International Journal of Pharmaceutics (v.346, #1-2)

The different film thicknesses of the sodium alginate–magnesium aluminum silicate (SA–MAS) microcomposite films were prepared by varying volumes of the composite dispersion for casting. Effect of film thickness on thermal behavior, solid-state crystallinity, mechanical properties, water uptake and erosion, and water vapor and drug permeability of the microcomposite films were investigated. The film thickness caused a small change in thermal behavior of the films when tested using DSC and TGA. The crystallinity of the thin films seemed to increase when compared with the thick films. The thin films gave higher tensile strength than the thick films, whereas % elongation of the films was on the contrary resulted in the lower Young's modulus of the films when the film thickness was increased. This was due to the weaker of the film bulk, suggesting that the microscopic matrix structure of the thick films was looser than that of the thin films. Consequently, water uptake and erosion, water vapor permeation and drug diffusion coefficient of the thick films were higher than those of the thin films. The different types of drug on permeability of the films also showed that a positive charge and large molecule of drug, propranolol HCl, had higher lag time and lower diffusion coefficient that acetaminophen, a non-electrolyte and small molecule. This was because of a higher affinity of positive charge drug on MAS in the films. The findings suggest that the evaporation rate of solvent in different volumes of the composite dispersion used in the preparation method could affect crystallinity and strength of the film surface and film bulk of the microcomposite films. This led to a change in water vapor and drug permeability of the films.
Keywords: Sodium alginate; Magnesium aluminum silicate; Film; Microcomposite; Mechanical property; Permeability;

Investigation of drug partition property in artificial sebum by Satyanarayana Valiveti; James Wesley; Guang Wei Lu (10-16).
Targeted delivery of a therapeutic agent into the hair and sebaceous follicles greatly depends on the extent of drug partitioning/diffusion in the sebum. The objective of the present research was to develop a method to determine the sebum partition coefficient in order to facilitate the selection of sebum-targeted drug candidates. Partition coefficients of model drugs with different chemical structures and 4-hydroxybenzoate series compounds were measured in artificial sebum/water (K sebum) and human stratum corneum/water (K sc) at 37 °C. The relationship was evaluated between log  K sebum, log  K sc and clog  P. The results of the partition coefficient studies indicate that the K sebum of some drugs was significantly higher than the K sc, whereas some drugs showed lower or similar K sebum when compared with K sc. Overall, a relatively poor correlation was observed between log  K sebum, log  K sc and clog P. However, a linear relationship exists between log  K sebum and clog P in the 4-hydroxybenzoate series compounds, indicating that K sebum depends on the lipophilicity and chemical structure of the compounds. The results of the present study demonstrate that K sebum is different from K sc and calculated P and is likely to be a critical parameter reflecting drug delivery into hair and sebaceous follicles.
Keywords: Artificial sebum; Partition coefficient; Sebaceous gland; Hair follicle; Targeted delivery; Human stratum corneum;

Unified compaction curve model for tensile strength of tablets made by roller compaction and direct compression by Leon Farber; Karen P. Hapgood; James N. Michaels; Xi-Young Fu; Robert Meyer; Mary-Ann Johnson; Feng Li (17-24).
A model that describes the relationship between roller-compaction conditions and tablet strength is proposed. The model assumes that compaction is cumulative during roller compaction and subsequent granule compaction, and compact strength (ribbon and tablet) is generated irreversibly as if strength is controlled by plastic deformation of primary particles only. Roller-compaction is treated as a compaction step where the macroscopic ribbon strength is subsequently destroyed in milling. This loss in strength is irreversible and tablets compressed from the resulting granulation are weaker than those compressed by direct compression at the same compression force. Roller-compacted ribbons were produced at a range of roll forces for three formulations and subsequently milled and compacted into tablets. Once the total compaction history is taken in account, the compaction behavior of the uncompacted blends and the roller-compacted granules ultimately follow a single master compaction curve—a unified compaction curve (UCC). The model successfully described the compaction behavior of DC grade starch and formulations of lactose monohydrate with 50% or more microcrystalline cellulose, and may be more generally applicable to systems containing significant proportions of any plastically deforming material, including MCC and starch.
Keywords: Roller compaction; Tensile strength; Compaction; Lactose; Microcrystalline cellulose; Hardness;

