Pharmaceutics

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Open AccessCorrection

Correction: Development of Novel Faster-Dissolving Microneedle Patches for Transcutaneous Vaccine Delivery. Pharmaceutics, 2017, 9(3), 27

by Akihiko Ono, Sayami Ito, Shun Sakagami, Hideo Asada, Mio Saito, Ying-Shu Quan, Fumio Kamiyama, Sachiko Hirobe and Naoki Okada

Pharmaceutics 2017, 9(4), 59; https://doi.org/10.3390/pharmaceutics9040059 - 18 Dec 2017

Cited by 2 | Viewed by 3609

Abstract

The authors wish to make a change to their published paper [1].[...] Full article

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Open AccessArticle

Resveratrol-Loaded Lipid Nanocarriers: Correlation between In Vitro Occlusion Factor and In Vivo Skin Hydrating Effect

by Lucia Montenegro, Carmela Parenti, Rita Turnaturi and Lorella Pasquinucci

Pharmaceutics 2017, 9(4), 58; https://doi.org/10.3390/pharmaceutics9040058 - 10 Dec 2017

Cited by 61 | Viewed by 6760

Abstract

Lipid nanocarriers show occlusive properties that may be related to their ability to improve skin hydration. The aim of this work was to evaluate the relationship between in vitro occlusion factor and in vivo skin hydration for three types of lipid nanocarriers: nanoemulsions [...] Read more.

Lipid nanocarriers show occlusive properties that may be related to their ability to improve skin hydration. The aim of this work was to evaluate the relationship between in vitro occlusion factor and in vivo skin hydration for three types of lipid nanocarriers: nanoemulsions (NEs), solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs). These lipid nanocarriers were loaded with trans-resveratrol (RSV) and incorporated in gel vehicles. In vitro occlusion factor was in the order SLNs > NLCs > NEs. Gels containing unloaded or RSV loaded lipid nanocarriers were applied on the back of a hand of 12 healthy volunteers twice a day for one week, recording skin hydration changes using the instrument Soft Plus. An increase of skin hydration was observed for all lipid nanocarriers (SLNs > NLCs > NEs). RSV loading into these nanocarriers did not affect in vitro and in vivo lipid nanocarriers effects. A linear relationship (r² = 0.969) was observed between occlusion factor and in vivo increase of skin hydration. Therefore, the results of this study showed the feasibility of using the occlusion factor to predict in vivo skin hydration resulting from topical application of different lipid nanocarriers loading an active ingredient with no inherent hydrating activity. Full article

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Open AccessArticle

Application of Pharmacokinetics Modelling to Predict Human Exposure of a Cationic Liposomal Subunit Antigen Vaccine System

by Raj K. S. Badhan, Swapnil Khadke and Yvonne Perrie

Pharmaceutics 2017, 9(4), 57; https://doi.org/10.3390/pharmaceutics9040057 - 7 Dec 2017

Cited by 3 | Viewed by 4845

Abstract

The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide (DDA) and the immunostimulatory agent trehalose 6,6-dibehenate (TDB) (8:1 molar ratio) combined with the Ag85B-ESAT-6 (H1) antigen were modelled using mouse in-vivo data. Compartment modelling and physiologically [...] Read more.

The pharmacokinetics of a liposomal subunit antigen vaccine system composed of the cationic lipid dimethyldioctadecylammonium bromide (DDA) and the immunostimulatory agent trehalose 6,6-dibehenate (TDB) (8:1 molar ratio) combined with the Ag85B-ESAT-6 (H1) antigen were modelled using mouse in-vivo data. Compartment modelling and physiologically based pharmacokinetics (PBPK) were used to predict the administration site (muscle) and target site (lymph) temporal concentration profiles and factors governing these. Initial estimates using compartmental modelling established that quadriceps pharmacokinetics for the liposome demonstrated a long half-life (22.6 days) compared to the associated antigen (2.62 days). A mouse minimal-PBPK model was developed and successfully predicted quadriceps liposome and antigen pharmacokinetics. Predictions for the popliteal lymph node (PLN) aligned well at earlier time-points. A local sensitivity analysis highlighted that the predicted AUC_muscle was sensitive to the antigen degradation constant k_deg (resulting in a 3-log change) more so than the fraction escaping the quadriceps (f_e) (resulting in a 10-fold change), and the predicted AUC_PLN was highly sensitive to f_e. A global sensitivity analysis of the antigen in the muscle demonstrated that model predictions were within the 50th percentile for predictions and showed acceptable fits. To further translate in-vitro data previously generated by our group, the mouse minimal-PBPK model was extrapolated to humans and predictions made for antigen pharmacokinetics in muscle and PLN. Global analysis demonstrated that both k_deg and f_e had a minimal impact on the resulting simulations in the muscle but a greater impact in the PLN. In summary, this study has predicted the in-vivo fate of DDA:TDB:H1 in humans and demonstrated the roles that formulation degradation and fraction escaping the depot site can play upon the overall depot effect within the site of administration. Full article

(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)

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Open AccessArticle

A Chitosan—Based Liposome Formulation Enhances the In Vitro Wound Healing Efficacy of Substance P Neuropeptide

by Tamara Mengoni, Manuela Adrian, Susana Pereira, Beatriz Santos-Carballal, Mathias Kaiser and Francisco M. Goycoolea

Pharmaceutics 2017, 9(4), 56; https://doi.org/10.3390/pharmaceutics9040056 - 6 Dec 2017

Cited by 52 | Viewed by 6983

Abstract

Currently, there is considerable interest in developing innovative biodegradable nanoformulations for controlled administration of therapeutic proteins and peptides. Substance P (SP) is a neuropeptide of 11 amino acids that belongs to the tachykinins family and it plays an important role in wound healing. [...] Read more.

