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1.  Evaluation of a new coprocessed compound based on lactose and maize starch for tablet formulation 
AAPS PharmSci  2004;6(2):27-38.
The development of new direct compression excipients should include a comprehensive and rapid determination of deformation properties. The aim of this study was to characterize StarLac, a new coprocessed compound for direct compression based on lactose and maize starch. For this purpose, the effects of the base materials (maize starch and spraydried lactose) were considered and the influence of the spray-drying process was investigated. This was performed by comparing the physical mixture of starch and spray-dried lactose at the same ratio as for StarLac. For analysis of the deformation behavior, the 3-D model and the Walker equation were applied; for verification, the Heckel equation and the pressure time function (a modified Weibull equation) were used. The advantages of StarLac are its good flowability depending on the spray-drying process, an acceptable crushing force due to its lactose content, its rapid disintegration depending on starch, and a brilliant fast release of an active ingredient, such as theophylline monohydrate. The volume-pressure deformation properties of StarLac were dependent on the lactose properties. Only at high maximum relative density (ϱrel,max) did the influence of starch cause a change in these properties. A network-like structure can be observed using scanning electron microscopy pictures. Overall, StarLac deformed plastically with a low portion of elasticity. The physical mixture exhibited a more elastic behavior than StarLac. However, the part of the powder that was irreversibly compressed was much lower than was observed for the single substances. This behavior is caused by an interaction between the components, which in StarLac is prevented by spray drying.
PMCID: PMC2751008  PMID: 18465268
compression; tableting behavior; lactose starch; drug release
2.  Evaluation of the potential use of poly(ethylene oxide) as tablet- and extrudate-forming material 
AAPS PharmSci  2004;6(2):17-26.
The purpose of this study was to assess the potential use of poly(ethylene oxide) (PEO) as matrix-forming mate-rial for tablets and extrudates. Raw materials were characterized for size, size distribution, and shape. Tablets with 2- and 10-mm diameter were prepared by direct compression at both 13 and 38 MPa from mixtures with poly(ethylene oxide)s, a model drug (propranolol hydrochloride) and lactose. To these mixtures water was added (16%–43%) prior to extrusion in a ram extruder fit with different dies (1-, 3-, 6-, and 9-mm diameter and 4-mm length). Tablets and extrudates were characterized for work of compression or extrusion, respectively, relaxation, tensile strength, friability, and drug release. Both PEOs produced tablets easily and with different properties. Some relaxation was observed, particularly for tablets with higher amounts of PEOs. Release of the drug occurred after swelling of the matrix, and between 10% and 70% drug released, a quasi zero-order release was observed for large tablets. Extrusion was possible for formulations with PEO only with amounts of water between 16% and 50%. Both radial and axial relaxation of both plugs and extrudates were observed. Moreover, different extrusion profiles reflected the different behaviors of the different formulations. The model drug was released in the same fashion as observed for the tablets. It was possible to produce tablets by direct compression and extrudates or pellets from those extrudates from different formulations with PEO. Tablets and pellets have shown distinct properties depending upon the PEO considered. Extrusion was particularly complex with different formulations with PEO.
PMCID: PMC2751007  PMID: 18465267
extrusion; minitablet, pellet; poly(ethylene oxide); tablet
3.  Acute and subchronic (28-day) oral toxicity study in rats fed with novel surfactants 
AAPS PharmSci  2004;6(2):7-16.
The toxicity of 2 new synthetic lipids, 1,2-dioleoyl-rac-glycerol-3-dodecaethylene glycol, GDO-12 (lipid 1) and 1,2-distearoyl-rac-glycerol-3-dodecaethylene glycol, GDS-12 (lipid 2) has been evaluated in acute and subchronic toxicity studies. Acute oral toxicity studies in male and female rats documented no deaths or treatment-related signs at high doses. The lipids were individually administered (by gavage) to male and female Sprague-Dawley rats at concentrations of 250, 500, and 1000 mg/Kg bodyweight for 28 days. All animals survived the duration of the study, with no significant changes in clinical signs, hematological parameters, organ weights, ophthalmology evaluations, or histopathological findings. These studies establish that both GDO-12 (lipid 1) and GDS-12 (lipid 2) are nontoxic in rats following oral administration. The no-observed-adverse-effect level ranged between 250 mg/Kg and 1000 mg/Kg following oral administration.
PMCID: PMC2751006  PMID: 15760044
oral toxicity; rats; polyoxyethylene glycol (PEG); liposomes
4.  Permeability classification of representative fluoroquinolones by a cell culture method 
AAPS PharmSci  2004;6(2):1-6.