Pharmacokinetics of raloxifene in male Wistar–Hannover rats: Influence of complexation with hydroxybutenyl-beta-cyclodextrin by Michael F. Wempe; Vincent J. Wacher; Karen M. Ruble; Michael G. Ramsey; Kevin J. Edgar; Norma L. Buchanan; Charles M. Buchanan (25-37).
Raloxifene is a highly insoluble, highly metabolized serum estrogen receptor modulator approved for use in the treatment of osteoporosis. Hydroxybutenyl-beta-cyclodextrin (HBenBCD) is a novel solubility enhancer previously demonstrated to increase the oral bioavailability of tamoxifen, letrozole, and itraconazole. The current study evaluated the pharmacokinetics of raloxifene in oral and intravenous formulations with HBenBCD in male Wistar–Hannover rats. Analytical methodology to measure raloxifene and its metabolites was developed by measuring raloxifene metabolism in vitro. Formulation with HBenBCD significantly increased raloxifene oral bioavailability. Mean ± S.D. oral bioavailabilities were 2.6 ± 0.4% for raloxifene formulated with microcrystalline cellulose, 7.7 ± 2.1% for a solid capsule formulation of raloxifene:HBenBCD complex, and 5.7 ± 1.3% for a liquid-filled capsule formulation containing raloxifene:HBenBCD/PEG400/H2O. Relative to raloxifene/microcrystalline filled capsules, the presence of HBenBCD in the solid capsule formulation afforded: (i) a decrease in raloxifene T max (2.5 ± 0.5 h versus 4.0 ± 0.5 h); (ii) a two-fold increase in raloxifene C max and a three-fold increase in raloxifene AUC; and (iii) a 12-fold increase in raloxifene glucuronide C max and a 6.5-fold increase in raloxifene glucuronide AUC. Hence, these studies demonstrate that raloxifene formulations containing HBenBCD significantly increased the oral bioavailability in rats relative to formulations that did not contain HBenBCD.
Keywords: Hydroxybutenyl-beta-cyclodextrin; Raloxifene; Pharmacokinetic studies; Bioavailability; Dissolution; Liquid chromatography–mass spectrometry/mass spectrometry;

Aqueous mixture of β-glucan and poly(vinyl alcohol) (PVA) was cast into films and dried at 110 °C without chemical crosslinking. The content of glucan in the film varied from 7% to 50%. The hydrophilicity of the resulting films was evaluated with swelling tests, wet area diffusion tests, and water vapor transmission tests. The swelling ratio, the wetting ratio, and the water vapor transmission rate increased with the glucan content. When contacting water, glucan was released, and the percent release of glucan increased with the glucan content. The addition of glucan made the film more ductile than pure PVA. The results of hemocompatibility test showed no significant effect on the activated partial thromboplastin time (APTT) and thrombin time (TT) and minor adsorption of human serum albumin (HSA). On observing the wound healing of rat skin, the healing time was shortened by 48% using PVA/glucan film comparing to cotton gauze. Therefore, a wound dressing made of PVA/glucan can greatly accelerate the healing without causing irritation.
Keywords: Glucan; Poly(vinyl alcohol); Films; Wound dressing;

The purpose of this study is to develop a less painful intravenous clarithromycin emulsion (ClaE) and investigate its thermal sterile stability. The formulation of ClaE is composed of clarithromycin 0.25% (w/v), vitamin E 5% (w/v), medium chain triglyceride (MCT) 10% (w/v), egg lecithin 1.0% (w/v), Cremophor EL-40 (EL-40) 2% (w/v), Pluronic F-68 (F-68) 0.2% (w/v), Tween80 0.2% (w/v), glycerol 2.5% (w/v) and l-cysteine 0.05% (w/v) in water. High-pressure homogenization, photon correlation spectroscopy (PCS) and electrophoretic light scattering (ELS) technology, light microscopy and high-performance liquid chromatography (HPLC) methods were used in the preparation and evaluation of ClaE. Investigation of thermal sterile stability included the effects of different thermal sterile methods, thermal sterile time, drug concentrations and pH values. Sterilization in a 100 °C rotating water bath for 30 min was finally adopted as the sterilization method. The drug remaining was 98.6% and 96.5%, respectively, before and after thermal sterilization. Moreover, the pH value, particle size distribution (PSD), ζ-potential and entrapment efficiency (EE) of ClaE after sterilization were 7.95, 213.6 nm, −22.29 mV and 96.35%, respectively. This showed that ClaE had sufficient physicochemical stability to resist the sterilization process. Tests using animal models demonstrated that there was a marked pain reduction following the injection of ClaE compared with clarithromycin solution. Overall, ClaE described in this paper may be very suitable for industrial-scale production and clinical application.
Keywords: Clarithromycin; Formulation; Thermal sterile stability; Intravenous emulsion; Less painful; Vitamin E;