Currently, there is considerable interest in developing innovative biodegradable nanoformulations for controlled administration of therapeutic proteins and peptides. Substance P (SP) is a neuropeptide of 11 amino acids that belongs to the tachykinins family and it plays an important role in wound healing. However, SP is easily degradable in vivo and has a very short half-life, so the use of chitosan-based nanocarriers could enhance its pharmaceutical properties. In light of the above, the aim of this work was to produce and characterize chitosan-coated liposomes loaded with SP (SP-CH-LP) as novel biomaterials with potential application in mucosal wound healing. The loaded system’s biophysical properties were characterized by dynamic light scattering with non-invasive back scattering (DLS-NIBS), mixed mode measurements and phase analysis light scattering (M3-PALS) and high performance liquid chromatography with ultraviolet/visible light detection (HPLC-UV/VIS). Then, the efficacy of the obtained nanoformulations was examined via proof-of-principle experiments using in vitro cell assays. These assays showed an increment on cell motility and proliferation after treatment with free and encapsulated neuropeptides. Additionally, the effect of SP on wound healing was enhanced by the entrapment on CH-LP. Overall, the amenability of chitosan-based nanomaterials to encapsulate peptides and proteins constitutes a promising approach towards potential novel therapies to treat difficult wounds. Full article

(This article belongs to the Special Issue Chitosan Biomedical Applications: Opportunities and Challenges)

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Open AccessArticle

A Comparative Study of Coupled Preferential Crystallizers for the Efficient Resolution of Conglomerate-Forming Enantiomers

by Aniruddha Majumder and Zoltan K. Nagy

Pharmaceutics 2017, 9(4), 55; https://doi.org/10.3390/pharmaceutics9040055 - 5 Dec 2017

Cited by 15 | Viewed by 4639

Abstract

The separation of enantiomers is of great importance due to their possible differences in therapeutic properties. Preferential crystallization in various configurations of coupled batch crystallizers is used as an attractive means to separate the conglomerate-forming enantiomers from racemic mixtures. However, the productivity of [...] Read more.

The separation of enantiomers is of great importance due to their possible differences in therapeutic properties. Preferential crystallization in various configurations of coupled batch crystallizers is used as an attractive means to separate the conglomerate-forming enantiomers from racemic mixtures. However, the productivity of such batch processes can be limited by the nucleation of the counter enantiomer and consumption of the supersaturation. In this work, a recently proposed process configuration, which uses coupled mixed suspension mixed product removal (MSMPR) with liquid phase exchange, is investigated by simulation studies. A detailed study on the effect of process parameters (e.g., feed flow rate, seed mass, and liquid phase exchange) on the productivity and yield of the coupled MSMPR has been presented. Moreover, a comparison of various coupled crystallizer configurations is carried out. It is shown through simulation studies that the productivity of the enantiomeric separation can be significantly improved compared to the previously proposed batch modes when the continuous configuration is used. The effect of nucleation kinetic parameters on the performances of various crystallizer configurations is studied as well. A set of coupled population balance equations (PBEs) was used to describe the evolution of the crystal phase of the both enantiomers in each vessel. These equations were solved numerically using the quadrature method of moments. The insights obtained in this study will be useful in the process design of coupled crystallizer systems. Full article

(This article belongs to the Special Issue Pharmaceutical Crystallisation Science and Engineering)

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Open AccessArticle

Preparation and Characterization of Carbamazepine Cocrystal in Polymer Solution

by Hao Zhang, Ying Zhu, Ning Qiao, Yang Chen and Linghuan Gao

Pharmaceutics 2017, 9(4), 54; https://doi.org/10.3390/pharmaceutics9040054 - 1 Dec 2017

Cited by 21 | Viewed by 10893

Abstract

In this study, we attempted to prepare carbamazepine (CBZ) cocrystal through the solution method in ethanol-water solvent mixture (volume ratio 1:1) and polyvinyl pyrrolidone (PVP) solution. Nicotinamide (NIC) and saccharin (SAC) were selected as cocrystal coformers. Cocrystal screening products were characterized by Fourier [...] Read more.

