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Pharmaceutics, Volume 10, Issue 4 (December 2018)

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Open AccessReview The Delivery Challenge in Neurodegenerative Disorders: The Nanoparticles Role in Alzheimer’s Disease Therapeutics and Diagnostics
Pharmaceutics 2018, 10(4), 190; https://doi.org/10.3390/pharmaceutics10040190 (registering DOI)
Received: 26 August 2018 / Revised: 17 September 2018 / Accepted: 13 October 2018 / Published: 17 October 2018
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Abstract
Alzheimer’s disease (AD) is one of the main causes of disability and dependency among elderly people. AD is a neurodegenerative disorder characterized by a progressive and irreversible cognitive impairment, whose etiology is unclear because of the complex molecular mechanisms involved in its pathophysiology.
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Alzheimer’s disease (AD) is one of the main causes of disability and dependency among elderly people. AD is a neurodegenerative disorder characterized by a progressive and irreversible cognitive impairment, whose etiology is unclear because of the complex molecular mechanisms involved in its pathophysiology. A global view of the AD pathophysiology is described in order to understand the need for an effective treatment and why nanoparticles (NPs) could be an important weapon against neurodegenerative diseases by solving the general problem of poor delivery into the central nervous system (CNS) for many drugs. Drug delivery into the CNS is one of the most challenging objectives in pharmaceutical design, due to the limited access to the CNS imposed by the blood-brain barrier (BBB). The purpose of this review is to present a comprehensive overview of the use of NPs as delivery systems for therapeutic and diagnostic purposes in models of AD. Full article
(This article belongs to the Special Issue Dendrimers in Nanomedical Applications: Update and Future Directions)
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Open AccessFeature PaperReview Grinding as Solvent-Free Green Chemistry Approach for Cyclodextrin Inclusion Complex Preparation in the Solid State
Pharmaceutics 2018, 10(4), 189; https://doi.org/10.3390/pharmaceutics10040189
Received: 1 October 2018 / Revised: 11 October 2018 / Accepted: 14 October 2018 / Published: 16 October 2018
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Abstract
Among the different techniques proposed for preparing cyclodextrin inclusion complex in the solid state, mechanochemical activation by grinding appears as a fast, highly efficient, convenient, versatile, sustainable, and eco-friendly solvent-free method. This review is intended to give a systematic overview of the currently
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Among the different techniques proposed for preparing cyclodextrin inclusion complex in the solid state, mechanochemical activation by grinding appears as a fast, highly efficient, convenient, versatile, sustainable, and eco-friendly solvent-free method. This review is intended to give a systematic overview of the currently available data in this field, highlighting both the advantages as well as the shortcomings of such an approach. The possible mechanisms involved in the inclusion complex formation in the solid state, by grinding, have been illustrated. For each type of applied milling device, the respective process variables have been examined and discussed, together with the characteristics of the obtained products, also in relation with the physicochemical characteristics of both the drug and cyclodextrin subjected to grinding. The critical process parameters were evidenced in order to provide a useful guide for a rational selection of the most suitable conditions for an efficient inclusion complex preparation by grinding, with the final purpose of promoting a wider use of this effective solvent-free cyclodextrin inclusion complex preparation method in the solid state. Full article
(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)
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Open AccessArticle Ascorbyl Palmitate Hydrogel for Local, Intestinal Delivery of Macromolecules
Pharmaceutics 2018, 10(4), 188; https://doi.org/10.3390/pharmaceutics10040188
Received: 5 September 2018 / Revised: 11 October 2018 / Accepted: 11 October 2018 / Published: 15 October 2018
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Abstract
Biologics have changed the management of inflammatory bowel disease (IBD), but there are concerns with unexpected systemic toxicity and loss of therapeutic response following administration by injection. Rectal administration of biologics offers potentially reduced therapy costs, as well as safer and more effective
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Biologics have changed the management of inflammatory bowel disease (IBD), but there are concerns with unexpected systemic toxicity and loss of therapeutic response following administration by injection. Rectal administration of biologics offers potentially reduced therapy costs, as well as safer and more effective local delivery to inflammation sites. Hydrogels are potentially useful carriers of biologics for improved delivery to the inflamed intestinal mucosa. Here, we prepared a hydrogel system based on ascorbyl palmitate (AP) and incorporated a model macromolecular drug (fluorescently-labelled dextran) into the system. Characterization of gel properties included rheology, drug loading and release, cytotoxicity, and drug delivery in an in vitro intestinal model. We report that this hydrogel can be formed under a moderate environment that is amenable to incorporation of some biologics. The system showed a shear-thinning behavior. AP hydrogel released approximately 60% of the drug within 5 h and showed reasonable a cytotoxicity profile. The study therefore provides evidence that AP hydrogel has potential for local delivery of macromolecules to the intestinal mucosa in IBD. Full article
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Open AccessArticle Enhanced Bioavailability of Tadalafil after Intranasal Administration in Beagle Dogs
Pharmaceutics 2018, 10(4), 187; https://doi.org/10.3390/pharmaceutics10040187
Received: 14 September 2018 / Revised: 12 October 2018 / Accepted: 13 October 2018 / Published: 15 October 2018
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Abstract
Tadalafil is an oral selective phosphodiesterase type-5 inhibitor with demonstrated efficacy and safety that is used to treat erectile dysfunction. The purpose of this study is to compare the pharmacokinetic properties of tadalafil after conventional oral tablet administration and novel intranasal administration in
