Open AccessReview
Hydrogels for Atopic Dermatitis and Wound Management: A Superior Drug Delivery Vehicle
Pharmaceutics 2018, 10(2), 71; https://doi.org/10.3390/pharmaceutics10020071 -
Abstract
Wound management, in addition to presenting a significant burden to patients and their families, also contributes significantly to a country’s healthcare costs. Treatment strategies are numerous, but in most cases not ideal. Hydrogels, three-dimensional polymeric materials that can withstand a great degree of
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Wound management, in addition to presenting a significant burden to patients and their families, also contributes significantly to a country’s healthcare costs. Treatment strategies are numerous, but in most cases not ideal. Hydrogels, three-dimensional polymeric materials that can withstand a great degree of swelling without losing structural integrity, are drawing great attention for their use as topical wound management solutions in the form of films and as vehicles for drug delivery, due to their unique properties of high water content, biocompatibility, and flexibility. Hydrogels, both naturally and synthetically derived, can be tuned to respond to specific stimuli such as pH, temperature and light and they are ideally suited as drug delivery vehicles. Here we provide a brief overview of the history and characteristics of hydrogels, assess their uses in wound management and drug delivery, and compare them with other types of common drug delivery vehicle. Full article
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Open AccessArticle
Skull Bone Regeneration Using Chitosan–Siloxane Porous Hybrids—Long-Term Implantation
Pharmaceutics 2018, 10(2), 70; https://doi.org/10.3390/pharmaceutics10020070 -
Abstract
Burr holes in craniotomy are not self-repairing bone defects. To regenerate new bone at the sites of these defects, a good scaffold is required. Biodegradable hybrids including silica or siloxane networks have been investigated as bone tissue scaffolds. This study examined skull bone
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Burr holes in craniotomy are not self-repairing bone defects. To regenerate new bone at the sites of these defects, a good scaffold is required. Biodegradable hybrids including silica or siloxane networks have been investigated as bone tissue scaffolds. This study examined skull bone regeneration using chitosan-siloxane hybrids after long-term implantation (two and three years). After implantation of the hybrids, the surrounding cells migrated and formed fibrous tissues and blood vessels. Then, bone formation occurred from the surrounding blood vessels. Addition of calcium ions and coating with hydroxyapatite improved bone regeneration. Finally, the regenerated tissue area became smaller than the initial hole, and some areas changed to completed bone tissues. Full article
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Open AccessArticle
A Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometric Assay for the Quantification of Fabry Disease Biomarker Globotriaosylceramide (GB3) in Fabry Model Mouse
Pharmaceutics 2018, 10(2), 69; https://doi.org/10.3390/pharmaceutics10020069 -
Abstract
Fabry disease is a rare lysosomal storage disorder resulting from the lack of α-Gal A gene activity. Globotriaosylceramide (GB3, ceramide trihexoside) is a novel endogenous biomarker which predicts the incidence of Fabry disease. At the early stage efficacy/biomarker study, a rapid method to
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Fabry disease is a rare lysosomal storage disorder resulting from the lack of α-Gal A gene activity. Globotriaosylceramide (GB3, ceramide trihexoside) is a novel endogenous biomarker which predicts the incidence of Fabry disease. At the early stage efficacy/biomarker study, a rapid method to determine this biomarker in plasma and in all relevant tissues related to this disease simultaneously is required. However, the limited sample volume, as well as the various levels of GB3 in different matrices makes the GB3 quantitation very challenging. Hereby we developed a rapid method to identify GB3 in mouse plasma and various tissues. Preliminary stability tests were also performed in three different conditions: short-term, freeze-thaw, long-term. The calibration curve was well fitted over the concentration range of 0.042–10 μg/mL for GB3 in plasma and 0.082–20 μg/g for GB3 in various tissues. This method was successfully applied for the comparison of GB3 levels in Fabry model mice (B6;129-Glatm1Kul/J), which has not been performed previously to the best of our knowledge. Full article
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Open AccessArticle
Twin Screw Granulation: Effects of Properties of Primary Powders
Pharmaceutics 2018, 10(2), 68; https://doi.org/10.3390/pharmaceutics10020068 -
Abstract
Lactose and mannitol are some of the most commonly used powders in the pharmaceutical industry. The limited research published so far highlights the effects of process and formulation parameters on the properties of the granules and the tablets produced using these two types
