ALBERT

Description: ABSTRACT Purpose   To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug–drug interaction (DDI) risk using static mechanistic models. Methods   Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of K I and k inact . Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI. Results   Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The k inact /K I ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent–drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected. Conclusions   13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors. Content Type Journal Article Category Research Paper Pages 1-17 DOI 10.1007/s11095-012-0724-6 Authors Jane R. Kenny, Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California 94080, USA Sophie Mukadam, Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California 94080, USA Chenghong Zhang, Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California 94080, USA Suzanne Tay, Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California 94080, USA Carol Collins, Department of Pharmaceutics, University of Washington, Seattle, USA Aleksandra Galetin, Center for Applied Pharmacokinetic Research School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, UK S. Cyrus Khojasteh, Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California 94080, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   The work aims at investigating the correlation of water sorption potential with different measures of molecular mobility in an annealed amorphous model compound (trehalose). Methods   Amorphous trehalose, prepared by freeze-drying, was annealed at 100°C (17°C 〈 T g ) for up to 120 h. Global molecular mobility was studied using a broadband dielectric spectrometer in the frequency range of 10 6 –10 −2  Hz. Enthalpic recovery was measured by differential scanning calorimetry and water sorption profiles were obtained using an automated vapor sorption balance. Results   As a function of annealing time, there was an increase, both in average α -relaxation time and enthalpic recovery and a decrease in the amount of sorbed water. A strong linear correlation was observed between the water sorption potential and the dielectric relaxation time, indicating a common underlying mechanism of the effect of annealing time on these properties. Enthalpic recovery, which is widely used as a measure of structural relaxation, did not correlate well with the extent of water sorption. Conclusions   The α -relaxation time can be used as a predictor of the water sorption potential of amorphous trehalose. It will be of interest and value to develop such predictive models for other amorphous compounds of pharmaceutical interest. Content Type Journal Article Category Research Paper Pages 1-7 DOI 10.1007/s11095-012-0910-6 Authors Sunny P. Bhardwaj, Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA Raj Suryanarayanan, Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   To evaluate skin permeation enhancement mediated by fractional laser for different permeants, including hydroquinone, imiquimod, fluorescein isothiocyanate-labeled dextran (FD), and quantum dots. Methods   Skin received a single irradiation of a fractional CO 2 laser, using fluence of 2 or 4 mJ with densities of 100 ∼ 400 spots/cm 2 . In vitro and in vivo skin penetration experiments were performed. Fluorescence and confocal microscopies for imaging delivery pathways were used. Results   The laser enhanced flux of small-molecule drugs 2 ∼ 5-fold compared to intact skin. A laser fluence of 4 mJ with a 400-spot/cm 2 density promoted FD flux at 20 and 40 kDa from 0 (passive transport) to 0.72 and 0.43 nmol/cm 2 /h, respectively. Microscopic images demonstrated a significant increase in fluorescence accumulation and penetration depth of macromolecules and nanoparticles after laser exposure. Predominant routes for laser-assisted delivery may be intercellular and follicular transport. CO 2 laser irradiation produced 13-fold enhancement in follicular deposition of imiquimod. Laser-mediated follicular transport could deliver permeants to deeper strata. Skin barrier function as determined by transepidermal water loss completely recovered by 12 h after irradiation, much faster than conventional laser treatment (4 days). Conclusions   Fractional laser could selectively enhance permeant targeting to follicles such as imiquimod and FD but not hydroquinone, indicating the importance of selecting feasible drugs for laser-assisted follicle delivery. Content Type Journal Article Category Research Paper Pages 1-11 DOI 10.1007/s11095-012-0920-4 Authors Woan-Ruoh Lee, Graduate Institute of Medical Sciences,, Taipei Medical University, Taipei, 110 Taiwan Shing-Chuan Shen, Graduate Institute of Medical Sciences,, Taipei Medical University, Taipei, 110 Taiwan Saleh A. Al-Suwayeh, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia Hung-Hsu Yang, Graduate Institute of Medical Sciences,, Taipei Medical University, Taipei, 110 Taiwan Yi-Ching Li, Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan Jia-You Fang, Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, 259 Wen-Hwa 1st Road, Kweishan, Taoyuan 333, Taiwan Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT   One of the most challenging problems facing modern medicine is how to deliver a given drug to a specific target at the exclusion of other regions. For example, a variety of compounds have beneficial effects within the central nervous system (CNS), but unwanted side effects in the periphery. For such compounds, traditional oral or intravenous drug delivery fails to provide benefit without cost. However, intranasal delivery is emerging as a noninvasive option for delivering drugs to the CNS with minimal peripheral exposure. Additionally, this method facilitates the delivery of large and/or charged therapeutics, which fail to effectively cross the blood-brain barrier (BBB). Thus, for a variety of growth factors, hormones, neuropeptides and therapeutics including insulin, oxytocin, orexin, and even stem cells, intranasal