Controlled dual release of basic fibroblast growth factor and indomethacin from heparin-conjugated polymeric micelle by Jung Seok Lee; Jin Woo Bae; Yoon Ki Joung; Seung Jin Lee; Dong Keun Han; Ki Dong Park (57-63).
This work describes the development of heparinized polymeric micelle as a novel injectable carrier for the dual drug delivery that can simultaneously release basic fibroblast growth factor (bFGF) and indomethacin (IMC), which can promote the regeneration of damaged tissue and prevent the inflammatory response after implantation. Tetronic®–PCL–heparin for the preparation of heparinized polymeric micelle was synthesized by introducing PCL as a biodegradable linkage on Tetronic, following the conjugation of heparin. The mean diameter of the formed TCH micelle was around 114 nm and increases in the micelle size after single and dual drug loading were observed. Loading efficiencies of IMC and bFGF were 30.9% and 70.5%, respectively. In vitro dual drug release profiles from TCH micelles were investigated. IMC was more slowly released from dual drug-loaded micelle over 3 weeks as compared with single drug-loaded one. bFGF was released over 2 months in a controlled manner. Therefore, the release profile results support that TCH micelle could not only incorporate a hydrophobic drug into the core but also bind with bFGF to heparin that exists on its outer shell. The TCH micelle will have enhanced therapeutic effects on the target site which may be required the multi-function of drugs to use.
Keywords: Polymeric micelle; Heparin; Dual drug release; Growth factors; Tissue engineering;

Partitioning, diffusivity and clearance of skin permeants in mammalian dermis by Kosmas Kretsos; Matthew A. Miller; Grettel Zamora-Estrada; Gerald B. Kasting (64-79).
The partition coefficients (K de) and diffusivities (D de) of compounds in mammalian dermis were examined through an analysis of in vitro permeation data obtained from the literature combined with experimental results with the test permeant, 3H-testosterone. The literature data involved 26 compounds ranging in molecular weight from 18 to 476 Da and four species—human, guinea pig, rat and mouse. Testosterone was studied by permeation and desorption measurements employing excised human dermis in the presence and absence of external serum albumin. Mathematical models for both K de and D de were developed. The K de model involved ionization, binding to extravascular serum proteins and partitioning into a small lipid compartment. The D de model employed a free diffusivity with a liquid-like size dependence multiplied by a binding factor derived from K de. An additional analysis considered in vivo dermal concentration profiles of topically applied permeants. Literature data for 5 of 6 permeants were shown to be well described by a previously published model for capillary clearance in the dermis, which leads to an exponential decay of concentration with depth. Computed decay lengths (1/e values) ranged from 210 to 920 μm, and the corresponding clearance rate constants k de ranged from 0.9 × 10−4 to 14 × 10−4  s−1 (n  = 8). Departures from the exponential decay profile are discussed in terms of non-uniform capillary clearance and incomplete attainment of a steady-state.
Keywords: Skin; In silico prediction; Mathematical model; Topical delivery; Percutaneous absorption; Transdermal;

