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Pharmaceutics, Volume 12, Issue 4 (April 2020) – 97 articles

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Cover Story (view full-size image) Nanoparticles and their cargo are taken up by the cells through different pathways, including [...] Read more.
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Open AccessArticle
Ionic Liquid-In-Oil Microemulsions Prepared with Biocompatible Choline Carboxylic Acids for Improving the Transdermal Delivery of a Sparingly Soluble Drug
Pharmaceutics 2020, 12(4), 392; https://doi.org/10.3390/pharmaceutics12040392 - 24 Apr 2020
Viewed by 406
Abstract
The transdermal delivery of sparingly soluble drugs is challenging due to of the need for a drug carrier. In the past few decades, ionic liquid (IL)-in-oil microemulsions (IL/O MEs) have been developed as potential carriers. By focusing on biocompatibility, we report on an [...] Read more.
The transdermal delivery of sparingly soluble drugs is challenging due to of the need for a drug carrier. In the past few decades, ionic liquid (IL)-in-oil microemulsions (IL/O MEs) have been developed as potential carriers. By focusing on biocompatibility, we report on an IL/O ME that is designed to enhance the solubility and transdermal delivery of the sparingly soluble drug, acyclovir. The prepared MEs were composed of a hydrophilic IL (choline formate, choline lactate, or choline propionate) as the non-aqueous polar phase and a surface-active IL (choline oleate) as the surfactant in combination with sorbitan laurate in a continuous oil phase. The selected ILs were all biologically active ions. Optimized pseudo ternary phase diagrams indicated the MEs formed thermodynamically stable, spherically shaped, and nano-sized (<100 nm) droplets. An in vitro drug permeation study, using pig skin, showed the significantly enhanced permeation of acyclovir using the ME. A Fourier transform infrared spectroscopy study showed a reduction of the skin barrier function with the ME. Finally, a skin irritation study showed a high cell survival rate (>90%) with the ME compared with Dulbecco’s phosphate-buffered saline, indicates the biocompatibility of the ME. Therefore, we conclude that IL/O ME may be a promising nano-carrier for the transdermal delivery of sparingly soluble drugs. Full article
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Open AccessArticle
HER2-Specific Pseudomonas Exotoxin A PE25 Based Fusions: Influence of Targeting Domain on Target Binding, Toxicity, and In Vivo Biodistribution
Pharmaceutics 2020, 12(4), 391; https://doi.org/10.3390/pharmaceutics12040391 - 24 Apr 2020
Viewed by 579
Abstract
The human epidermal growth factor receptor 2 (HER2) is a clinically validated target for cancer therapy, and targeted therapies are often used in regimens for patients with a high HER2 expression level. Despite the success of current drugs, a number of patients succumb [...] Read more.
The human epidermal growth factor receptor 2 (HER2) is a clinically validated target for cancer therapy, and targeted therapies are often used in regimens for patients with a high HER2 expression level. Despite the success of current drugs, a number of patients succumb to their disease, which motivates development of novel drugs with other modes of action. We have previously shown that an albumin binding domain-derived affinity protein with specific affinity for HER2, ADAPT6, can be used to deliver the highly cytotoxic protein domain PE25, a derivative of Pseudomonas exotoxin A, to HER2 overexpressing malignant cells, leading to potent and specific cell killing. In this study we expanded the investigation for an optimal targeting domain and constructed two fusion toxins where a HER2-binding affibody molecule, ZHER2:2891, or the dual-HER2-binding hybrid ZHER2:2891-ADAPT6 were used for cancer cell targeting. We found that both targeting domains conferred strong binding to HER2; both to the purified extracellular domain and to the HER2 overexpressing cell line SKOV3. This resulted in fusion toxins with high cytotoxic potency toward cell lines with high expression levels of HER2, with EC50 values between 10 and 100 pM. For extension of the plasma half-life, an albumin binding domain was also included. Intravenous injection of the fusion toxins into mice showed a profound influence of the targeting domain on biodistribution. Compared to previous results, with ADAPT6 as targeting domain, ZHER2:2891 gave rise to further extension of the plasma half-life and also shifted the clearance route of the fusion toxin from the liver to the kidneys. Collectively, the results show that the targeting domain has a major impact on uptake of PE25-based fusion toxins in different organs. The results also show that PE25-based fusion toxins with high affinity to HER2 do not necessarily increase the cytotoxicity beyond a certain point in affinity. In conclusion, ZHER2:2891 has the most favorable characteristics as targeting domain for PE25. Full article
(This article belongs to the Special Issue Recombinant Therapeutic Proteins for Drug Delivery)
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Open AccessArticle
Acamprosate Is a Substrate of the Human Organic Anion Transporter (OAT) 1 without OAT3 Inhibitory Properties: Implications for Renal Acamprosate Secretion and Drug–Drug Interactions
Pharmaceutics 2020, 12(4), 390; https://doi.org/10.3390/pharmaceutics12040390 - 24 Apr 2020
Viewed by 626
Abstract
Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in [...] Read more.
Acamprosate is an anionic drug substance widely used in treating symptoms of alcohol withdrawal. It was recently shown that oral acamprosate absorption is likely due to paracellular transport. In contrast, little is known about the eliminating mechanism clearing acamprosate from the blood in the kidneys, despite the fact that studies have shown renal secretion of acamprosate. The hypothesis of the present study was therefore that renal organic anion transporters (OATs) facilitate the renal excretion of acamprosate in humans. The aim of the present study was to establish and apply OAT1 (gene product of SLC22A6) and OAT3 (gene product of SLC22A8) expressing cell lines to investigate whether acamprosate is a substrate or inhibitor of OAT1 and/or OAT3. The studies were performed in HEK293-Flp-In cells stably transfected with SLC22A6 or SLC22A8. Protein and functional data showed that the established cell lines are useful for studying OAT1- and OAT3-mediated transport in bi-laboratory studies. Acamprosate inhibited OAT1-mediated p-aminohippuric acid (PAH) uptake but did not inhibit substrate uptake via OAT3 expressing cells, neither when applied concomitantly nor after a 3 h preincubation with acamprosate. The uptake of PAH via OAT1 was inhibited in a competitive manner by acamprosate and cellular uptake studies showed that acamprosate is a substrate for OAT1 with a Km-value of approximately 700 µM. Probenecid inhibited OAT1-mediated acamprosate uptake with a Ki-value of approximately 13 µM, which may translate into an estimated clinically significant DDI index. In conclusion, acamprosate was identified as a substrate of OAT1 but not OAT3. Full article
(This article belongs to the Special Issue Drug Transporters in Absorption, Disposition and Elimination)
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Open AccessArticle
Senescence of IPF Lung Fibroblasts Disrupt Alveolar Epithelial Cell Proliferation and Promote Migration in Wound Healing
Pharmaceutics 2020, 12(4), 389; https://doi.org/10.3390/pharmaceutics12040389 - 24 Apr 2020
Viewed by 755
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair [...] Read more.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive accumulation of lung fibroblasts (LFs) and collagen in the lung parenchyma. The mechanisms that underlie IPF pathophysiology are thought to reflect repeated alveolar epithelial injury leading to an aberrant wound repair response. Recent work has shown that IPF-LFs display increased characteristics of senescence including growth arrest and a senescence-associated secretory phenotype (SASP) suggesting that senescent LFs contribute to dysfunctional wound repair process. Here, we investigated the influence of senescent LFs on alveolar epithelial cell repair responses in a co-culture system. Alveolar epithelial cell proliferation was attenuated when in co-culture with cells or conditioned media from, senescence-induced control LFs or IPF-LFs. Cell-cycle analyses showed that a larger number of epithelial cells were arrested in G2/M phase when co-cultured with IPF-LFs, than in monoculture. Paradoxically, the presence of LFs resulted in increased A549 migration after mechanical injury. Our data suggest that senescent LFs may contribute to aberrant re-epithelialization by inhibiting proliferation in IPF. Full article
(This article belongs to the Special Issue Antifibrotic Drugs)
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Open AccessArticle
Investigating the Effect of Encapsulation Processing Parameters on the Viability of Therapeutic Viruses in Electrospraying
Pharmaceutics 2020, 12(4), 388; https://doi.org/10.3390/pharmaceutics12040388 - 24 Apr 2020
Viewed by 275
Abstract
The ability of viruses to introduce genetic material into cells can be usefully exploited in a variety of therapies and also vaccination. Encapsulating viruses to limit inactivation by the immune system before reaching the desired target and allowing for controlled release is a [...] Read more.