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Tadalafil is an oral selective phosphodiesterase type-5 inhibitor with demonstrated efficacy and safety that is used to treat erectile dysfunction. The purpose of this study is to compare the pharmacokinetic properties of tadalafil after conventional oral tablet administration and novel intranasal administration in beagle dogs. Fourteen 13-month-old male beagle dogs were randomly divided into two groups, and were given 5 mg tadalafil orally or intranasally in a parallel design. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 36 h after administration. The plasma concentration of tadalafil was determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The systemic exposure and absorption rate of tadalafil were significantly greater in the intranasal administration group than in the oral administration group. A one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characteristics observed after both oral and intranasal administration. This study indicates that the development of tadalafil nasal delivery systems is feasible and may lead to better results than the conventional oral route. Full article
(This article belongs to the Special Issue New Approaches to Enhance Drug Solubility and Bioavailability)
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Open AccessArticle Development of Novel Intramolecular FRET-Based ABC Transporter Biosensors to Identify New Substrates and Modulators
Pharmaceutics 2018, 10(4), 186; https://doi.org/10.3390/pharmaceutics10040186
Received: 17 September 2018 / Revised: 10 October 2018 / Accepted: 12 October 2018 / Published: 13 October 2018
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Abstract
Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and
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Multidrug resistance protein 1 (MRP1) can efflux a wide variety of molecules including toxic chemicals, drugs, and their derivatives out of cells. Substrates of MRP1 include anti-cancer agents, antibiotics, anti-virals, anti-human immunodeficiency virus (HIV), and many other drugs. To identify novel substrates and modulators of MRP1 by exploiting intramolecular fluorescence resonance energy transfer (FRET), we genetically engineered six different two-color MRP1 proteins by changing green fluorescent protein (GFP) insertion sites, while keeping the red fluorescent protein (RFP) at the C-terminal of MRP1. Four of six recombinant proteins showed normal expression, localization, and transport activity. We quantified intramolecular FRET using ensemble fluorescence spectroscopy in response to binding of known substrate or ATP alone, substrate/ATP, and trapping of the transporter in closed conformation by vanadate. Recombinant MRP1 proteins GR-881, GR-888, and GR-905 exhibited reproducible and higher FRET changes under all tested conditions and are very promising for use as MRP1 biosensors. Furthermore, we used GR-881 to screen 40 novel anti-cancer drugs and identified 10 hits that potentially directly interact with MRP1 and could be substrates or modulators. Profiling of drug libraries for interaction with MRP1 can provide very useful information to improve the efficacy and reduce the toxicity of various therapies. Full article
(This article belongs to the Special Issue ABC Transporter-Mediated Drug Disposition)
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Open AccessArticle Brief Effect of a Small Hydrophobic Drug (Cinnarizine) on the Physicochemical Characterisation of Niosomes Produced by Thin-Film Hydration and Microfluidic Methods
Pharmaceutics 2018, 10(4), 185; https://doi.org/10.3390/pharmaceutics10040185
Received: 20 July 2018 / Revised: 5 October 2018 / Accepted: 9 October 2018 / Published: 13 October 2018
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Abstract
Novel niosomal formulations containing cinnarizine were developed to enhance its drug characteristics. In this work, niosomes (non-ionic surfactant vesicles) were prepared by conventional thin-film hydration (TFH) and microfluidic (MF) methods with sorbitan monostearate (Span® 60), cholesterol, and co-surfactants (Cremophor® ELP, Cremophor
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Novel niosomal formulations containing cinnarizine were developed to enhance its drug characteristics. In this work, niosomes (non-ionic surfactant vesicles) were prepared by conventional thin-film hydration (TFH) and microfluidic (MF) methods with sorbitan monostearate (Span® 60), cholesterol, and co-surfactants (Cremophor® ELP, Cremophor® RH40 and Solutol® HS15) as key excipients. The aim was to study the effect of cinnarizine on the characteristics of different niosomal formulations manufactured by using different methods. For effective targeted oral drug delivery, the efficacy of niosomes for therapeutic applications is correlated to their physiochemical properties. Niosome vesicles prepared were characterised using dynamic light scattering technique and the morphology of niosomes dispersion was characterised using optical microscopy. Dialysis was carried out to purify niosome suspensions to determine drug loading and drug release studies was performed to study the potential use of niosomal systems for cinnarizine. Full article
(This article belongs to the Special Issue Non-Ionic Surfactant Vesicles for Drug Delivery)
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Open AccessArticle Characterization of Mechanical Property Distributions on Tablet Surfaces
Pharmaceutics 2018, 10(4), 184; https://doi.org/10.3390/pharmaceutics10040184
Received: 21 September 2018 / Revised: 3 October 2018 / Accepted: 9 October 2018 / Published: 12 October 2018
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Abstract
Powder densification through uniaxial compaction is governed by a number of simultaneous processes taking place on a reduced time as the result of the stress gradients within the packing, as well as the frictional and adhesive forces between the powder and the die
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Powder densification through uniaxial compaction is governed by a number of simultaneous processes taking place on a reduced time as the result of the stress gradients within the packing, as well as the frictional and adhesive forces between the powder and the die walls. As a result of that, a density and stiffness anisotropy is developed across the axial and radial directions. In this study, microindentation has been applied to assess and quantify the variation of the module of elasticity ( E m o d ) throughout the surface of cylindrical tablets. A representative set of deformation behaviors was analyzed by pharmaceutical excipients ranging from soft/plastic behavior (microcrystalline cellulose) over medium (lactose) to hard/brittle behavior (calcium phosphate) for different compaction pressures. The results of the local stiffness distribution over tablet faces depicted a linear and directly proportional tendency between a solid fraction and E m o d for the upper and lower faces, as well as remarkable stiffness anisotropy between the axial and radial directions of compaction. The highest extent of the stiffness anisotropy that was found for ductile grades of microcrystalline cellulose (MCC) in comparison with brittle powders has been attributed to the dual phenomena of overall elastic recovery and Poisson’s effect on the relaxation kinetics. As a reinforcement of this analysis, the evolution of the specific surface area elucidated the respective densification mechanism and its implementations toward anisotropy. For ductile excipients, the increase in the contact surface area as well as the reduction and closing of interstitial pores explain the reduction of surface area with increasing compaction pressure. For brittle powders, densification evolves through fragmentation and the subsequent filling of voids. Full article