In this study, we attempted to prepare carbamazepine (CBZ) cocrystal through the solution method in ethanol-water solvent mixture (volume ratio 1:1) and polyvinyl pyrrolidone (PVP) solution. Nicotinamide (NIC) and saccharin (SAC) were selected as cocrystal coformers. Cocrystal screening products were characterized by Fourier Transform Infrared Spectroscopy (FTIR), Differential Scanning Calorimetry (DSC), and Powder X-ray Diffraction (PXRD) techniques. Characterization results show that in ethanol-water solvent mixture, pure CBZ-NIC cocrystal can be prepared, while CBZ-SAC cocrystal cannot be obtained. The addition of PVP can inhibit CBZ-NIC cocrystal formation and facilitate CBZ-SAC cocrystal formation. Full article

(This article belongs to the Special Issue Pharmaceutical Crystallisation Science and Engineering)

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Open AccessFeature PaperReview

An Overview of Chitosan Nanoparticles and Its Application in Non-Parenteral Drug Delivery

by Munawar A. Mohammed, Jaweria T. M. Syeda, Kishor M. Wasan and Ellen K. Wasan

Pharmaceutics 2017, 9(4), 53; https://doi.org/10.3390/pharmaceutics9040053 - 20 Nov 2017

Cited by 1033 | Viewed by 32748

Abstract

The focus of this review is to provide an overview of the chitosan based nanoparticles for various non-parenteral applications and also to put a spotlight on current research including sustained release and mucoadhesive chitosan dosage forms. Chitosan is a biodegradable, biocompatible polymer regarded [...] Read more.

The focus of this review is to provide an overview of the chitosan based nanoparticles for various non-parenteral applications and also to put a spotlight on current research including sustained release and mucoadhesive chitosan dosage forms. Chitosan is a biodegradable, biocompatible polymer regarded as safe for human dietary use and approved for wound dressing applications. Chitosan has been used as a carrier in polymeric nanoparticles for drug delivery through various routes of administration. Chitosan has chemical functional groups that can be modified to achieve specific goals, making it a polymer with a tremendous range of potential applications. Nanoparticles (NP) prepared with chitosan and chitosan derivatives typically possess a positive surface charge and mucoadhesive properties such that can adhere to mucus membranes and release the drug payload in a sustained release manner. Chitosan-based NP have various applications in non-parenteral drug delivery for the treatment of cancer, gastrointestinal diseases, pulmonary diseases, drug delivery to the brain and ocular infections which will be exemplified in this review. Chitosan shows low toxicity both in vitro and some in vivo models. This review explores recent research on chitosan based NP for non-parenteral drug delivery, chitosan properties, modification, toxicity, pharmacokinetics and preclinical studies. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessArticle

A High-Performance Liquid Chromatography Assay Method for the Determination of Lidocaine in Human Serum

by Hamdah M. Al Nebaihi, Matthew Primrose, James S. Green and Dion R. Brocks

Pharmaceutics 2017, 9(4), 52; https://doi.org/10.3390/pharmaceutics9040052 - 18 Nov 2017

Cited by 21 | Viewed by 6094

Abstract

Here we report on the development of a selective and sensitive high-performance liquid chromatographic method for the determination of lidocaine in human serum. The extraction of lidocaine and procainamide (internal standard) from serum (0.25 mL) was achieved using diethyl ether under alkaline conditions. [...] Read more.

Here we report on the development of a selective and sensitive high-performance liquid chromatographic method for the determination of lidocaine in human serum. The extraction of lidocaine and procainamide (internal standard) from serum (0.25 mL) was achieved using diethyl ether under alkaline conditions. After liquid–liquid extraction, the separation of analytes was accomplished using reverse phase extraction. The mobile phase, a combination of acetonitrile and monobasic potassium phosphate, was pumped isocratically through a C18 analytical column. The ultraviolet (UV) wavelength was at 277 nm for the internal standard, and subsequently changed to 210 for lidocaine. The assay exhibited excellent linearity (r² > 0.999) in peak response over the concentration ranges of 50–5000 ng/mL lidocaine HCl in human serum. The mean absolute recoveries for 50 and 1000 ng/mL lidocaine HCl in serum using the present extraction procedure were 93.9 and 80.42%, respectively. The intra- and inter-day coefficients of variation in the serum were <15% at the lowest, and <12% at other concentrations, and the percent error values were less than 9%. The method displayed a high caliber of sensitivity and selectivity for monitoring therapeutic concentrations of lidocaine in human serum. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessArticle

In Vitro Phase I Metabolism of CRV431, a Novel Oral Drug Candidate for Chronic Hepatitis B

by Daniel J. Trepanier, Daren R. Ure and Robert T. Foster

Pharmaceutics 2017, 9(4), 51; https://doi.org/10.3390/pharmaceutics9040051 - 9 Nov 2017

Cited by 9 | Viewed by 5172

Abstract

The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0–80 min with [...] Read more.