The ability of viruses to introduce genetic material into cells can be usefully exploited in a variety of therapies and also vaccination. Encapsulating viruses to limit inactivation by the immune system before reaching the desired target and allowing for controlled release is a promising strategy of delivery. Conventional encapsulation methods, however, can significantly reduce infectivity. The aim of this study was to investigate electrospraying as an alternative encapsulation technique. Two commonly used therapeutic viruses, adenovirus (Ad) and modified vaccinia Ankara (MVA), were selected. First, solutions containing the viruses were electrosprayed in a single needle configuration at increasing voltages to examine the impact of the electric field. Second, the effect of exposing the viruses to pure organic solvents was investigated and compared to that occurring during coaxial electrospraying. Infectivity was determined by measuring the luminescence produced from lysed A549 cells after incubation with treated virus. Neither Ad nor MVA exhibited any significant loss in infectivity when electrosprayed within the range of electrospraying parameters relevant for encapsulation. A significant decrease in infectivity was only observed when MVA was electrosprayed at the highest voltage, 24 kV, and when MVA and Ad were exposed to selected pure organic solvents. Thus, it was concluded that electrospraying would be a viable method for virus encapsulation. Full article
(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)
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Open AccessReview
Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones
Pharmaceutics 2020, 12(4), 387; https://doi.org/10.3390/pharmaceutics12040387 - 23 Apr 2020
Cited by 1 | Viewed by 321
Abstract
Pulmonary drug delivery is a promising strategy to treat lung infectious disease as it allows for a high local drug concentration and low systemic side effects. This is particularly true for low-permeability drugs, such as tobramycin or colistin, that penetrate the lung at [...] Read more.
Pulmonary drug delivery is a promising strategy to treat lung infectious disease as it allows for a high local drug concentration and low systemic side effects. This is particularly true for low-permeability drugs, such as tobramycin or colistin, that penetrate the lung at a low rate after systemic administration and greatly benefit from lung administration in terms of the local drug concentration. However, for relatively high-permeable drugs, such as fluoroquinolones (FQs), the rate of absorption is so high that the pulmonary administration has no therapeutic advantage compared to systemic or oral administration. Formulation strategies have thus been developed to decrease the absorption rate and increase FQs’ residence time in the lung after inhalation. In the present review, some of these strategies, which generally consist of either decreasing the lung epithelium permeability or decreasing the release rate of FQs into the epithelial lining fluid after lung deposition, are presented in regards to their clinical aspects. Full article
(This article belongs to the Special Issue Fate of Drugs and Delivery Systems in the Lungs)
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Open AccessArticle
Influence of Aqueous Solubility-Enhancing Excipients on the Microstructural Characteristics of Furosemide-Loaded Electrospun Nanofibers
Pharmaceutics 2020, 12(4), 385; https://doi.org/10.3390/pharmaceutics12040385 - 23 Apr 2020
Viewed by 296
Abstract
Electrospun nanofibers were prepared from furosemide-containing hydroxypropyl cellulose and poly(vinylpyrrolidone) aqueous solutions using different solubility enhancers. In one case, a solubilizer, triethanolamine, was applied, while in the other case a pH-modifier, sodium hydroxide, was applied. Scanning electron microscopy (SEM) was carried out for [...] Read more.
Electrospun nanofibers were prepared from furosemide-containing hydroxypropyl cellulose and poly(vinylpyrrolidone) aqueous solutions using different solubility enhancers. In one case, a solubilizer, triethanolamine, was applied, while in the other case a pH-modifier, sodium hydroxide, was applied. Scanning electron microscopy (SEM) was carried out for morphological characterization of the fibers. The SEM images indicated similar mean diameter size of the two fibrous formulations. However, in contrast to the NaOH-containing fibers of normal diameter distribution, the triethanolamine-containing fibers showed approximately normal diameter distribution, possibly due to their plasticizing effect and the consequent slightly ribbon-like morphology. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), powder X-ray diffraction (XRD) and positron annihilation lifetime spectroscopy (PALS) were applied for microstructural characterization. The FTIR measurements confirmed that furosemide salt was formed in both cases. There was no sign of any crystallinity based on the XRD measurements. However, the PALS highlighted the differences in the average o-Ps lifetime values and distributions of the furosemide-loaded fibrous formulations. The two types of electrospun nanofibrous formulations containing amorphous furosemide salt showed similar macrostructures but different microstructural characteristics depending on the type of solubility enhancers, which lead to altered storage stability. Full article
(This article belongs to the Special Issue Recent Development of Electrospinning for Drug Delivery Volume II)
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Open AccessArticle
β-Sitosterol Loaded Nanostructured Lipid Carrier: Physical and Oxidative Stability, In Vitro Simulated Digestion and Hypocholesterolemic Activity
Pharmaceutics 2020, 12(4), 386; https://doi.org/10.3390/pharmaceutics12040386 - 22 Apr 2020
Viewed by 289
Abstract
The objective of the present study was to explore the potential of nanostructured lipid carriers (NLCs) for improving the oral delivery of β-sitosterol, a poorly water-soluble bioactive component with hypocholesterolemic activity. Two β-sitosterol formulations with different solid lipid compositions were prepared by melt [...] Read more.