The fluxes (J IPM) of a series of alkylcarbonyloxymethyl (ACOM) ethers of acetaminophen (APAP) were measured through hairless mouse skin from suspensions of each prodrug in isopropyl myristate (IPM). Solubilities in IPM, estimated solubilities in pH 4.0 buffer (S 4.0) and flux data for the 4-ACOM-APAP prodrugs were incorporated into the Roberts–Sloan (RS) database to give new estimates for the independent variables of the RS equation: log  J IPM  =  x  +  y  log  S IPM  + (1 −  y) log  S 4.0  −  z M W. All but one of the 4-ACOM-APAP derivatives hydrolyzed completely on permeation through mouse skin. Three out of the five prodrugs permeated the skin better than APAP, with a maximum fourfold increase in flux. Biphasic solubility – not solubility in a single solvent – was shown to have the greatest impact on flux. A fit of the new n  = 66 database to the RS equation gave the following values for x, y, z, and r 2: x  = −0.545, y  = 0.511, z  = 0.00253, r 2  = 0.915. These results demonstrate that the topical delivery of a model phenol, acetaminophen, can be improved by transiently masking the phenolic hydroxyl group as an ACOM ether.
Keywords: Prodrugs; Diffusion cell experiments; Topical delivery; Roberts–Sloan equation; Transformed Potts–Guy equation; Water solubility;

The need for stringent temperature control provides significant challenges to pharmaceutical distributors operating in all sectors of the industry. Products with a frozen storage label requirement can be significantly problematic. This study aimed to provide evidence of robust and reproducible frozen shipment arrangements to be operated by a Phase I clinical trial unit. Dry ice was used to achieve a deep frozen internal parcel environment and was tested in a laboratory setting using ultra low temperature loggers within dummy product packs within the test parcels. The laboratory dry ice packing configuration was then repeatedly tested in real time transits using a Glasgow to London delivery schedule. An internal temperature specification was set to not exceed −10 °C during the transport. During each delivery, external temperature monitoring measured the temperature stress experienced by the box in transit. Results demonstrated the ability of the chosen system to not exceed −13.6 °C on average (−10 °C maximum) when exposed to external temperatures of up to +20.1 °C (mean kinetic temperature). The effect was maintained for at least 52.5 h.
Keywords: Phase I; Frozen; Dry ice; Distribution;

A single lot of MCC powder (Avicel PH102) was equilibrated at 0%, 11.35%, 21.6%, 38.2%, 52%, 57.5%, 75% and 84.3% relative humidity. Each equilibrated powder was compressed. Tablet density and tensile strength were measured as a function of pressure. Powder true density, tabletability, compressibility, compactibility and plasticity were obtained as a function of water content. The true density of MCC ranged 1.42–1.46 g/cm3 and exhibited a maximum between ∼3% and ∼5% (wt%) moisture. Moisture up to ∼3.3%, corresponding to monolayer coverage, did not induce profound change in MCC plasticity nor bonding strength despite reduced T g. Consequently, the compaction properties were largely insensitive to moisture variation below 3.3% water. Above 3.3% water, higher moisture content corresponded to improved plasticity, due to the plasticizing effects of water above the critical water content, and consequently larger interparticulate bonding area when compressed. Effects of plasticization by water on bonding area were significant at low compaction pressures but diminish at higher pressures. At above 3.3% water, increasing moisture content also reduced bonding strength. Due to the interplay among the plasticity, compaction pressure and bonding strength, tablet tensile strength peaked in the range of 3.3–5.6% moisture.
Keywords: Microcrystalline cellulose; Compaction; Moisture; Antiplasticization; Plasticity; Tabletability; Compressibility; Compactibility;

Stable sugar-based protein formulations by supercritical fluid drying by Nataša Jovanović; Andréanne Bouchard; Marc Sutter; Michiel Van Speybroeck; Gerard W. Hofland; Geert-Jan Witkamp; Daan J.A. Crommelin; Wim Jiskoot (102-108).
The aim of this work was to produce stable, sugar-containing protein formulations by supercritical fluid (SCF) drying. Lysozyme solutions with and without added sucrose or trehalose were dried by spraying them in an SCF composed of CO2 and ethanol or CO2 only. The protein-to-sugar ratio was varied between 1:0 and 1:10 (w/w). Dried formulations were stored at 4 °C for three months and analyzed by Karl Fischer titration, scanning electron microscopy, X-ray powder diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy. Lysozyme stability after reconstitution was determined by an enzymatic activity assay, UV/Vis spectroscopy, and SDS-PAGE. Smooth, spherical particles of 1–25 μm size were obtained. All formulations were initially amorphous. Crystallization during storage only occurred with a protein-to-sugar ratio of 1:10 and could be avoided by performing SCF drying without ethanol. Absence of residual ethanol in dried trehalose formulations increased the glass transition temperature up to 120 °C. Lysozyme in dried formulations was structurally stable, with exception of the 1:0 and 1:1 protein-to-sugar ratios, where reversible protein aggregation occurred. The results show that by avoiding ethanol, which up to now has been considered mandatory for efficient drying of aqueous solutions, and by choosing the proper protein-to-sugar ratio, it is possible to obtain stable, sugar-based protein formulations through SCF drying.
Keywords: Supercritical fluid drying; Protein stabilization; FTIR; Protein structure; Sucrose; Trehalose; Lysozyme;