The cytochrome P450-mediated Phase I in vitro metabolism of CRV431 was studied using selective chemical inhibition and recombinant human enzymes. Additionally, the metabolic profile of CRV431 in human, rat, and monkey liver microsomes was investigated. Liver microsomes were incubated for 0–80 min with CRV431, and the metabolite profile was assessed by electrospray ionization liquid chromatography mass spectrometry (ESI-LCMS). CRV431 was extensively metabolized through oxidation to produce various hydroxylated and demethylated species. Species identified included monohydroxylated CRV431 (two distinct products), dihydroxylated CRV431, demethylated CRV431 (two distinct products), demethylated and hydroxylated CRV431 (two distinct products), didemethylated and hydroxylated CRV431, and didemethylated and dihydroxylated CRV431. The magnitude of metabolism was greatest in monkey, followed by human, followed by rat. Importantly, all of the species identified in human microsomes were correspondingly identified in monkey and/or rat microsomes. Human liver microsome studies using selective chemical inhibition, as well as studies using recombinant human cytochrome P450 enzymes, revealed that the major enzymes involved are cytochromes P450 3A4 and 3A5. Enzymes 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6 are not involved in the in vitro metabolism of CRV431. This information will be useful for the further development of CRV431 both preclinically and clinically. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessReview

Self-Emulsifying Granules and Pellets: Composition and Formation Mechanisms for Instant or Controlled Release

by Ioannis Nikolakakis and Ioannis Partheniadis

Pharmaceutics 2017, 9(4), 50; https://doi.org/10.3390/pharmaceutics9040050 - 3 Nov 2017

Cited by 64 | Viewed by 9263

Abstract

Many articles have been published in the last two decades demonstrating improvement in the dissolution and absorption of low solubility drugs when formulated into self-emulsifying drug delivery systems (SEDDS). Several such pharmaceutical products have appeared in the market for medium dose (Neoral^® [...] Read more.

Many articles have been published in the last two decades demonstrating improvement in the dissolution and absorption of low solubility drugs when formulated into self-emulsifying drug delivery systems (SEDDS). Several such pharmaceutical products have appeared in the market for medium dose (Neoral^® for Cyclsoprin A, Kaletra^® for Lopinavir and Ritonavir), or low dose medications (Rocaltrol^® for Calcitriol and Avodart^® for Dutasteride). However, these are in the form of viscous liquids or semisolid presentations, characterized by the disadvantages of high production cost, stability problems and the requirement of large quantities of surfactants. Solid SEDDS (S-SEDDS), as coarse powders, granules or pellets, besides solubility improvement, can be filled easily into capsules or processed into tablets providing a handy dosage form with instant release, which can be further developed into controlled release by mixing with suitable polymers or coating with polymeric films. In this review, the materials used for the preparation of S-SEDDS, their properties and role in the formulations are detailed. Factors affecting the physical characteristics, mechanical properties of S-SEDDS as well as their in vitro release and in vivo absorption are discussed. The mechanisms involved in the formation of instant and sustained release self-emulsifying granules or pellets are elucidated. Relationships are demonstrated between the characteristics of S-SEDDS units (size, shape, mechanical properties, re-emulsification ability, drug migration and drug release) and the properties of the submicron emulsions used as massing liquids, with the aim to further elucidate the formation mechanisms. The influence of the composition of the powdered ingredients forming the granule or pellet on the properties of S-SEDDS is also examined. Examples of formulations of S-SEDDS that have been reported in the literature in the last thirteen years (2004–2017) are presented. Full article

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Open AccessFeature PaperArticle

The Role of PXR Genotype and Transporter Expression in the Placental Transport of Lopinavir in Mice

by Sarabjit S. Gahir and Micheline Piquette-Miller

Pharmaceutics 2017, 9(4), 49; https://doi.org/10.3390/pharmaceutics9040049 - 24 Oct 2017

Cited by 5 | Viewed by 5045

Abstract

Lopinavir (LPV), an antiretroviral protease inhibitor frequently prescribed in HIV-positive pregnancies, is a substrate of Abcb1 and Abcc2. As differences in placental expression of these transporters were seen in Pregnane X Receptor (PXR) −/− mice, we examined the impact of placental transporter expression [...] Read more.

Lopinavir (LPV), an antiretroviral protease inhibitor frequently prescribed in HIV-positive pregnancies, is a substrate of Abcb1 and Abcc2. As differences in placental expression of these transporters were seen in Pregnane X Receptor (PXR) −/− mice, we examined the impact of placental transporter expression and fetal PXR genotype on the fetal accumulation of LPV. PXR +/− dams bearing PXR +/+, PXR +/−, and PXR −/− fetuses were generated by mating PXR +/− female mice with PXR +/− males. On gestational day 17, dams were administered 10 mg/kg LPV (i.v.) and sacrificed 30 min post injection. Concentrations of LPV in maternal plasma and fetal tissue were measured by LC-MS/MS, and transporter expression was determined by quantitative RT-PCR. As compared to the PXR +/+ fetal units, placental expression of Abcb1a, Abcc2, and Abcg2 mRNA were two- to three-fold higher in PXR −/− fetuses (p < 0.05). Two-fold higher fetal:maternal LPV concentration ratios were also seen in the PXR +/+ as compared to the PXR −/− fetuses (p < 0.05), and this significantly correlated to the placental expression of Abcb1a (r = 0.495; p < 0.005). Individual differences in the expression of placental transporters due to genetic or environmental factors can impact fetal exposure to their substrates. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessArticle

Rosemary Essential Oil-Loaded Lipid Nanoparticles: In Vivo Topical Activity from Gel Vehicles

by Lucia Montenegro, Lorella Pasquinucci, Agata Zappalà, Santina Chiechio, Rita Turnaturi and Carmela Parenti

Pharmaceutics 2017, 9(4), 48; https://doi.org/10.3390/pharmaceutics9040048 - 21 Oct 2017

Cited by 69 | Viewed by 9981

Abstract

Although rosemary essential oil (EO) shows many biological activities, its topical benefits have not been clearly demonstrated. In this work, we assessed the effects on skin hydration and elasticity of rosemary EO after topical application via gel vehicles in human volunteers. To improve [...] Read more.