The objective of the present study was to explore the potential of nanostructured lipid carriers (NLCs) for improving the oral delivery of β-sitosterol, a poorly water-soluble bioactive component with hypocholesterolemic activity. Two β-sitosterol formulations with different solid lipid compositions were prepared by melt emulsification, followed by the sonication technique, and the effect of storage conditions and simulated digestion on the physical, chemical and oxidative stability, bioaccessibility and release were extensively studied. Both NLC preparations remained relatively stable during the four weeks of storage at different conditions (4, 25 and 40 °C), with more superior stability at lower temperatures. The in vitro digestion experiment indicated a high physical stability after exposure to the simulated mouth and stomach stages and an improved overall β-sitosterol bioaccessibility at the end of the digestion. The NLCs presented an increased solubility and gradual release which could be justified by the remarkable affinity of β-sitosterol to the complex lipid mixture. An in vivo study demonstrated an improved reduction in the total cholesterol and low-density lipoprotein cholesterol plasma levels in mice compared with the drug suspension. These investigations evidenced the potential of the developed NLC formulations for the enhancement of solubility and in vivo performance of β-sitosterol. Full article
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Open AccessArticle
Importance of Mesoporous Silica Particle Size in the Stabilization of Amorphous Pharmaceuticals—The Case of Simvastatin
Pharmaceutics 2020, 12(4), 384; https://doi.org/10.3390/pharmaceutics12040384 - 22 Apr 2020
Viewed by 321
Abstract
In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid® XDP 3050 and Syloid® 244 FP) were employed. The [...] Read more.
In this paper, the role of mesoporous silica (MS) particle size in the stabilization of amorphous simvastatin (SVT) is revealed. For inhibiting recrystallization of the supercooled drug, the two MS materials (Syloid® XDP 3050 and Syloid® 244 FP) were employed. The crystallization tendency of SVT alone and in mixture with the MS materials was investigated by Differential Scanning Calorimetry (DSC) and Broadband Dielectric Spectroscopy (BDS). Neither confinement of the SVT molecules inside the MS pores nor molecular interactions between functional groups of the SVT molecules and the surface of the stabilizing excipient could explain the observed stabilization effect. The stabilization effect might be correlated with diffusion length of the SVT molecules in the MS materials that depended on the particle size. Moreover, MS materials possessing different particle sizes could offer free spaces with different sizes, which might influence crystal growth of SVT. All of these factors must be considered when mesoporous materials are used for stabilizing pharmaceutical glasses. Full article
(This article belongs to the Special Issue Advances in Amorphous Drug Formulations)
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Open AccessArticle
In Vivo Antidepressant Effect of Passiflora edulis f. flavicarpa into Cationic Nanoparticles: Improving Bioactivity and Safety
Pharmaceutics 2020, 12(4), 383; https://doi.org/10.3390/pharmaceutics12040383 - 21 Apr 2020
Viewed by 435
Abstract
A variety of neuroactive flavonoids can be found in the species of the Passiflora genus; however, their difficulty in crossing the blood–brain barrier limits their in vivo neuropharmacological activity. In this study, cationic nanoparticles were developed as a novel nanocarrier for improving the [...] Read more.
A variety of neuroactive flavonoids can be found in the species of the Passiflora genus; however, their difficulty in crossing the blood–brain barrier limits their in vivo neuropharmacological activity. In this study, cationic nanoparticles were developed as a novel nanocarrier for improving the antidepressant activity of Passiflora edulis f. flavicarpa leaf extract. Formulations obtained using Eudragit E PO polymethylmethacrylate copolymer, as polymeric matrix had their physicochemical properties investigated. The analytical content of the flavonoids vicenin-2, orientin, isoorientin, vitexin, and isovitexin was determined in the plant extract. Small-sized and spherical nanoparticles loaded with Passiflora edulis f. flavicarpa were obtained with positive zeta potential and high encapsulation efficiency. In addition, the nanosystems were shown to be stable for at least 6 months. The antidepressant activity of P. edulis extract (50 and 100 mg/kg) as well as the extract-loaded nanoparticles (5 mg/kg) were investigated in mice using the forced swimming test, where the latter increased the potency of the former by 10-fold. In addition, histopathological and biochemical analysis confirmed the biocompatibility of the extract-loaded nanoparticles. This study demonstrated that the Eudragit cationic nanoparticles were able to improve the antidepressant activity of P. edulis in the central nervous system of mice. Full article
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Open AccessArticle
Spatially Resolved Effects of Protein Freeze-Thawing in a Small-Scale Model Using Monoclonal Antibodies
Pharmaceutics 2020, 12(4), 382; https://doi.org/10.3390/pharmaceutics12040382 - 21 Apr 2020
Viewed by 250
Abstract
Protein freeze-thawing is frequently used to stabilize and store recombinantly produced proteins after different unit operations in upstream and downstream processing. However, freeze-thawing is often accompanied by product damage and, hence, loss of product. Different effects are responsible, including cold denaturation, aggregation effects, [...] Read more.
Protein freeze-thawing is frequently used to stabilize and store recombinantly produced proteins after different unit operations in upstream and downstream processing. However, freeze-thawing is often accompanied by product damage and, hence, loss of product. Different effects are responsible, including cold denaturation, aggregation effects, which are caused by inhomogeneities in protein concentration, as well as pH and buffer ingredients, especially during the freeze cycle. In this study, we tested a commercially available small-scale protein freezing unit using immunoglobin G (IgG) as monoclonal antibody in a typical formulation buffer containing sodium phosphate, sodium chloride, and Tween 80. Different freezing rates were used respectively, and the product quality was tested in the frozen sample. Spatially resolved tests for protein concentration, pH, conductivity, and aggregation revealed high spatial differences in the frozen sample. Usage of slow freezing rates revealed high inhomogeneities in terms of buffer salt and protein distribution, while fast rates led to far lower spatial differences. These protein and buffer salt inhomogeneities can be reliably monitored using straight forward analytics, like conductivity and photometric total protein concentration measurements, reducing the need for HPLC analytics in screening experiments. Summarizing, fast freezing using steep rates shows promising results concerning homogeneity of the final frozen product and inhibits increased product aggregation. Full article
(This article belongs to the Special Issue Drug Stability and Stabilization Techniques)
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Open AccessArticle
Polyphenols-Loaded Sericin Self-Assembling Nanoparticles: A Slow-Release for Regeneration by Tissue-Resident Mesenchymal Stem/Stromal Cells
Pharmaceutics 2020, 12(4), 381; https://doi.org/10.3390/pharmaceutics12040381 - 21 Apr 2020
Viewed by 341
Abstract
Mesenchymal stem/stromal cells (MSCs) are a therapeutic target to promote tissue regeneration, mainly when oxidative stress-mediated damage is involved in disease pathogenesis. Here, slow-release silk sericin nanoparticles (SNPs) loaded with natural antioxidant polyphenols were developed to sustain regeneration by tissue-resident MSCs. SNPs were [...] Read more.
