).
Display OmittedTerahertz pulsed imaging (TPI) is a recent and nondestructive technique to quantify coating thickness of pharmaceutical tablet film coatings. In this study, TPI is used for the first time to quantify the progress of an active coating process. The dosage form consisted of a push–pull osmotic system comprising a two-layer tablet core with a functional film coating and a laser drilled hole. On top of this system an active coating was applied. The coating thickness data acquired by TPI and optical microscopy was compared to the quantification of the active pharmaceutical ingredient (API) via HPLC. Good correlation of TPI and HPLC data was shown for coating thicknesses up to 500 μm. Due to the special structure of the dosage form, the TPI detection limit of 38 μm layer thickness was circumvented by analysing the coating thickness of active coating and functional subcoat in one. Therefore it was possible to monitor the active coating process from the very beginning of the process. Optical microscopy was no suitable reference technique for TPI thickness measurements. The active coating showed deformation artefacts during sample preparation, which biased the subsequent thickness measurements.
Keywords: Terahertz pulsed imaging; Active coating; Coating thickness; Pan coating; Optical microscopy;

Porous core/sheath composite nanofibers fabricated by coaxial electrospinning as a potential mat for drug release system by Thuy Thi Thu Nguyen; Chiranjit Ghosh; Seong-Gu Hwang; Noppavan Chanunpanich; Jun Seo Park (296-306).
This study focused on fabrication and characterization of porous core/sheath structured composite nanofibers with a core of blended salicylic acid (SA) and poly(ethylene glycol) (PEG) and a sheath of poly(lactic acid) (PLA) using a dual-capillary electrospinning system. Results of water contact angle measurements, field-emission scanning electron microscopy, and transmission electron microscopy indicated that feed rates of the core and sheath strongly affect the stability of the core/sheath structure and porous density of the composite nanofibers obtained, significantly influencing their SA release characteristics. At a lower ratio of feed rates of the core and the sheath, better stable core/sheath structures of nanofibers with higher porous density on the surface were formed resulting in a sustained release of SA over 5 days. Non-porous fibers showed a lower amount of drug release because the drug was embedded inside the core layer of the non-porous sheath layer. SA release from porous core/sheath nanofibers was described based on a one-dimensional Fickian diffusion mechanism, indicating that drug diffusion is a predominant factor in drug release. A cytotoxicity test suggested that the porous core/sheath nanofibers are non-toxic and support cell attachment. Therefore, this fiber mat may find application in the design of wound-healing patches with long-term activity.
Keywords: Drug release system; Coaxial electrospinning; Porous nanofibers; Salicylic acid; Poly(lactic acid);

Assembled nanomedicines as efficient and safe therapeutics for articular inflammation by Ling Che; Jianzhi Zhou; Shuhui Li; Hongmei He; Yuxuan Zhu; Xing Zhou; Yi Jia; Yao Liu; Jianxiang Zhang; Xiaohui Li (307-316).
Highly efficient nanomedicines were successfully fabricated by the indomethacin (IND) directed self-assembly of β-cyclodextrin (β-CD)-conjugated polyethyleneimine (PEI-CD), taking advantage of the multiple interactions between drug and polymer. These nanoscaled assemblies exhibited spherical shape and positively charged surface. Compared with the commercial tablet, the relative oral bioavailability of IND-nanomedicines was significantly enhanced. Evaluation based on either carrageenan-induced paw edema or complete Freund's adjuvant (CFA)-induced arthritis suggested the newly developed nanomedicines were more effective than raw IND or IND tablet in terms of prophylactic effect and therapeutic activity. Even the low dose of nanomedicines offered the comparable results to those of control groups at the high dosage in most cases. Moreover, the nanoformulation exhibited ameliorated gastrointestinal stimulation. All these positive results indicated that this type of nanomedicines might serve as a highly efficient and effective delivery nanoplatform for the oral delivery of water-insoluble therapeutics.
Keywords: Indomethacin; Nanomedicine; Self-assembly; Anti-inflammation; Drug delivery;

Binding of a surfactant to proteins can affect their physicochemical stability and solubility in a formulation. The extent of the effect depends on the binding stoichiometry. In this study, we have utilized the technique of maximum bubble pressure surface tensiometry to characterize the binding between human serum albumin (HSA) and surfactants (sodium dodecyl sulfate (SDS) and polysorbate 80) by dynamic surface tension measurements. Results show that two classes of binding sites are present in HSA for SDS, 5 primary binding sites with high binding affinity (K a  = 5.38 × 105  M−1) and 12 secondary binding sites with low affinity (K a  = 6.7 × 104  M−1). The binding is high affinity and limited capacity due to both, ionic and hydrophobic interactions between HSA and SDS. For polysorbate 80, the binding does not follow the Scatchard plot, and is low affinity and high capacity, indicating that polysorbate 80 interacts with HSA through hydrophobic interactions. The results show that maximal bubble pressure surface tensiometry is a fast and convenient technique to determine the concentration of free and bound surfactants in the presence of proteins.
Keywords: Protein–surfactant interactions; Interface; Dynamic surface tension; Bubble pressure tensiometer;

Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation by Sherif I.F. Badawy; Ajit S. Narang; Keirnan LaMarche; Ganeshkumar Subramanian; Sailesh A. Varia (324-333).
Three model compounds were used to study the effect of process parameters on in-process critical material attributes and a final product critical quality attribute. The effect of four process parameters was evaluated using design of experiment approach. Batches were characterized for particle size distribution, density (porosity), flow, compaction, and dissolution rate. The mechanisms of the effect of process parameters on primary granule properties (size and density) were proposed. Water amount showed significant effect on granule size and density. The effect of impeller speed was dependent on the granule mechanical properties and efficiency of liquid distribution in the granulator. Blend density was found to increase rapidly during wet massing. Liquid addition rate was the least consequential factor and showed minimal impact on granule density and growth. Correlations of primary properties with granulation bulk powder properties (compaction and flow) and tablet dissolution were also identified. The effects of the process parameters on the bulk powder properties and tablet dissolution were consistent with their proposed link to primary granule properties. Understanding the impact of primary granule properties on bulk powder properties and final product critical quality attributes provides the basis for modulating granulation parameters in order to optimize product performance.
Keywords: Wet granulation; Porosity; Particle size; Granulation parameters; Dissolution; Compaction;

The influence of solvent supramolecular structuring on the transmembrane transport rate (♦) and lag time to steady-state transport (♢) of diclofenac diethylamine (DDEA).Weak ion–ion interactions, such as those associated with ion-pair formation, are difficult to isolate and characterise in the liquid state, but they have the potential to alter significantly the physicochemical behaviour of molecules in solution. The aim of this work was to gain a better understanding of how ion–ion interactions influenced passive membrane transport. The test system was composed of propylene (PG) glycol, water and diclofenac diethylamine (DDEA). Infrared spectroscopy was employed to determine the nature of the DDEA ion-pair interactions and the drug-vehicle association. Passive transport was assessed using homogeneous synthetic membranes. Solution-state analysis demonstrated that the ion-pair was unperturbed by vehicle composition changes, but the solvent-DDEA interactions were modified. DDEA–PG/water hydrogen bonding influenced the ion-pair solubility (X dev) and the solvent interactions slowed transport rate in PG-rich vehicles (0.84 ± 0.05 μg cm−2  h−1, at ln(X dev) = 0.57). In water-rich co-solvents, the presence of strong water structuring facilitated a significant increase (p  < 0.05) in transmembrane penetration rate (e.g. 4.33 ± 0.92 μg cm−2  h−1, at ln(X dev) = −0.13). The data demonstrates that weak ion–ion interactions can result in the embedding of polar entities within a stable solvent complex and spontaneous supramolecular assembly should be considered when interpreting transmembrane transport processes of ionic molecules.
Keywords: Diclofenac diethylamine; Ion-pair; Supramolecular structuring; Propylene glycol; Transmembrane transport;

A nanosized delivery system of superparamagnetic iron oxide for tumor MR imaging by Eun Seong Lee; Chaemin Lim; Ho-Taek Song; Jeong Min Yun; Kyung Soo Lee; Beom-Jin Lee; Yu Seok Youn; Young Taik Oh; Kyung Teak Oh (342-348).
SPIO loading micelle formation with PLA–PEG and the proposed concept for the MR imaging in an animal tumor model experiment.Superparamagnetic iron oxide (SPIO) nanoparticles have been intensively investigated as MRI probes due to the noninvasive detection of in vivo pathological changes. In the study, a nanosized system for SPIO delivery to a tumor was prepared to overcome the common challenges of SPIO nanoparticles such as insufficient uptake of SPIO by specific cells due to instability, short half-life by macrophage, and low efficiency of internalization. SPIO with ca. 6 nm sizes as a MRI probe and PLA–PEG (5K–2K) as a biocompatible stable system were prepared. The hydrophobic modified SPIO were loaded into the core of micelles and showed a stable dispersion with 140–170 nm particle sizes. The SPIO loading micelles showed higher relaxivity coefficients and increases of T 2 relaxation in vivo MR imaging. This SPIO delivery system with high stability and sensitivity can be a promising imaging formulation as MRI T 2 probes for tumor detection.
Keywords: Polymeric micelle; Superparamagnetic iron oxide (SPIO); Hyperspectrum; T 2 relaxivity coefficients; Animal imaging;

Nanostructured lipid carriers (NLC) based topical gel of flurbiprofen: Design, characterization and in vivo evaluation by Fei Han; Ran Yin; Xin Che; Jing Yuan; Yanan Cui; He Yin; Sanming Li (349-357).
Nanostructured lipid carriers (NLC)-based gel was developed as potential topical system for flurbiprofen (FP) topical delivery. The characterizations of the prepared semisolid formulation for topical application on skin were assessed by means of particle size distribution, zeta potential analysis, X-ray analysis, in vitro percutaneous penetration, rheological study, skin irritation test, in vivo pharmacodynamic evaluation and in vivo pharmacokinetic study. The NLC remained within the colloidal range and it was uniformly dispersed after suitably gelled by carbopol preparation. It was indicated in vitro permeation studies through rat skin that FP-NLC-gel had a more pronounced permeation profile compared with that of FP-loaded common gel. Pseudoplastic flows with thixotropy were obtained for all NLC-gels after storage at three different temperatures. No oedema and erythema were observed after administration of FP-NLC-gel on the rabbit skin, and the ovalbumin induced rat paw edema could be inhibited by the gel. The maximum concentration in plasma was 29.44 μg/ml and 2.49 μg/ml after oral and topical administration, respectively. While the amount of drug accumulated in skin after topical application was much higher than oral application. In conclusion, NLC-based gel could be a promising vehicle for topical delivery of FP.
Keywords: Nanostructured lipid carriers; Topical gel; Flurbiprofen; Pharmacodynamic; Pharmacokinetic;

Corrigendum to “Di-(2-ethylhexyl) phthalate migration from irradiated poly(vinyl chloride) blood bags for graft-vs-host disease prevention” [Int. J. Pharm. 430 (2012) 86–88] by Marcella Ferri; Federica Chiellini; Giorgio Pili; Luca Grimaldi; Elena Tiziana Florio; Stefania Pili; Francesco Cucci; Giuseppe Latini (358).