ALBERT

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

Description: ABSTRACT Purpose   To develop PEGylated multi-walled carbon nanotubes as a sustained release drug delivery system. Methods   Oxaliplatin was incorporated into inner cavity of PEGylated multi-walled carbon nanotubes (MWCNT-PEG) using nano-extraction. Oxaliplatin release rates from MWCNT-PEG-Oxaliplatin were investigated using dialysis tubing. Cytotoxicity of oxaliplatin, MWCNT-Oxaliplatin and MWCNT-PEG-Oxaliplatin were evaluated in HT29 cell by MTT assay, Pt-DNA adducts formation, γ-H2AX formation and cell apoptosis assay. Results   Loading of oxaliplatin into MWCNT-PEG was ~43.6%. Sustained release occurred to MWCNT-PEG-Oxaliplatin, with only 34% of oxaliplatin released into medium within 6 h. In MTT assay, MWCNT-PEG-Oxaliplatin showed slightly decreased cytotoxic effect when cell viability was assessed at 12 and 24 h. A drastic increase of cytotoxicity was found when cell viability was assessed at 48 and 96 h. Pt-DNA adducts formation, γ-H2AX formation and cell apoptosis assay results showed the same trend as the MTT assay, suggesting sustained-release for MWCNT-Oxaliplatin and MWCNT-PEG-Oxaliplatin formulations. Conclusions   PEGylated multi-walled carbon nanotubes can be used as sustained release drug delivery system, thus remarkably improving cytotoxicity of oxaliplatin on HT-29 cells. Content Type Journal Article Category Research Paper Pages 1-12 DOI 10.1007/s11095-012-0883-5 Authors Linlin Wu, Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital & Shandong University, 16766 Jingshi Road, Jinan, People’s Republic of China 250014 Changjun Man, Department of Clinical Laboratory, Jining Hospital of Infectious Diseases, Jiumiguzui Northern Suburb of Jining, Jining, People’s Republic of China 272031 Hong Wang, Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Rd., Jinan, People’s Republic of China 250014 Xiaohe Lu, Shandong Academy of Medical Sciences, Shandong Provincial Qianfoshan Hospital, 16766 Jingshi Rd., Jinan, People’s Republic of China 250014 Qinghai Ma, Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital & Shandong University, 16766 Jingshi Road, Jinan, People’s Republic of China 250014 Yu Cai, School of Pharmacy, Jinan University, 601 W Huangpu Rd., Guangzhou, People’s Republic of China 510632 Wanshan Ma, Department of Laboratory Medicine, Shandong Provincial Qianfoshan Hospital & Shandong University, 16766 Jingshi Road, Jinan, People’s Republic of China 250014 Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   To understand the transformation pathways amongst anhydrate/hydrate solid forms of sodium naproxen and to highlight the importance of a polymorphic dihydrate within this context. Methods   Multi-temperature dynamic vapour sorption (DVS) analysis combined with variable-humidity X-ray powder diffraction (XRPD) to establish the transformation pathways as a function of temperature and humidity. XRPD and thermogravimetric analysis (TGA) to characterise bulk samples. Monitoring of in-situ dehydration using solid-state 13 C CP/MAS spectroscopy. Results   At 25°C, anhydrous sodium naproxen (AH) transforms directly to one dihydrate polymorph (DH-II). At 50°C, AH transforms stepwise to a monohydrate (MH) then to the other dihydrate polymorph (DH-I). DH-II transforms to a tetrahydrate (TH) more readily than DH-I transforms to TH. Both dihydrate polymorphs transform to the same MH. Conclusions   The properties of the polymorphic dihydrate control the transformation pathways of sodium naproxen. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0872-8 Authors Dhara Raijada, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100 Denmark Andrew D. Bond, Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Odense, 5230 Denmark Flemming H. Larsen, Department of Food Science, Faculty of Life Sciences, University of Copenhagen, Frederiksberg C, 1958 Denmark Claus Cornett, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100 Denmark Haiyan Qu, Institute of Chemical Engineering, Biotechnology and Environmental Technology, University of Southern Denmark, Odense, 5230 Denmark Jukka Rantanen, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100 Denmark Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   Pulmonary administration of polymeric nanoparticle drug delivery systems is of great interest for both systemic and local therapies. However, little is understood about the relationship of particle size and pulmonary absorption. We investigated uptake and biodistribution of polystyrene nanoparticles (PN) of 50 nm, 100 nm, 250 nm, and 900 nm diameters in mice following administration to lungs via pharyngeal aspiration. Methods   The amount of PN in tissues was analyzed by gel permeation chromatography (GPC). Results   At 1 h, larger diameter PN (250 nm and 900 nm) had the highest total uptake at around 15% of administered dose, whereas the smaller diameter PN (50 nm and 100 nm) had uptake of only 5–6%. However, at 3 h, the 50 nm PN had the highest total uptake at 24.4%. For each size tested, the highest nanoparticle deposition was observed in the lymph nodes (LN) as compared to other tissues accounting for a total of about 35–50% of absorbed nanoparticles. Conclusion   PN size impacts