Mesenchymal stem/stromal cells (MSCs) are a therapeutic target to promote tissue regeneration, mainly when oxidative stress-mediated damage is involved in disease pathogenesis. Here, slow-release silk sericin nanoparticles (SNPs) loaded with natural antioxidant polyphenols were developed to sustain regeneration by tissue-resident MSCs. SNPs were prepared by exploiting a self-assembly method with poloxamer and were loaded with proanthocyanidins (P), quercetin (Q) or epigallocatechin gallate (E). SNPs, with a diameter less than 150 nm, were able to encapsulate both hydrophilic (P and E) and hydrophobic (Q) drugs. A slow and controlled release was obtained from SNPs for all the actives in PBS, while in EtOH, Q and E showed a burst release but P did not. Kinetic models revealed lower diffusion of P than other biomolecules, probably due to the higher steric hindrance of P. The in vitro anti-oxidant, anti-elastase and anti-tyrosinase properties of SNPs were assessed: loading the P and E into SNPs preserved the in vitro biological activities whereas for Q, the anti-elastase activity was strongly improved. Moreover, all formulations promoted MSC metabolic activity over 72 h. Finally, SNPs exhibited a strong ability to protect MSCs from oxidative stress, which supports their potential use for regenerative purposes mediated by tissue-resident MSCs. Full article
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Open AccessArticle
Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?
Pharmaceutics 2020, 12(4), 380; https://doi.org/10.3390/pharmaceutics12040380 - 21 Apr 2020
Viewed by 434
Abstract
We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting [...] Read more.
We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto. Full article
(This article belongs to the Special Issue Pharmacokinetics in Optimizing Dosing)
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Open AccessArticle
Influence of Carbamazepine Dihydrate on the Preparation of Amorphous Solid Dispersions by Hot Melt Extrusion
Pharmaceutics 2020, 12(4), 379; https://doi.org/10.3390/pharmaceutics12040379 - 20 Apr 2020
Viewed by 703
Abstract
Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs [...] Read more.
Amorphous solid dispersions (ASDs) are commonly used in the pharmaceutical industry to improve the dissolution and bioavailability of poorly water-soluble drugs. Hot melt extrusion (HME) has been employed to prepare ASD based products. However, due to the narrow processing window of HME, ASDs are normally obtained with high processing temperatures and mechanical stress. Interestingly, one-third of pharmaceutical compounds reportedly exist in hydrate forms. In this study, we selected carbamazepine (CBZ) dihydrate to investigate its solid-state changes during the dehydration process and the impact of the dehydration on the preparation of CBZ ASDs using a Leistritz micro-18 extruder. Various characterization techniques were used to study the dehydration kinetics of CBZ dihydrate under different conditions. We designed the extrusion runs and demonstrated that: 1) the dehydration of CBZ dihydrate resulted in a disordered state of the drug molecule; 2) the resulted higher energy state CBZ facilitated the drug solubilization and mixing with the polymer matrix during the HME process, which significantly decreased the required extrusion temperature from 140 to 60 °C for CBZ ASDs manufacturing compared to directly processing anhydrous crystalline CBZ. This work illustrated that the proper utilization of drug hydrates can significantly improve the processability of HME for preparing ASDs. Full article
(This article belongs to the Special Issue Hot-Melt Extrusion)
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Open AccessArticle
Stability and Safety Traits of Novel Cyclosporine A and Tacrolimus Ophthalmic Galenic Formulations Involved in Vernal Keratoconjunctivitis Treatment by a High-Resolution Mass Spectrometry Approach
Pharmaceutics 2020, 12(4), 378; https://doi.org/10.3390/pharmaceutics12040378 - 20 Apr 2020
Viewed by 292
Abstract
In this study, a sensitive quantitative method based on high performance liquid chromatography combined with high-resolution mass spectrometry, Q ExactiveTM-Orbitrap® was set up and applied for the determination of the immunosuppressor agents cyclosporine A and tacrolimus in novel ethanol-free ophthalmic [...] Read more.
In this study, a sensitive quantitative method based on high performance liquid chromatography combined with high-resolution mass spectrometry, Q ExactiveTM-Orbitrap® was set up and applied for the determination of the immunosuppressor agents cyclosporine A and tacrolimus in novel ethanol-free ophthalmic formulations for the treatment of Vernal keratoconjunctivitis. Different storage parameters in terms of storage temperatures and practical usage conditions were investigated to assess the stability of all formulations during shelf life simulating the real conditions as well to confirm the feasibility of use of ethanol-free products. The methodology was linear (r2 = 0.995) over the concentration range 0–200 ng/mL, and its selectivity, precision, accuracy and recovery were all within the required limits. Under different conditions (storage period 0–90 days, 5–25 °C, unopened/usage simulated conditions), our results revealed that both active pharmaceutical ingredients (API) show satisfactory stability up to 30 days of storage/usage, with a significant and consistent concentration decline of cyclosporine A after this time point when its hydroalcoholic formulation was kept at 25 °C. Full article
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Open AccessArticle
Melt Amorphisation of Orlistat with Mesoporous Silica Using a Supercritical Carbon Dioxide: Effects of Pressure, Temperature, and Drug Loading Ratio and Comparison with Other Conventional Amorphisation Methods
Pharmaceutics 2020, 12(4), 377; https://doi.org/10.3390/pharmaceutics12040377 - 20 Apr 2020
Viewed by 333
Abstract
The aim of this work was to develop an amorphous orlistat-loaded mesoporus silica formulation using the melt-amorphisation by supercritical fluid (MA-SCF) and to investigate the effects of pressure and temperature on the pharmaceutical properties of the developed formulation. In addition, the effect of [...] Read more.