Uptake of inert microparticles in normal and immune deficient mice by S.H. Smyth; S. Feldhaus; U. Schumacher; K.E. Carr (109-118).
Intestinal microparticle uptake is important for drug delivery, environmental pollution and multiple organ dysfunction syndrome. This paper explores further whether uptake occurs at mucosa associated lymphoid tissue (MALT) via the microfold (M) cells of Peyer's patch domes or through villous epithelium. It does this by comparing the results of exposure of either severe combined immunodeficient (SCID) mice (lacking MALT) or normal BALBc mice, to oral gavage with 2 μm fluorescent latex microparticles. At 5 and 30 min after gavage, full circumference samples along the small intestine were processed for fluorescence microscopy and microparticle numbers were collected for surface and tissue sites. Uptake occurred in both BALBc and SCID mice within 5 min of particle administration and increased further in the following 25 min. In BALBc mice, almost all particles (96%) are in non-MALT sites in MALT circumference samples, with very few at the domes: uptake was also substantial in entirely villous samples. In SCID mice, particle numbers were only slightly lower than those of the BALBc mice, and occurred exclusively by the villous route. These findings confirm that the villous uptake route must be considered when assessing the extent of the dose delivered following pharmaceutical or toxicological oral exposure to microparticles.
Keywords: Small intestine; Latex microparticles; Uptake; Severe combined immunodeficiency (SCID); Mouse;

Positively charged microemulsions for topical application by Elena Peira; M. Eugenia Carlotti; Chiara Trotta; Roberta Cavalli; Michele Trotta (119-123).
The study reports pig-skin permeation and skin accumulation of miconazole nitrate (MCZ) from positively charged microemulsions containing water, 1-decanol/1-dodecanol (2:1, w/w), lecithin and/or decyl polyglucoside at different weight ratios, propylene glycol, 1,2 hexanediol and a cationic charge-inducing agent (stearylamine (ST), l-alanine benzyl ester (ALAB) or cetyltrimethylammonium bromide (CTAB)). Zeta-potential values of the positively charged microemulsions ranged from 14.2 to 37.5 mV and mean droplet size from 6.0 to 16.8 nm.In vitro pig-skin permeation of MCZ after a single 24 h application was negligible for all microemulsions; accumulation from positively charged microemulsions was nearly twice that from their negatively charged counterparts.The increased accumulation might be ascribed to the interaction between positive microemulsive systems and negatively charged skin sites; no significant difference was observed among the various cationic charge-inducing agents.Skin accumulation from the microemulsion containing most lecithin was lower than those of other microemulsions; this was ascribed to the phase transformation from microemulsion to a liquid crystal system after skin contact.These results suggest that positively charged microemulsions could be used to optimize drug targeting without a concomitant increase in systemic absorption; ALAB, an ester of a natural aminoacid, is an appropriate cationic charge-inducing agent.
Keywords: Positively charged microemulsion; Miconazole; Topical application; Skin accumulation;