the rate and extent of uptake from lungs and, further, the extent of LN deposition. The extent of uptake and lymph distribution of the model, non-degradable PN lends potential to pulmonary administered, biodegradable polymeric nanoparticles for delivery of therapeutics to regional lymph nodes. Content Type Journal Article Category Research Paper Pages 1-11 DOI 10.1007/s11095-012-0884-4 Authors Abdul Khader Mohammad, Department of Pharmaceutical Sciences Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan 48201, USA Lenah K. Amayreh, Department of Pharmaceutical Sciences Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan 48201, USA John M. Mazzara, Department of Pharmaceutical Sciences Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan 48201, USA Joshua J. Reineke, Department of Pharmaceutical Sciences Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan 48201, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To evaluate using cationic polymeric nanoparticles that interact with hyaluronate to form ionically cross-linked hydrogels to increase the intra-articular retention time of osteoarthritis drugs in the synovial cavity. Methods   In vitro tests included nanoparticle release from cross-linked hydrogels using syringe and membrane dissolution tests, viscosity measurement of synovial fluid containing hydrogels, and release-rate measurement for a model active conjugated to a cationically substituted dextran using a hydrolyzable ester linkage in a sink dissolution test. Nanoparticle retention after intra-articular injection into rat knees was measured in vivo using fluorescence molecular tomography. Results   Diffusional and convective transport of cationic nanoparticles from ionically cross-linked hydrogels formed in synovial fluid was slower in vitro than for uncharged nanoparticles. Hydrogels formed after the nanoparticles were mixed with synovial fluid did not appreciably alter the viscosity of the synovial fluid in vitro . In vitro release of a conjugated peptide from the cationic nanoparticles was approximately 20% per week. After intra-articular injection in rat knees, 70% of the nanoparticles were retained in the joint for 1 week. Conclusions   This study demonstrates the feasibility of using cationic polymeric nanoparticles to increase the retention of therapeutic agents in articular joints for indications such as osteoarthritis. Content Type Journal Article Category Research Paper Pages 1-12 DOI 10.1007/s11095-012-0870-x Authors Michael Morgen, Bend Research Inc., 64550 Research Road, Bend, Oregon 97701, USA David Tung, BioMed Valley Discoveries, Kansas City, Missouri, USA Britton Boras, Departments of Medicine and Bioengineering, University of California—San Diego, San Diego, California, USA Warren Miller, Bend Research Inc., 64550 Research Road, Bend, Oregon 97701, USA Anne-Marie Malfait, Rush University Medical Center, Chicago, Illinois, USA Micky Tortorella, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Beijing, China Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   Computer simulations are utilized during pharmaceutical development in order to design appropriate formulation based on the absorption, distribution, metabolism, and excretion (ADME) and physicochemical properties of target compounds, so that adequate prescriptions are offered to patients. Oro-cecal transit time (OCTT) is an important factor affecting these simulations because the absorption of drug that administered orally and the resultant pharmacokinetic profile are expressed as a function of time. Given the large intra- and inter-individual variance in OCTT, it is unsurprising that an accurate model has not yet been proposed. Methods   We conducted a meta-analysis using subject-level data to construct a statistical model that predicted OCTT. Literature that utilized lactulose to measure OCTT was identified and analyzed using a mixed-effects model. Results   The OCTTs of fasting healthy subjects were expressed using a linear model, with the amount of lactulose as the single significant explanatory factor. We found that this model could statistically distinguish the OCTTs of subjects with altered physical status from those of healthy people. Specifically, cystic fibrosis and celiac disease most significantly affected OCTT. Conclusion   The OCTT models developed herein incorporate inter-subject variations and can contribute to providing more accurate predictions of drug pharmacokinetic profiles. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0882-6 Authors Tohru Kokubo, The Graduate University for Advanced Studies, Shonan Village, Hayama, Kanagawa 240-0193, Japan Shigeyuki Matsui, The Graduate University for Advanced Studies, Shonan Village, Hayama, Kanagawa 240-0193, Japan Makio Ishiguro, The Graduate University for Advanced Studies, Shonan Village, Hayama, Kanagawa 240-0193, Japan Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: AAPS Connection Content Type Journal Article Pages 1-3 DOI 10.1007/s11095-012-0887-1 Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description:    Pulmonary vaccine delivery has gained significant attention as an alternate route for vaccination without the use of needles. Immunization through the pulmonary route induces both mucosal