Pharmaceutical Research

Carvalho, Gabriela Corrêa; Sábio, Rafael Miguel; de Cássia Ribeiro, Tais; Monteiro, Andreia Sofia; Pereira, Daniela Vassalo; Ribeiro, Sidney José Lima; Chorilli, Marlus

doi: 10.1007/s11095-020-02917-6pmid: 32895867

ABSTRACTInfectious diseases are a major global concern being responsible for high morbidity and mortality mainly due to the development and enhancement of multidrug-resistant microorganisms exposing the fragility of medicines and vaccines commonly used to these treatments. Taking into account the scarcity of effective formulation to treat infectious diseases, nanotechnology offers a vast possibility of ground-breaking platforms to design new treatment through smart nanostructures for drug delivery purposes. Among the available nanosystems, mesoporous silica nanoparticles (MSNs) stand out due their multifunctionality, biocompatibility and tunable properties make them emerging and actual nanocarriers for specific and controlled drug release. Considering the high demand for diseases prevention and treatment, this review exploits the MSNs fabrication and their behavior in biological media besides highlighting the most of strategies to explore the wide MSNs functionality as engineered, smart and effective controlled drug release nanovehicles for infectious diseases treatment.Graphical AbstractSchematic representation of multifunctional MSNs-based nanoplatforms for infectious diseases treatment[graphic not available: see fulltext]

Ballard, Jeanine E.; Pall, Parul; Vardigan, Joshua; Zhao, Fuqiang; Holahan, Marie A.; Kraus, Richard; Li, Yuxing; Henze, Darrell; Houghton, Andrea; Burgey, Christopher S.; Gibson, Christopher

doi: 10.1007/s11095-020-02914-9pmid: 32888082

PurposeThis work describes a staged approach to the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling in the voltage-gated sodium ion channel (NaV1.7) inhibitor drug discovery effort to address strategic questions regarding in vitro to in vivo translation of target modulation.MethodsPK-PD analysis was applied to data from a functional magnetic resonance imaging (fMRI) technique to non-invasively measure treatment mediated inhibition of olfaction signaling in non-human primates (NHPs). Initial exposure-response was evaluated using single time point data pooled across 27 compounds to inform on in vitro to in vivo correlation (IVIVC). More robust effect compartment PK-PD modeling was conducted for a subset of 10 compounds with additional PD and PK data to characterize hysteresis.ResultsThe pooled compound exposure-response facilitated an early exploration of IVIVC with a limited dataset for each individual compound, and it suggested a 2.4-fold in vitro to in vivo scaling factor for the NaV1.7 target. Accounting for hysteresis with an effect compartment PK-PD model as compounds advanced towards preclinical development provided a more robust determination of in vivo potency values, which resulted in a statistically significant positive IVIVC with a slope of 1.057 ± 0.210, R-squared of 0.7831, and p value of 0.006. Subsequent simulations with the PK-PD model informed the design of anti-nociception efficacy studies in NHPs.ConclusionsA staged approach to PK-PD modeling and simulation enabled integration of in vitro NaV1.7 potency, plasma protein binding, and pharmacokinetics to describe the exposure-response profile and inform future study design as the NaV1.7 inhibitor effort progressed through drug discovery.

Dutta, Rabijit; Spence, Benjamin; Wei, Xiangyin; Dhapare, Sneha; Hindle, Michael; Longest, P. Worth

doi: 10.1007/s11095-020-02923-8pmid: 32968848

PurposeThe objective of this study was to optimize nose-to-lung aerosol delivery in an adult upper airway model using computational fluid dynamics (CFD) simulations in order to guide subsequent human subject aerosol delivery experiments.MethodsA CFD model was developed that included a new high-flow nasal cannula (HFNC) and pharmaceutical aerosol delivery unit, nasal cannula interface, and adult upper airway geometry. Aerosol deposition predictions in the system were validated with existing and new experimental results. The validated CFD model was then used to explore aerosol delivery parameters related to synchronizing aerosol generation with inhalation and inhalation flow rate.ResultsThe low volume of the new HFNC unit minimized aerosol transit time (0.2 s) and aerosol bolus spread (0.1 s) enabling effective synchronization of aerosol generation with inhalation. For aerosol delivery correctly synchronized with inhalation, a small particle excipient-enhanced growth delivery strategy reduced nasal cannula and nasal depositional losses each by an order of magnitude and enabled ~80% of the nebulized dose to reach the lungs. Surprisingly, nasal deposition was not sensitive to inhalation flow rate due to use of a nasal cannula interface with co-flow inhaled air and the small initial particle size.ConclusionsThe combination of correct aerosol synchronization and small particle size enabled high efficiency nose-to-lung aerosol delivery in adults, which was not sensitive to inhalation flow rate.

Shin, Soo Hyeon; Rantou, Elena; Raney, Sam G.; Ghosh, Priyanka; Hassan, Hazem; Stinchcomb, Audra

doi: 10.1007/s11095-020-02821-zpmid: 33001286

PurposeThe in vitro permeation test (IVPT) with a new statistical approach was investigated to evaluate the utility of an IVPT methodology as a sensitive tool to support a demonstration of bioequivalence (BE) for topical dermatological drug products.MethodsIVPT experiments were performed utilizing ex vivo human skin. The initial screening tests involved four differently formulated acyclovir 5% creams: the U.S. Zovirax® as the reference product and the U.K. Zovirax®, Aciclovir 1A Pharma® and Aciclostad® as test products. Subsequently, a pivotal BE study was conducted comparing the two Zovirax® creams. The resulting data was used to evaluate BE of test (T) versus reference (R), T versus T, and R versus R, with an adaption of scaled average BE approach to address high variability in IVPT data.ResultsMore acyclovir permeated into and through the skin from the two Zovirax® creams compared to the two non-Zovirax® creams. The U.S. Zovirax® cream showed a significantly higher Jmax and total amount permeated over 48 h, compared to the U.K. Zovirax® cream. The statistical analysis indicated that the test and reference products were not bioequivalent, whereas each product tested against itself was shown to be bioequivalent.ConclusionsThe current study demonstrated that the IVPT method, with an appropriate statistical analysis of the results, is a sensitive and discriminating test that can detect differences in the rate and extent of acyclovir bioavailability in the skin from differently formulated cream products.