Nanostructured lipid carrier (NLC) based gel of celecoxib by Medha Joshi; Vandana Patravale (124-132).
Nanostructured lipid carriers (NLC) based topical gel of celecoxib was formulated for the treatment of inflammation and allied conditions. NLC prepared by the microemulsion template technique were characterized by photon correlation spectroscopy for size and scanning electron micrograph (SEM) studies. Drug encapsulation efficiency was determined using Nanosep® centrifugal device. The nanoparticulate dispersion was suitably gelled and assessed for in vitro release and in vitro skin permeation using rat skin. Efficacy of the NLC gel was established using a pharmacodynamic study, i.e., aerosil-induced rat paw edema model. The skin permeation and rat paw edema pharmacodynamic studies were carried out in comparison with a micellar gel which had the same composition as that of the NLC gel except for the solid lipid and oil. The NLC based gel described in this study showed faster onset and elicited prolonged activity until 24 h.
Keywords: Celecoxib; Nanosturctured lipid carriers (NLC); Topical gels; Micellar; Anti-inflammatory; Prolonged action;

Preparation and characterization of thermo-responsive albumin nanospheres by Zhe-Yu Shen; Guang-Hui Ma; Toshiaki Dobashi; Yasuyuki Maki; Zhi-Guo Su (133-142).
Thermo-responsive poly(N-isopropylacrylamide-co-acrylamide)-block-polyallylamine-conjugated albumin nanospheres (PAN), new thermal targeting anti-cancer drug carrier, was developed by conjugating poly(N-isopropylacrylamide-co-acrylamide)-block-polyallylamine (PNIPAM-AAm-b-PAA) on the surface of albumin nanospheres (AN). PAN may selectively accumulate onto solid tumors that are maintained above physiological temperature due to local hyperthermia. PNIPAM-AAm-b-PAA was synthesized by radical polymerization, and AN was prepared by ultrasonic emulsification. AN with diameter below 200 nm and narrow size distribution was obtained by optimizing the preparative conditions. Rose Bengal (RB) was used as model drug for entrapment into the AN and PAN during the particle preparation. The release rate of RB from PAN compared with AN in trypsin solution was slower, and decreased with the increase of PNIPAM-AAm-b-PAA molecular weight, which suggested that the existence of a steric hydrophilic barrier on AN made digestion of AN more difficult. Moreover, the release of RB from PAN above the cloud-point temperature (T cp) of PNIPAM-AAm-b-PAA became faster. This was because the density of temperature-responsive polymers on AN was not so high, so that the interspace between the polymer chains increased after they shrunk due to the high temperature. As a result, the biodegradable AN was attacked more easily by trypsin. The design of PAN overcame the disadvantages of temperature-responsive polymeric micelles.
Keywords: Poly(N-isopropylacrylamide-co-acrylamide)-block-polyallylamine; Albumin nanospheres; Rose Bengal; Entrapment efficiency; Controlled release;

Effective anti-tumor activity of oxaliplatin encapsulated in transferrin–PEG-liposome by Ryo Suzuki; Tomoko Takizawa; Yasuhiro Kuwata; Mahito Mutoh; Nobuyuki Ishiguro; Naoki Utoguchi; Atsuko Shinohara; Masazumi Eriguchi; Hironobu Yanagie; Kazuo Maruyama (143-150).
Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum, l-OHP) is a novel cisplatin derivative that can improve the side effects of cisplatin such as toxicity to the kidneys and peripheral nerve system. However, l-OHP is effective only when combined with 5-Fluorouracil (5-FU) and Leucovorin. The relatively low anti-tumor index of l-OHP alone is because low levels accumulate in tumor tissues due to high partitioning to erythrocytes in vivo. A successful outcome of cancer therapy using l-OHP requires the selective delivery of a relatively high concentration of the drug to tumors. The present study examines tumor-selective delivery of l-OHP using liposomes modified with transferrin-conjugated polyethyleneglycol (TF–PEG-liposomes). Delivery using these liposomes significantly reduced l-OHP partitioning to erythrocytes and improved the circulation time of l-OHP in vivo, resulting in enhanced extravasation of liposomes into tumors. The TF–PEG-liposomes maintained a high l-OHP concentration in tumors for over 72 h after intravenous injection, which was longer than that of the liposomes modified with PEG (PEG-liposomes). Intravenously administered l-OHP encapsulated within TF–PEG-liposomes (l-OHP: 5 mg/kg) suppressed tumor growth more effectively than PEG-liposomes, Bare-liposomes and free l-OHP. Although l-OHP is usually combined with 5-FU and Leucovorin, our results suggest that l-OHP encapsulated within TF–PEG-liposomes has potential for cancer therapy.
Keywords: Liposomes; Transferrin; Oxaliplatin; Targeting; Cancer therapy; Polyethyleneglycol (PEG);