This study was undertaken to categorize representative fluoroquinolone drug substance permeability based on the methods outlined in the Food and Drug Administration's biopharmaceutic classification system (BCS) Guidance for Industry. The permeability of ciprofloxacin, levofloxacin, lomefloxacin, and ofloxacin was measured in an in vitro Caco-2 assay with previously demonstrated method suitability. The permeability class and efflux potential were ascertained by comparing test drug results with standard compounds (metoprolol, atenolol, labetalol, and rhodamine-123). All 4 quinolones drugs demonstrated concentration-dependent permeability, indicating active drug transport. In comparing absorptive versus secretive in vitro transport, the tested fluoroquinolones were found to be subject to efflux in varying degrees (ciprofloxacin > lomefloxacin > rhodamine 123 > levofloxacin > ofloxacin). Based on comparison to labetalol, the high permeability internal standard, ciprofloxacin was classified as a low permeability drug, whereas lomefloxacin, levofloxacin, and ofloxacin were classified as high permeability drugs. The in vitro permeability results matched human in vivo data based on absolute bioavailabilities. This laboratory exercise demonstrated the applicability of an in vitro permeability method for classifying drugs as outlined in the BCS Guidance.
PMCID: PMC2751005  PMID: 18465265
permeability; Caco-2; biopharmaceutics classification system; fluoroquinolones
5.  Encapsulation of water-insoluble drug by a cross-linking technique: Effect of process and formulation variables on encapsulation efficiency, particle size, and in vitro dissolution rate 
AAPS PharmSci  2004;6(1):112-119.
Ibuprofen-gelatin micropellets were prepared by the cross-linking technique using formaldehyde. Spherical micropellets having an entrapment efficiency of 65% to 85% were obtained. The effect of core to coat ratio, speed of agitation, temperature, and volume of oil phase was studied with respect to entrapment efficiency, micropellet size, and surface characteristics. Fourier transform infrared spectroscopy and differential scanning calorimetric analysis confirmed the absence of any drug-polymer interaction. X-ray diffraction patterns showed that there is a decrease in crystallinity of the drug. The micromeritic properties of micropellets were found to be slightly changed by changing various processing parameters to give micropellets of good flow property. The in vitro release profile could be altered significantly by changing various processing parameters to give a controlled release of drug from the micropellets. The stability studies of the drug-loaded micropellets showed that the drug was stable at storage conditions of room temperature, 37°C, 25°/60% relative humidity (RH) and 45°/60% RH, for 12 weeks.
PMCID: PMC2750947  PMID: 18465264
ibuprofen; micropellets; gelatin micropellets
6.  Assuring quality and performance of sustained and controlled release parenterals: EUFEPS workshop report 
AAPS PharmSci  2004;6(1):100-111.
This is a summary report of the workshop, organized by the European Federation of Pharmaceutical Scientists in association with the American Association of Pharmaceutical Scientists, the European Agency for the Evaluation of Medicinal Products, the European Pharmacopoeia, the US Food and Drug Administration and the United States Pharmacopoeia, on “Assuring Quality and Performance of Sustained and Controlled Release Parenterals” held in Basel, Switzerland, February 2003. Experts from the pharmaceutical industry, regulatory authorities and academia participated in this workshop to review, discuss and debate formulation, processing and manufacture of sustained and controlled release parenterals, and identify critical process parameters and their control. This workshop was a follow-up workshop to a previous workshop on Assuring Quality and Performance of Sustained and Controlled Release Parenterals that was held in Washington, DC in April 2001. This report reflects the outcome of the Basel 2003 meeting and the advances in the field since the Washington, DC meeting in 2001. As necessary, the reader is referred to the report on the 2001 meeting. Areas were identified at the 2003 Basel meeting where research is needed in order to understand the performance of these drug delivery systems and to assist in the development of appropriate testing procedures. Recommendations were made for future workshops and meetings.
PMCID: PMC2750946  PMID: 18465263
7.  Assessment of fertility in male rats after extended chemical castration with a GnRH antagonist 
AAPS PharmSci  2004;6(1):94-99.
The purpose of this study was to assess whether male rats whose testosterone levels were suppressed to castration levels (<0.5 ng/mL) for a 1-year period by the sustained delivery of orntide acetate, a GnRH antagonist, would return to fertility (ie, produce offspring) after serum testosterone returned to control levels. Male rats comprising a treatment group (orntide microspheres, dose=27 mg/kg/y), a vehicle control group, and a control group of proven male breeders were used. For the treatment and vehicle control groups, serum orntide and testosterone levels were monitored at periodic intervals for 14 months from the initiation of treatment. After serum testosterone levels returned to vehicle control levels and orntide serum levels were no longer discernible for the treated group, each of the animals was housed with 2 drug-naive, female, proven breeders. All the breeder females produced offspring with the exception of 1 female housed with a male rat from the treatment group and the 2 females housed with a single male rat from the vehicle control group. The mean size and weight of the litters from each group were not statistically different. Further, fertility of the offspring from each group was assessed. The male and female offspring studied were all shown to be fertile. The results suggest that lack of fertility due to testosterone suppression in male rats is reversible after cessation of treatment with the GnRH analog, orntide.