and systemic immunity, and the delivery of antigens in a dry powder state can overcome some challenges such as cold-chain and availability of medical personnel compared to traditional liquid-based vaccines. Antigens formulated as nanoparticles (NPs) reach the respiratory airways of the lungs providing greater chance of uptake by relevant immune cells. In addition, effective targeting of antigens to the most ‘professional’ antigen presenting cells (APCs), the dendritic cells (DCs) yields an enhanced immune response and the use of an adjuvant further augments the generated immune response thus requiring less antigen/dosage to achieve vaccination. This review discusses the pulmonary delivery of vaccines, methods of preparing NPs for antigen delivery and targeting, the importance of targeting DCs and different techniques involved in formulating dry powders suitable for inhalation. Content Type Journal Article Category Expert Review Pages 1-17 DOI 10.1007/s11095-012-0891-5 Authors Nitesh K. Kunda, Formulation and Drug Delivery Research School of Pharmacy and Biomolecular Science, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool, L3 3AF UK Satyanarayana Somavarapu, Department of Pharmaceutics, School of Pharmacy, University College London, London, UK Stephen B. Gordon, Respiratory Infection Group, Liverpool School of Tropical Medicine, Liverpool, UK Gillian A. Hutcheon, Formulation and Drug Delivery Research School of Pharmacy and Biomolecular Science, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool, L3 3AF UK Imran Y. Saleem, Formulation and Drug Delivery Research School of Pharmacy and Biomolecular Science, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool, L3 3AF UK Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To identify the effects of cross-linkers and drug-binding linkers on physicochemical and biological properties of polymer nanoassembly drug carriers. Methods   Four types of polymer nanoassemblies were synthesized from poly(ethylene glycol)-poly(aspartate) [PEG-p(Asp)] block copolymers: self-assembled nanoassemblies (SNAs) and cross-linked nanoassemblies (CNAs) to each of which an anticancer drug doxorubicin (DOX) was loaded by either physical entrapment or chemical conjugation (through acid-sensitive hydrazone linkers). Results   Drug loading in nanoassemblies was 27 ~ 56% by weight. The particle size of SNA changed after drug and drug-binding linker entrapment (20 ~ 100 nm), whereas CNAs remained 30 ~ 40 nm. Drug release rates were fine-tunable by using amide cross-linkers and hydrazone drug-binding linkers in combination. In vitro cytotoxicity assays using a human lung cancer A549 cell line revealed that DOX-loaded nanoassemblies were equally potent as free DOX with a wide range of drug release half-life (t 1/2  = 3.24 ~ 18.48 h, at pH 5.0), but 5 times less effective when t 1/2  = 44.52 h. Conclusion   Nanoassemblies that incorporate cross-linkers and drug-binding linkers in combination have pharmaceutical advantages such as uniform particle size, physicochemical stability, fine-tunable drug release rates, and maximum cytotoxicity of entrapped drug payloads. Content Type Journal Article Category Research Paper Pages 1-11 DOI 10.1007/s11095-012-0893-3 Authors Hyun Jin Lee, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536, USA Younsoo Bae, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone, Lexington, Kentucky 40536, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To identify the aggregation mechanism and the stability characteristics of three different monoclonal antibodies under acidic conditions. Methods   The aggregation kinetics is analyzed by a combination of light scattering, size exclusion chromatography and fluorescence techniques and the aggregation data are correlated to protein structure, hydrophobicity, charge and antibody subclass. Results   In the investigated conditions, the antibody aggregation follows a mechanism consisting of two-steps: reversible monomer oligomerization followed by irreversible cluster-cluster aggregation. The kinetics of the two steps is differently affected by the operating conditions: mild destabilizing conditions induce formation of oligomers which are stable within weeks, while stronger denaturing conditions promote aggregation of oligomers to larger aggregates which eventually precipitate. For different antibodies significant differences in both oligomerization and growth rates are found, even for antibodies belonging to the same subclass. For all antibodies the aggregate formation is accompanied by a structure re-organization with an increase in the ordered β-sheet structures. At low pH the aggregation propensity of the investigated antibodies does not correlate with antibody subclass, surface net charge and hydrophobicity of the non-native state. Conclusions   The aggregation mechanism of three antibodies in acidic conditions as well as differences and analogies in their stability behavior has been characterized. Content Type Journal Article Category Research Paper Pages 1-14 DOI 10.1007/s11095-012-0885-3 Authors Paolo Arosio, Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, ETH Zurich, 8093 Zurich, Switzerland Simonetta Rima, Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, ETH