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Lactose and mannitol are some of the most commonly used powders in the pharmaceutical industry. The limited research published so far highlights the effects of process and formulation parameters on the properties of the granules and the tablets produced using these two types of powders separately. However, the comparison of the performance of these two types of powders during twin screw wet granulation has received no attention. The present research is focused on understanding the granulation mechanism of different grades of two pharmaceutical powders with varying properties (i.e., primary particle size, structure, and compressibility). Three grades each of lactose and mannitol were granulated at varying liquid to solid ratios (L/S) and screw speed. It was noticed that primary powder morphology plays an important role in determining the granule size and structure, and tablet tensile strength. It was indicated that the processed powders such as spray-dried and granulated lactose and mannitol can be used in formulation for wet granulation where flowability of active pharmaceutical ingredient (API) is poor. Full article
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Open AccessArticle
Twin Screw Granulation: An Investigation of the Effect of Barrel Fill Level
Pharmaceutics 2018, 10(2), 67; https://doi.org/10.3390/pharmaceutics10020067 -
Abstract
This paper focuses on investigating the influence of varying barrel fill levels on the mean residence time, granule properties (median size, size distribution, and shape), and tensile strength of tablets. Specific feed load (SFL) (powder feed rate divided by screw speed) and powder
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This paper focuses on investigating the influence of varying barrel fill levels on the mean residence time, granule properties (median size, size distribution, and shape), and tensile strength of tablets. Specific feed load (SFL) (powder feed rate divided by screw speed) and powder feed number (PFN) (i.e., powder mass flow rate divided by the product of screw speed, screw diameter, and the material density in the denominator) were considered as surrogates for the barrel fill level. Two type of powders (lactose and microcrystalline cellulose (MCC)) were granulated separately at varying fill levels at different liquid-to-solid ratios (L/S). It was observed that by controlling the barrel fill level, the granule size, shape, and tablet tensile strength can be maintained at specific L/S. It was also noticed that the mean residence time decreased with increasing fill levels in the case of both lactose and MCC powder. However, it was only found to be related to the change in granule size in case of granulating microcrystalline cellulose at varying fill levels. At very high fill levels, granule size decreased, owing to a limited interaction between MCC powder and liquid at high throughput force and short residence time. Full article
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Open AccessReview
Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis
Pharmaceutics 2018, 10(2), 66; https://doi.org/10.3390/pharmaceutics10020066 -
Abstract
Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of
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Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of the preclinical pharmacokinetic parameters obtained in different studies of intravitreal injections of anti-infectives performed on animals, mainly rabbits. The two aspects with the biggest influence on pharmacokinetics are the distribution in the vitreous humour and the elimination through the posterior segment. The distribution can be affected by the molecular weight of the drug, the convection flow of the vitreous, the condition of the vitreous humour depending on the age of the patient, the possible interactions between the drug and the components of the vitreous, and the presence of vitrectomy. Meanwhile, the elimination includes the metabolism of the drug, the clearance via the anterior and posterior routes, and the possible inflammation of the eye resulting from the disease. Understanding the pharmacokinetics of the anti-infectives used in clinical practice is essential for a correct application. The information provided in this review could offer guidance for selecting the best therapeutic option according to the characteristics of the drugs. Full article
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Open AccessReview
Therapeutic Potency of Nanoformulations of siRNAs and shRNAs in Animal Models of Cancers
Pharmaceutics 2018, 10(2), 65; https://doi.org/10.3390/pharmaceutics10020065 -
Abstract
RNA Interference (RNAi) has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made