PMCID: PMC2750945  PMID: 18465262
orntide acetate; PLA microspheres; return to fertility; chemical castration; GnRH antagonist
8.  Pharmacokinetic model of target-mediated disposition of thrombopoietin 
AAPS PharmSci  2004;6(1):86-93.
Thrombopoietin, TPO, a 353 amino acid cytokine, is a primary regulator of platelet production that was cloned recently. A target-mediated (platelet receptors) pharmacokinetic model was developed to characterize the disposition of TPO. Receptor-mediated endocytosis was assigned as the major elimination pathway in the model. A nonspecific binding compartment was also incorporated into the model. TPO concentration vs time profiles from a published phase 1 and 2 clinical trial were used to apply this model. Noncompartmental analysis demonstrated that TPO exhibits nonlinear kinetics. The proposed model captured the concentration-time profiles relatively well. The first-order internalization rate constant was estimated as 0.1 h−1. The endogenous binding capacity was estimated as 164.0 pM. The second-order binding association constant (kon) was 0.055 h−1·pM−1 and the first-order dissociation constant (koff) was estimated as 2.5 h−1, rendering the equilibrium dissociation constant Kd as 45.5 pM. This model may be relevant to other therapeutic agents with receptor-mediated endocytotic disposition.
PMCID: PMC2750944  PMID: 18465261
thrombopoietin; receptor-mediated drug disposition; pharmacodynamic model
9.  Development and characterization of a recombinant madin-darby canine kidney cell line that expresses rat multidrug resistance-associated protein 1 (rMRP1) 
AAPS PharmSci  2004;6(1):77-85.
Multidrug resistance-associated protein 1 (MRP1) is one of the major proteins shown to mediate efflux transport of a broad range of antitumor drugs, glucuronide conjugates, and glutathione, in addition to endogenous substrates. Significant differences in substrate selectivity were reported for murine and human MRP1. As preclinical drug disposition and pharmacokinetics studies are often conducted in rats, we have recently cloned the rat MRP1 (rMRP1) and demonstrated that rMRP1 expressed in transfected cells effluxes calcein, a commonly used fluorescence substrate for human MRP1. To further characterize the rat ortholog of MRP1, we isolated a cell line stably expressing recombinant rMRP1. These cells were tested for their ability to transport calcein and a range of chemotherapeutic drugs. Our results showed that cells expressing rMRP1 consistently efflux calcein at a rate 5-fold greater than control cells. The rMRP1 transfected cells, like their human ortholog, can confer drug resistance to vinca alkaloid (vinblastine and vincristine) and anthracycline drugs (daunorubcin and doxorubicin), and the resistance conferred by the MRP1 can be partially abolished by the MRP-specific inhibitors. The transepithelial permeability due to rMRP1 expression in differentiated Madin-Darby canine kidney cells (MDCK) cells was also investigated. The MRP1 transport activity is directional, as demonstrated by directional vinblastine transport. Collectively, our results demonstrate that the cellular expression of rMRP1, like its human ortholog, could confer resistance to anticancer drugs.
PMCID: PMC2750943  PMID: 18465260
rat; MRP1; drug resistance; chemotherapeutic agents; cytotoxicity; transport; ATP-binding cassette; transwell
10.  β-cyclodextrin complexes of celecoxib: Molecular-modeling, characterization, and dissolution studies 
AAPS PharmSci  2004;6(1):68-76.
Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of β-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and β-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of β-cyclodextrin and was classified as AL-type, indicating the 1∶1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with β-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.
PMCID: PMC2750942  PMID: 15198508
celecoxib; β-cyclodextrin; complexation; molecular-modeling; phase solubility; characterization; dissolution rate
11.  Physiologically based pharmacokinetics in Drug Development and Regulatory Science: A workshop report (Georgetown University, Washington, DC, May 29–30, 2002) 
AAPS PharmSci  2004;6(1):56-67.