Zurich, 8093 Zurich, Switzerland Massimo Morbidelli, Department of Chemistry and Applied Biosciences, Institute for Chemical and Bioengineering, ETH Zurich, 8093 Zurich, Switzerland Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To investigate the metabolism of phospho-aspirin (PA, MDC-22), a novel anti-cancer and anti-inflammatory agent. Methods   The metabolism of PA was studied in the liver and intestinal microsomes from mouse, rat and human. Results   PA is rapidly deacetylated to phospho-salicylic acid (PSA), which undergoes regioselective oxidation to generate 3-OH-PSA and 5-OH-PSA. PSA also can be hydrolyzed to give salicylic acid (SA), which can be further glucuronidated. PA is far more stable in human liver or intestinal microsomes compared to those from mouse or rat due to its slowest deacetylation in human microsomes. Of the five major human cytochrome P450 (CYP) isoforms, CYP2C19 and 2D6 are the most active towards PSA. In contrast to PSA, conventional SA is not appreciably oxidized by the CYPs and liver microsomes, indicating that PSA is a preferred substrate of CYPs. Similarly, PA, in contrast to PSA, cannot be directly oxidized by CYPs and liver microsomes, indicating that the acetyl group of PA abrogates its oxidation by CYPs. Conclusions   Our findings establish the metabolism of PA, reveal significant inter-species differences in its metabolic transformations, and provide an insight into the role of CYPs in these processes. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0821-6 Authors Gang Xie, Stony Brook University, Division of Cancer Prevention, HSC, T17-080, Stony Brook, New York 11794-8175, USA Chi C. Wong, Stony Brook University, Division of Cancer Prevention, HSC, T17-080, Stony Brook, New York 11794-8175, USA Ka-Wing Cheng, Stony Brook University, Division of Cancer Prevention, HSC, T17-080, Stony Brook, New York 11794-8175, USA Liqun Huang, Stony Brook University, Division of Cancer Prevention, HSC, T17-080, Stony Brook, New York 11794-8175, USA Panayiotis P. Constantinides, Medicon Pharmaceuticals, Inc., Stony Brook, New York 11790, USA Basil Rigas, Stony Brook University, Division of Cancer Prevention, HSC, T17-080, Stony Brook, New York 11794-8175, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To build a fast, user-friendly computational model to predict the intravitreal half-lives of drug-like compounds. Methods   We used multivariate analysis to build intravitreal half-life models using two data sets, one with experimental data derived from both pigmented and albino rabbits and another including only data from experiments with albino rabbits. Results   The final models had a Q 2 value of 0.65 and 0.75 for the mixed and albino rabbit models, respectively. The models performed well in predicting the intravitreal half-life of an external test set. In addition, the models are physiologically interpretable, containing mainly hydrogen bonding and lipophilicity descriptors. Conclusion   The developed models enable reliable predictions of intravitreal half-lives for use in the early drug development stages, without the need for prior experimental data. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0822-5 Authors Heidi Kidron, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland Eva M. del Amo, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland Kati-Sisko Vellonen, Division of Biopharmacy and Pharmacokinetics, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland Arto Urtti, Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, FIN-00014 Helsinki, Finland Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To predict precision and other performance characteristics of chromatographic purity methods, which represent the most widely used form of analysis in the biopharmaceutical industry. Methods   We have conducted a comprehensive survey of purity methods, and show that all performance characteristics fall within narrow measurement ranges. This observation was used to develop a model called Uncertainty Based on Current Information (UBCI), which expresses these performance characteristics as a function of the signal and noise levels, hardware specifications, and software settings. Results   We applied the UCBI model to assess the uncertainty of purity measurements, and compared the results to those from conventional qualification. We demonstrated that the UBCI model is suitable to dynamically assess method performance characteristics, based on information extracted from individual chromatograms. Conclusions   The model provides an opportunity for streamlining qualification and validation studies by implementing a “live validation” of test results utilizing UBCI as a concurrent assessment of measurement uncertainty. Therefore, UBCI can potentially mitigate the challenges associated with laborious conventional method validation and facilitates the introduction of more advanced analytical technologies during the method lifecycle. Content Type Journal Article Category Research Paper Pages 1-16 DOI 10.1007/s11095-012-0836-z Authors Izydor Apostol, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Drew Kelner, Amgen, Global Analytical Sciences, Longmont, Colorado 80503, USA Xinzhao Grace Jiang, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Gang