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Open AccessArticle Cysteines and Disulfide-Bridged Macrocyclic Mimics of Teixobactin Analogues and Their Antibacterial Activity Evaluation against Methicillin-Resistant Staphylococcus Aureus (MRSA)
Pharmaceutics 2018, 10(4), 183; https://doi.org/10.3390/pharmaceutics10040183
Received: 22 August 2018 / Revised: 2 October 2018 / Accepted: 9 October 2018 / Published: 11 October 2018
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Abstract
Teixobactin is a highly potent cyclic depsipeptide which kills a broad range of multi-drug resistant, Gram-positive bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA) without detectable resistance. In this work, we describe the design and rapid synthesis of novel teixobactin analogues containing two cysteine
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Teixobactin is a highly potent cyclic depsipeptide which kills a broad range of multi-drug resistant, Gram-positive bacteria, such as Methicillin-resistant Staphylococcus aureus (MRSA) without detectable resistance. In this work, we describe the design and rapid synthesis of novel teixobactin analogues containing two cysteine moieties, and the corresponding disulfide-bridged cyclic analogues. These analogues differ from previously reported analogues, such as an Arg10-teixobactin, in terms of their macrocyclic ring size, and feature a disulfide bridge instead of an ester linkage. The new teixobactin analogues were screened against Methicillin-resistant Staphylococcus aureus and Methicillin-sensitive Staphylococcus aureus. Interestingly, one teixobactin analogue containing all l-amino acid building blocks showed antibacterial activity against MRSA for the first time. Our data indicates that macrocyclisation of teixobactin analogues with disulfide bridging is important for improved antibacterial activity. In our work, we have demonstrated the unprecedented use of a disulfide bridge in constructing the macrocyclic ring of teixobactin analogues. Full article
(This article belongs to the Special Issue Protein Therapeutics)
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Open AccessArticle Hydrophobic Amino Acid Tryptophan Shows Promise as a Potential Absorption Enhancer for Oral Delivery of Biopharmaceuticals
Pharmaceutics 2018, 10(4), 182; https://doi.org/10.3390/pharmaceutics10040182
Received: 24 August 2018 / Revised: 18 September 2018 / Accepted: 8 October 2018 / Published: 10 October 2018
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Abstract
Cell-penetrating peptides (CPPs) have great potential to efficiently deliver drug cargos across cell membranes without cytotoxicity. Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. We recently found that l-arginine could increase
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Cell-penetrating peptides (CPPs) have great potential to efficiently deliver drug cargos across cell membranes without cytotoxicity. Cationic arginine and hydrophobic tryptophan have been reported to be key component amino acids for cellular internalization of CPPs. We recently found that l-arginine could increase the oral delivery of insulin in its single amino acid form. Therefore, in the present study, we evaluated the ability of another key amino acid, tryptophan, to enhance the intestinal absorption of biopharmaceuticals. We demonstrated that co-administration with l-tryptophan significantly facilitated the oral and intestinal absorption of the peptide drug insulin administered to rats. Furthermore, l-tryptophan exhibited the ability to greatly enhance the intestinal absorption of other peptide drugs such as glucagon-like peptide-1 (GLP-1), its analog Exendin-4 and macromolecular hydrophilic dextrans with molecular weights ranging from 4000 to 70,000 g/mol. However, no intermolecular interaction between insulin and l-tryptophan was observed and no toxic alterations to epithelial cellular integrity—such as changes to cell membranes, cell viability, or paracellular tight junctions—were found. This suggests that yet to be discovered inherent biological mechanisms are involved in the stimulation of insulin absorption by co-administration with l-tryptophan. These results are the first to demonstrate the significant potential of using the single amino acid l-tryptophan as an effective and versatile bioavailability enhancer for the oral delivery of biopharmaceuticals. Full article
(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)
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Open AccessReview Targeted Theranostic Nanoparticles for Brain Tumor Treatment
Pharmaceutics 2018, 10(4), 181; https://doi.org/10.3390/pharmaceutics10040181
Received: 9 August 2018 / Revised: 21 September 2018 / Accepted: 27 September 2018 / Published: 9 October 2018
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Abstract
The poor prognosis and rapid recurrence of glioblastoma (GB) are associated to its fast-growing process and invasive nature, which make difficult the complete removal of the cancer infiltrated tissues. Additionally, GB heterogeneity within and between patients demands a patient-focused method of treatment. Thus,
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The poor prognosis and rapid recurrence of glioblastoma (GB) are associated to its fast-growing process and invasive nature, which make difficult the complete removal of the cancer infiltrated tissues. Additionally, GB heterogeneity within and between patients demands a patient-focused method of treatment. Thus, the implementation of nanotechnology is an attractive approach considering all anatomic issues of GB, since it will potentially improve brain drug distribution, due to the interaction between the blood–brain barrier and nanoparticles (NPs). In recent years, theranostic techniques have also been proposed and regarded as promising. NPs are advantageous for this application, due to their respective size, easy surface modification and versatility to integrate multiple functional components in one system. The design of nanoparticles focused on therapeutic and diagnostic applications has increased exponentially for the treatment of cancer. This dual approach helps to understand the location of the tumor tissue, the biodistribution of nanoparticles, the progress and efficacy of the treatment, and is highly useful for personalized medicine-based therapeutic interventions. To improve theranostic approaches, different active strategies can be used to modulate the surface of the nanotheranostic particle, including surface markers, proteins, drugs or genes, and take advantage of the characteristics of the microenvironment using stimuli responsive triggers. This review focuses on the different strategies to improve the GB treatment, describing some cell surface markers and their ligands, and reports some strategies, and their efficacy, used in the current research. Full article
(This article belongs to the Special Issue Nanotheranostics and Cancer: Where Are We Now?)