Although rosemary essential oil (EO) shows many biological activities, its topical benefits have not been clearly demonstrated. In this work, we assessed the effects on skin hydration and elasticity of rosemary EO after topical application via gel vehicles in human volunteers. To improve its topical efficacy, rosemary EO was loaded into lipid nanoparticles (NLCs) consisting of cetyl palmitate as a solid lipid, and non-ionic surfactants. Such NLCs were prepared using different ratios of EO/solid lipid and those containing EO 3% w/w and cetyl pamitate 7% w/w were selected for in vivo studies, showing the best technological properties (small particle size, low polydispersity index and good stability). Gels containing free EO or EO-loaded NLCs were applied on the hand skin surface of ten healthy volunteers twice a day for one week. Skin hydration and elasticity changes were recorded using the instrument Soft Plus. Gels containing EO-loaded NLCs showed a significant increase in skin hydration in comparison with gels containing free EO. Skin elasticity increased, as well, although to a lesser extent. The results of this study point out the usefulness of rosemary EO-loaded NLCs for the treatment of cutaneous alterations involving loss of skin hydration and elasticity. Full article

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Open AccessArticle

Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

by Alanna McEneny-King, Pierre Chelle, Severine Henrard, Cedric Hermans, Alfonso Iorio and Andrea N. Edginton

Pharmaceutics 2017, 9(4), 47; https://doi.org/10.3390/pharmaceutics9040047 - 17 Oct 2017

Cited by 18 | Viewed by 5571

Abstract

The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. [...] Read more.

The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessReview

Targeting Strategies for the Combination Treatment of Cancer Using Drug Delivery Systems

by Janel Kydd, Rahul Jadia, Praveena Velpurisiva, Aniket Gad, Shailee Paliwal and Prakash Rai

Pharmaceutics 2017, 9(4), 46; https://doi.org/10.3390/pharmaceutics9040046 - 14 Oct 2017

Cited by 132 | Viewed by 10822

Abstract

Cancer cells have characteristics of acquired and intrinsic resistances to chemotherapy treatment—due to the hostile tumor microenvironment—that create a significant challenge for effective therapeutic regimens. Multidrug resistance, collateral toxicity to normal cells, and detrimental systemic side effects present significant obstacles, necessitating alternative and [...] Read more.

Cancer cells have characteristics of acquired and intrinsic resistances to chemotherapy treatment—due to the hostile tumor microenvironment—that create a significant challenge for effective therapeutic regimens. Multidrug resistance, collateral toxicity to normal cells, and detrimental systemic side effects present significant obstacles, necessitating alternative and safer treatment strategies. Traditional administration of chemotherapeutics has demonstrated minimal success due to the non-specificity of action, uptake and rapid clearance by the immune system, and subsequent metabolic alteration and poor tumor penetration. Nanomedicine can provide a more effective approach to targeting cancer by focusing on the vascular, tissue, and cellular characteristics that are unique to solid tumors. Targeted methods of treatment using nanoparticles can decrease the likelihood of resistant clonal populations of cancerous cells. Dual encapsulation of chemotherapeutic drug allows simultaneous targeting of more than one characteristic of the tumor. Several first-generation, non-targeted nanomedicines have received clinical approval starting with Doxil^® in 1995. However, more than two decades later, second-generation or targeted nanomedicines have yet to be approved for treatment despite promising results in pre-clinical studies. This review highlights recent studies using targeted nanoparticles for cancer treatment focusing on approaches that target either the tumor vasculature (referred to as ‘vascular targeting’), the tumor microenvironment (‘tissue targeting’) or the individual cancer cells (‘cellular targeting’). Recent studies combining these different targeting methods are also discussed in this review. Finally, this review summarizes some of the reasons for the lack of clinical success in the field of targeted nanomedicines. Full article

(This article belongs to the Special Issue Nanotechnology Advances in Cancer Treatment)

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Open AccessArticle

Disposition, Metabolism and Histone Deacetylase and Acetyltransferase Inhibition Activity of Tetrahydrocurcumin and Other Curcuminoids

by Júlia T. Novaes, Ryan Lillico, Casey L. Sayre, Kalyanam Nagabushanam, Muhammed Majeed, Yufei Chen, Emmanuel A. Ho, Ana Luísa de P. Oliveira, Stephanie E. Martinez, Samaa Alrushaid, Neal M. Davies and Ted M. Lakowski

Pharmaceutics 2017, 9(4), 45; https://doi.org/10.3390/pharmaceutics9040045 - 12 Oct 2017

Cited by 29 | Viewed by 6541

Abstract

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, [...] Read more.

Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC–MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate. In-vitro antioxidant activity, histone deacetylase (HDAC) activity, histone acetyltransferase (HAT) activity and anti-inflammatory inhibitory activity were examined using commercial assay kits. Anticancer activity was determined in Sup-T1 lymphoma cells. Our results indicate THC was poorly absorbed after oral administration and primarily excreted via non-renal routes. All curcuminoids exhibited multiple pharmacological effects in vitro, including potent antioxidant activity as well as inhibition of CYP2C9, CYP3A4 and lipoxygenase activity without affecting the release of TNF-α. Unlike curcumin and calebin-A, THC did not inhibit HDAC1 and PCAF and displayed a weaker growth inhibition activity against Sup-T1 cells. We show evidence for the first time that curcumin and calebin-A inhibit HAT and PCAF, possibly through a Michael-addition mechanism. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessArticle

Altered Protein Expression of Cardiac CYP2J and Hepatic CYP2C, CYP4A, and CYP4F in a Mouse Model of Type II Diabetes—A Link in the Onset and Development of Cardiovascular Disease?

by Benoit Drolet, Sylvie Pilote, Carolanne Gélinas, Alida-Douce Kamaliza, Audrey Blais-Boilard, Jessica Virgili, Dany Patoine and Chantale Simard

Pharmaceutics 2017, 9(4), 44; https://doi.org/10.3390/pharmaceutics9040044 - 12 Oct 2017

Cited by 18 | Viewed by 5364

Abstract

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) and hydroxyeicosatetraenoic acids (HETEs-cardiotoxic). Type II diabetes is a well-recognized risk factor for developing cardiovascular disease. A mouse [...] Read more.

Arachidonic acid can be metabolized by cytochrome P450 (CYP450) enzymes in a tissue- and cell-specific manner to generate vasoactive products such as epoxyeicosatrienoic acids (EETs-cardioprotective) and hydroxyeicosatetraenoic acids (HETEs-cardiotoxic). Type II diabetes is a well-recognized risk factor for developing cardiovascular disease. A mouse model of Type II diabetes (C57BLKS/J-db/db) was used. After sacrifice, livers and hearts were collected, washed, and snap frozen. Total proteins were extracted. Western blots were performed to assess cardiac CYP2J and hepatic CYP2C, CYP4A, and CYP4F protein expression, respectively. Significant decreases in relative protein expression of cardiac CYP2J and hepatic CYP2C were observed in Type II diabetes animals compared to controls (CYP2J: 0.80 ± 0.03 vs. 1.05 ± 0.06, n = 20, p < 0.001); (CYP2C: 1.56 ± 0.17 vs. 2.21 ± 0.19, n = 19, p < 0.01). In contrast, significant increases in relative protein expression of both hepatic CYP4A and CYP4F were noted in Type II diabetes mice compared to controls (CYP4A: 1.06 ± 0.09 vs. 0.18 ± 0.01, n = 19, p < 0.001); (CYP4F: 2.53 ± 0.22 vs. 1.10 ± 0.07, n = 19, p < 0.001). These alterations induced by Type II diabetes in the endogenous pathway (CYP450) of arachidonic acid metabolism may increase the risk for cardiovascular disease by disrupting the fine equilibrium between cardioprotective (CYP2J/CYP2C-generated) and cardiotoxic (CYP4A/CYP4F-generated) metabolites of arachidonic acid. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessFeature PaperReview

Revolutionizing Therapeutic Drug Monitoring with the Use of Interstitial Fluid and Microneedles Technology

by Tony K.L. Kiang, Sahan A. Ranamukhaarachchi and Mary H.H. Ensom

Pharmaceutics 2017, 9(4), 43; https://doi.org/10.3390/pharmaceutics9040043 - 11 Oct 2017

Cited by 69 | Viewed by 8652

Abstract

While therapeutic drug monitoring (TDM) that uses blood as the biological matrix is the traditional gold standard, this practice may be impossible, impractical, or unethical for some patient populations (e.g., elderly, pediatric, anemic) and those with fragile veins. In the context of finding [...] Read more.

While therapeutic drug monitoring (TDM) that uses blood as the biological matrix is the traditional gold standard, this practice may be impossible, impractical, or unethical for some patient populations (e.g., elderly, pediatric, anemic) and those with fragile veins. In the context of finding an alternative biological matrix for TDM, this manuscript will provide a qualitative review on: (1) the principles of TDM; (2) alternative matrices for TDM; (3) current evidence supporting the use of interstitial fluid (ISF) for TDM in clinical models; (4) the use of microneedle technologies, which is potentially minimally invasive and pain-free, for the collection of ISF; and (5) future directions. The current state of knowledge on the use of ISF for TDM in humans is still limited. A thorough literature review indicates that only a few drug classes have been investigated (i.e., anti-infectives, anticonvulsants, and miscellaneous other agents). Studies have successfully demonstrated techniques for ISF extraction from the skin but have failed to demonstrate commercial feasibility of ISF extraction followed by analysis of its content outside the ISF-collecting microneedle device. In contrast, microneedle-integrated biosensors built to extract ISF and perform the biomolecule analysis on-device, with a key feature of not needing to transfer ISF to a separate instrument, have yielded promising results that need to be validated in pre-clinical and clinical studies. The most promising applications for microneedle-integrated biosensors is continuous monitoring of biomolecules from the skin’s ISF. Conducting TDM using ISF is at the stage where its clinical utility should be investigated. Based on the advancements described in the current review, the immediate future direction for this area of research is to establish the suitability of using ISF for TDM in human models for drugs that have been found suitable in pre-clinical experiments. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessArticle

Study of Statin- and Loratadine-Induced Muscle Pain Mechanisms Using Human Skeletal Muscle Cells

by Yat Hei Leung, Jacques Turgeon and Veronique Michaud

Pharmaceutics 2017, 9(4), 42; https://doi.org/10.3390/pharmaceutics9040042 - 10 Oct 2017

Cited by 5 | Viewed by 6329

Abstract

Many drugs can cause unexpected muscle disorders, often necessitating the cessation of an effective medication. Inhibition of monocarboxylate transporters (MCTs) may potentially lead to perturbation of l-lactic acid homeostasis and muscular toxicity. Previous studies have shown that statins and loratadine have the [...] Read more.

Many drugs can cause unexpected muscle disorders, often necessitating the cessation of an effective medication. Inhibition of monocarboxylate transporters (MCTs) may potentially lead to perturbation of l-lactic acid homeostasis and muscular toxicity. Previous studies have shown that statins and loratadine have the potential to inhibit l-lactic acid efflux by MCTs (MCT1 and 4). The main objective of this study was to confirm the inhibitory potentials of atorvastatin, simvastatin (acid and lactone forms), rosuvastatin, and loratadine on l-lactic acid transport using primary human skeletal muscle cells (SkMC). Loratadine (IC₅₀ 31 and 15 µM) and atorvastatin (IC₅₀ ~130 and 210 µM) demonstrated the greatest potency for inhibition of l-lactic acid efflux at pH 7.0 and 7.4, respectively (~2.5-fold l-lactic acid intracellular accumulation). Simvastatin acid exhibited weak inhibitory potency on l-lactic acid efflux with an intracellular lactic acid increase of 25–35%. No l-lactic acid efflux inhibition was observed for simvastatin lactone or rosuvastatin. Pretreatment studies showed no change in inhibitory potential and did not affect lactic acid transport for all tested drugs. In conclusion, we have demonstrated that loratadine and atorvastatin can inhibit the efflux transport of l-lactic acid in SkMC. Inhibition of l-lactic acid efflux may cause an accumulation of intracellular l-lactic acid leading to the reported drug-induced myotoxicity. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessReview

Predicting Oral Drug Absorption: Mini Review on Physiologically-Based Pharmacokinetic Models

by Louis Lin and Harvey Wong

Pharmaceutics 2017, 9(4), 41; https://doi.org/10.3390/pharmaceutics9040041 - 26 Sep 2017

Cited by 123 | Viewed by 16159

Abstract

Most marketed drugs are administered orally, despite the complex process of oral absorption that is difficult to predict. Oral bioavailability is dependent on the interplay between many processes that are dependent on both compound and physiological properties. Because of this complexity, computational oral [...] Read more.

Most marketed drugs are administered orally, despite the complex process of oral absorption that is difficult to predict. Oral bioavailability is dependent on the interplay between many processes that are dependent on both compound and physiological properties. Because of this complexity, computational oral physiologically-based pharmacokinetic (PBPK) models have emerged as a tool to integrate these factors in an attempt to mechanistically capture the process of oral absorption. These models use inputs from in vitro assays to predict the pharmacokinetic behavior of drugs in the human body. The most common oral PBPK models are compartmental approaches, in which the gastrointestinal tract is characterized as a series of compartments through which the drug transits. The focus of this review is on the development of oral absorption PBPK models, followed by a brief discussion of the major applications of oral PBPK models in the pharmaceutical industry. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessArticle

Tissue Specific Modulation of cyp2c and cyp3a mRNA Levels and Activities by Diet-Induced Obesity in Mice: The Impact of Type 2 Diabetes on Drug Metabolizing Enzymes in Liver and Extra-Hepatic Tissues

by Sarah Maximos, Michel Chamoun, Sophie Gravel, Jacques Turgeon and Veronique Michaud

Pharmaceutics 2017, 9(4), 40; https://doi.org/10.3390/pharmaceutics9040040 - 26 Sep 2017

Cited by 23 | Viewed by 7016

Abstract

Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The [...] Read more.

Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals (n = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes. Expression levels of cyp3a11 and cyp3a25 mRNA were decreased in the liver (>2–14-fold) and kidneys (>2-fold) of HFD groups which correlated with a significant reduction in midazolam metabolism (by 21- and 5-fold in hepatic and kidney microsomes, respectively, p < 0.001). HFD was associated with decreased activities of cyp2b and cyp2c subfamilies in all organs tested except in the kidneys (for tolbutamide). Other cyp450 hepatic activities were minimally or not affected by HFD. Taken together, our data suggest that substrate-dependent and tissue-dependent modulation of cyp450 metabolic capacities by early phases of T2D are observed, which could modulate drug disposition and pharmacological effects in various tissues. Full article

(This article belongs to the Special Issue Pharmacokinetics and Drug Metabolism in Canada: The Current Landscape)

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Open AccessFeature PaperReview

Nanotechnologies in Pancreatic Cancer Therapy

by Ayesha Manzur, Adeolu Oluwasanmi, Darren Moss, Anthony Curtis and Clare Hoskins

Pharmaceutics 2017, 9(4), 39; https://doi.org/10.3390/pharmaceutics9040039 - 25 Sep 2017

Cited by 41 | Viewed by 7129

Abstract

Pancreatic cancer has been classified as a cancer of unmet need. After diagnosis the patient prognosis is dismal with few surviving over 5 years. Treatment regimes are highly patient variable and often the patients are too sick to undergo surgical resection or chemotherapy. [...] Read more.