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RNA Interference (RNAi) has brought revolutionary transformations in cancer management in the past two decades. RNAi-based therapeutics including siRNA and shRNA have immense scope to silence the expression of mutant cancer genes specifically in a therapeutic context. Although tremendous progress has been made to establish catalytic RNA as a new class of biologics for cancer management, a lot of extracellular and intracellular barriers still pose a long-lasting challenge on the way to clinical approval. A series of chemically suitable, safe and effective viral and non-viral carriers have emerged to overcome physiological barriers and ensure targeted delivery of RNAi. The newly invented carriers, delivery techniques and gene editing technology made current treatment protocols stronger to fight cancer. This review has provided a platform about the chronicle of siRNA development and challenges of RNAi therapeutics for laboratory to bedside translation focusing on recent advancement in siRNA delivery vehicles with their limitations. Furthermore, an overview of several animal model studies of siRNA- or shRNA-based cancer gene therapy over the past 15 years has been presented, highlighting the roles of genes in multiple cancers, pharmacokinetic parameters and critical evaluation. The review concludes with a future direction for the development of catalytic RNA vehicles and design strategies to make RNAi-based cancer gene therapy more promising to surmount cancer gene delivery challenges. Full article
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Open AccessArticle
Solubility Improvement of Benexate through Salt Formation Using Artificial Sweetener
Pharmaceutics 2018, 10(2), 64; https://doi.org/10.3390/pharmaceutics10020064 -
Abstract
Benexate, a drug used clinically as a defensive type anti-ulcer agent, has poor solubility and a bitter taste. To improve its solubility, a crystal engineering approach was proposed with the formation of novel salts using an artificial sweetener as a salt co-former. This
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Benexate, a drug used clinically as a defensive type anti-ulcer agent, has poor solubility and a bitter taste. To improve its solubility, a crystal engineering approach was proposed with the formation of novel salts using an artificial sweetener as a salt co-former. This was also expected to address the bitter taste of the drug. In this work, we report on the preparation and evaluation of the physicochemical properties of the novel salts benexate saccharinate monohydrate and benexate cyclamate whose crystal structures were determined by single-crystal X-ray structure analysis. These novel salts showed higher solubility and faster dissolution profiles that were associated with the occurrence of local layered-like structures. They also showed better moisture uptake profiles and were classified as non-hygroscopic materials. Therefore, benexate saccharinate monohydrate and benexate cyclamate expedited the development of sweet pharmaceutical salts of benexate with improved performances. Full article
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Open AccessArticle
Dual Acting Polymeric Nano-Aggregates for Liver Cancer Therapy
Pharmaceutics 2018, 10(2), 63; https://doi.org/10.3390/pharmaceutics10020063 -
Abstract
Liver cancer treatments are often hindered by poor drug physicochemical properties, hence there is a need for improvement in order to increase patient survival and outlook. Combination therapies have been studied in order to evaluate whether increased overall efficacy can be achieved. This
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Liver cancer treatments are often hindered by poor drug physicochemical properties, hence there is a need for improvement in order to increase patient survival and outlook. Combination therapies have been studied in order to evaluate whether increased overall efficacy can be achieved. This study reports the combined treatment of liver cancer cells with a combination treatment of chemotherapeutic agent paclitaxel and pro-apoptotic protein cytochrome C. In order to administer both agents in a single formulation, a poly(allylamine)-based amphiphile has been fabricated with the incorporation of a hybrid iron oxide-gold nanoparticle into its structure. Here, the insoluble paclitaxel becomes incorporated into the hydrophobic core of the self-assemblies formed in an aqueous environment (256 nm), while the cytochrome C attaches irreversibly onto the hybrid nanoparticle surface via gold-thiol dative covalent binding. The self-assemblies were capable of solubilising up to 0.698 mg/mL of paclitaxel (700-fold improvement) with 0.012 mg/mL of cytochrome C also attached onto the hybrid iron oxide-gold nanoparticles (HNPs) within the hydrophobic core. The formulation was tested on a panel of liver cancer cells and cytotoxicity was measured. The findings suggested that indeed a significant improvement in combined therapy (33-fold) was observed when compared with free drug, which was double the enhancement observed after polymer encapsulation without the cytochrome C in hepatocellular carcinoma (Huh-7D12) cells. Most excitingly, the polymeric nanoparticles did result in improved cellular toxicity in human endothelian liver cancer (SK-hep1) cells, which proved completely resistant to the free drug. Full article