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Open AccessArticle Chitosan-Based Polyelectrolyte Complexes for Doxorubicin and Zoledronic Acid Combined Therapy to Overcome Multidrug Resistance
Pharmaceutics 2018, 10(4), 180; https://doi.org/10.3390/pharmaceutics10040180
Received: 4 September 2018 / Revised: 2 October 2018 / Accepted: 5 October 2018 / Published: 9 October 2018
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Abstract
This study aimed to develop nanovectors co-encapsulating doxorubicin (Doxo) and zoledronic acid (Zol) for a combined therapy against Doxo-resistant tumors. Chitosan (CHI)-based polyelectrolyte complexes (PECs) prepared by ionotropic gelation technique were proposed. The influence of some experimental parameters was evaluated in order to
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This study aimed to develop nanovectors co-encapsulating doxorubicin (Doxo) and zoledronic acid (Zol) for a combined therapy against Doxo-resistant tumors. Chitosan (CHI)-based polyelectrolyte complexes (PECs) prepared by ionotropic gelation technique were proposed. The influence of some experimental parameters was evaluated in order to optimize the PECs in terms of size and polydispersity index (PI). PEC stability was studied by monitoring size and zeta potential over time. In vitro studies were carried out on wild-type and Doxo-resistant cell lines, to assess both the synergism between Doxo and Zol, as well as the restoring of Doxo sensitivity. Polymer concentration, incubation time, and use of a surfactant were found to be crucial to achieving small size and monodisperse PECs. Doxo and Zol, only when encapsulated in PECs, showed a synergistic antiproliferative effect in all the tested cell lines. Importantly, the incubation of Doxo-resistant cell lines with Doxo/Zol co-encapsulating PECs resulted in the restoration of Doxo sensitivity. Full article
(This article belongs to the Special Issue Self-Organizing Nanovectors for Drug Delivery)
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Open AccessArticle Fabrication and Characterization of Strontium-Substituted Hydroxyapatite-CaO-CaCO3 Nanofibers with a Mesoporous Structure as Drug Delivery Carriers
Pharmaceutics 2018, 10(4), 179; https://doi.org/10.3390/pharmaceutics10040179
Received: 28 August 2018 / Revised: 4 October 2018 / Accepted: 6 October 2018 / Published: 8 October 2018
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Abstract
Hydroxyapatite (HAp) is the main inorganic component and an essential part of hard bone and teeth. Due to its excellent biocompatibility, bioactivity, and osteoconductivity, synthetic HAp has been widely used as a bone substitute, cell carrier, and therapeutic gene or drug carrier. Recently,
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Hydroxyapatite (HAp) is the main inorganic component and an essential part of hard bone and teeth. Due to its excellent biocompatibility, bioactivity, and osteoconductivity, synthetic HAp has been widely used as a bone substitute, cell carrier, and therapeutic gene or drug carrier. Recently, numerous studies have demonstrated that strontium-substituted hydroxyapatite (SrHAp) not only enhances osteogenesis but also inhibits adipogenesis in mesenchymal stem cells. Mesoporous SrHAp has been successfully synthesized via a traditional template-based process and has been found to possess better drug loading and release efficiencies than SrHAp. In this study, strontium-substituted hydroxyapatite-CaO-CaCO3 nanofibers with a mesoporous structure (mSrHANFs) were fabricated using a sol–gel method followed by electrospinning. X-ray diffraction analysis revealed that the contents of CaO and CaCO3 in the mSrHANFs decreased as the doping amount of Sr increased. Scanning electron microscopy (SEM) images showed that the average diameter of the mSrHANFs was approximately 200~300 nm. The N2 adsorption–desorption isotherms demonstrated that the mSrHANFs possessed a mesoporous structure and that the average pore size was approximately 20~25 nm. Moreover, the mSrHANFs had excellent drug- loading efficiency and could retard the burst release of tetracycline (TC) to maintain antibacterial activity for over 3 weeks. Hence, mSrHANFs have the potential to be used as drug carriers in bone tissue engineering. Full article
(This article belongs to the Special Issue Porous Inorganic Drug Delivery Systems)
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Open AccessArticle Metabolic Stability and Metabolite Characterization of Capilliposide B and Capilliposide C by LC–QTRAP–MS/MS
Pharmaceutics 2018, 10(4), 178; https://doi.org/10.3390/pharmaceutics10040178
Received: 13 August 2018 / Revised: 27 September 2018 / Accepted: 4 October 2018 / Published: 8 October 2018
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Abstract
Capilliposide B (LC-B) and Capilliposide C (LC-C), two new triterpenoid saponins extracted from Lysimachia capillipes Hemsl, exhibit potential anticancer activity both in vitro and in vivo. However, their metabolic process remains unclear. In this study, the metabolic stability of LC-B, LC-C, and Capilliposide
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Capilliposide B (LC-B) and Capilliposide C (LC-C), two new triterpenoid saponins extracted from Lysimachia capillipes Hemsl, exhibit potential anticancer activity both in vitro and in vivo. However, their metabolic process remains unclear. In this study, the metabolic stability of LC-B, LC-C, and Capilliposide A (LC-A, a bioactive metabolite of LC-B and LC-C) was investigated in human, rat, and mouse liver microsomes, respectively. Thereafter, their metabolites were identified and characterized after oral administration in mice. As a result, species difference was found in the metabolic stability of LC-B and LC-C. All three compounds of interest were stable in human and rat liver microsomes, but LC-B and LC-C significantly degraded in mouse liver microsomes. The metabolic instability of LC-B and LC-C was mainly caused by esterolysis. Moreover, 19 metabolites were identified and characterized in mouse biological matrices. LC-B and LC-C mainly underwent deglycosylation and esterolysis, accompanied by dehydration, dehydrogenation, and hydroxylation as minor metabolic reactions. Finally, the metabolic pathway of LC-B and LC-C in mice was proposed. Our results updated the preclinical metabolism and disposition process of LC-B and LC-C, which provided additional information for better understanding efficacy and safety. Full article
(This article belongs to the Special Issue Preclinical Pharmacokinetics and Bioanalysis)
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Open AccessArticle Pharmacokinetic Properties of Acetyl Tributyl Citrate, a Pharmaceutical Excipient
Pharmaceutics 2018, 10(4), 177; https://doi.org/10.3390/pharmaceutics10040177
Received: 14 August 2018 / Revised: 1 October 2018 / Accepted: 6 October 2018 / Published: 8 October 2018
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Abstract
Acetyl tributyl citrate (ATBC) is an (the Food and Drug Administration) FDA-approved substance for use as a pharmaceutical excipient. It is used in pharmaceutical coating of solid oral dosage forms such as coated tablets or capsules. However, the information of ATBC on its
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Acetyl tributyl citrate (ATBC) is an (the Food and Drug Administration) FDA-approved substance for use as a pharmaceutical excipient. It is used in pharmaceutical coating of solid oral dosage forms such as coated tablets or capsules. However, the information of ATBC on its pharmacokinetics is limited. The aim of this study is to investigate the pharmacokinetic properties of ATBC using liquid chromatography–tandem mass spectrometric (LC–MS/MS) analysis. ATBC was rapidly absorbed and eliminated and the bioavailability was 27.4% in rats. The results of metabolic stability tests revealed that metabolic clearance may have accounted for a considerable portion of the total clearance of ATBC. These pharmacokinetic data would be useful in studies investigating the safety and toxicity of ATBC. Full article
(This article belongs to the Special Issue Drug Metabolism, Pharmacokinetics and Bioanalysis)
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Open AccessReview Oral Modified Release Multiple-Unit Particulate Systems: Compressed Pellets, Microparticles and Nanoparticles
Pharmaceutics 2018, 10(4), 176; https://doi.org/10.3390/pharmaceutics10040176
Received: 8 August 2018 / Revised: 7 September 2018 / Accepted: 16 September 2018 / Published: 4 October 2018
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Abstract
Oral modified-release multiparticulate dosage forms, which are also referred to as oral multiple-unit particulate systems, are becoming increasingly popular for oral drug delivery applications. The compaction of polymer-coated multiparticulates into tablets to produce a sustained-release dosage form is preferred over hard gelatin capsules.