Huang, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Jette Wypych, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Xin Zhang, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Jessica Gastwirt, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Kenneth Chen, Amgen, Clinical Quality, Thousand Oaks, California 91320, USA Szilan Fodor, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Suminda Hapuarachchi, Amgen, Analytical Sciences, Thousand Oaks, California 91320, USA Dave Meriage, Amgen, Product Attribute Sciences, Thousand Oaks, California 91320, USA Frank Ye, Amgen, Corporate Quality Engineering, Thousand Oaks, California 91320, USA Leszek Poppe, Amgen, Molecular Structure, Thousand Oaks, California 91320, USA Wojciech Szpankowski, Purdue University, Department of Computer Science, West Lafayette, Indiana 47907, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   Biological drugs in circulation can interfere with anti-drug antibody (ADA) assays and cause false ADA negatives. We surveyed the applications of biological products approved by FDA during 2005–2011 for prevalence of drug interferences and proposed approaches to address this issue scientifically. Methods   The immunogenicity assay drug tolerance, steady-state drug concentrations, and immunogenicity rates were reviewed for 26 BLA/NDA and 2 sBLA. Results   Many FDA approved biologics had higher steady-state drug concentrations than the drug tolerance of ADA assays, by 1.2- to 800-fold. Reported immunogenicity rates may be negatively impacted. Some sponsors triaged immunogenicity samples according to the drug tolerance, leaving some samples un-assayed or reporting them as inconclusive ADA; but these samples were interpreted as ADA− for calculating immunogenicity rates. Conclusions   Implementation of ADA assays that can tolerate therapeutic drug concentrations is imperative. Given drug interferences, we propose in this paper the following practices: (i) to measure drug concentrations in ADA samples, (ii) to explicitly list all ADA status, including inconclusive ADA and un-assayed samples, (iii) to calculate population immunogenicity rates based on only subjects with confirmed ADA+ and ADA−, and (iv) to make available ADA assay specifics relevant to the use of ADA data in disease management. Content Type Journal Article Category Research Paper Pages 1-9 DOI 10.1007/s11095-012-0833-2 Authors Yow-Ming C. Wang, Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA Lanyan Fang, Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA Lin Zhou, Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA Jie Wang, Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA Hae-Young Ahn, Division of Clinical Pharmacology III, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description:    The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by “bottom up” or “top down” technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail. Content Type Journal Article Category Expert Review Pages 1-18 DOI 10.1007/s11095-012-0889-z Authors Lei Gao, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Guiyang Liu, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Jianli Ma, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Xiaoqing Wang, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Liang Zhou, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Xiang Li, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Fang Wang, Department of Pharmacy, The First Affiliated Hospital of General Hospital of PLA, No. 51 Fucheng Road, Beijing, 100048 China Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To examine the effect of the fluoroquinolone DX-619 on CYP3A4 and urinary excretion of 6β-hydroxycortisol, an endogenous probe of hepatic CYP3A4 activity, in healthy subjects. Methods   The effect of DX-619 on CYP3A4 was examined in human liver microsomes. The apparent formation and renal clearance of 6β-hydroxycortisol (CL 6β−OHF and CL renal,6β−OHF , respectively) were determined in placebo- and DX-619-treated subjects. 6β-hydroxycortisol uptake was determined in HEK293 cells expressing OAT1, OAT3, OCT2, MATE1, and MATE2-K. Results   DX-619 was a mechanism-based inhibitor of CYP3A4, with K I and k inact of 67.9 ± 7.3 μmol/l and 0.0730 ± 0.0033 min −1 , respectively. Pharmacokinetic simulation suggested in vivo relevance of CYP3A4 inhibition by DX-619. CL 6β−OHF and CL renal,6β−OHF were decreased 72% and 70%, respectively, on day 15 in DX-619-treated group compared with placebo ( P  〈 0.05). 