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Open AccessArticle
Magnetic Nanoparticles Conjugated with Peptides Derived from Monocyte Chemoattractant Protein-1 as a Tool for Targeting Atherosclerosis
Pharmaceutics 2018, 10(2), 62; https://doi.org/10.3390/pharmaceutics10020062 -
Abstract
Atherosclerosis is a multifactorial inflammatory disease that may progress silently for long period, and it is also widely accepted as the main cause of cardiovascular diseases. To prevent atherosclerotic plaques from generating, imaging early molecular markers and quantifying the extent of disease progression
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Atherosclerosis is a multifactorial inflammatory disease that may progress silently for long period, and it is also widely accepted as the main cause of cardiovascular diseases. To prevent atherosclerotic plaques from generating, imaging early molecular markers and quantifying the extent of disease progression are desired. During inflammation, circulating monocytes leave the bloodstream and migrate into incipient lipid accumulation in the artery wall, following conditioning by local growth factors and proinflammatory cytokines; therefore, monocyte accumulation in the arterial wall can be observed in fatty streaks, rupture-prone plaques, and experimental atherosclerosis. In this work, we synthesized monocyte-targeting iron oxide magnetic nanoparticles (MNPs), which were incorporated with the peptides derived from the chemokine receptor C-C chemokine receptor type 2 (CCR2)-binding motif of monocytes chemoattractant protein-1 (MCP-1) as a diagnostic tool for potential atherosclerosis. MCP-1-motif MNPs co-localized with monocytes in in vitro fluorescence imaging. In addition, with MNPs injection in ApoE knockout mice (ApoE KO mice), the well-characterized animal model of atherosclerosis, MNPs were found in specific organs or regions which had monocytes accumulation, especially the aorta of atherosclerosis model mice, through in vivo imaging system (IVIS) imaging and magnetic resonance imaging (MRI). We also performed Oil Red O staining and Prussian Blue staining to confirm the co-localization of MCP-1-motif MNPs and atherosclerosis. The results showed the promising potential of MCP-1-motif MNPs as a diagnostic agent of atherosclerosis. Full article
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Open AccessArticle
Qualification and Application of a Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometric Method for the Determination of Adalimumab in Rat Plasma
Pharmaceutics 2018, 10(2), 61; https://doi.org/10.3390/pharmaceutics10020061 -
Abstract
A liquid chromatography–quadrupole time-of-flight (Q-TOF) mass spectrometric method was developed for early-stage research on adalimumab in rats. The method consisted of immunoprecipitation followed by tryptic digestion for sample preparation and LC-QTOF-MS/MS analysis of specific signature peptides of adalimumab in the positive ion mode
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A liquid chromatography–quadrupole time-of-flight (Q-TOF) mass spectrometric method was developed for early-stage research on adalimumab in rats. The method consisted of immunoprecipitation followed by tryptic digestion for sample preparation and LC-QTOF-MS/MS analysis of specific signature peptides of adalimumab in the positive ion mode using electrospray ionization. This specific signature peptide is derived from the complementarity-determining region (CDR) of adalimumab. A quadratic regression (weighted 1/concentration), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range of 1–100 μg/mL for adalimumab. The qualification run met the acceptance criteria of ±25% accuracy and precision values for quality control (QC) samples. This qualified LC-QTOF-MS/MS method was successfully applied to a pharmacokinetic study of adalimumab in rats as a case study. This LC-QTOF-MS/MS approach would be useful as a complementary method for adalimumab or its biosimilars at an early stage of research. Full article
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Open AccessArticle
A Repurposed Drug for Brain Cancer: Enhanced Atovaquone Amorphous Solid Dispersion by Combining a Spontaneously Emulsifying Component with a Polymer Carrier
Pharmaceutics 2018, 10(2), 60; https://doi.org/10.3390/pharmaceutics10020060 -
Abstract
Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in the