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Oral modified-release multiparticulate dosage forms, which are also referred to as oral multiple-unit particulate systems, are becoming increasingly popular for oral drug delivery applications. The compaction of polymer-coated multiparticulates into tablets to produce a sustained-release dosage form is preferred over hard gelatin capsules. Moreover, multiparticulate tablets are a promising solution to chronic conditions, patients’ adherence, and swallowing difficulties if incorporated into orodispersible matrices. Nonetheless, the compaction of multiparticulates often damages the functional polymer coat, which results in a rapid release of the drug substance and the subsequent loss of sustained-release properties. This review brings to the forefront key formulation variables that are likely to influence the compaction of coated multiparticulates into sustained-release tablets. It focusses on the tabletting of coated drug-loaded pellets, microparticles, and nanoparticles with a designated section on each. Furthermore, it explores the various approaches that are used to evaluate the compaction behaviour of particulate systems. Full article
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Open AccessArticle Combining Microbubble Contrast Agent with Pulsed-Laser Irradiation for Transdermal Drug Delivery
Pharmaceutics 2018, 10(4), 175; https://doi.org/10.3390/pharmaceutics10040175
Received: 5 September 2018 / Revised: 27 September 2018 / Accepted: 1 October 2018 / Published: 3 October 2018
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Abstract
The optodynamic process of laser-induced microbubble (MB) cavitation in liquids is utilized in various medical applications. However, how incident laser radiation interacts with MBs as an ultrasound contrast agent is rarely estimated when the liquid already contains stable MBs. The present study investigated
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The optodynamic process of laser-induced microbubble (MB) cavitation in liquids is utilized in various medical applications. However, how incident laser radiation interacts with MBs as an ultrasound contrast agent is rarely estimated when the liquid already contains stable MBs. The present study investigated the efficacy of the laser-mediated cavitation of albumin-shelled MBs in enhancing transdermal drug delivery. Different types and conditions of laser-mediated inertial cavitation of MBs were first evaluated. A CO2 fractional pulsed laser was selected for combining with MBs in the in vitro and in vivo experiments. The in vitro skin penetration by β-arbutin after 2 h was 2 times greater in the group combining a laser with MBs than in the control group. In small-animal experiments, the whitening effect on the skin of C57BL/6J mice in the group combining a laser with MBs on the skin plus penetrating β-arbutin increased (significantly) by 48.0% at day 11 and 50.0% at day 14, and then tended to stabilize for the remainder of the 20-day experimental period. The present results indicate that combining a CO2 laser with albumin-shelled MBs can increase skin permeability so as to enhance the delivery of β-arbutin to inhibit melanogenesis in mice without damaging the skin. Full article
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Open AccessArticle Regional Absorption of Fimasartan in the Gastrointestinal Tract by an Improved In Situ Absorption Method in Rats
Pharmaceutics 2018, 10(4), 174; https://doi.org/10.3390/pharmaceutics10040174
Received: 27 August 2018 / Revised: 28 September 2018 / Accepted: 1 October 2018 / Published: 3 October 2018
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Abstract
The aim of the present study was to assess the regional absorption of fimasartan by an improved in situ absorption method in comparison with the conventional in situ single-pass perfusion method in rats. After each gastrointestinal segment of interest was identified, fimasartan was
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The aim of the present study was to assess the regional absorption of fimasartan by an improved in situ absorption method in comparison with the conventional in situ single-pass perfusion method in rats. After each gastrointestinal segment of interest was identified, fimasartan was injected into the starting point of each segment and the unabsorbed fimasartan was discharged from the end point of the segment. Blood samples were collected from the jugular vein to evaluate the systemic absorption of the drug. The relative fraction absorbed (Fabs,relative) values in the specific gastrointestinal region calculated based on the area under the curve (AUC) values obtained after the injection of fimasartan into the gastrointestinal segment were 8.2% ± 3.2%, 23.0% ± 12.1%, 49.7% ± 11.5%, and 19.1% ± 11.9% for the stomach, duodenum, small intestine, and large intestine, respectively, which were comparable with those determined by the conventional in situ single-pass perfusion. By applying the fraction of the dose available at each gastrointestinal segment following the oral administration, the actual fraction absorbed (F′abs) values at each gastrointestinal segment were estimated at 10.9% for the stomach, 27.1% for the duodenum, 40.7% for the small intestine, and 5.4% for the large intestine, which added up to the gastrointestinal bioavailability (FX·FG) of 84.1%. The present method holds great promise to assess the regional absorption of a drug and aid to design new drug formulations. Full article
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Open AccessArticle Preparation of Reduction-Responsive Camptothecin Nanocapsules by Combining Nanoprecipitation and In Situ Polymerization for Anticancer Therapy
Pharmaceutics 2018, 10(4), 173; https://doi.org/10.3390/pharmaceutics10040173
Received: 5 September 2018 / Revised: 23 September 2018 / Accepted: 26 September 2018 / Published: 3 October 2018
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Abstract
Stimuli-responsive systems for controlled drug release have been extensively explored in recent years. In this work, we developed a reduction-responsive camptothecin (CPT) nanocapsule (CPT-NC) by combining nanoprecipitation and in situ polymerization using a polymerized surface ligand and a disulfide bond-containing crosslinker. Dissolution rate
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Stimuli-responsive systems for controlled drug release have been extensively explored in recent years. In this work, we developed a reduction-responsive camptothecin (CPT) nanocapsule (CPT-NC) by combining nanoprecipitation and in situ polymerization using a polymerized surface ligand and a disulfide bond-containing crosslinker. Dissolution rate studies proved that the CPT-NCs have robust drug-release profiles in the presence of glutathione (GSH) owing to the division of the disulfide bond crosslinker which triggers the collapse of the polymer layer. Furthermore, the in vitro investigations demonstrated that the CPT-NCs exhibited a high-cellular uptake efficiency and cytotoxicity for cancer cells of squamous cell carcinoma (SCC-15). Our approach thus presents an effective intracellular drug delivery strategy for anticancer therapy. Full article
(This article belongs to the Special Issue Nanotheranostics and Cancer: Where Are We Now?)