6β-hydroxycortisol was a substrate of OAT3 (K m  = 183 ± 25 μmol/l), OCT2, MATE1, and MATE2-K. Maximum unbound concentration of DX-619 (9.1 ± 0.4 μmol/l) was above K i of DX-619 for MATE1 (4.32 ± 0.79 μmol/l). Conclusions   DX-619 caused a moderate inhibition of hepatic CYP3A4-mediated formation and significant inhibition of MATE-mediated efflux of 6β-hydroxycortisol into urine. Caution is needed in applying CL 6β−OHF as an index of hepatic CYP3A4 activity without evaluating CL renal,6β−OHF . Content Type Journal Article Category Research Paper Pages 1-11 DOI 10.1007/s11095-012-0890-6 Authors Yuichiro Imamura, Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Nobuyuki Murayama, Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Noriko Okudaira, Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Atsushi Kurihara, Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Katsuhisa Inoue, Department of Biopharmaceutics Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan Hiroaki Yuasa, Department of Biopharmaceutics Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan Takashi Izumi, Drug Metabolism & Pharmacokinetics Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Hiroyuki Kusuhara, Laboratory of Molecular Pharmaceutics Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Yuichi Sugiyama, Sugiyama Laboratory, RIKEN Innovation Center Research Cluster for Innovation, RIKEN, The Institute of Physical and Chemical Research, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   Diphencyprone (DPCP) is a therapeutic agent for treating alopecia areata. To improve skin absorption and follicular targeting nanostructured lipid carriers (NLCs) were developed. Methods   Nanoparticles were characterized by size, zeta potential, molecular environment, differential scanning calorimetry (DSC), and nuclear magnetic resonance (NMR). In vitro and in vivo skin absorption experiments were performed. Fluorescence and confocal microscopes for imaging skin distribution were used. Results   NLCs with different designs were 208 ~ 265 nm with  〉 77% DPCP encapsulation. NLCs incorporating a cationic surfactant or more soybean phosphatidylcholine (SPC) showed higher lipophilicity compared to typical NLCs by Nile red emission. All NLCs tested revealed controlled DPCP release; burst release was observed for control. The formulation with more SPC provided 275 μg/g DPCP skin retention, which was greater than control and other NLCs. Intersubject deviation was reduced after DPCP loading into NLCs. Cyanoacrylate skin biopsy demonstrated greater follicular deposition for NLCs with more SPC compared to control. Cationic NLCs but not typical or SPC-containing carriers were largely internalized into keratinocytes. In vivo skin retention of NLCs with more SPC was higher than free control. Confocal imaging confirmed localization of NLCs in follicles and intercellular lipids of stratum corneum. Conclusions   This work encourages further investigation of DPCP absorption using NLCs with a specific formulation design. Content Type Journal Article Category Research Paper Pages 1-12 DOI 10.1007/s11095-012-0888-0 Authors Yin-Ku Lin, School of Traditional Chinese Medicine, Chang Gung University, Kweishan, Taoyuan, Taiwan Saleh A. Al-Suwayeh, Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia Yann-Lii Leu, Natural Products Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan Feng-Ming Shen, 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: Purpose   To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol. Methods   Different mannitol powders were sieved to collect 63–90 μm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance. Results   Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF = 46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, α-+β-+δ- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, α-+β- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, β- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase. Conclusions   Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance. Content Type Journal Article Category Research Paper Pages 1-20 DOI 10.1007/s11095-012-0892-4 Authors Waseem Kaialy, Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent, ME4 4TB Kent, UK Ali Nokhodchi, Chemistry and Drug Delivery Group, Medway School of Pharmacy, University of Kent, ME4 4TB Kent, UK Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   A novel application of oscillatory shear rheology was used to directly monitor global phase behavior of protein formulations in the frozen state and study its correlation with physical instability of frozen protein formulations. Methods   Oscillatory rheology was used to measure changes in rheological parameters and to identify mechanical softening temperature (Ts*) and related properties of an IgG2 mAb formulation. Rheological measurements were compared to DSC/MDSC. Physical stability of IgG2 formulations was monitored by SE-HPLC. Results   Rheological parameters and Ts* of an IgG2 formulation were sensitive to physical/morphological phase changes during freezing and thawing. Ts* of the frozen formulation was a function of concentration of protein and excipient. Complex modulus, G*, and phase angle, δ, for IgG2 at 70 mg/mL in a sucrose-containing formulation showed the system was not completely frozen at −10°C, which correlated to stability data consistent with ice-induced protein aggregation. Conclusions   We report the first application of oscillatory shear rheology to study phase behavior of IgG2 in a sucrose-containing formulation and its correspondence with physical stability not explained by glass transition (Tg’). We provide a mechanism and data suggesting that protein instability occurs at the ice/water interface. Content Type Journal Article Category Research Paper Pages 1-15 DOI 10.1007/s11095-012-0879-1 Authors Jian Hua Gu, Drug Product Development Process and Product Development, Amgen Inc., MS 8-1-C, One Amgen Center Drive, Thousand Oaks, California 91320, USA