delivery is emerging as an efficient method of administration, and represents a promising therapeutic strategy for the treatment of diseases with CNS involvement, such as obesity, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, depression, anxiety, autism spectrum disorders, seizures, drug addiction, eating disorders, and stroke. Content Type Journal Article Category Expert Review Pages 1-10 DOI 10.1007/s11095-012-0915-1 Authors Colin D. Chapman, Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden William H. Frey II, Alzheimer’s Research Center at Regions Hospital HealthPartners Research Foundation, St. Paul, Minnesota, USA Suzanne Craft, J. Paul Sticht Center on Aging Dept. of Internal Medicine Section on Gerontology & Geriatric Medicine Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA Lusine Danielyan, Department of Clinical Pharmacology, University Hospital of Tübingen, Tübingen, Germany Manfred Hallschmid, Department of Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany Helgi B. Schiöth, Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden Christian Benedict, Department of Neuroscience, Uppsala University, Box 593, Husargatan 3, Uppsala, Sweden Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To investigate the heating-induced dehydration and melting behavior of the trihydrate phase of the calcium salt of atorvastatin. Methods   Multivariate curve resolution (MCR) was used to decompose a variable-temperature synchrotron X-ray powder diffraction (VT-XRPD) data matrix into diffraction patterns and concentration profiles of pure drug phases. Results   By means of the MCR-estimated diffraction patterns and concentration profiles, the trihydrate phase of the drug salt was found to dehydrate sequentially into two partially dehydrated hydrate structures upon heating from 25 to 110°C, with no associated breakage of the original crystal lattice. During heating from 110 to 140°C, the remaining water was lost from the solid drug salt, which instantly collapsed into a liquid crystalline phase. An isotropic melt was formed above 155°C. Thermogravimetric analysis, hot-stage polarized light microscopy, and hot-stage Raman spectroscopy combined with principal component analysis (PCA) was shown to provide consistent results. Conclusions   This study demonstrates that MCR combined with VT-XRPD is a powerful tool for rapid interpretation of complex dehydration behavior of drug hydrates, and it is also the first report on a liquid crystalline phase of the calcium salt of atorvastatin. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0923-1 Authors Niels Peter Aae Christensen, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Bernard Van Eerdenbrugh, Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA Kaho Kwok, Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA Lynne S. Taylor, Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, Indiana, USA Andrew D. Bond, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, Denmark Thomas Rades, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Jukka Rantanen, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Claus Cornett, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   To evaluate the potential usage of D 2 receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development. Methods   In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 ( n  = 3), 1 ( n  = 2), or 3 mg ( n  = 3) of haloperidol once daily for 7 days. PET’s were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D 2 receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens. Results   One compartment model with a saturable binding compartment, and inhibitory E max model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose. Conclusion   This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D 2 antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation. Content Type Journal Article Category Research Paper Pages 1-11 DOI 10.1007/s11095-012-0906-2 Authors Hyeong-Seok Lim, Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea Su Jin Kim, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Yook-Hwan Noh, Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea Byung Chul Lee, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Seok-Joon Jin, Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea Hyun Soo Park, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Soohyeon Kim, Clinical Trial Center, Asan Medical Center, Seoul, Republic of Korea In-Jin Jang, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea Sang Eun Kim, Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumi-dong, Bundang-gu, Seongnam, 463-707 Republic of Korea Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   To improve the solubility and penetration of Ceramide AP (CER [AP]) into the stratum corneum that potentially restores the barrier function of aged and affected skin. Methods   CER [AP] microemulsions (MEs) were formulated using lecithin, Miglyol® 812 (miglyol) and water-1,2 pentandiol (PeG) mixture as amphiphilic, oily and hydrophilic components, respectively. The nanostructure of the MEs was revealed using electrical conductivity, differential scanning calorimeter (DSC) and electron paramagnetic resonance (EPR) techniques. Photon correlation spectroscopy (PCS) was used to measure the sizes and shape of ME droplets. The release and penetration of the CER into the stratum corneum was investigated in vitro using a multi-layer membrane model. Results   The MEs exhibited excellent thermodynamic stability (〉2 years) and loading capacity (0.5% CER [AP]). The pseudo-ternary phase diagrams of the MEs were obtained and PCS results showed that the droplets are spherical in shape and bigger in size. In vitro investigations showed that the MEs exhibited excellent rate and extent of release and penetration. Conclusions   Stable lecithin-based CER [AP] MEs that significantly enhance the solubility and penetration of CER [AP] into the stratum corneum were developed. The MEs also have better properties than the previously reported polyglycerol fatty acid