The aim of this work was to develop an amorphous orlistat-loaded mesoporus silica formulation using the melt-amorphisation by supercritical fluid (MA-SCF) and to investigate the effects of pressure and temperature on the pharmaceutical properties of the developed formulation. In addition, the effect of orlistat mass ratio to the mesoporus silica was also evaluated. The carbon dioxide was used as a supercritical fluid, and Neusilin®UFL2 was selected as the mesoporous silica. For comparison with conventional amorphisation methods, orlistat formulations were also prepared by solvent evaporation and hot melt methods. Various pharmaceutical evaluations including differential scanning calorimetry, powder X-ray diffraction, scanning electron microscopy, specific surface area, total pore volume, and content uniformity were performed to characterise the prepared orlistat formulation. The melting point depression and the solubility of orlistat in supercritical carbon dioxide (SC-CO2) were selected for the interpretation of evaluated results in relation to temperature and pressure. The total pore volume of the prepared orlistat-loaded mesoporus silica decreased with an increasing density of SC-CO2 to about 500 g/L at a constant temperature or pressure. From these results, it was suggested that increasing the density of SC-CO2 to about 500 g/L could result in the easier penetration of CO2 into molten orlistat and lower viscosity, hence facilitating the introduction and loading of orlistat into the pores of Neusilin®UFL2. However, when the density of SC-CO2 increased to more than 500 g/L, the total pore volume increased, and this may be due to the release out of orlistat from the pores of Neusilin®UFL2 by the increased orlistat solubility in SC-CO2. Interestingly, as the total pore volume decreased by the filling of the drug, the drug crystallinity decreased; hence, the dissolution rate increased. Furthermore, it was shown that the most desirable mass ratio of Neusilin®UFL2:orlistat for the amorphisation was 1:0.8 at an optimised supercritical condition of 318 K and 10 MPa. Compared with other amorphisation methods, only the sample prepared by the MA-SCF method was in pure amorphous state with the fastest dissolution rate. Therefore, it was concluded that the amorphous orlistat-loaded mesoporus silica prepared using MA-SCF under optimised conditions was more advantageous for enhancing the dissolution rate of orlistat than other conventional amorphisation methods. Full article
(This article belongs to the Special Issue Advances in Oral and Buccal Drug Delivery)
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Open AccessArticle
Carminic Acid Linked to Silica Nanoparticles as Pigment/Antioxidant Bifunctional Excipient for Pharmaceutical Emulsions
Pharmaceutics 2020, 12(4), 376; https://doi.org/10.3390/pharmaceutics12040376 - 19 Apr 2020
Viewed by 320
Abstract
The incorporation of pigments and natural polyphenols into inorganic matrices, resulting in a hybrid material that improves the resistance and chemical stability of the pigments and the antioxidant capacity of the materials, has been of great interest to the pharmaceutical, chemical and food [...] Read more.
The incorporation of pigments and natural polyphenols into inorganic matrices, resulting in a hybrid material that improves the resistance and chemical stability of the pigments and the antioxidant capacity of the materials, has been of great interest to the pharmaceutical, chemical and food industries. The aim of this work was to prepare and characterize a bifunctional pigment–antioxidant nanomaterial-based carminic acid-decorated solid core-mesoporous shell silica nanoparticles, evaluating its properties as a pigment, its antioxidant capacity and its properties as a chemical stabilizer of emulsions. The chemical stability of oil-in-water (O/W) Pickering emulsions was evaluated determining the stability of vitamin E solubilized in the oil phase. Carminic acid was attached through the action of coupling ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS) agents, and the resulting spherical and homogeneous nanoparticles showed a diameter close to 175 nm. A notorious change of emulsion color was observed by the addition of the nanomaterial. Emulsions showed an attractive pink color, and when the pH was adjusted to pH 3 and pH 9, a change in color was observed, analogous to carminic acid in solution. The nanomaterial incorporation also improved chemical stability, decreasing vitamin E consumption to 9.26% of the initial value, demonstrating an important antioxidant effect of the developed nanomaterial. Full article
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Open AccessArticle
Comparing Two Methods of Tablet Manipulation to Adjust the Warfarin Dose in Paediatric Care
Pharmaceutics 2020, 12(4), 375; https://doi.org/10.3390/pharmaceutics12040375 - 18 Apr 2020
Viewed by 366
Abstract
Tablets containing prescribed doses are not always available, and this is of particular importance in paediatric care where suitable age-appropriate formulations are generally lacking. To obtain a child-adjusted dose, tablets are manipulated in several ways; e.g., they may be dispersed in water before [...] Read more.
Tablets containing prescribed doses are not always available, and this is of particular importance in paediatric care where suitable age-appropriate formulations are generally lacking. To obtain a child-adjusted dose, tablets are manipulated in several ways; e.g., they may be dispersed in water before a fraction is extracted, or they may be split before the resulting fragment is dispersed. In this study, the accuracy attained through these manipulation methods was investigated for two generic tablets containing the anticoagulant warfarin. Tablets were dispersed in water (10 mL) before a fraction (10%) was withdrawn, alternatively tablets were split in half or quarter fragments before the fragments were dispersed in water. To investigate the contribution of variability from the different steps in the manipulation processes, the amount of warfarin recovered from the various dispersions was determined, as was the accuracy of the splitting. A validated UHPLC-method was used for quantitative determination of warfarin. Splitting of the tablets could result in deviation >30% from the ideal, theoretical weight. The amount of drug substance extracted as a fraction from the dispersed tablets deviated no more than 10% from the intended amount. To obtain the most accurate child-adjusted fraction dose of warfarin, the tablets investigated in this study should be dispersed and the desired proportion extracted. Practices that involve splitting tablets are likely to increase the variation, and should be avoided. Full article
(This article belongs to the Special Issue Paediatric Drug Delivery)
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Open AccessArticle
Population Pharmacokinetic Analysis of Tiropramide in Healthy Korean Subjects
Pharmaceutics 2020, 12(4), 374; https://doi.org/10.3390/pharmaceutics12040374 - 18 Apr 2020
Viewed by 310
Abstract
The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related [...] Read more.
The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related diseases as an antispasmodic, PPK reporting and factors affecting PKs are not clearly reported. Thus, this study for healthy subjects is very significant because it could find new covariates in patients that had not been reported before or predict PPK for patients in the clinic by establishing PPK in healthy adults. By using Phoenix NLME, PK, demographic, and genetic data (collected to explain PK diversity of tiropramide in population) analyses were performed. As a basic model, a one-compartment with first-order absorption and lag-time was established and extended to include covariates that influenced the inter-subject variability. The total protein significantly influenced the distribution volume and systemic clearance of tiropramide, but genetic factors such as ABCB1 (1236C>T, 2677G>T/A, and 3435C>T), CYP2D6 (*1 and *10), OCT2 (808G>T), and PEPT1 (1287G>C) genes did not show any significant association with PK parameters of tiropramide. The final PPK model of tiropramide was validated, and suggested that some of the PK diversity in the population could be explained. Herein, we first describe the establishment of the PPK model of tiropramide for healthy Korean subjects, which may be useful as a dosing algorithm for the diseased population. Full article
(This article belongs to the Special Issue Drug Metabolism/Transport and Pharmacokinetics)
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Open AccessArticle
A Portable Device for the Generation of Drug-Loaded Three-Compartmental Fibers Containing Metronidazole and Iodine for Topical Application
Pharmaceutics 2020, 12(4), 373; https://doi.org/10.3390/pharmaceutics12040373 - 18 Apr 2020
Viewed by 464
Abstract
The use of combination therapies for the treatment of a range of conditions is now well established, with the component drugs usually being delivered either as distinct medicaments or combination products that contain physical mixes of the two active ingredients. There is, however, [...] Read more.