Alice Beekman, Drug Product Development Process and Product Development, Amgen Inc., MS 8-1-C, One Amgen Center Drive, Thousand Oaks, California 91320, USA Tian Wu, Pharmaceutical R&D Small Molecule Process and Product Development, Amgen Inc., Thousand Oaks, California 91320, USA Deirdre Murphy Piedmonte, Drug Product Development Process and Product Development, Amgen Inc., MS 8-1-C, One Amgen Center Drive, Thousand Oaks, California 91320, USA Priti Baker, Drug Product Development Process and Product Development, Amgen Inc., MS 8-1-C, One Amgen Center Drive, Thousand Oaks, California 91320, USA Michael Eschenberg, Medical Sciences Biostatistics, Amgen Inc., Thousand Oaks, California 91320, USA Michael Hale, Medical Sciences Biostatistics, Amgen Inc., Thousand Oaks, California 91320, USA Merrill Goldenberg, Drug Product Development Process and Product Development, Amgen Inc., MS 8-1-C, One Amgen Center Drive, Thousand Oaks, California 91320, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs). Methods   Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross-linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe 3 O 4 IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe 3 O 4 IONPs (Citrate-IONPs). Results   CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43°C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (〉 400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (〉 0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40 ~ 42°C) with an alternating magnetic field (AMF). Conclusion   Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications. Content Type Journal Article Category Research Paper Pages 1-10 DOI 10.1007/s11095-012-0900-8 Authors Mo Dan, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA Daniel F. Scott, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA Peter A. Hardy, Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, USA Robert J. Wydra, Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky 40506, USA J. Zach Hilt, Chemical and Materials Engineering, University of Kentucky, Lexington, Kentucky 40506, USA Robert A. Yokel, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA Younsoo Bae, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   Trastuzumab treatment is associated with occurrence of cardiac toxicity, for which monitoring of the left ventricular ejection fraction (LVEF) is indicated. The performance of the currently used monitoring protocol as defined in the summary of product characteristics (SPC) is however unknown. The objective of this analysis was to develop a model-based framework for evaluation and optimization of cardiac monitoring strategies. Methods   The model-based framework comprised a previously developed exposure-response model for trastuzumab induced changes in LVEF, and a protocol-execution model that allowed incorporation of treatment interventions as described by a monitoring protocol. Metrics for evaluation of toxicity, dose intensity and monitoring burden were defined to allow evaluation and optimization of cardiac monitoring protocols. Results   The success of a protocol-defined dose reduction was improved from 40% for the SPC-based protocol, to 79% for a scoring-based protocol, thereby decreasing the observed severity of cardiotoxicity. Including adaptation based on risk-profile allowed reduction of the mean number of LVEF measurements by 19%. Conclusions   This model-based evaluation approach enabled evaluation and optimization of cardiac monitoring protocols that would be difficult to evaluate in a clinical setting. This approach can potentially be applied for other drugs that use repeated evaluation of continuous biomarkers for toxicity. Content Type Journal Article Category Research Paper Pages 1-13 DOI 10.1007/s11095-012-0845-y Authors J. G. Coen van Hasselt, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Jan H. M. Schellens, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Melvin R. Mac Gillavry, Department of Cardiology, Slotervaart Hospital, Amsterdam, The Netherlands Jos H. Beijnen, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Alwin D. R. Huitema, Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   Salts of active pharmaceutical ingredients are often used to enhance solubility, dissolution rate, or take advantage of other improved solid-state properties. The selected form must be maintained during processing and shelf-life to ensure quality. We aimed to develop a model to quantify risk of disproportionation, where the salt dissociates back to the freebase form. Methods   A mechanistic model based on thermodynamics was built to predict disproportionation. Stress testing of molecules in combination with excipients was used to benchmark model predictions. X-ray powder diffraction and solid-state NMR were used to quantify the formation of freebase experimentally. Results   13 pharmaceutical compounds were screened in 4 formulations containing different combinations of excipients. The test set spanned molecules which did and did not disproportionate and also formulations which did and did not induce disproportionation. Model predictions were in qualitative agreement with the experimental data, recovering trends of how disproportionation varies with humidity, formulation