A 2-day workshop on “Physiologically Based Pharmacokinetics (PBPK) in Drug Development and Regulatory Science” came to a successful conclusion on May 30, 2002, in Washington, DC. More than 120 international participants from the environmental and predominantly pharmaceutical industries, Food and Drug Administration (FDA), and universities attended this workshop, organized by the Center for Drug Development Science, Georgetown University, Washington, DC. The first of its kind specifically devoted to the subject, this intensive workshop, comprising 7 plenary presentations and 10 breakout sessions addressed 2 major objectives: (1) to “define demonstrated and potential contributions of PBPK in drug development and regulatory science,” and (2) to “assess current PBPK methodologies with the identification of their limitations and outstanding issues.” This report summarizes the presentations and recommendations that emerged from the workshop, while providing key references, software, and PBPK data sources in the appendices. The first day was initially devoted to presentations setting the stage and providing demonstrated applications to date. This was followed by breakout sessions that considered further opportunities and limitations, and which extended into Day 2 to deal with developments in methodologies and tools. Although the primary emphasis was on pharmacokinetics, consideration was also given to its integration specifically with mechanism-based pharmacodynamics.
PMCID: PMC2750941  PMID: 18465258
12.  Preparation, characterization, and biodistribution study of technetium-99m-labeled leuprolide acetate-loaded liposomes in ehrlich ascites tumor-bearing mice 
AAPS PharmSci  2004;6(1):45-56.
The purpose of this study was to prepare conventional and sterically stabilized liposomes containing leuprolide acetate in an attempt to prolong the biological half life of the drug, to reduce the uptake by reticuloendothelial system (RES), and to reduce the injection frequency of intravenously administered peptide drugs. The conventional and sterically stabilized liposomes containing leuprolide acetate were prepared by reverse phase evaporation method and characterized for entrapment efficiency and particle size. Radiolabeling of leuprolide acetate and its liposomes was performed by direct labeling with reduced technetium-99m. Its biodistribution and imaging characteristics were studied in ehrlich ascites tumor (EAT)-bearing mice after labeling with technetium-99m. The systemic pharmacokinetic studies were performed in rabbits. A high uptake by tumor was observed by sterically stabilized liposome containing leuprolide acetate compared with free drug and conventional liposomes. The liver/tumor uptake ratio of free drug, conventional (LL), and sterically stabilized liposomes (SLL5000 and SLL2000) was found to be 20, 7.99, 1.63, and 1.23, respectively, which showed the increased accumulation of sterically stabilized liposomes in tumor compared with the free drug and conventional liposomes at 24 hours postinjection. Liver uptake of sterically stabilized liposomes was still 7-fold less than the conventional liposomes. The marked accumulation of liposomes in the tumor-bearing mice was also documented by gamma scintigraphic studies. The findings demonstrate the distribution of these liposomes within solid tumor and prove that the sterically stabilized liposomes experience increased tumor uptake and prolonged circulation half life. Hence these findings will be relevant for the optimal design of long circulating liposomes for the peptide drugs and for targeting of liposomes toward tumor.
PMCID: PMC2750940  PMID: 15198506
sterically stabilized liposomes; leuprolide acetate; technetium-99m; biodistribution; gamma imaging
13.  Polyethylene glycol-induced precipitation of interferon alpha-2a followed by vacuum drying: Development of a novel process for obtaining a dry, stable powder 
AAPS PharmSci  2004;6(1):31-44.
Feasibility studies were performed on the development of a novel process based on polyethylene glycol (PEG)-induced precipitation of proteins followed by vacuum drying in the presence of sugars to obtain dry protein powders. Apparent solubility of interferon alpha-2a (IFNα2a) was determined in the presence of various PEGs and the effect of solution pH, ionic strength, and temperature was investigated. IFNα2a precipitate was dried at a shelf temperature of 25°C at 100 mTorr either as it is or in the presence of mannitol and/or trehalose. The dried IFNα2a formulations were subjected to accelerated stability studies at 40°C (3 months), and the stability was compared with that of a similar lyophilized formulation. The results indicated that more than 90% of the protein could be precipitated using 10% wt/vol PEG the protein could be precipitated using 10% wt/vol PEG 1450 at pH 6.5 at a solution ionic strength of 71 mM. Vacuum drying of the precipitate only resulted in the formation of insoluble aggregates of IFNα2a; however, this was prevented by the addition of either mannitol or trehalose. The addition of excess mannitol resulted in low residual moisture content and better handling of the final dried product. Accelerated storage stability did not show any aggregation and showed less than 5% formation of oxidized IFNα2a in the dried formulation containing IFNα2a: trehalose: mannitol in a 1∶10∶100 wt/wt ratio upon storage at 40°C for 3 months. The stability of this vacuum dried formulation was comparable with that of a similar lyophilized formulation.