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Glioblastoma multiforme (GBM) is the most common and lethal central nervous system tumor. Recently, atovaquone has shown inhibition of signal transducer and activator transcription 3, a promising target for GBM therapy. However, it is currently unable to achieve therapeutic drug concentrations in the brain with the currently reported and marketed formulations. The present study sought to explore the efficacy of atovaquone against GBM as well as develop a formulation of atovaquone that would improve oral bioavailability, resulting in higher amounts of drug delivered to the brain. Atovaquone was formulated as an amorphous solid dispersion using an optimized formulation containing a polymer and a spontaneously emulsifying component (SEC) with greatly improved wetting, disintegration, dispersibility, and dissolution properties. Atovaquone demonstrated cytotoxicity against GBM cell lines as well as provided a confirmed target for atovaquone brain concentrations in in vitro cell viability studies. This new formulation approach was then assessed in a proof-of-concept in vivo exposure study. Based on these results, the enhanced amorphous solid dispersion is promising for providing therapeutically effective brain levels of atovaquone for the treatment of GBM. Full article
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Open AccessArticle
Pre-Clinical and Clinical Efficiency of Complexes of Oligoribonucleotides with D-Mannitol against Respiratory Viruses
Pharmaceutics 2018, 10(2), 59; https://doi.org/10.3390/pharmaceutics10020059 -
Abstract
Oligoribonucleotides-D-mannitol (ORNs-D-M) complexes possess antiviral, anti-inflammatory, and immunomodulatory actions. The aim of the present study was to evaluated an antiviral effect of ORNs-D-M against parainfluenza virus type 3 (PIV3); influenza CA709, PR834; avian influenza virus H5N2 (AIV) in vitro by a TCID50
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Oligoribonucleotides-D-mannitol (ORNs-D-M) complexes possess antiviral, anti-inflammatory, and immunomodulatory actions. The aim of the present study was to evaluated an antiviral effect of ORNs-D-M against parainfluenza virus type 3 (PIV3); influenza CA709, PR834; avian influenza virus H5N2 (AIV) in vitro by a TCID50; hemadsorption and neuraminidase activity assays; and clinical efficiency of ORNs-D-M in patients with acute respiratory infections (ARIs) of various etiologies by PCR assay and AmpliSens test systems. It was observed that ORNs-D-M have an antiviral activity against the influenza CA709, PR834, PIV3, and AIV in vitro. The injectable dosage form of ORNs-D-M was shown to have a stronger antiviral effect compared to capsule form. It was also detected that the injectable form of ORNs-D-M significantly reduced the neuraminidase activity of influenza PR834. A complex treatment of patients with ORNs-D-M had a positive effect on the course of the disease, it accelerated patients’ recovery. Treatment with ORNs-D-M caused eradication of adeno- and influenza viruses in patients with ARI. This drug contributed to significant decrease in duration of febrile period and cough. Comprehensive treatment with ORNs-D-M improved the disease clinical findings significantly. Collectively, these results suggested that ORNs-D-M may be used at co-infection with influenza and other respiratory viruses as a medical antiviral drug. Full article
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Open AccessArticle
A Miniaturized Extruder to Prototype Amorphous Solid Dispersions: Selection of Plasticizers for Hot Melt Extrusion
Pharmaceutics 2018, 10(2), 58; https://doi.org/10.3390/pharmaceutics10020058 -
Abstract
Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion
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Hot-melt extrusion is an option to fabricate amorphous solid dispersions and to enhance oral bioavailability of poorly soluble compounds. The selection of suitable polymer carriers and processing aids determines the dissolution, homogeneity and stability performance of this solid dosage form. A miniaturized extrusion device (MinEx) was developed and Hypromellose acetate succinate type L (HPMCAS-L) based extrudates containing the model drugs neurokinin-1 (NK1) and cholesterylester transfer protein (CETP) were manufactured, plasticizers were added and their impact on dissolution and solid-state properties were assessed. Similar mixtures were manufactured with a lab-scale extruder, for face to face comparison. The properties of MinEx extrudates widely translated to those manufactured with a lab-scale extruder. Plasticizers, Polyethyleneglycol 4000 (PEG4000) and Poloxamer 188, were homogenously distributed but decreased the storage stability of the extrudates. Stearic acid was found condensed in ultrathin nanoplatelets which did not impact the storage stability of the system. Depending on their distribution and physicochemical properties, plasticizers can modulate storage stability and dissolution performance of extrudates. MinEx is a valuable prototyping-screening method and enables rational selection of plasticizers in a time and material sparing manner. In eight out of eight cases the properties of the extrudates translated to products manufactured in lab-scale extrusion trials. Full article
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Open AccessFeature PaperReview
