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Pharmaceutics, Volume 11, Issue 5 (May 2019)

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Cover Story (view full-size image) An illustration showing that chemotherapy drug (doxorubicin, DOX)-loaded bubbles can serve as [...] Read more.
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Open AccessArticle
Drug Delivery Technology to the CNS in the Treatment of Brain Tumors: The Sherbrooke Experience
Pharmaceutics 2019, 11(5), 248; https://doi.org/10.3390/pharmaceutics11050248
Received: 8 April 2019 / Revised: 21 May 2019 / Accepted: 22 May 2019 / Published: 27 May 2019
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Abstract
Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes [...] Read more.
Drug delivery to the central nervous system (CNS) remains a challenge in neuro-oncology. Despite decades of research in this field, no consensus has emerged as to the best approach to tackle this physiological limitation. Moreover, the relevance of doing so is still sometimes questioned in the community. In this paper, we present our experience with CNS delivery strategies that have been developed in the laboratory and have made their way to the clinic in a continuum of translational research. Using the intra-arterial (IA) route as an avenue to deliver chemotherapeutics in the treatment of brain tumors, complemented by an osmotic breach of the blood-brain barrier (BBB) in specific situations, we have developed over the years a comprehensive research effort on this specialized topic. Looking at pre-clinical work supporting the rationale for this approach, and presenting results discussing the safety of the strategy, as well as results obtained in the treatment of malignant gliomas and primary CNS lymphomas, this paper intends to comprehensively summarize our work in this field. Full article
(This article belongs to the Special Issue Drug Delivery Technology Development in Canada)
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Open AccessArticle
pH-Responsive i-motif Conjugated Hyaluronic Acid/Polyethylenimine Complexes for Drug Delivery Systems
Pharmaceutics 2019, 11(5), 247; https://doi.org/10.3390/pharmaceutics11050247
Received: 1 May 2019 / Revised: 21 May 2019 / Accepted: 24 May 2019 / Published: 27 May 2019
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Abstract
i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated [...] Read more.
i-motif is cytosine (C)-rich oligonucleotide (ODN) which shows pH-responsive structure change in acidic condition. Therefore, it has been utilized for the trigger of intercalated drug release, responding to environmental pH change. In this study, 2.76 molecules of i-motif binding ODNs (IBOs) were conjugated to each hyaluronic acid (HA) via amide bond linkages. Synthesis of HA-IBO conjugate (HB) was confirmed by FT-IR and agarose gel electrophoresis with Stains-All staining. After hybridization of HB with i-motif ODN (IMO), it was confirmed that doxorubicin (DOX) could be loaded in HB-IMO hybrid structure (HBIM) with 65.6% of drug loading efficiency (DLE) and 25.0% of drug loading content (DLC). At pH 5.5, prompt and significant DOX release from HBIM was observed due to the disruption of HBIM hybrid structure via i-motif formation of IMO, contrary to pH 7.4 condition. Then, HBIM was complexed with low molecular weight polyethylenimine (PEI1.8k), forming positively charged nanostructures (Z-average size: 126.0 ± 0.4 nm, zeta-potential: 16.1 ± 0.3 mV). DOX-loaded HBIM/PEI complexes displayed higher anticancer efficacy than free DOX in A549 cells, showing the potential for pH-responsive anticancer drug delivery systems. Full article
(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)
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Open AccessArticle
Hyaluronic Acid Nanocapsules as a Platform for Needle-Free Vaccination
Pharmaceutics 2019, 11(5), 246; https://doi.org/10.3390/pharmaceutics11050246
Received: 2 May 2019 / Revised: 23 May 2019 / Accepted: 23 May 2019 / Published: 26 May 2019
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Abstract
Vaccination faces many challenges nowadays, and among them the use of adjuvant molecules and needle-free administration are some of the most demanding. The combination of transcutaneous vaccination and nanomedicine through a rationally designed new-formulation could be the solution to this problem. This study [...] Read more.