Rao, V. Ashutosh; Kim, Jennifer J.; Patel, Dipti S.; Rains, Kimberly; Estoll, Corey R.

doi: 10.1007/s11095-020-02919-4pmid: 32968854

PurposeThe steady development of biotechnology-derived therapeutic biologics over the last few decades has generated drugs that are now standard medical treatments for a range of indications. While the development of protein products has surged in recent years, the formulation and delivery of these complex molecules have relied on drug-specific studies and, in some instances, data from non-proteinaceous drug products. The commonalities, trends, and gaps in excipient technologies used to support the development of therapeutic proteins largely remain unexplored due to the drug-specific nature of many formulations.MethodsUsing a comprehensive and relational database approach, we aimed to provide a scientific survey of all approved or licensed biotechnology-derived drug products with the goal of providing evidence-based information on common attributes and trending features in protein product excipients. We examined 665 formulations, and 395 unique formulations based on having unique excipients within them, that supported 211 therapeutic proteins as of June 2020.ResultsWe report the prevalence of each excipient class and excipient chemical used in eight different drug types including monoclonal antibodies, antibody conjugates, cytokines and growth factors, enzymes, polypeptide hormones, pulmonary surfactants, recombinant fusion proteins, and toxins. We also report the prevalence by excipient type among all therapeutic proteins, in the context of each drug’s recommended pH range, concentration ranges for excipients, and route of administration.ConclusionsThe results of our analyses indicate certain excipients common to monoclonal antibodies, cytokines, and polypeptide hormones. We also report on excipients unique to protein drug products, such as amino acids, solubilizers, and lyoprotectants. Overall, our report summarizes the current landscape of excipients used in marketed biotechnology-derived therapeutic biologic products.

Izadi, Sepideh; Moslehi, Asma; Kheiry, Hadiseh; Karoon Kiani, Fariba; Ahmadi, Armin; Masjedi, Ali; Ghani, Sepideh; Rafiee, Behnam; Karpisheh, Vahid; Hajizadeh, Farnaz; Atyabi, Fatemeh; Assali, Akram; Mirzazadeh tekie, Farnaz Sadat; Namdar, Afshin;

Bodenlenz, Manfred; Augustin, Thomas; Birngruber, Thomas; Tiffner, Katrin I.; Boulgaropoulos, Beate; Schwingenschuh, Simon; Raney, Sam G.; Rantou, Elena; Sinner, Frank

doi: 10.1007/s11095-020-02920-xpmid: 32989514

PurposeDermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study.MethodsExploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products.ResultsThe overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject’s skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability.ConclusionsInter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.

Allmendinger, Andrea; Fischer, Stefan

doi: 10.1007/s11095-020-02906-9pmid: 32888065

PurposeInjection devices for administration of biopharmaceuticals enable subcutaneous self-administration by patients. To meet patient specific capabilities, injection forces need to be characterized. We address the open question of whether tissue resistance significantly contributes to overall injection forces, especially for large injection volumes.MethodsSubcutaneous tissue resistance was systematically quantified for injection volumes up to 11 mL depending on viscosity (1–20 mPa·s) and injection rates (0.025–0.2 mL/s) using Göttingen Minipigs as the animal model. The contribution of an artificially applied external force at the injection site simulating autoinjector needle cover depression was tested between 2.5–7.5 N.ResultsTissue resistance reached average values of ~120 mbar for injection volumes up to 11 mL independent of viscosity and injection rate, and maximum values of 300 mbar were determined. Artificially applied external forces led to higher values, independent of the absolute applied force — maximum values of 1 bar were obtained when injecting 4.5 mL of the 20 mPa·s solution at an injection rate of 0.1 mL/s with the application of an artificial 5 N force, corresponding to ~450 mbar. All conditions yield defined injection sites suggesting tissue resistance is defined by mechanical properties of the subcutaneous tissue.ConclusionsWe set our results in relation to overall injection forces, concluding that maximum values in tissue resistance may cause challenges during subcutaneous injection when using injection devices.Graphical abstract[graphic not available: see fulltext]

Lalatsa, Aikaterini; Sun, Yujiao; Gamboa, Jose Ignacio; Knafo, Shira

doi: 10.1007/s11095-020-02915-8pmid: 32888078

PurposeAmyloid β (Aβ) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aβ drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aβ-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability.MethodsLipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken.ResultsThe mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp0-4h: 6.28 ± 1.85 × 10−6 cm s−1).ConclusionThis increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery.Graphical Abstract[graphic not available: see fulltext]

Chiang, Manting; Back, Hyun-moon; Lee, Jong Bong; Oh, Sarah; Guo, Tiffany; Girgis, Simone; Park, Celine; Haroutounian, Simon; Kagan, Leonid

doi: 10.1007/s11095-020-02929-2pmid: 32989520

PurposeModulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model.MethodsPlasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose.ResultsPgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39–5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision.ConclusionsThe study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.