Impact of Particle Size and Polydispersity Index on the Clinical Applications of Lipidic Nanocarrier Systems
Pharmaceutics 2018, 10(2), 57; https://doi.org/10.3390/pharmaceutics10020057 -
Abstract
Lipid-based drug delivery systems, or lipidic carriers, are being extensively employed to enhance the bioavailability of poorly-soluble drugs. They have the ability to incorporate both lipophilic and hydrophilic molecules and protecting them against degradation in vitro and in vivo. There is a number
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Lipid-based drug delivery systems, or lipidic carriers, are being extensively employed to enhance the bioavailability of poorly-soluble drugs. They have the ability to incorporate both lipophilic and hydrophilic molecules and protecting them against degradation in vitro and in vivo. There is a number of physical attributes of lipid-based nanocarriers that determine their safety, stability, efficacy, as well as their in vitro and in vivo behaviour. These include average particle size/diameter and the polydispersity index (PDI), which is an indication of their quality with respect to the size distribution. The suitability of nanocarrier formulations for a particular route of drug administration depends on their average diameter, PDI and size stability, among other parameters. Controlling and validating these parameters are of key importance for the effective clinical applications of nanocarrier formulations. This review highlights the significance of size and PDI in the successful design, formulation and development of nanosystems for pharmaceutical, nutraceutical and other applications. Liposomes, nanoliposomes, vesicular phospholipid gels, solid lipid nanoparticles, transfersomes and tocosomes are presented as frequently-used lipidic drug carriers. The advantages and limitations of a range of available analytical techniques used to characterize lipidic nanocarrier formulations are also covered. Full article
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Open AccessArticle
Combining MucilAir™ and Vitrocell® Powder Chamber for the In Vitro Evaluation of Nasal Ointments in the Context of Aerosolized Pollen
Pharmaceutics 2018, 10(2), 56; https://doi.org/10.3390/pharmaceutics10020056 -
Abstract
Hay fever is notoriously triggered when nasal mucosa is exposed to allergenic pollen. One possibility to overcome this pollen exposure may be the application of an ointment with physical protective effects. In this context, we have investigated Bepanthen® Eye and Nose Ointment
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Hay fever is notoriously triggered when nasal mucosa is exposed to allergenic pollen. One possibility to overcome this pollen exposure may be the application of an ointment with physical protective effects. In this context, we have investigated Bepanthen® Eye and Nose Ointment and the ointment basis petrolatum as reference while using contemporary in vitro techniques. Pollen from false ragweed (Iva xanthiifolia) was used as an allergy-causing model deposited as aerosol using the Vitrocell® Powder Chamber (VPC) on Transwell® inserts, while being coated with either Bepanthen® Eye and Nose Ointment and petrolatum. No pollen penetration into ointments was observed upon confocal scanning laser microscopy during an incubation period of 2 h at 37 °C. The cellular response was further investigated by integrating the MucilAir™ cell system in the VPC and by applying pollen to Bepanthen® Eye and Nose Ointment covered cell cultures. For comparison, MucilAir™ were stimulated by lipopolysaccharides (LPS). No increased cytokine release of IL-6, TNF-α, or IL-8 was found after 4 h of pollen exposure, which demonstrates the safety of such ointments. Since nasal ointments act as a physical barrier against pollen, such preparations might support the prevention and management of hay fever. Full article
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Open AccessReview
Sustained Release Drug Delivery Applications of Polyurethanes
Pharmaceutics 2018, 10(2), 55; https://doi.org/10.3390/pharmaceutics10020055 -
Abstract
Since their introduction over 50 years ago, polyurethanes have been applied to nearly every industry. This review describes applications of polyurethanes to the development of modified release drug delivery. Although drug delivery research leveraging polyurethanes has been ongoing for decades, there has been
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Since their introduction over 50 years ago, polyurethanes have been applied to nearly every industry. This review describes applications of polyurethanes to the development of modified release drug delivery. Although drug delivery research leveraging polyurethanes has been ongoing for decades, there has been renewed and substantial interest in the field in recent years. The chemistry of polyurethanes and the mechanisms of drug release from sustained release dosage forms are briefly reviewed. Studies to assess the impact of intrinsic drug properties on release from polyurethane-based formulations are considered. The impact of hydrophilic water swelling polyurethanes on drug diffusivity and release rate is discussed. The role of pore formers in modulating drug release rate is examined. Finally, the value of assessing mechanical properties of the dosage form and approaches taken in the literature are described. Full article