Vaccination faces many challenges nowadays, and among them the use of adjuvant molecules and needle-free administration are some of the most demanding. The combination of transcutaneous vaccination and nanomedicine through a rationally designed new-formulation could be the solution to this problem. This study focuses on this rational design. For this purpose, new hyaluronic acid nanocapsules (HA-NCs) have been developed. This new formulation has an oily nucleus with immunoadjuvant properties (due to α tocopherol) and a shell made of hyaluronic acid (HA) and decorated with ovalbumin (OVA) as the model antigen. The resulting nanocapsules are smaller than 100 nm, have a negative superficial charge and have a population that is homogeneously distributed. The systems show high colloidal stability in storage and physiological conditions and high OVA association without losing their integrity. The elevated interaction of the novel formulation with the immune system was demonstrated through complement activation and macrophage viability studies. Ex vivo studies using a pig skin model show the ability of these novel nanocapsules to penetrate and retain OVA in higher quantities in skin when compared to this antigen in the control solution. Due to these findings, HA-NCs are an interesting platform for needle-free vaccination. Full article
(This article belongs to the Special Issue Hyaluronic Acid for Biomedical Applications)
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Open AccessReview
Established and Emerging Strategies for Drug Delivery Across the Blood-Brain Barrier in Brain Cancer
Pharmaceutics 2019, 11(5), 245; https://doi.org/10.3390/pharmaceutics11050245
Received: 4 April 2019 / Revised: 5 May 2019 / Accepted: 20 May 2019 / Published: 24 May 2019
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Abstract
Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles to improve current treatments is represented by the impermeability of the blood vessels residing within [...] Read more.
Brain tumors are characterized by very high mortality and, despite the continuous research on new pharmacological interventions, little therapeutic progress has been made. One of the main obstacles to improve current treatments is represented by the impermeability of the blood vessels residing within nervous tissue as well as of the new vascular net generating from the tumor, commonly referred to as blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), respectively. In this review, we focused on established and emerging strategies to overcome the blood-brain barrier to increase drug delivery for brain cancer. To date, there are three broad strategies being investigated to cross the brain vascular wall and they are conceived to breach, bypass, and negotiate the access to the nervous tissue. In this paper, we summarized these approaches highlighting their working mechanism and their potential impact on the quality of life of the patients as well as their current status of development. Full article
(This article belongs to the Special Issue Drug Delivery across Biological Barriers)
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Open AccessArticle
Application of Direct Sonoporation from a Defined Surface Area of the Peritoneum: Evaluation of Transfection Characteristics in Mice
Pharmaceutics 2019, 11(5), 244; https://doi.org/10.3390/pharmaceutics11050244
Received: 11 April 2019 / Revised: 14 May 2019 / Accepted: 20 May 2019 / Published: 22 May 2019
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Abstract
In the present study, we developed a sonoporation system, namely “direct sonoporation”, for transfecting the peritoneum from a defined surface area to avoid systematic side effects. Here, the transfection characteristics are explained because there is less information about direct sonoporation. Naked pDNA and [...] Read more.
In the present study, we developed a sonoporation system, namely “direct sonoporation”, for transfecting the peritoneum from a defined surface area to avoid systematic side effects. Here, the transfection characteristics are explained because there is less information about direct sonoporation. Naked pDNA and nanobubbles were administered to diffusion cell attached to the visceral and parietal peritoneum from the liver and peritoneal wall surface, respectively. Then, ultrasound was irradiated. Direct sonoporation showed a higher transfection efficacy at the applied peritoneum site from the liver surface while other sites were not detected. Moreover, transgene expression was observed in the peritoneal mesothelial cells (PMCs) at the applied peritoneum site. No abnormality was observed in the inner part of the liver. Although transgene expression of the visceral peritoneum was tenfold higher than that of the parietal peritoneum, transgene expression was observed in the PMCs on both the applied peritoneum sites. These results suggest that direct sonoporation is a site-specific transfection method of the PMCs on the applied peritoneum site without transgene expression at other sites and show little toxicity in the inner tissues at the applied site via cavitation energy. This information is valuable for the development of an intraperitoneal sonoporation device for treatment of peritoneal diseases such as peritoneal fibrosis. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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Open AccessArticle
Design and Characterization of Inulin Conjugate for Improved Intracellular and Targeted Delivery of Pyrazinoic Acid to Monocytes
Pharmaceutics 2019, 11(5), 243; https://doi.org/10.3390/pharmaceutics11050243
Received: 26 April 2019 / Revised: 10 May 2019 / Accepted: 16 May 2019 / Published: 22 May 2019
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Abstract
The propensity of monocytes to migrate into sites of mycobacterium tuberculosis (TB) infection and then become infected themselves makes them potential targets for delivery of drugs intracellularly to the tubercle bacilli reservoir. Conventional TB drugs are less effective because of poor intracellular delivery [...] Read more.