excipients, base p K a and solubility of the API. Conclusions   The model can predict the balance between different driving forces for disproportionation with limited experimental data resulting in a tool to aid in early-phase risk assessment and formulation design with respect to disproportionation. Content Type Journal Article Category Research Paper Pages 1-15 DOI 10.1007/s11095-012-0863-9 Authors Jeremy M. Merritt, Chemical Product Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46221, USA Shekhar K. Viswanath, Chemical Product Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46221, USA Gregory A. Stephenson, Pharmaceutical Sciences Research and Development, Eli Lilly and Company, Indianapolis, Indiana 46221, USA Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: Purpose   In principle, maximum transepidermal fluxes of solutes should be similar for different vehicles, except when the solute or vehicle modifies the skin. Here we estimated maximum flux, stratum corneum solubility, diffusivity and permeability coefficient for a range of similarly sized phenolic compounds with varying lipophilicity from polar and lipophilic vehicles. Methods   Maximum flux and other skin transport parameters through human epidermis were obtained from lipophilic vehicles (mineral oil (MO) and isopropyl myristate (IPM)) and compared with values from water and propylene glycol (PG)-water solutions. Solvent uptake and changes in stratum corneum infrared spectroscopy and multiphoton microscopy imaging were also investigated. Results   Maximum fluxes for MO and water were similar but IPM has a higher value for more polar phenols due to a higher diffusivity and PG-water had a higher flux due to higher solubility in the stratum corneum. Whereas maximum flux for various phenols was directly related to solubility in the stratum corneum independent of vehicle, increasing phenol lipophilicity increased and decreased permeability coefficient for aqueous solvents and lipophilic solvents, respectively. Conclusion   The maximum fluxes for phenols with a similar molecular size and varying lipophilicity were comparable between water and MO vehicles but higher for IPM and PG-water mixtures. Content Type Journal Article Category Research Paper Pages 1-9 DOI 10.1007/s11095-012-0846-x Authors Qian Zhang, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia Peng Li, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia David Liu, Therapeutics Research Centre, School of Medicine University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia Michael S. Roberts, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA 5001, Australia Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741

Description: ABSTRACT Purpose   To resolve contradictions found in morphology of hydrating hydroxypropylmethyl cellulose (HPMC) matrix as studied using Magnetic Resonance Imaging (MRI) techniques. Until now, two approaches were used in the literature: either two or three regions that differ in physicochemical properties were identified. Methods   Multiparametric, spatially and temporally resolved T 2 MR relaxometry in situ was applied to study the hydration progress in HPMC matrix tablets using a 11.7 T MRI system. Two spin-echo based pulse sequences—one of them designed to specifically study short T 2 signals—were used. Results   Two components in the T 2 decay envelope were estimated and spatial distributions of their parameters, i.e. amplitudes and T 2 values, were obtained. Based on the data, five different regions and their temporal evolution were identified: dry glassy, hydrated solid like, two interface layers and gel layer. The regions were found to be separated by four evolving fronts identified as penetration, full hydration, total gelification and apparent erosion. Conclusions   The MRI results showed morphological details of the hydrating HPMC matrices matching compound theoretical models. The proposed method will allow for adequate evaluation of controlled release polymeric matrix systems loaded with drug substances of different solubility. Content Type Journal Article Category Research Paper Pages 1-14 DOI 10.1007/s11095-012-0837-y Authors Piotr Kulinowski, Department of Magnetic Resonance Imaging, Institute of Nuclear Physics PAN, ul. Radzikowskiego 152, 31-342 Kraków, Poland Anna Młynarczyk, Department of Magnetic Resonance Imaging, Institute of Nuclear Physics PAN, ul. Radzikowskiego 152, 31-342 Kraków, Poland Przemysław Dorożyński, Department of Pharmaceutical Technology and Biopharmaceutics Pharmaceutical Faculty, Jagiellonian University, ul. Medyczna 9, 30-688 Kraków, Poland Krzysztof Jasiński, Department of Magnetic Resonance Imaging, Institute of Nuclear Physics PAN, ul. Radzikowskiego 152, 31-342 Kraków, Poland Marco L. H. Gruwel, National Research Council Canada, Institute for Biodiagnostics, 435 Ellice Avenue, Winnipeg, Manitoba, Canada R3B 1Y6 Bogusław Tomanek, Department of Magnetic Resonance Imaging, Institute of Nuclear Physics PAN, ul. Radzikowskiego 152, 31-342 Kraków, Poland Władysław P. Węglarz, Department of Magnetic Resonance Imaging, Institute of Nuclear Physics PAN, ul. Radzikowskiego 152, 31-342 Kraków, Poland Journal Pharmaceutical Research Online ISSN 1573-904X Print ISSN 0724-8741