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Open AccessReview
Anticancer Activity of Bacterial Proteins and Peptides
Pharmaceutics 2018, 10(2), 54; https://doi.org/10.3390/pharmaceutics10020054 -
Abstract
Despite much progress in the diagnosis and treatment of cancer, tumour diseases constitute one of the main reasons of deaths worldwide. The side effects of chemotherapy and drug resistance of some cancer types belong to the significant current therapeutic problems. Hence, searching for
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Despite much progress in the diagnosis and treatment of cancer, tumour diseases constitute one of the main reasons of deaths worldwide. The side effects of chemotherapy and drug resistance of some cancer types belong to the significant current therapeutic problems. Hence, searching for new anticancer substances and medicines are very important. Among them, bacterial proteins and peptides are a promising group of bioactive compounds and potential anticancer drugs. Some of them, including anticancer antibiotics (actinomycin D, bleomycin, doxorubicin, mitomycin C) and diphtheria toxin, are already used in the cancer treatment, while other substances are in clinical trials (e.g., p28, arginine deiminase ADI) or tested in in vitro research. This review shows the current literature data regarding the anticancer activity of proteins and peptides originated from bacteria: antibiotics, bacteriocins, enzymes, nonribosomal peptides (NRPs), toxins and others such as azurin, p28, Entap and Pep27anal2. The special attention was paid to the still poorly understood active substances obtained from the marine sediment bacteria. In total, 37 chemical compounds or groups of compounds with antitumor properties have been described in the present article. Full article
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Open AccessArticle
Polymer–Surfactant System Based Amorphous Solid Dispersion: Precipitation Inhibition and Bioavailability Enhancement of Itraconazole
Pharmaceutics 2018, 10(2), 53; https://doi.org/10.3390/pharmaceutics10020053 -
Abstract
The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually
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The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer–surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0–24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer–surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water-soluble drug. Full article
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Open AccessArticle
Wool-Like Hollow Polymeric Nanoparticles for CML Chemo-Combinatorial Therapy
Pharmaceutics 2018, 10(2), 52; https://doi.org/10.3390/pharmaceutics10020052 -
Abstract
Chronic myeloid leukaemia (CML) is caused by the BCR-ABL oncogene, which encodes the constitutively active BCR-ABL tyrosine kinase. Targeted therapy with tyrosine-kinase inhibitors induces a partial cytogenetic response in most patients. Nanosystems can represent an opportunity for combinatorial therapy with the capacity to
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Chronic myeloid leukaemia (CML) is caused by the BCR-ABL oncogene, which encodes the constitutively active BCR-ABL tyrosine kinase. Targeted therapy with tyrosine-kinase inhibitors induces a partial cytogenetic response in most patients. Nanosystems can represent an opportunity for combinatorial therapy with the capacity to simultaneously release different therapeutic agents, checking the pharmacokinetic properties. In this work, we have developed a novel poly-(ε-caprolactone) (PCL) nanosystem for combinatorial therapy in CML, composed of a biodegradable pH sensitive core releasing Nilotinib (Nil) and an enzymatic sensitive outer shell releasing Imatinib Mesylate (IM), resulting in wool-like nanoparticles (NPs). The resulting double loaded wool-like hollow PCL NPs showed a high dual-drug encapsulation efficiency, pH and enzymatic sensitivity and synchronized drug release capability. The combinatorial delivery of IM and Nil exhibited an importantly reduced IC50 value of IM and Nil on leukaemia cells compared to single free drugs administration. In vitro results, showed that combinatorial nanomixures preserved the biological activity of loaded drugs for extensive time windows and led to a constant release of active drug. In addition, the combination of IM and Nil in single PCL NPs have shown a more therapeutic efficiency at a low dose with respect to the single drug nanomixures, confirming that both drugs reached the target cell precisely, maximizing the cytotoxicity while minimizing the chances of cell resistance to drugs. Full article
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