PMCID: PMC2750939  PMID: 18465256
protein formulation; polyethylene glycol (PEG); precipitation; vacuum drying; protein powders
14.  Solvation and hydration characteristics of ibuprofen and acetylsalicylic acid 
AAPS PharmSci  2004;6(1):22-30.
Ibuprofen and acetylsalicylic acid were studied by thermoanalytical methods: sublimation calorimetry, solution calorimetry, and with respect to solubility. Upon measuring the temperature dependences of the saturated vapor pressure, enthalpies of sublimation, ΔHsub0, as well as the entropies of sublimation, ΔHsub0, and their respective relative fractions in the total process were calculated. The Gibbs energy of solvation in aliphatic alcohols as well as the enthalpic and entropic fractions thereof were also studied and compared with the respective properties of model substances and other nonsteroidal antiinflammatory drugs (benzoic acid, diflunisal, flurbiprofen, ketoprofen, and naproxen). In all cases, enthalpy was found to be the driving force of the solvation process. Correlations were derived between Gibbs energy of solvation in octanol, ΔGsolvOct, and the transfer Gibbs energy from water to octanol, ΔGtr0. Influence of mutual octanol and water solubilities on the driving force of partitioning is discussed. An enthalpy-entropy-compensation effect in octanol was observed, and consequences of deviation from the general trend are also discussed.
PMCID: PMC2750938  PMID: 18465255
ibuprofen; acetylsalicylic acid; NSAID; sublimation; solvation; hydration; plasma half-life
15.  Pharmacokinetics of the time-dependent elimination of all-trans-retinoic acid in rats 
AAPS PharmSci  2004;6(1):1-9.
The time-dependent elimination kinetics of all-transretinoic acid (ATRA) has been associated with autoinduction of its metabolism and has led to the hypothesis that rapid development of acquired clinical resistance to ATRA may be prevented by coadministration of metabolic inhibitors. This study in rats was performed to investigate the pharmacokinetics and onset of timedependent elimination of ATRA, with the purpose of establishing an animal model suitable for in vivo preclinical studies of compounds capable of inhibiting ATRA metabolism. After the intravenous (IV) bolus administration of single doses of ATRA (1.60 mg kg−1 and 0.40 mg kg−1), the plasma concentration-time curves showed an accelerated decline at 180 minutes after dosing. The plasma clearance (Cl) of ATRA, determined after IV administration of a second dose (1.60 mg kg−1), at 180 minutes was greater than Cl after a single dose, thus indicating the existence of a time-dependent elimination process detectable 180 minutes after administration of the first dose. Such time-dependent elimination was confirmed by means of an IV constant-rate infusion of 0.48 mg h−1 kg−1 of ATRA during 10 hours. Peak plasma ATRA concentration was achieved at 180 minutes, after which the plasma concentration decreased to reach a much lower apparent steady-state drug concentration at 420 minutes. The area under the plasma concentration-time curve (AUC) obtained after oral administration of a second ATRA dose (1.60 mg kg−1) was ∼8% of the AUC obtained after a single oral dose; consistent with a time-dependent increase in the elimination of ATRA, as was observed after IV administration.
PMCID: PMC2750936  PMID: 18465253
all-trans-retinoic acid; time-dependent elimination; pharmacokinetic model; rat; intravenous administration; oral administration
16.  A photo-crosslinked poly(vinyl alcohol) hydrogel growth factor release vehicle for wound healing applications 
AAPS PharmSci  2003;5(4):101-111.
The objective of this study was to develop and evaluate a hydrogel vehicle for sustained release of growth factors for wound healing applications. Hydrogels were fabricated using ultraviolet photo-crosslinking of acrylamide-functionalized nondegradable poly(vinyl alcohol) (PVA). Protein permeability was initially assessed using trypsin inhibitor (TI), a 21 000 MW model protein drug. TI permeability was altered by changing the solids content of the gel and by adding hydrophilic PVA fillers. As the PVA content increased from 10% to 20%, protein flux decreased, with no TI permeating through 20% PVA hydrogels. Further increase in model drug release was achieved by incorporating hydrophilic PVA fillers into the hydrogel. As filler molecular weight increased, TI flux increased. The mechanism for this is most likely an alteration in protein/gel interactions and transient variations in water content. The percent protein released was also altered by varying protein loading concentration. Release studies conducted using growth factor in vehicles with hydrophilic filler showed sustained release of platelet-derived growth factor (PDGF-β,β) for up to 3 days compared with less than 24 hours in the controls. In vitro bioactivity was demonstrated by doubling of normal human dermal fibroblas numbers when exposed to growth factor-loaded vehicle compared to control. The release vehicle developed in this study uses a rapid and simple fabrication method, and protein release can be tailored by modifying solid content, incorporating biocompatible hydrophilic fillers, and varying protein loading concentration.