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Open AccessArticle Probing the Action of Permeation Enhancers Sodium Cholate and N-dodecyl-β-D-maltoside in a Porcine Jejunal Mucosal Explant System
Pharmaceutics 2018, 10(4), 172; https://doi.org/10.3390/pharmaceutics10040172
Received: 28 August 2018 / Revised: 27 September 2018 / Accepted: 28 September 2018 / Published: 2 October 2018
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Abstract
The small intestinal epithelium constitutes a major permeability barrier for the oral administration of therapeutic drugs with poor bioavailability, and permeation enhancers (PEs) are required to increase the paracellular and/or transcellular uptake of such drugs. Many PEs act as surfactants by perturbing cell
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The small intestinal epithelium constitutes a major permeability barrier for the oral administration of therapeutic drugs with poor bioavailability, and permeation enhancers (PEs) are required to increase the paracellular and/or transcellular uptake of such drugs. Many PEs act as surfactants by perturbing cell membrane integrity and causing permeabilization by leakage or endocytosis. The aim of the present work was to study the action of sodium cholate (NaC) and N-dodecyl-β-D-maltoside (DDM), using a small intestinal mucosal explant system. At 2 mM, both NaC and DDM caused leakage into the enterocyte cytosol of the fluorescent probe Lucifer Yellow, but they also blocked the constitutive endocytotic pathway from the brush border. In addition, an increased paracellular passage of 3-kDa Texas Red Dextran into the lamina propria was observed. By electron microscopy, both PEs disrupted the hexagonal organization of microvilli of the brush border and led to the apical extrusion of vesicle-like and amorphous cell debris to the lumen. In conclusion, NaC and DDM acted in a multimodal way to increase the permeability of the jejunal epithelium both by paracellular and transcellular mechanisms. However, endocytosis, commonly thought to be an uptake mechanism that may be stimulated by PEs, was not involved in the transcellular process. Full article
(This article belongs to the Special Issue Transmucosal Absorption Enhancers in the Drug Delivery Field)
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Open AccessArticle Kinetics of the Solution-Mediated Polymorphic Transformation of the Novel l-Carnitine Orotate Polymorph, Form-II
Pharmaceutics 2018, 10(4), 171; https://doi.org/10.3390/pharmaceutics10040171
Received: 18 August 2018 / Revised: 27 September 2018 / Accepted: 29 September 2018 / Published: 1 October 2018
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Abstract
Research studies related to the polymorphs of l-Carnitine orotate (CO), a medication used for the treatment and prevention of liver diseases, are insignificant or almost nonexistent. Accordingly, in the present study, l-Carnitine orotate (CO) was prepared for investigating CO polymorphs. Here,
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Research studies related to the polymorphs of l-Carnitine orotate (CO), a medication used for the treatment and prevention of liver diseases, are insignificant or almost nonexistent. Accordingly, in the present study, l-Carnitine orotate (CO) was prepared for investigating CO polymorphs. Here, a reactive crystallization was induced by reacting 1g of l-Carn (1 equivalent) and 0.97 g of OA (1 equivalent) in methanol (MeOH); as a result, CO form-I and CO form-II polymorphs were obtained after 1 h and 16 h of stirring, respectively. The characterization of CO polymorphs was carried out utilizing Powder X-ray diffraction (PXRD), Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA) and solid-state Nuclear Magnetic Resonance Spectroscopy (solid-state CP/MAS 13C-NMR). The solution-mediated polymorphic transformation (SMPT) of CO polymorphs was investigated in MeOH at controlled temperature and fixed rotational speed. The results revealed that CO form-I is a metastable polymorph while CO form-II is a stable polymorph. From the same results, it was confirmed that CO form-I was converted to CO form-II during the polymorphic phase transformation process. Moreover, it was assessed that the increase in temperature and supersaturation level significantly promotes the rate of nucleation, as well as the rate of mass transfer of CO form-II. In addition, nucleation and mass transfer equations were employed for the quantitative determination of SMPT experimental results. Lastly, it was suggested that CO form-II was more thermodynamically stable than CO form-I and that both polymorphs belong to the monotropic system. Full article
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Open AccessArticle Development of an Oral Compound Pickering Emulsion Composed of Nanocrystals of Poorly Soluble Ingredient and Volatile Oils from Traditional Chinese Medicine
Pharmaceutics 2018, 10(4), 170; https://doi.org/10.3390/pharmaceutics10040170
Received: 22 August 2018 / Revised: 27 September 2018 / Accepted: 28 September 2018 / Published: 1 October 2018
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Abstract
In this study, an oral drug nanocrystals self-stabilized Pickering emulsion (NSSPE), which used nanocrystals of a poorly soluble ingredient from Puerariae Radix called puerarin as solid particle stabilizers and Ligusticum chuanxiong essential oil since the main oil phase had been developed to improve
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In this study, an oral drug nanocrystals self-stabilized Pickering emulsion (NSSPE), which used nanocrystals of a poorly soluble ingredient from Puerariae Radix called puerarin as solid particle stabilizers and Ligusticum chuanxiong essential oil since the main oil phase had been developed to improve the oral bioavailability of puerarin. The appearance of emulsions, size and zeta potential of droplets, and content of puerarin in emulsified layer during a storage of six months at 4, 25, and 40 °C were investigated. The centrifugation stability at 4000× g was also studied. The micro-structure of emulsion droplets was characterized by a scanning electron micrograph (SEM), confocal laser scanning microscopy (CLSM), a fluorescence microscope (FM), and differential scanning calorimetry (DSC). The in vivo oral bioavailability of puerarin NSSPE was investigated in rats. Results showed that appearances of puerarin NSSPE kept stable after centrifugation at 4000× g for 15 min or storage for six months at 4, 25, and 40 °C. SEM, CLSM, FM, and DSC showed that the puerarin NSSPE had a stable core-shell structure of emulsion droplets formed by the adsorption of puerarin nanocrystals on the surface of oil droplets of mixed oil of Ligusticum chuanxiong essential oil and Labrafil M 1944 CS (9:1, v/v). The relative bioavailability of puerarin NSSPE to puerarin coarse powder suspension, nanocrystal suspension, and surfactant emulsion were 262.43%, 155.92%, and 223.65%, respectively. All these results indicated that puerarin nanocrystals could stabilize Pickering emulsion of Ligusticum chuanxiong essential oil without any other stabilizers and Pickering emulsion could improve the oral bioavailability of puerarin, which suggests that the drug nanocrystal self-stabilized Pickering emulsion as a promising oral drug delivery system for Traditional Chinese Medicine containing poorly soluble ingredients and volatile oils. Full article
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Open AccessArticle Encapsulation of Babchi Oil in Cyclodextrin-Based Nanosponges: Physicochemical Characterization, Photodegradation, and In Vitro Cytotoxicity Studies
Pharmaceutics 2018, 10(4), 169; https://doi.org/10.3390/pharmaceutics10040169
Received: 24 June 2018 / Revised: 16 August 2018 / Accepted: 20 August 2018 / Published: 26 September 2018