The use of combination therapies for the treatment of a range of conditions is now well established, with the component drugs usually being delivered either as distinct medicaments or combination products that contain physical mixes of the two active ingredients. There is, however, a compelling argument for the development of compartmentalised systems whereby the release, stability and incorporation environment of the different drugs may be tailored. Here we outline the development of polymeric fine fiber systems whereby two drugs used for the treatment of wounds may be separately incorporated. Fibers were delivered using a newly developed handheld electrospinning device that allows treatment at the site of need. Crucially, the delivery system is portable and may be used for the administration of drug-loaded fibers directly into the wound in situ, thereby potentially allowing domiciliary or site-of-trauma administration. The three-layered fiber developed in this study has polyethylene glycol as the outermost layer, serving as a structural support for the inner layers. The inner layers comprised iodine complexed with polyvinylpyrrolidone (PVP) and metronidazole dispersed in polycaprolactone (PCL) as a slow release core. The systems were characterized in terms of structure and architecture using scanning electron microscopy, transmission electron microscopy, attenuated total reflection Fourier transform infrared spectroscopy and diffractometry. As antibacterial creams are still used for managing infected wounds, the performance of our trilayered fiber was studied in comparison with creams containing similar active drugs. Drug release was measured by UV analysis, while antimicrobial efficiency was measured using agar diffusion and suspension methods. It was found that the trilayered systems, averaging 3.16 µm in diameter, released more drug over the study period and were confirmed by the microbacterial studies to be more effective against P. aeruginosa, a bacterium commonly implicated in infected wounds. Overall, the portable system has been shown to be capable of not only incorporating the two drugs in distinct layers but also of delivering adequate amounts of drugs for a more effective antibacterial activity. The portability of the device and its ability to generate distinct layers of multiple active ingredients make it promising for further development for wound healing applications in terms of both practical applicability and antimicrobial efficacy. Full article
(This article belongs to the Special Issue Emerging Micro- and Nanofabrication Technologies for Drug Delivery)
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Open AccessArticle
Tumor-Homing pH-Sensitive Extracellular Vesicles for Targeting Heterogeneous Tumors
Pharmaceutics 2020, 12(4), 372; https://doi.org/10.3390/pharmaceutics12040372 - 17 Apr 2020
Viewed by 367
Abstract
In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, [...] Read more.
In this study, we fabricated tumor-homing pH-sensitive extracellular vesicles for efficient tumor treatment. These vesicles were prepared using extracellular vesicles (EVs; BTEVs extracted from BT-474 tumor cells or SKEVs extracted from SK-N-MC tumor cells), hyaluronic acid grafted with 3-(diethylamino)propylamine (HDEA), and doxorubicin (DOX, as a model antitumor drug). Consequently, HDEA/DOX anchored EVs ([email protected]) can interact with origin tumor cells owing to EVs’ homing ability to origin cells. Therefore, EV blends of [email protected] and [email protected] demonstrate highly increased cellular uptake in both BT-474 and SK-N-MC cells: [email protected] for BT-474 tumor cells and [email protected] for SK-N-MC tumor cells. Furthermore, the hydrophobic HDEA present in [email protected] at pH 7.4 can switch to hydrophilic HDEA at pH 6.5 as a result of acidic pH-induced protonation of 3-(diethylamino)propylamine (DEAP) moieties, resulting in an acidic pH-activated EVs’ disruption, accelerated release of encapsulated DOX molecules, and highly increased cell cytotoxicity. However, EV blends containing pH-insensitive HA grafted with deoxycholic acid (HDOC) ([email protected] and [email protected]) showed less cell cytotoxicity for both BT-474 and SK-N-MC tumor cells, because they did not act on EVs’ disruption and the resulting DOX release. Consequently, the use of these tumor-homing pH-sensitive EV blends may result in effective targeted therapies for various tumor cells. Full article
(This article belongs to the Special Issue Novel Anticancer Strategies)
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Open AccessReview
Endocytosis: The Nanoparticle and Submicron Nanocompounds Gateway into the Cell
Pharmaceutics 2020, 12(4), 371; https://doi.org/10.3390/pharmaceutics12040371 - 17 Apr 2020
Cited by 1 | Viewed by 548
Abstract
Nanoparticles (NPs) and submicron particles are increasingly used as carriers for delivering therapeutic compounds to cells. Their entry into the cell represents the initial step in this delivery process, being most of the nanoparticles taken up by endocytosis, although other mechanisms can contribute [...] Read more.
Nanoparticles (NPs) and submicron particles are increasingly used as carriers for delivering therapeutic compounds to cells. Their entry into the cell represents the initial step in this delivery process, being most of the nanoparticles taken up by endocytosis, although other mechanisms can contribute to the uptake. To increase the delivery efficiency of therapeutic compounds by NPs and submicron particles is very relevant to understand the mechanisms involved in the uptake process. This review covers the proposed pathways involved in the cellular uptake of different NPs and submicron particles types as well as the role that some of the physicochemical nanoparticle characteristics play in the uptake pathway preferentially used by the nanoparticles to gain access and deliver their cargo inside the cell. Full article
(This article belongs to the Special Issue Cancer Nanomedicine—From the Bench to the Bedside)
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Open AccessArticle
Targeting the Tumor Microenvironment with Fluorescence-Activatable Bispecific Endoglin/Fibroblast Activation Protein Targeting Liposomes
Pharmaceutics 2020, 12(4), 370; https://doi.org/10.3390/pharmaceutics12040370 - 17 Apr 2020
Viewed by 362
Abstract
Liposomes are biocompatible nanocarriers with promising features for targeted delivery of contrast agents and drugs into the tumor microenvironment, for imaging and therapy purposes. Liposome-based simultaneous targeting of tumor associated fibroblast and the vasculature is promising, but the heterogeneity of tumors entails a [...] Read more.