PMCID: PMC2750995  PMID: 15198521
photo-crosslinkable hydrogel; poly(vinyl alcohol); platelet-derived growth factor; bioactivity; sustained release
17.  Pharmacokinetics of paclitaxel-containing liposomes in rats 
AAPS PharmSci  2003;5(4):90-100.
In animal models, liposomal formulations of paclitaxel possess lower toxicity and equal antitumor efficacy compared with the clinical formulation, Taxol. The goal of this study was to determine the formulation dependence of paclitaxel pharmacokinetics in rats, in order to test the hypothesis that altered biodistribution of paclitaxel modifies the exposure of critical normal tissues. Paclitaxel was administered intravenously in either multilamellar (MLV) liposomes composed of phosphatidylglycerol/phosphatidylcholine (L-pac) or in the Cremophor EL/ethanol vehicle used for the Taxol formulation (Cre-pac). The dose was 40 mg/kg, and the infusion time was 8 to 9 minutes. Animals were killed at various times, and pharmacokinetic parameters were determined from the blood and tissue distribution of paclitaxel. The area under the concentration vs time curve (AUC) for blood was similar for the 2 formulations (L-pac: 38.1±3.32 μg-h/mL; Cre-pac: 34.5±0.994 μg-h/mL), however, the AUC for various tissues was formulation-dependent. For bone marrow, skin, kidney, brain, adipose, and muscle tissue, the AUC was statistically higher for Cre-pac. For spleen, a tissue of the reticuloendothelial system that is important in the clearance of liposomes, the AUC was statistically higher for L-pac. Apparent tissue partition coefficients (Kp) also were calculated. For bone marrow, a tissue in which paclitaxel exerts significant toxicity, Kp was 5-fold greater for paclitaxel in Cre-pac. The data are consistent with paclitaxel release from circulating liposomes, but with efflux delayed sufficiently to retain drug to a greater extent in the central (blood) compartment and reduce penetration into peripheral tissues. These effects may contribute to the reduced toxicity of liposomal formulations of paclitaxel.
PMCID: PMC2750994  PMID: 15198520
drug delivery; paclitaxel; liposomes; physiological modeling; cancer chemotherapy
18.  Properties of microcrystalline cellulose and powder cellulose after extrusion/spheronization as studied by fourier transform Raman spectroscopy and environmental scanning electron microscopy 
AAPS PharmSci  2003;5(4):77-89.
In this study, the effect of powder cellulose (PC) and 2 types of microcrystalline cellulose (MCC 101 and MCC 301) on pellet properties produced by an extrusion/spheronization process was investigated. The different investigated types of cellulose displayed different behavior during the extrusion/spheronization process. Pure PC was unsuitable for extrusion, because too much water was required and the added water was partly squeezed during the extrusion process. In contrast, MCC 101 and MCC 301 were extrudable at a wide range of water content, but the quality of the resulting products varied. In the extrusion/spheronization process, MCC 101 was the best substance, with easy handling and acceptable product properties. The properties of the extrudates and pellets were determined by Fourier transform (FT) Raman spectroscopy and environmental scanning electron microscopy (ESEM). FT-Raman spectroscopy was able to distinguish between the original substances and also between the wet and dried extrudates. The particle sizes of the raw material and of the extrudates were determined by ESEM without additional preparation. For MCC, the size of the resulting particles within the extrudate or pellet was smaller. However, in the extrudates of PC, changes in particle size could not be observed.
PMCID: PMC2750993  PMID: 15198519
powder cellulose; microcrystalline cellulose; pellet; Raman spectroscopy; environmental scanning electron microscopy; extrusion/spheronization
19.  Lipid-based supramolecular systems for topical application: A preformulatory study 
AAPS PharmSci  2003;5(4):62-76.
This article describes the production and characterization of monoglyceride-based supramolecular systems by a simple processing technique, avoiding time-consuming procedures, high energy input, and the use of organic solvents. A preformulatory study was performed to study the influence of the experimental parameters on the production of monoglyceride-based disperse systems. In particular the effects of (1) stirring speed, (2) type and concentration of monoglyceride mixture, and (3) type and concentration of surfactant were investigated on the recovery, fraction of larger particles, mean diameter, and shape of smaller particles (so called nanosomes). Dispersions were first characterized by optical microscopy and freeze-fracture electron microscopy. The mean diameter of standard nanosomes, analyzed by photon correlation spectroscopy (PCS) after elimination of larger particles by filtration, was 193.5 nm. Cryotransmission electron microscopy studies, conducted in order to investigate the structure of dispersions, showed the coexistence of vesicles and particles characterized by a cubic organization. X-ray diffraction data revealed the coexistence of 2 different cubic phases, the first being a bicontinuous cubic phase of spatial symmetry Im3m (Q229) and the second belonging to the Pn3m spatial symmetry. A study on the stability of monoglyceride-based dispersions based on macroscopical analysis of organoleptic properties and dimensional analysis by time was performed after elimination of larger particles by filtration. Organoleptic and morphological features do not change by time, appearing free from phase-separation phenomena for almost 1 year from production. PCS studies showed that nanosomes undergo an initial increase in mean diameter within the first month following production; afterwards they generally maintain their dimensions for the next 4 months.