The propensity of monocytes to migrate into sites of mycobacterium tuberculosis (TB) infection and then become infected themselves makes them potential targets for delivery of drugs intracellularly to the tubercle bacilli reservoir. Conventional TB drugs are less effective because of poor intracellular delivery to this bacterial sanctuary. This study highlights the potential of using semicrystalline delta inulin particles that are readily internalised by monocytes for a monocyte-based drug delivery system. Pyrazinoic acid was successfully attached covalently to the delta inulin particles via a labile linker. The formation of new conjugate and amide bond was confirmed using zeta potential, Proton Nuclear Magnetic Resonance (1HNMR) and Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) confirmed that no significant change in size after conjugation which is an important parameter for monocyte targeting. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were used to establish the change in thermal properties. The analysis of in-vitro release demonstrated pH-triggered drug cleavage off the delta inulin particles that followed a first-order kinetic process. The efficient targeting ability of the conjugate for RAW 264.7 monocytic cells was supported by cellular uptake studies. Overall, our finding confirmed that semicrystalline delta inulin particles (MPI) can be modified covalently with drugs and such conjugates allow intracellular drug delivery and uptake into monocytes, making this system potentially useful for the treatment of TB. Full article
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Open AccessArticle
Folic Acid-Functionalized Black Phosphorus Quantum Dots for Targeted Chemo-Photothermal Combination Cancer Therapy
Pharmaceutics 2019, 11(5), 242; https://doi.org/10.3390/pharmaceutics11050242
Received: 15 April 2019 / Revised: 11 May 2019 / Accepted: 17 May 2019 / Published: 21 May 2019
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Abstract
Due to the inherent limitations, single chemo or photothermal therapies (PTT) are always inefficient. The combination of chemotherapy and PTT for the treatment of cancers has attracted a great interest during the past few years. As a photothermal agent, black phosphorus quantum dots [...] Read more.
Due to the inherent limitations, single chemo or photothermal therapies (PTT) are always inefficient. The combination of chemotherapy and PTT for the treatment of cancers has attracted a great interest during the past few years. As a photothermal agent, black phosphorus quantum dots (BPQDs) possess an excellent extinction coefficient, high photothermal conversion efficacy, and good biocompatibility. Herein, we developed a photo- and pH-sensitive nanoparticle based on BPQDs for targeted chemo-photothermal therapy. Doxorubicin (DOX) was employed as a model drug. This nanosystem displayed outstanding photothermal performance both in vitro and in vivo. Folic acid conjugation onto the surface endowed this system an excellent tumor-targeting effect, which was demonstrated by the cellular targeting assay. The BPQDs-based drug delivery system exhibited pH- and photo-responsive release properties, which could reduce the potential damage to normal cells. The in vitro cell viability study showed a synergistic effect in suppressing cancer cell proliferation. Therefore, this BPQDs-based drug delivery system has substantial potential for future clinical applications. Full article
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Open AccessArticle
Elucidating the Influence of Tumor Presence on the Polymersome Circulation Time in Mice
Pharmaceutics 2019, 11(5), 241; https://doi.org/10.3390/pharmaceutics11050241
Received: 24 April 2019 / Revised: 14 May 2019 / Accepted: 16 May 2019 / Published: 20 May 2019
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Abstract
The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on [...] Read more.