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Abstract
Babchi (Psoralea corylifolia) oil is an important essential oil used in several traditional medicines to cure various disorders. This phytotherapeutic agent possesses a number of pharmacological activities including antibacterial, antifungal, antioxidant, anti-inflammatory, immunomodulatory, and antitumor factors. However, volatile nature, poor stability,
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Babchi (Psoralea corylifolia) oil is an important essential oil used in several traditional medicines to cure various disorders. This phytotherapeutic agent possesses a number of pharmacological activities including antibacterial, antifungal, antioxidant, anti-inflammatory, immunomodulatory, and antitumor factors. However, volatile nature, poor stability, and solubility of babchi oil (BO) restrict its pharmaceutical applications. Therefore, the aim of the present work was to encapsulate this oil in β-cyclodextrin nanosponges (NS) in order to overcome the above limitations. To fabricate nanosponges, β-cyclodextrin was cross-linked with diphenyl carbonate in different molar ratios viz. 1:2, 1:4, 1:6, 1:8, and 1:10. The blank nanosponges were loaded with BO using the freeze-drying method. The particle size of the BO loaded nanosponges was found to lie between 200 and 500 nm with low polydispersity index. Furthermore, the zeta potential, the Fourier transform infrared spectroscopy, X-ray diffraction, thermal analysis, and electron microscopy were carried out for characterization of BO nanosponges. Results obtained from spectral analysis ascertained the formation of inclusion complexes. Additionally, solubilisation efficiency of BO was checked in distilled water and found enhanced by 4.95 times with optimized β-cyclodextrin nanosponges. The cytotoxicity study was carried out by the MTT assay using HaCaT cell lines. A significant improvement in photo-stability of essential oil was also observed by inclusion innanosponges. Lastly, the optimized formulation was tested for antibacterial activity using Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. Therefore, encapsulation of BO in nanosponges resulted in efficacious carrier system in terms of solubility, photo-stability, and safety of this oil along with handling benefits. Full article
(This article belongs to the Special Issue Cyclodextrins in Drug Formulation and Delivery)
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Open AccessReview Concepts and Challenges of Biosimilars in Breast Cancer: The Emergence of Trastuzumab Biosimilars
Pharmaceutics 2018, 10(4), 168; https://doi.org/10.3390/pharmaceutics10040168
Received: 29 August 2018 / Revised: 18 September 2018 / Accepted: 22 September 2018 / Published: 25 September 2018
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Abstract
With the development of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies, trastuzumab-based therapy has become the standard of care among patients with early or advanced HER2-positive breast cancer. However, real-world data have shown that up to a half of patients do
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With the development of anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibodies, trastuzumab-based therapy has become the standard of care among patients with early or advanced HER2-positive breast cancer. However, real-world data have shown that up to a half of patients do not receive trastuzumab or any other HER2-targeted agent, mainly due to high treatments costs. The prospect of a more enlarged access to trastuzumab treatment lies in the use of biosimilars, as the European and the US patent of the reference products has or will soon expire. Biosimilars are biologics highly similar in terms of quality characteristics, biological activity, safety and efficacy to already approved biologics. The biosimilarity of any European Union (EU)-approved biosimilar is guaranteed based on the comprehensive comparability exercise which includes comparative analytical, non-clinical and clinical studies. In the matter of biosimilars’ interchangeability and substitution, the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) have adopted different positions, triggering various discussions on the potential immunogenicity and efficacy in individual patients. As more biosimilars are gaining approval, the present review aims to offer concise information for oncologists and pharmacists about the production, approval, interchangeability, and substitution policies of biosimilars used in breast cancer therapy, with a special focus on trastuzumab. Full article
(This article belongs to the Special Issue Protein Therapeutics)
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Open AccessReview Porous Inorganic Carriers Based on Silica, Calcium Carbonate and Calcium Phosphate for Controlled/Modulated Drug Delivery: Fresh Outlook and Future Perspectives
Pharmaceutics 2018, 10(4), 167; https://doi.org/10.3390/pharmaceutics10040167
Received: 16 August 2018 / Revised: 12 September 2018 / Accepted: 19 September 2018 / Published: 25 September 2018
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Abstract
Porous inorganic nanostructured materials are widely used nowadays as drug delivery carriers due to their adventurous features: suitable architecture, large surface area and stability in the biological fluids. Among the different types of inorganic porous materials, silica, calcium carbonate, and calcium phosphate have
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Porous inorganic nanostructured materials are widely used nowadays as drug delivery carriers due to their adventurous features: suitable architecture, large surface area and stability in the biological fluids. Among the different types of inorganic porous materials, silica, calcium carbonate, and calcium phosphate have received significant attention in the last decade. The use of porous inorganic materials as drug carriers for cancer therapy, gene delivery etc. has the potential to improve the life expectancy of the patients affected by the disease. The main goal of this review is to provide general information on the current state of the art of synthesis of the inorganic porous particles based on silica, calcium carbonate and calcium phosphate. Special focus is dedicated to the loading capacity, controllable release of drugs under internal biological stimuli (e.g., pH, redox, enzymes) and external noninvasive stimuli (e.g., light, magnetic field, and ultrasound). Moreover, the diverse compounds to deliver with silica, calcium carbonate and calcium phosphate particles, ranging from the commercial drugs to genetic materials are also discussed. Full article
(This article belongs to the Special Issue Porous Inorganic Drug Delivery Systems)
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Open AccessArticle In-Line UV-Vis Spectroscopy as a Fast-Working Process Analytical Technology (PAT) during Early Phase Product Development Using Hot Melt Extrusion (HME)
Pharmaceutics 2018, 10(4), 166; https://doi.org/10.3390/pharmaceutics10040166
Received: 21 May 2018 / Revised: 4 September 2018 / Accepted: 11 September 2018 / Published: 23 September 2018
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Abstract
This paper displays the potential of an in-line PAT system for early phase product development during pharmaceutical continuous manufacturing following a Quality by Design (QbD) framework. Hot melt extrusion (HME) is used as continuous manufacturing process and UV–Vis spectroscopy as an in-line monitoring