PMCID: PMC2750992  PMID: 15198518
monoglycerides; nanosome dispersions; photon correlation spectroscopy
20.  Pharmacogenomics of multigenic diseases: Sex-specific differences in disease and treatment outcome 
AAPS PharmSci  2003;5(4):49-61.
Numerous genetic variations have been shown to affect disease susceptibility and drug response. Pharmacogenomics aims at improving therapy on the basis of genetic information for each individual patient. Furthermore, sex chromosomes broadly determine biological differences between males and females. Consequently, substantial sex differences exist in phenotypic manifestation of disease and treatment response. This review discusses the role of sex in coronary artery disease, schizophrenia, and depression—complex multigenic disorders with considerable sex differences in frequency and presentation. Moreover, genetic factors underlying disease and drug response appear to differ between male and female patients. This appears to result at least in part from different physiological effects exerted by sex hormones such that polymorphisms in susceptibility genes may have physiological relevance only in males or females. However, few examples have been discovered to play a role in complex multigenic diseases, and the mechanistic basis of genetic variants as sex-dependent susceptibility factors has yet to be explored. Therefore, pharmacogenomic studies must consider sex differences in an effort to optimize individual drug therapy.
PMCID: PMC2750991  PMID: 15198517
pharmacogenomics; sex differences; multigenic disease; candidate genes; coronary artery disease; depression; schizophrenia
21.  Hydroxyzine from topical phospholipid liposomal formulations: Evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model 
AAPS PharmSci  2003;5(4):41-48.
Hydroxyzine, an effective but sedating H1-antihistamine is given orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of hydroxyzine from liposomes applied to the skin. Using L-α-phosphatidylcholine (PC), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) containing hydroxyzine were prepared. Hydroxyzine in Glaxal Base (GB) was used as the control. Using a randomized, crossover design, each formulation, containing 10 mg of hydroxyzine, was applied to the shaved backs of 6 rabbits (3.08±0.05 kg). Histamine-induced wheal tests and blood sampling were performed at designated time intervals up to 24 hours. Compared with baseline, hydroxyzine from all formulations significantly suppressed histamine-induced wheal formation by 75% to 95% for up to 24 hours. Mean maximum suppression, 85% to 94%, occurred from 2 to 6 hours, with no differences among the formulations. The areas of plasma hydroxyzine concentration versus time area under the curve (AUCs) from PC-SUV and PC-MLV, 80.1±20.8 and 78.4±33.9 ng/mL/h, respectively, were lower than that from GB, 492±141 ng/mL/h (P<.05) over 24 hours. Plasma concentrations of cetirizine arising in-vivo as the active metabolite of hydroxyzine, from PC-SUV, PC-MLV, and GB, were similar with AUCs of 765±50, 1035±202, and 957±227 ng/mL/h, respectively (P<.05). Only 0.02% to 0.06% of the initial hydroxyzine dose remained on the skin after 24 hours. In this model, hydroxyzine from SUV and MLV had excellent topical H1-antihistaminic activity, and minimal systemic exposure occurred. Cetirizine formed in-vivo contributed to some of H1-antihistaminic activity.
PMCID: PMC2750990  PMID: 15198516
hydroxyzine; L-α-phosphatidylcholine; liposomes; antihistamine; skin; rabbit
22.  AAPS/RAPS/CAPRA collaborative program: Exploring the challenges of drug regulation in a global environment: Clinical concerns 
AAPS PharmSci  2003;5(4):13-40.
Globalization of the pharmaceutical industry has led to a need to harmonize the regulatory requirements governing the marketing of medicinal products. To minimize the barriers impeding global drug product registration, the International Conference on the Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) was established in 1990. The ICH has developed a series of guidelines that reflect agreements reached by participating nations on aspects of the chemistry and clinical technical sections that will fulfill the regulatory requirements of these various jurisdications. Nevertheless, there continue to be points of divergent perspectives and barriers that can impede the use of foreign clinical data. Given the importance of these issues, the Regulatory Science (RS) section of the American Association of Pharmaceutical Scientists (AAPS), in conjunction with the Regulatory Affairs Professional Society (RAPS) and the Canadian Association of Professional Regulatory Affairs (CAPRA) cosponsored a public forum on this topic. This manuscript provides a summary of the speaker presentations and audience discussions regarding the design of clinical trials and the extrapolation of results from these trials to support international drug registration.