The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on nanocarrier circulation times. This paper reports on the influence of tumor presence on the in vivo circulation time and biodistribution of polybutadiene-polyethylene oxide (PBd-PEO) polymersomes. For this purpose, polymersomes were loaded with the gamma-emitter 111In and administered intravenously, followed by timed ex vivo biodistribution. A large reduction in circulation time was observed for tumor-bearing mice, with a circulation half-life of merely 5 min (R2 = 0.98) vs 117 min (R2 = 0.95) in healthy mice. To determine whether the rapid polymersome clearance observed in tumor-bearing mice was mediated by macrophages, chlodronate liposomes were administered to both healthy and tumor-bearing mice prior to the intravenous injection of radiolabeled polymersomes to deplete their macrophages. Pretreatment with chlodronate liposomes depleted macrophages in the spleen and liver and restored the circulation time of the polymersomes with no significant difference in circulation time between healthy mice and tumor-bearing mice pretreated with clodronate liposomes (15.2 ± 1.2% ID/g and 13.6 ± 2.7% ID/g, respectively, at 4 h p.i. with p = 0.3). This indicates that activation of macrophages due to tumor presence indeed affected polymersome clearance rate. Thus, next to particle design, the presence of a tumor can also greatly impact circulation times and should be taken into account when designing studies to evaluate the distribution of polymersomes. Full article
(This article belongs to the Special Issue Targeted Radionuclide Tumor Therapy)
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Open AccessArticle
Micro-Injection Moulding of Poly(vinylpyrrolidone-vinyl acetate) Binary and Ternary Amorphous Solid Dispersions
Pharmaceutics 2019, 11(5), 240; https://doi.org/10.3390/pharmaceutics11050240
Received: 25 April 2019 / Revised: 14 May 2019 / Accepted: 15 May 2019 / Published: 18 May 2019
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Abstract
Micro-injection moulding (µIM) was used for the production of enteric tablets of plasticised and unplasticised solid dispersions of poly(vinylpyrrolidone-vinyl acetate) (PVPVA), and the effect of the mechanical and thermal treatment on the properties of the dispersions was investigated. The physical state of the [...] Read more.
Micro-injection moulding (µIM) was used for the production of enteric tablets of plasticised and unplasticised solid dispersions of poly(vinylpyrrolidone-vinyl acetate) (PVPVA), and the effect of the mechanical and thermal treatment on the properties of the dispersions was investigated. The physical state of the systems showed to be unaltered by the µIM step, maintaining the drug in the amorphous state. The dissolution profile of the tablets showed a slower dissolution rate due to the lower surface to volume ratio compared to the extruded strands. The lack of solubility of the doses in the acidic medium as a consequence of the acidity of indomethacin (IND) was observed. However, in neutral pH the drug dissolution showed slower rates without affecting the dissolution extent, showing a potential application for the development of controlled release doses. Overall, the production of tablets of amorphous solid dispersions (ASD), coupling hot-melt extrusion (HME) and µIM, proved to be a successful approach towards a continuous automated manufacturing process to improve the aqueous solubility of poorly water-soluble drugs. Full article
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Open AccessArticle
Vibrating Mesh Nebulisation of Pro-Antimicrobial Peptides for Use in Cystic Fibrosis
Pharmaceutics 2019, 11(5), 239; https://doi.org/10.3390/pharmaceutics11050239
Received: 18 April 2019 / Revised: 12 May 2019 / Accepted: 13 May 2019 / Published: 17 May 2019
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Abstract
Background: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung [...] Read more.
Background: There has been considerable interest in the use of antimicrobial peptides (AMPs) as antimicrobial therapeutics in many conditions including cystic fibrosis (CF). The aim of this study is to determine if the prodrugs of AMPs (pro-AMPs) can be delivered to the lung by a vibrating mesh nebuliser (VMN) and whether the pro-AMP modification has any effect on delivery. Methods: Physical characteristics of the peptides (AMP and pro-AMP) and antimicrobial activity were compared before and after nebulisation. Droplet size distribution was determined by laser diffraction and cascade impaction. Delivery to a model lung was determined in models of spontaneously-breathing and mechanically-ventilated patients. Results: The physical characteristics and antimicrobial activities were unchanged after nebulisation. Mean droplet size diameters were below 5 μm in both determinations, with the fine particle fraction approximately 67% for both peptides. Approximately 25% of the nominal dose was delivered in the spontaneously-breathing model for both peptides, with higher deliveries observed in the mechanically-ventilated model. Delivery times were approximately 170 s per mL for both peptides and the residual volume in the nebuliser was below 10% in nearly all cases. Conclusions: These results demonstrate that the delivery of (pro-)AMPs to the lung using a VMN is feasible and that the prodrug modification is not detrimental. They support the further development of pro-AMPs as therapeutics in CF. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Open AccessArticle
Repurposing of FDA-Approved NSAIDs for DPP-4 Inhibition as an Alternative for Diabetes Mellitus Treatment: Computational and in Vitro Study
Pharmaceutics 2019, 11(5), 238; https://doi.org/10.3390/pharmaceutics11050238
Received: 8 March 2019 / Revised: 8 May 2019 / Accepted: 14 May 2019 / Published: 17 May 2019
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Abstract
A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, [...] Read more.