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This paper displays the potential of an in-line PAT system for early phase product development during pharmaceutical continuous manufacturing following a Quality by Design (QbD) framework. Hot melt extrusion (HME) is used as continuous manufacturing process and UV–Vis spectroscopy as an in-line monitoring system. A sequential design of experiments (DoE) (screening, optimisation and verification) was used to gain process understanding for the manufacture of piroxicam (PRX)/Kollidon® VA64 amorphous solid dispersions. The influence of die temperature, screw speed, solid feed rate and PRX concentration on the critical quality attributes (CQAs) absorbance and lightness of color (L*) of the extrudates was investigated using multivariate tools. Statistical analysis results show interaction effects between concentration and temperature on absorbance and L* values. Solid feed rate has a significant effect on absorbance only and screw speed showed least impact on both responses for the screening design. The optimum HME process conditions were confirmed by 4 independent studies to be 20% w/w of PRX, temperature 140 °C, screw speed 200 rpm and feed rate 6 g/min. The in-line UV-Vis system was used to assess the solubility of PRX in Kollidon® VA64 by measuring absorbance and L* values from 230 to 700 nm. Oversaturation was observed for PRX concentrations higher than 20% w/w. Oversaturation can be readily identified as it causes scattering in the visible range. This is observed by a shift of the baseline in the visible part of the spectrum. Extrudate samples were analyzed for degradation using off-line High-Performance Liquid Chromatography (HPLC) standard methods. Results from off-line experiments using differential scanning calorimetry (DSC), and X-ray diffraction (XRD) are also presented. Full article
(This article belongs to the Special Issue Pharmaceutical Applications of Hot-melt Extrusion)
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Open AccessFeature PaperReview An Evaluation of the Potential of NMR Spectroscopy and Computational Modelling Methods to Inform Biopharmaceutical Formulations
Pharmaceutics 2018, 10(4), 165; https://doi.org/10.3390/pharmaceutics10040165
Received: 11 July 2018 / Revised: 11 September 2018 / Accepted: 17 September 2018 / Published: 21 September 2018
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Abstract
Protein-based therapeutics are considered to be one of the most important classes of pharmaceuticals on the market. The growing need to prolong stability of high protein concentrations in liquid form has proven to be challenging. Therefore, significant effort is being made to design
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Protein-based therapeutics are considered to be one of the most important classes of pharmaceuticals on the market. The growing need to prolong stability of high protein concentrations in liquid form has proven to be challenging. Therefore, significant effort is being made to design formulations which can enable the storage of these highly concentrated protein therapies for up to 2 years. Currently, the excipient selection approach involves empirical high-throughput screening, but does not reveal details on aggregation mechanisms or the molecular-level effects of the formulations under storage conditions. Computational modelling approaches have the potential to elucidate such mechanisms, and rapidly screen in silico prior to experimental testing. Nuclear Magnetic Resonance (NMR) spectroscopy can also provide complementary insights into excipient–protein interactions. This review will highlight the underpinning principles of molecular modelling and NMR spectroscopy. It will also discuss the advancements in the applications of computational and NMR approaches in investigating excipient–protein interactions. Full article
(This article belongs to the Special Issue Protein Therapeutics)
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Open AccessArticle The Influence of Polymers on the Supersaturation Potential of Poor and Good Glass Formers
Pharmaceutics 2018, 10(4), 164; https://doi.org/10.3390/pharmaceutics10040164
Received: 16 August 2018 / Revised: 11 September 2018 / Accepted: 19 September 2018 / Published: 21 September 2018
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Abstract
The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its
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The increasing number of poorly water-soluble drug candidates in pharmaceutical development is a major challenge. Enabling techniques such as amorphization of the crystalline drug can result in supersaturation with respect to the thermodynamically most stable form of the drug, thereby possibly increasing its bioavailability after oral administration. The ease with which such crystalline drugs can be amorphized is known as their glass forming ability (GFA) and is commonly described by the critical cooling rate. In this study, the supersaturation potential, i.e., the maximum apparent degree of supersaturation, of poor and good glass formers is investigated in the absence or presence of either hypromellose acetate succinate L-grade (HPMCAS-L) or vinylpyrrolidine-vinyl acetate copolymer (PVPVA64) in fasted state simulated intestinal fluid (FaSSIF). The GFA of cinnarizine, itraconazole, ketoconazole, naproxen, phenytoin, and probenecid was determined by melt quenching the crystalline drugs to determine their respective critical cooling rate. The inherent supersaturation potential of the drugs in FaSSIF was determined by a solvent shift method where the respective drugs were dissolved in dimethyl sulfoxide and then added to FaSSIF. This study showed that the poor glass formers naproxen, phenytoin, and probenecid could not supersaturate on their own, however for some drug:polymer combinations of naproxen and phenytoin, supersaturation of the drug was enabled by the polymer. In contrast, all of the good glass formers—cinnarizine, itraconazole, and ketoconazole—could supersaturate on their own. Furthermore, the maximum achievable concentration of the good glass formers was unaffected by the presence of a polymer. Full article
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Open AccessArticle Combined Use of N-Palmitoyl-Glycine-Histidine Gel and Several Penetration Enhancers on the Skin Permeation and Concentration of Metronidazole
Pharmaceutics 2018, 10(4), 163; https://doi.org/10.3390/pharmaceutics10040163
Received: 25 July 2018 / Revised: 11 September 2018 / Accepted: 19 September 2018 / Published: 20 September 2018
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Abstract
N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than
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N-Palmitoyl-Glycine-Histidine (Pal-GH) is a novel low molecular weight gelator. In our previous report, ivermectin, a lipophilic drug, was effectively delivered to skin tissue after topical application with Pal-GH as a spray gel formulation, and a much higher skin concentration was confirmed than with the administration of a conventional oral formulation. The objective of this study was to increase the skin permeation of metronidazole (MTZ), a hydrophilic drug, after the topical application of Pal-GH gel. An evaluation of the combined effect of chemical penetration enhancers (CPEs), such as isopropyl myristate (IPM), propylene glycol (PG), ethanol, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO), on skin permeation was also conducted. We found that a 5% Pal-GH gel containing 1% MTZ (F5MTZ) exhibited a 2.7-fold higher MTZ permeation through excised hairless rat skin than its solution. Furthermore, F5PG-MTZ and F5IPM-MTZ further increased the skin permeation of MTZ when compared to F5MTZ. Interestingly, F5PG-MTZ enhanced the skin penetration of MTZ, although no enhancement effect was observed for an MTZ solution containing PG. Thus, a Pal-GH formulation containing PG and IPM may enhance the skin permeation of MTZ. Full article
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