Liposomes are biocompatible nanocarriers with promising features for targeted delivery of contrast agents and drugs into the tumor microenvironment, for imaging and therapy purposes. Liposome-based simultaneous targeting of tumor associated fibroblast and the vasculature is promising, but the heterogeneity of tumors entails a thorough validation of suitable markers for targeted delivery. Thus, we elucidated the potential of bispecific liposomes targeting the fibroblast activation protein (FAP) on tumor stromal fibroblasts, together with endoglin which is overexpressed on tumor neovascular cells and some neoplastic cells. Fluorescence-quenched liposomes were prepared by hydrating a lipid film with a high concentration of the self-quenching near-infrared fluorescent dye, DY-676-COOH, to enable fluorescence detection exclusively upon liposomal degradation and subsequent activation. A non-quenched green fluorescent phospholipid was embedded in the liposomal surface to fluorescence-track intact liposomes. FAP- and murine endoglin-specific single chain antibody fragments were coupled to the liposomal surface, and the liposomal potentials validated in tumor cells and mice models. The bispecific liposomes revealed strong fluorescence quenching, activatability, and selectivity for target cells and delivered the encapsulated dye selectively into tumor vessels and tumor associated fibroblasts in xenografted mice models and enabled their fluorescence imaging. Furthermore, detection of swollen lymph nodes during intra-operative simulations was possible. Thus, the bispecific liposomes have potentials for targeted delivery into the tumor microenvironment and for image-guided surgery. Full article
(This article belongs to the Special Issue Biocompatible Materials in Drug Delivery System in Oncology)
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Open AccessArticle
Multi-Methodological Quantitative Taste Assessment of Anti-Tuberculosis Drugs to Support the Development of Palatable Paediatric Dosage Forms
Pharmaceutics 2020, 12(4), 369; https://doi.org/10.3390/pharmaceutics12040369 - 17 Apr 2020
Viewed by 377
Abstract
The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two [...] Read more.
The unpalatability of antituberculosis drugs is often cited as a major cause of non-adherence in children, yet limited quantitative taste assessment data are available. The aim of this research was to quantify the bitterness of isoniazid, rifampicin, pyrazinamide, and ethambutol dihydrochloride using two in vivo (a human taste panel and a rat brief-access taste aversion (BATA) model) and one in vitro (sensor) method. The response of the Insent TS-5000Z electronic tongue was compared to the in vivo drug concentration found to elicit and suppress half the maximum taste response (EC50 in human and IC50 in rats). Using dose-relevant concentrations, an overarching rank order of bitterness was derived (rifampicin > ethambutol > pyrazinamid~isoniazid). In vitro, only ethambutol exhibited a linear response for all sensors/concentrations. Based on the EC50/IC50 generated, a ‘taste index’ was proposed to allow for anticipation of the likelihood of taste issues in practice, taking in account the saturability in the saliva and therapeutic doses; ethambutol and isoniazid were found to be the worst tasting using this measure. The study presents the first quantitative taste analysis of these life-saving drugs and has allowed for a comparison of three methods of obtaining such data. Such information allows the operator to identify and prioritise the drugs requiring taste masking to produce palatable formulations. Full article
(This article belongs to the Special Issue Paediatric Drug Delivery)
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Open AccessArticle
Anticrystal Engineering of Ketoprofen and Ester Local Anesthetics: Ionic Liquids or Deep Eutectic Mixtures?
Pharmaceutics 2020, 12(4), 368; https://doi.org/10.3390/pharmaceutics12040368 - 17 Apr 2020
Viewed by 462
Abstract
Ionic liquids (ILs) and deep eutectic mixtures (DEMs) are potential solutions to the problems of low solubility, polymorphism, and low bioavailability of drugs. The aim of this work was to develop and investigate ketoprofen (KET)-based ILs/DEMs containing an ester local anesthetic (LA): benzocaine [...] Read more.
Ionic liquids (ILs) and deep eutectic mixtures (DEMs) are potential solutions to the problems of low solubility, polymorphism, and low bioavailability of drugs. The aim of this work was to develop and investigate ketoprofen (KET)-based ILs/DEMs containing an ester local anesthetic (LA): benzocaine (BEN), procaine (PRO) and tetracaine (TET) as the second component. ILs/DEMs were prepared via a mechanosynthetic process that involved the mixing of KET with an LA in a range of molar ratios and applying a thermal treatment. After heating above the melting point and quench cooling, the formation of supercooled liquids with Tgs that were dependent on the composition was observed for all KET-LA mixtures with exception of that containing 95 mol% of BEN. The KET-LA mixtures containing either ≥ 60 mol% BEN or 95 mol% of TET showed crystallization to BEN and TET, respectively, during either cooling or second heating. KET decreased the crystallization tendency of BEN and TET and increased their glass-forming ability. The KET-PRO systems showed good glass-forming ability and did not crystallize either during the cooling or during the second heating cycle irrespective of the composition. Infrared spectroscopy and molecular modeling indicated that KET and LAs formed DEMs, but in the KET-PRO systems small quantities of carboxylate anions were present. Full article
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Open AccessArticle
Quality by Design Optimization of Cold Sonochemical Synthesis of Zidovudine-Lamivudine Nanosuspensions
Pharmaceutics 2020, 12(4), 367; https://doi.org/10.3390/pharmaceutics12040367 - 17 Apr 2020
Viewed by 382
Abstract
Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium [...] Read more.
Lamivudine (3TC) and zidovudine (AZT) are antiviral agents used to manage HIV/AIDS infection. The compounds require frequent dosing, exhibit unpredictable bioavailability and a side effect profile that includes hepato- and haema-toxicity. A novel pseudo one-solvent bottom-up approach and Design of Experiments using sodium dodecyl sulphate (SDS) and α-tocopheryl polyethylene glycol succinate 1000 (TPGS 1000) to electrosterically stablize the nano co-crystals was used to develop, produce and optimize 3TC and AZT nano co-crystals. Equimolar solutions of 3TC in surfactant dissolved in de-ionised water and AZT in methanol were rapidly injected into a vessel and sonicated at 4 °C. The resultant suspensions were characterized using a Zetasizer and the particle size, polydispersity index and Zeta potential determined. Optimization of the nanosuspensions was conducted using a Central Composite Design to produce nano co-crystals with specific identified and desirable Critical Quality Attributes including particle size (PS) < 1000 nm, polydispersity index (PDI) < 0.500 and Zeta potential (ZP) < −30mV. Further characterization was undertaken using Fourier Transform infrared spectroscopy, energy dispersive X-ray spectroscopy, differential scanning calorimetry, powder X-ray diffraction and transmission electron microscopy. In vitro cytotoxicity studies revealed that the optimized nano co-crystals reduced the toxicity of AZT and 3TC to HeLa cells. Full article
(This article belongs to the Special Issue Cocrystal Applications in Drug Delivery)
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Open AccessArticle
Dissolving Microneedles for Rapid and Painless Local Anesthesia
Pharmaceutics 2020, 12(4), 366; https://doi.org/10.3390/pharmaceutics12040366 - 17 Apr 2020
Viewed by 458
Abstract
Microneedles are emerging drug delivery methods for painless treatment. The current study tested dissolving microneedles containing lidocaine (Li-DMN) for use in local anesthesia. An Li-DMN patch was fabricated by centrifugal lithography with carboxymethyl cellulose as a structural polymer and assessed for physical properties [...] Read more.