A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein–ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus. Full article
(This article belongs to the Special Issue Computational Drug Repurposing)
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Open AccessReview
Ocular Biodistribution Studies Using Molecular Imaging
Pharmaceutics 2019, 11(5), 237; https://doi.org/10.3390/pharmaceutics11050237
Received: 14 April 2019 / Revised: 5 May 2019 / Accepted: 7 May 2019 / Published: 16 May 2019
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Abstract
Classical methodologies used in ocular pharmacokinetics studies have difficulties to obtain information about topical and intraocular distribution and clearance of drugs and formulations. This is associated with multiple factors related to ophthalmic physiology, as well as the complexity and invasiveness intrinsic to the [...] Read more.
Classical methodologies used in ocular pharmacokinetics studies have difficulties to obtain information about topical and intraocular distribution and clearance of drugs and formulations. This is associated with multiple factors related to ophthalmic physiology, as well as the complexity and invasiveness intrinsic to the sampling. Molecular imaging is a new diagnostic discipline for in vivo imaging, which is emerging and spreading rapidly. Recent developments in molecular imaging techniques, such as positron emission tomography (PET), single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI), allow obtaining reliable pharmacokinetic data, which can be translated into improving the permanence of the ophthalmic drugs in its action site, leading to dosage optimisation. They can be used to study either topical or intraocular administration. With these techniques it is possible to obtain real-time visualisation, localisation, characterisation and quantification of the compounds after their administration, all in a reliable, safe and non-invasive way. None of these novel techniques presents simultaneously high sensitivity and specificity, but it is possible to study biological procedures with the information provided when the techniques are combined. With the results obtained, it is possible to assume that molecular imaging techniques are postulated as a resource with great potential for the research and development of new drugs and ophthalmic delivery systems. Full article
(This article belongs to the Special Issue Molecular Imaging in Targeted Drug Delivery)
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Open AccessArticle
Bacteria-Targeted Clindamycin Loaded Polymeric Nanoparticles: Effect of Surface Charge on Nanoparticle Adhesion to MRSA, Antibacterial Activity, and Wound Healing
Pharmaceutics 2019, 11(5), 236; https://doi.org/10.3390/pharmaceutics11050236
Received: 9 April 2019 / Revised: 2 May 2019 / Accepted: 14 May 2019 / Published: 15 May 2019
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Abstract
Adhesion of nanoparticles (NPs) to the bacterial cell wall by modifying their physicochemical properties can improve the antibacterial activity of antibiotic. In this study, we prepared positively charged clindamycin-loaded poly (lactic-co-glycolic acid)-polyethylenimine (PLGA-PEI) nanoparticles (Cly/PPNPs) and negatively charged clindamycin-loaded PLGA NPs [...] Read more.
Adhesion of nanoparticles (NPs) to the bacterial cell wall by modifying their physicochemical properties can improve the antibacterial activity of antibiotic. In this study, we prepared positively charged clindamycin-loaded poly (lactic-co-glycolic acid)-polyethylenimine (PLGA-PEI) nanoparticles (Cly/PPNPs) and negatively charged clindamycin-loaded PLGA NPs (Cly/PNPs) and investigated the effect of NP adhesion to bacteria on the treatment of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. The Cly/PPNPs and Cly/PNPs were characterized according to particle size, polydispersity index, surface charge, and drug loading. Both Cly/PPNPs and Cly/PNPs exhibited sustained drug release over 2 days. The Cly/PPNPs bind to the MRSA surface, thereby enhancing bactericidal efficacy against MRSA compared with the Cly/PNPs. Furthermore, compared with other groups, Cly/PPNPs significantly accelerated the healing and re-epithelialization of wounds in a mouse model of a MRSA-infected wounds. We also found that both NPs are harmless to healthy fibroblast cells. Therefore, our results suggest that the Cly/PPNPs developed in this study improve the efficacy of clindamycin for the treatment of MRSA-infected wounds. Full article
(This article belongs to the Special Issue Advanced Formulation Approaches for Targeted Drug Delivery)
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Open AccessArticle
Microneedle-Assisted Transdermal Delivery of Etanercept for Rheumatoid Arthritis Treatment
Pharmaceutics 2019, 11(5), 235; https://doi.org/10.3390/pharmaceutics11050235
Received: 9 April 2019 / Revised: 9 May 2019 / Accepted: 13 May 2019 / Published: 15 May 2019
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Abstract
Rheumatoid arthritis (RA) is a complicated autoimmune disease. The clinical applications of etanercept (EN), a TNF-α inhibitor, can efficiently halt the development of RA. EN is mainly administrated by subcutaneous injection, which may cause low compliance, side effects, and infection risk. In this [...] Read more.