Controlling the in vitro release profiles for a system of haloperidol-loaded PLGA nanoparticles by Avinash Budhian; Steven J. Siegel; Karen I. Winey (151-159).
We have used a systematic methodology to tailor the in vitro drug release profiles for a system of PLGA/PLA nanoparticles encapsulating a hydrophobic drug, haloperidol. We applied our previously developed sonication and homogenization methods to produce haloperidol-loaded PLGA/PLA nanoparticles with 200–1000 nm diameters and 0.2–2.5% drug content. The three important properties affecting release behavior were identified as: polymer hydrophobicity, particle size and particle coating. Increasing the polymer hydrophobicity reduces the initial burst and extends the period of release. Increasing the particle size reduces the initial burst and increases the rate of release. It was also shown that coating the particles with chitosan significantly reduces the initial burst without affecting other parts of the release profile. Various combinations of the above three properties were used to achieve in vitro release of drug over a period of 8, 25 and >40 days, with initial burst <25% and a steady release rate over the entire period of release. Polymer molecular weight and particle drug content were inconsequential for drug release in this system. Experimental in vitro drug release data were fitted with available mathematical models in literature to establish that the mechanism of drug release is predominantly diffusion controlled. The average value of drug diffusivities for PLGA and PLA nanoparticles was calculated and its variation with particle size was established.
Keywords: Controlled release; Haloperidol; Nanoparticles; PLGA end groups; Drug diffusivity; Drug release mechanism;

Preparation, physicochemical characterization, and antioxidant effects of quercetin nanoparticles by Tzu-Hui Wu; Feng-Lin Yen; Liang-Tzung Lin; Tong-Rong Tsai; Chun-Ching Lin; Thau-Ming Cham (160-168).
The purpose of this study was to develop quercetin-loaded nanoparticles (QUEN) by a nanoprecipitation technique with Eudragit® E (EE) and polyvinyl alcohol (PVA) as carriers, and to evaluate the antioxidant effects of quercetin (QU) and of its nanoparticles. The novel QUEN systems were characterized by particle size and morphology, yield and encapsulation efficiency, differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), 1H nuclear magnetic resonance (1H NMR), and dissolution study. It was observed that the weight ratio of QU:EE:PVA at 1:10:10 carried a particle size of <85 nm, a particle distribution with polydispersity index <0.3, and its yield and encapsulation efficiency were over 99%. The results from XRD and DSC of the QUEN showed that the crystal of the drug might be converted to an amorphous state. The FT-IR and 1H NMR demonstrated that QU formed intermolecular hydrogen bonding with carriers. The release of the drug from the QUEN was 74-fold higher compared with the pure drug. In addition, the antioxidant activity of the QUEN was more effective than pure QU on DPPH scavenging, anti-superoxide formation, superoxide anion scavenging, and anti-lipid peroxidation.
Keywords: Quercetin; Nanoparticles; 1H nuclear magnetic resonance; Free radical-scavenging activity; Anti-lipid peroxidation;

Reliable predictions of the role of P-glycoprotein in the pharmacokinetics are needed already at the early stage of drug development. In order to obtain meaningful in vitroin vivo scaling factors, it is essential to know the factors affecting the in vitro results. In this study, the apparent P-glycoprotein–ATPase activation kinetics were determined using the cell membrane fraction of human MDR1-transfected insect cells. The apparent affinities to P-glycoprotein of basic verapamil and quinidine were higher at pH 7.4 than at pH 6.8. However, this shift in pH did not have a significant effect on the apparent affinity of acidic monensin. The protein concentration used in the assay did not affect the apparent activator affinities, but was inversely related to the maximum activation achieved. Thus, pH and protein concentration should be taken into account when interpreting the Pgp–ATPase data.
Keywords: P-glycoprotein; MDR1; ABCB1; ATPase activity; Kinetic parameter;

Noticeboard (173).

Guide for Authors (174-178).