Microneedles are emerging drug delivery methods for painless treatment. The current study tested dissolving microneedles containing lidocaine (Li-DMN) for use in local anesthesia. An Li-DMN patch was fabricated by centrifugal lithography with carboxymethyl cellulose as a structural polymer and assessed for physical properties by optical microscopy and a fracture force analyzer. The biocompatibility was evaluated by a histology section in vitro and by ear thickness in vivo. The efficacy of the Li-DMN patch was assessed by electrophysiological recordings in primary cultured sensory neurons in vitro and a von Frey test on rats’ hind paws in vivo. The physical properties of the microneedle showed enough rigidity for transdermal penetration. The maximal capacity of lidocaine-HCl in the Li-DMN patch was 331.20 ± 6.30 µg. The cytotoxicity of the dissolving microneedle to neuronal cells was negligible under an effective dose of lidocaine for 18 h. Electrophysiological recordings verified the inhibitory effect of the voltage-gated sodium channel current by the Li-DMN patch in vitro. A skin reaction to the edema test and histologic analysis of the rats’ ears after application of the Li-DMN patch were negligible. Also, the application of the Li-DMN patch reduced the nocifensive behavior of the rats almost immediately. In conclusion, the dissolving microneedle patch with carboxymethyl cellulose is a promising candidate method for the painless delivery of lidocaine-HCl. Full article
(This article belongs to the Special Issue Advances in Microneedle-Based Drug Delivery Systems)
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Open AccessReview
Current Status of Supersaturable Self-Emulsifying Drug Delivery Systems
Pharmaceutics 2020, 12(4), 365; https://doi.org/10.3390/pharmaceutics12040365 - 16 Apr 2020
Viewed by 397
Abstract
Self-emulsifying drug delivery systems (SEDDSs) are a vital strategy to enhance the bioavailability (BA) of formulations of poorly water-soluble compounds. However, these formulations have certain limitations, including in vivo drug precipitation, poor in vitro in vivo correlation due to a lack of predictive [...] Read more.
Self-emulsifying drug delivery systems (SEDDSs) are a vital strategy to enhance the bioavailability (BA) of formulations of poorly water-soluble compounds. However, these formulations have certain limitations, including in vivo drug precipitation, poor in vitro in vivo correlation due to a lack of predictive in vitro tests, issues in handling of liquid formulation, and physico-chemical instability of drug and/or vehicle components. To overcome these limitations, which restrict the potential usage of such systems, the supersaturable SEDDSs (su-SEDDSs) have gained attention based on the fact that the inclusion of precipitation inhibitors (PIs) within SEDDSs helps maintain drug supersaturation after dispersion and digestion in the gastrointestinal tract. This improves the BA of drugs and reduces the variability of exposure. In addition, the formulation of solid su-SEDDSs has helped to overcome disadvantages of liquid or capsule dosage form. This review article discusses, in detail, the current status of su-SEDDSs that overcome the limitations of conventional SEDDSs. It discusses the definition and range of su-SEDDSs, the principle mechanisms underlying precipitation inhibition and enhanced in vivo absorption, drug application cases, biorelevance in vitro digestion models, and the development of liquid su-SEDDSs to solid dosage forms. This review also describes the effects of various physiological factors and the potential interactions between PIs and lipid, lipase or lipid digested products on the in vivo performance of su-SEDDSs. In particular, several considerations relating to the properties of PIs are discussed from various perspectives. Full article
(This article belongs to the Special Issue Self-Emulsifying Drug Delivery System)
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Open AccessArticle
Recombinant Peptide Production Platform Coupled with Site-Specific Albumin Conjugation Enables a Convenient Production of Long-Acting Therapeutic Peptide
Pharmaceutics 2020, 12(4), 364; https://doi.org/10.3390/pharmaceutics12040364 - 16 Apr 2020
Viewed by 512
Abstract
The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a [...] Read more.
The number of therapeutic peptides for human treatment is growing rapidly. However, their development faces two major issues: the poor yield of large peptides from conventional solid-phase synthesis, and the intrinsically short serum half-life of peptides. To address these issues, we investigated a platform for the production of a recombinant therapeutic peptide with an extended serum half-life involving the site-specific conjugation of human serum albumin (HSA). HSA has an exceptionally long serum half-life and can be used to extend the serum half-lives of therapeutic proteins and peptides. We used glucagon-like-peptide 1 (GLP-1) as a model peptide in the present study. A “clickable” non-natural amino acid—p-azido-l-phenylalanine (AzF)—was incorporated into three specific sites (V16, Y19, and F28) of a GLP-1 variant, followed by conjugation with HSA through strain-promoted azide–alkyne cycloaddition. All three HSA-conjugated GLP-1 variants (GLP1_16HSA, GLP1_19HSA, and GLP1_28HSA) exhibited comparable serum half-lives in vivo. However, the three GLP1_HSA variants had different in vitro biological activities and in vivo glucose-lowering effects, demonstrating the importance of site-specific HSA conjugation. The platform described herein could be used to develop other therapeutic peptides with extended serum half-lives. Full article
(This article belongs to the Section Biopharmaceutics)
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Open AccessArticle
Influence of Formulation Parameters on Redispersibility of Naproxen Nanoparticles from Granules Produced in a Fluidized Bed Process
Pharmaceutics 2020, 12(4), 363; https://doi.org/10.3390/pharmaceutics12040363 - 16 Apr 2020
Viewed by 525
Abstract
The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient’s convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the [...] Read more.
The particle size reduction of active pharmaceutical ingredients is an efficient method to overcome challenges associated with a poor aqueous solubility. With respect to stability and patient’s convenience, the corresponding nanosuspensions are often further processed to solid dosage forms. In this regard, the influence of several formulation parameters (i.e., type of carrier material, type and amount of additional polymeric drying excipient in the nanosuspension) on the redispersibility of naproxen nanoparticle-loaded granules produced in a fluidized bed process was investigated. The dissolution rate of the carrier material (i.e., sucrose, mannitol, or lactose) was identified as a relevant material property, with higher dissolution rates (sucrose > mannitol > lactose) resulting in better redispersibility of the products. Additionally, the redispersibility of the product granules was observed to improve with increasing amounts of polymeric drying excipient in the nanosuspension. The redispersibility was observed to qualitatively correlate with the degree of nanoparticle embedding on the surface of the corresponding granules. This embedding was assumed to be either caused by a partial dissolution and subsequent resolidification of the carrier surface dependent on the dissolution rate of the carrier material or by resolidification of the dissolved polymeric drying excipient upon drying. As the correlation between the redispersibility and the morphology of the corresponding granules was observed for all investigated formulation parameters, it may be assumed that the redispersibility of the nanoparticles is determined by their distance in the dried state. Full article
(This article belongs to the Special Issue Powder Processing in Pharmaceutical Applications)
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