Rheumatoid arthritis (RA) is a complicated autoimmune disease. The clinical applications of etanercept (EN), a TNF-α inhibitor, can efficiently halt the development of RA. EN is mainly administrated by subcutaneous injection, which may cause low compliance, side effects, and infection risk. In this study, a hyaluronic acid crosslinked microneedle system (MN) was constructed as the transdermal alternative to deliver EN. We describe the formulation, fabrication, characterization, and transdermal insertion study of MN. In vitro bioactivity of EN was conducted and analyzed by dynamic light scattering and circular dichroism spectrum. In vivo evaluation of MN was studied on adjuvant-induced arthritis mice. The MN possessed sufficient mechanical strength, good biocompatibility, little influence on the bioactivity of EN, and high anti-inflammatory efficacy. This work represents a successful example of delivering macromolecule therapeutic treatment by MN for RA treatment. The transdermal delivery of EN by MN offers a new treatment option for RA patients. Full article
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Open AccessArticle
Antimicrobial Effect of Thymus capitatus and Citrus limon var. pompia as Raw Extracts and Nanovesicles
Pharmaceutics 2019, 11(5), 234; https://doi.org/10.3390/pharmaceutics11050234
Received: 11 April 2019 / Revised: 2 May 2019 / Accepted: 5 May 2019 / Published: 14 May 2019
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Abstract
In view of the increasing interest in natural antimicrobial molecules, this study screened the ability of Thymus capitatus (TC) essential oil and Citrus limon var. pompia (CLP) extract as raw extracts or incorporated in vesicular nanocarriers against Streptococcus mutans and Candida albicans. [...] Read more.
In view of the increasing interest in natural antimicrobial molecules, this study screened the ability of Thymus capitatus (TC) essential oil and Citrus limon var. pompia (CLP) extract as raw extracts or incorporated in vesicular nanocarriers against Streptococcus mutans and Candida albicans. After fingerprint, TC or CLP were mixed with lecithin and water to produce liposomes, or different ratios of water/glycerol or water/propylene glycol (PG) to produce glycerosomes and penetration enhancer vesicles (PEVs), respectively. Neither the raw extracts nor the nanovesicles showed cytotoxicity against human gingival fibroblasts at all the concentrations tested (1, 10, 100 μg/mL). The disc diffusion method, MIC-MBC/MFC, time-kill assay, and transmission electron microscopy (TEM) demonstrated the highest antimicrobial potential of TC against S. mutans and C. albicans. The very high presence of the phenol, carvacrol, in TC (90.1%) could explain the lethal effect against the yeast, killing up to 70% of Candida and not just arresting its growth. CLP, rich in polyphenols, acted in a similar way to TC in reducing S. mutans, while the data showed a fungistatic rather than a fungicidal activity. The phospholipid vesicles behaved similarly, suggesting that the transported extract was not the only factor to be considered in the outcomes, but also their components had an important role. Even if other investigations are necessary, TC and CLP incorporated in nanocarriers could be a promising and safe antimicrobial in caries prevention. Full article
(This article belongs to the Special Issue Self-Organizing Nanovectors for Drug Delivery)
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Open AccessArticle
Characterization and Formulation of Isoniazid for High-Dose Dry Powder Inhalation
Pharmaceutics 2019, 11(5), 233; https://doi.org/10.3390/pharmaceutics11050233
Received: 5 April 2019 / Revised: 8 May 2019 / Accepted: 9 May 2019 / Published: 13 May 2019
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Abstract
Tuberculosis is a major health problem and remains one of the main causes of mortality. In recent years, there has been an increased interest in the pulmonary delivery of antibiotics to treat tuberculosis. Isoniazid is one of these antibiotics. In this study, we [...] Read more.