Pancreatic cancer has been classified as a cancer of unmet need. After diagnosis the patient prognosis is dismal with few surviving over 5 years. Treatment regimes are highly patient variable and often the patients are too sick to undergo surgical resection or chemotherapy. These chemotherapies are not effective often because patients are diagnosed at late stages and tumour metastasis has occurred. Nanotechnology can be used in order to formulate potent anticancer agents to improve their physicochemical properties such as poor aqueous solubility or prolong circulation times after administration resulting in improved efficacy. Studies have reported the use of nanotechnologies to improve the efficacy of gemcitabine (the current first line treatment) as well as investigating the potential of using other drug molecules which have previously shown promise but were unable to be utilised due to the inability to administer through appropriate routes—often related to solubility. Of the nanotechnologies reported, many can offer site specific targeting to the site of action as well as a plethora of other multifunctional properties such as image guidance and controlled release. This review focuses on the use of the major nanotechnologies both under pre-clinical development and those which have recently been approved for use in pancreatic cancer therapy. Full article

(This article belongs to the Special Issue Nanotechnology Advances in Cancer Treatment)

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Open AccessArticle

The Development of a Melt-Extruded Shellac Carrier for the Targeted Delivery of Probiotics to the Colon

by Noel M. Gately and James E. Kennedy

Pharmaceutics 2017, 9(4), 38; https://doi.org/10.3390/pharmaceutics9040038 - 22 Sep 2017

Cited by 26 | Viewed by 5677

Abstract

Hot melt extrusion (HME) is considered an efficient technique in developing solid molecular dispersions, and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. However, most commercial enteric or pH-responsive polymers are relatively difficult to process or [...] Read more.

Hot melt extrusion (HME) is considered an efficient technique in developing solid molecular dispersions, and has been demonstrated to provide sustained, modified and targeted drug delivery resulting in improved bioavailability. However, most commercial enteric or pH-responsive polymers are relatively difficult to process or have high Glass Transition Temperature (Tg) values, making their use with temperature-sensitive drugs, probiotics or biologics not viable. Shellac is a natural thermoplastic, and after a review of current literature on the pharmaceutical HME process, a possible gap in the knowledge of the use of shellac to produce dosage forms by means of HME was identified. This work explores the possibility of SSB^® 55 pharmaceutical-grade shellac as a melt-extrudable encapsulation polymer to entrap freeze-dried probiotic powder and to determine bacterial cell viability post-processing. Well-defined strands were produced from the physical mixture of shellac and Biocare^® Bifidobacterium Probiotic. FTIR clarified that there are no significant interactions between the probiotic and polymer. All of the samples demonstrated less than 5% degradation over 24 h at pH of both 1.2 and 6.8. At pH 7.4, both loaded samples gave a similar dissolution trend with complete degradation achieved after 10–11 h. Following five-month storage, 57.8% reduction in viability was observed. Full article

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Open AccessReview

Topical Nano and Microemulsions for Skin Delivery

by Christofori M. R. R. Nastiti, Thellie Ponto, Eman Abd, Jeffrey E. Grice, Heather A. E. Benson and Michael S. Roberts

Pharmaceutics 2017, 9(4), 37; https://doi.org/10.3390/pharmaceutics9040037 - 21 Sep 2017

Cited by 287 | Viewed by 16648

Abstract

Nanosystems such as microemulsions (ME) and nanoemulsions (NE) offer considerable opportunities for targeted drug delivery to and via the skin. ME and NE are stable colloidal systems composed of oil and water, stabilised by a mixture of surfactants and cosurfactants, that have received [...] Read more.

Nanosystems such as microemulsions (ME) and nanoemulsions (NE) offer considerable opportunities for targeted drug delivery to and via the skin. ME and NE are stable colloidal systems composed of oil and water, stabilised by a mixture of surfactants and cosurfactants, that have received particular interest as topical skin delivery systems. There is considerable scope to manipulate the formulation components and characteristics to achieve optimal bioavailability and minimal skin irritancy. This includes the incorporation of established chemical penetration enhancers to fluidize the stratum corneum lipid bilayers, thus reducing the primary skin barrier and increasing permeation. This review discusses nanosystems with utility in skin delivery and focuses on the composition and characterization of ME and NE for topical and transdermal delivery. The mechanism of skin delivery across the stratum corneum and via hair follicles is reviewed with particular focus on the influence of formulation. Full article

(This article belongs to the Special Issue Recent Technology of Transdermal and Topical Drug Delivery)

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Pharmaceutics, Volume 9, Issue 4 (December 2017) – 23 articles

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