PMCID: PMC2750989  PMID: 15198515
clinical trials; regulatory requirements; international harmonization; foreign clinical data
23.  Amphiphilic star-like macromolecules as novel carriers for topical delivery of nonsteroidal anti-inflammatory drugs 
AAPS PharmSci  2003;5(4):1-12.
The objective of this study was to evaluate amphiphilic star-like macromolecules (ASMs) as a topical drug delivery system. Indomethacin, piroxicam, and ketoprofen were individually encapsulated into the ASMs using coprecipitation. The effects of the ASMs on percutaneous permeation of nonsteroidal anti-inflammatory drugs (NSAIDs) across full thickness, hairless mouse skin were evaluated in vitro using modified Franz diffusion cells. In addition, solubility and in vitro release experiments were performed to characterize ASMs behavior in aqueous media. Poly(ethylene glycol) (PEG) and Pluronic P-85 were used as polymer controls to compare the role of PEG and amphiphilic behavior in the ASMs. In vitro release experiments indicated that ASMs can delay drug release (P⋖05), whereas solubility measurements showed that ASMs can increase NSAIDs aqueous solubility (P⋖05). Percutaneous permeation studies revealed that ASMs decreased both flux and Q24 of drugs compared with the control (P⋖10). Skin pretreatment studies with ASM-containing solution before drug application demonstrated that pretreatment similarly influenced NSAID percutaneous permeation. In conclusion, ASMs likely slow drug permeation through 2 mechanisms, delayed drug diffusion from its core and skin dehydration by its shell. Thus, ASMs may be useful for delayed dermal delivery or prevention of compound permeation through the skin (eg, sunscreens, N,N-diethyl-m-toluamide [DEET]) from aqueous formulations.
PMCID: PMC2750988  PMID: 15198514
topical drug delivery; NSAIDs; polymeric micelle; permeation; drug release
24.  Nutraceutical-definition and introduction 
AAPS PharmSci  2003;5(3):27-28.
Dr Stephen DeFelice coined the term “Nutraceutical” from “Nutrition” and “Pharmaceutical” in 1989. The term nutraceutical is being commonly used in marketing but has no regulatory definition. An attempt to redefine nutraceuticals and functional foods is made in this article. The proposed definitions can help distinguish between functional foods, nutraceuticals, and dietary supplements. The advantages and disadvantages of nutraceuticals are also briefly discussed.
PMCID: PMC2750935  PMID: 14621960
nutraceutical; functional food; dietary supplement
25.  High glucose concentration in isotonic media alters Caco-2 cell permeability 
AAPS PharmSci  2003;5(3):17-25.
Caco-2 cell permeability was evaluated in isotonic media containing high (25mM) or physiological (5.5mM) glucose concentrations. Transepithelial electrical resistance (TEER) and membrane fluidity were measured to assess glucose-induced alterations in physical barrier properties. In parallel, distribution of the actin filament (F-actin) and zonula occludens-1 (ZO-1) proteins was assessed by confocal microscopy. Transepithelial fluxes of mannitol, hydrocortisone, digoxin, and glycyl sarcosine (Gly-Sar) that permeate the intestinal mucosa by various pathways were measured to quantify the effect of glucose-induced changes on Caco-2 cell permeability. High glucose decreased maximum TEER of cell monolayers by 47%, whereas membrane fluidity at the hydrophobic core and lipid/polar head interphase was significantly increased. F-actin distribution in high glucose cells appeared more diffuse while ZO-1 was unchanged. Mannitol and hydrocortisone fluxes across Caco-2 cells cultured in high glucose increased by 65% and 24%, respectively. In addition, high glucose decreased the maximum transport capacity (Vmax) of PepT-1. P-glycoprotein activity, however, was unchanged. In conclusion, high extracellular glucose concentration in isotonic media significantly alters physical barrier properties of Caco-2 cell monolayers, which predominantly affects transepithelial transport of solutes permeating the cell barrier by paracellular and transcellular passive diffusion and facilitated transport mediated by the proton-dependent oligopeptide transporter (PepT-1).
PMCID: PMC2750934  PMID: 14621959
Caco-2; glucose; tight junctions; TEER; membrane fluidity; solute flux

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