Tuberculosis is a major health problem and remains one of the main causes of mortality. In recent years, there has been an increased interest in the pulmonary delivery of antibiotics to treat tuberculosis. Isoniazid is one of these antibiotics. In this study, we aimed to characterize isoniazid and formulate it into a dry powder for pulmonary administration with little or no excipient, and for use in the disposable Twincer® inhaler. Isoniazid was jet milled and spray dried with and without the excipient l-leucine. Physiochemical characterization showed that isoniazid has a low Tg of −3.99 ± 0.18 °C and starts to sublimate around 80 °C. Milling isoniazid with and without excipients did not result in a suitable formulation, as it resulted in a low and highly variable fine particle fraction. Spray drying pure isoniazid resulted in particles too large for pulmonary administration. The addition of 5% l-leucine resulted in a fraction <5 µm = 89.61% ± 1.77% from spray drying, which dispersed well from the Twincer®. However, storage stability was poor at higher relative humidity, which likely results from dissolution-crystallization. Therefore, follow up research is needed to further optimize this spray dried formulation. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Open AccessArticle
Smart Freeze-Dried Bigels for the Prevention of the Sexual Transmission of HIV by Accelerating the Vaginal Release of Tenofovir during Intercourse
Pharmaceutics 2019, 11(5), 232; https://doi.org/10.3390/pharmaceutics11050232
Received: 29 March 2019 / Revised: 6 May 2019 / Accepted: 10 May 2019 / Published: 13 May 2019
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Abstract
Sub-Saharan African women are still at risk from the human immunodeficiency virus (HIV), and sex with men is the main route of transmission. Vaginal formulations containing antiretroviral drugs are promising tools to give women the power to protect themselves. The aim of this [...] Read more.
Sub-Saharan African women are still at risk from the human immunodeficiency virus (HIV), and sex with men is the main route of transmission. Vaginal formulations containing antiretroviral drugs are promising tools to give women the power to protect themselves. The aim of this work was to obtain freeze-dried bigels containing pectin, chitosan, or hypromellose for the vaginal controlled release of Tenofovir, which is accelerated in the presence of semen. Nine batches of bigels were formulated using different proportions of these polymers in the hydrogel (1, 2, and 3% w/w). The bigels obtained were freeze-dried and then underwent hardness and deformability, mucoadhesion, swelling, and drug release tests, the last two in simulated vaginal fluid (SVF) and SVF/simulated seminal fluid (SSF) mixture. The formulation containing 3% pectin (fd3P) has the highest values for hardness, resistance to deformation, and good mucoadhesivity. Its swelling is conditioned by the pH of the medium, which is responsive to the controlled release of Tenofovir in SVF, with the fastest release in the SVF/SSF mixture. fd3P would be an interesting smart microbicidal system to allow faster release of Tenofovir in the presence of semen, and thus increase women’s ability to protect themselves from the sexual transmission of HIV. Full article
(This article belongs to the Special Issue Vaginal Drug Delivery for Local and Systemic Applications)
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Open AccessArticle
Clotrimazole-Loaded Mediterranean Essential Oils NLC: A Synergic Treatment of Candida Skin Infections
Pharmaceutics 2019, 11(5), 231; https://doi.org/10.3390/pharmaceutics11050231
Received: 9 April 2019 / Revised: 6 May 2019 / Accepted: 9 May 2019 / Published: 13 May 2019
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Abstract
The increasing development of resistance of Candida species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (23 full factorial [...] Read more.
The increasing development of resistance of Candida species to traditional drugs represents a great challenge to the medical field for the treatment of skin infections. Essential oils were recently proposed to increase drug effectiveness. Herein, we developed and optimized (23 full factorial design) Mediterranean essential oil (Rosmarinus officinalis, Lavandula x intermedia “Sumian”, Origanum vulgare subsp. hirtum) lipid nanoparticles for clotrimazole delivery, exploring the potential synergistic effects against Candida spp. Small sized nanoparticles (<100 nm) with a very broad size distribution (PDI < 0.15) and long-term stability were successfully prepared. Results of the in vitro biosafety on HaCaT (normal cell line) and A431 (tumoral cell line), allowed us to select Lavandula and Rosmarinus as anti-proliferative agents with the potential to be used as co-adjuvants in the treatment of non-tumoral proliferative dermal diseases. Results of calorimetric studies on biomembrane models, confirmed the potential antimicrobial activity of the selected oils due to their interaction with membrane permeabilization. Nanoparticles provided a prolonged in vitro release of clotrimazole. In vitro studies against Candida albicans, Candida krusei and Candida parapsilosis, showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming nanostructured lipid carriers (NLC) containing Mediterranean essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis. Full article
(This article belongs to the Special Issue Advances in Solid Lipid Micro- and Nanoparticle Technology)
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Open AccessArticle
Nanoemulsion Based Vehicle for Effective Ocular Delivery of Moxifloxacin Using Experimental Design and Pharmacokinetic Study in Rabbits
Pharmaceutics 2019, 11(5), 230; https://doi.org/10.3390/pharmaceutics11050230
Received: 13 April 2019 / Revised: 7 May 2019 / Accepted: 8 May 2019 / Published: 11 May 2019
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Abstract
Nanoemulsion is one of the potential drug delivery strategies used in topical ocular therapy. The purpose of this study was to design and optimize a nanoemulsion-based system to improve therapeutic efficacy of moxifloxacin in ophthalmic delivery. Moxifloxacin nanoemulsions were prepared by testing their [...] Read more.