surfactant-based CER [AP] MEs. Content Type Journal Article Category Research Paper Pages 1-14 DOI 10.1007/s11095-012-0899-x Authors Fitsum F. Sahle, Dept. of Pharmaceutical Technology & Biopharmaceutics Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Hendrik Metz, Dept. of Pharmaceutical Technology & Biopharmaceutics Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Johannes Wohlrab, Department of Dermatology and Venereology Medical Faculty, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Reinhard H. H. Neubert, Dept. of Pharmaceutical Technology & Biopharmaceutics Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   Clinical application of cationic polymers for delivery of nucleic acids has been limited by their toxicity. The purpose of this study is to evaluate whether the polymer-in-lipid hybrid nanotechnology recently developed for controlled siRNA delivery can tackle this toxicity issue by reducing exposure of the cellular components to free cationic polymers. Methods   Lipid-polymer hybrid nanocarriers (LPNs) encapsulating complexes of hexadecylated polyethylenimine (H-PEI) and biologically inactive siRNA in lipids were prepared at different lipid-polymer ratios. Comparative toxicity of these LPNs and unencapsulated cationic materials on breast epithelial cell lines MDA-MB-231 and MCF-10a was evaluated. Results   Even at a low lipid-polymer ratio (3:1 w/w), encapsulation of H-PEI improved its LC 50 values measured within hours by 3–5 fold, and caused less reduction in the colony-formation rates in 10–14 days. The observed reductions in the acute and delayed carrier toxicity were associated with significantly less membrane damages, improved mitochondrial functions, reduced reactive oxidative species production, and lower caspase-3 activity (all p  〈 0.05) without sacrificing the siRNA transfection efficiency. Conclusions   This study has validated the hybrid nanotechnology for controlled RNA delivery from a toxicological perspective. This is especially valuable if local or long-term RNA therapy is intended for which low carrier toxicity is essential. Content Type Journal Article Category Research Paper Pages 1-12 DOI 10.1007/s11095-012-0902-6 Authors Hui Yi Xue, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, USA Mayuri Narvikar, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, USA Juan-Bao Zhao, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, USA Ho Lun Wong, Department of Pharmaceutical Sciences, Temple University School of Pharmacy, 3307 North Broad Street, Philadelphia, Pennsylvania 19140, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To develop liquid crystalline phases with monoglycerides, and assess whether the monoglyceride type favors cutaneous over transdermal paclitaxel delivery. Methods   BRIJ-based lamellar phases were prepared with 0.5% paclitaxel and 20% of either monocaprylin (LP-MC), monomyristolein (LP-MM) or monoolein (LP-MO). Skin electrical resistance, drug release and cutaneous delivery in vitro and in vivo were assessed. Viability of skin equivalents and release of IL-1α were assessed as indexes of irritation potential. Results   An inverse relationship between monoglyceride acyl chain length and amount of paclitaxel delivered was observed. Although the largest paclitaxel amounts were delivered by LP-MC, all formulations delivered higher levels of drug in the skin (56–64-fold) than across the tissue. The superiority of LP-MC seems related to a stronger decrease in skin resistance (as an index of permeability), and not to increased drug release. LP-MC displayed similar penetration-enhancing ability in vivo, and a much lower irritation potential than Triton-X100 (a moderate irritant), leading to 3-fold higher skin equivalent viability and release of 60-fold less IL-1α. Conclusions   Even though LP-MC delivered the largest amounts of paclitaxel, all formulations provided similar cutaneous/transdermal delivery ratios, suggesting that changing the monoglyceride acyl chain length did not affect the balance between cutaneous and transdermal delivery. Content Type Journal Article Category Research Paper Pages 1-13 DOI 10.1007/s11095-012-0908-0 Authors Jaclyn M. Hosmer, Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave., Albany, New York 12208, USA Alexandre A. Steiner, Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave., Albany, New York 12208, USA Luciana B. Lopes, Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, 106 New Scotland Ave., Albany, New York 12208, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   To improve the delivery of liposomes to tumors using P-selectin glycoprotein ligand 1 (PSGL1) mediated binding to selectin molecules, which are upregulated on tumorassociated endothelium. Methods   PSGL1 was orientated and presented on the surface of liposomes to achieve optimal selectin binding using a novel streptavidin-protein G linker molecule. Loading of PSGL1 liposomes with luciferin allowed their binding to e-selectin and activated HUVEC to be quantified in vitro and their stability, pharmacokinetics and tumor accumulation to be tested in vivo using murine models. Results   PSGL1 liposomes showed 5-fold ( p  〈 0.05) greater selectin binding than identically formulated control liposomes modified with ligand that did not contain the selectin binding domain. When added to HUVEC, PSGL1 liposomes showed 〉7-fold ( p  〈 0.001) greater attachment than control liposomes. In in vivo studies PSGL1 liposomes showed similar stability and circulation to control liposomes but demonstrated a 〉3-fold enhancement in the level of delivery to tumors ( p  〈 0.05). Conclusions   The technologies and strategies described here may contribute to clinical improvements in the selectivity and efficacy of liposomal drug delivery agents. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0875-5 Authors Robert Carlisle, University of Oxford, Oxford, UK Leonard W. Seymour, University of Oxford, Oxford, UK Constantin C. Coussios, University of Oxford, Oxford, UK Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741