Nanoemulsion is one of the potential drug delivery strategies used in topical ocular therapy. The purpose of this study was to design and optimize a nanoemulsion-based system to improve therapeutic efficacy of moxifloxacin in ophthalmic delivery. Moxifloxacin nanoemulsions were prepared by testing their solubility in oil, surfactants, and cosurfactants. A pseudoternary phase diagram was constructed by titration technique and nanoemulsions were obtained with four component mixtures of Tween 80, Soluphor® P, ethyl oleate and water. An experiment with simplex lattice design was conducted to assess the influence of formulation parameters in seven nanoemulsion formulations (MM1–MM7) containing moxifloxacin. Physicochemical characteristics and in vitro release of MM1–MM7 were examined and optimized formulation (MM3) was further evaluated for ex vivo permeation, antimicrobial activity, ocular irritation and stability. Drug pharmacokinetics in rabbit aqueous humor was assessed for MM3 and compared with conventional commercial eye drop formulation (control). MM3 exhibited complete drug release in 3 h by Higuchi diffusion controlled mechanism. Corneal steady state flux of MM3 (~32.01 µg/cm2/h) and control (~31.53 µg/cm2/h) were comparable. Ocular irritation study indicated good tolerance of MM3 and its safety for ophthalmic use. No significant changes were observed in the physicochemical properties of MM3 when stored in the refrigerator for 3 months. The greater aqueous humor concentration (Cmax; 555.73 ± 133.34 ng/mL) and delayed Tmax value (2 h) observed in MM3 suggest a reduced dosing frequency and increased therapeutic efficacy relative to control. The area under the aqueous humor concentration versus time curve (AUC0–8 h) of MM3 (1859.76 ± 424.51 ng·h/mL) was ~2 fold higher (p < 0.0005) than the control, suggesting a significant improvement in aqueous humor bioavailability. Our findings suggest that optimized nanoemulsion (MM3) enhanced the therapeutic effect of moxifloxacin and can therefore be used as a safe and effective delivery vehicle for ophthalmic therapy. Full article
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Open AccessArticle
Rotavirus VP6 as an Adjuvant for Bivalent Norovirus Vaccine Produced in Nicotiana benthamiana
Pharmaceutics 2019, 11(5), 229; https://doi.org/10.3390/pharmaceutics11050229
Received: 21 March 2019 / Revised: 18 April 2019 / Accepted: 5 May 2019 / Published: 11 May 2019
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Abstract
Rotaviruses (RVs) and noroviruses (NoVs) are major causes of childhood acute gastroenteritis. During development of a combination vaccine based on NoV virus-like particles (VLP) and RV VP6 produced in baculovirus expression system in insect cells, a dual role of VP6 as a vaccine [...] Read more.
Rotaviruses (RVs) and noroviruses (NoVs) are major causes of childhood acute gastroenteritis. During development of a combination vaccine based on NoV virus-like particles (VLP) and RV VP6 produced in baculovirus expression system in insect cells, a dual role of VP6 as a vaccine antigen and an adjuvant for NoV-specific immune responses was discovered. Here the VP6 adjuvant effect on bivalent GI.4 and GII.4-2006a NoV VLPs produced in Nicotiana benthamiana was investigated. BALB/c mice were immunized intradermally with suboptimal (0.3 µg) dose of each NoV VLP alone or combined with 10 µg of VP6, or equal doses of NoV VLPs and VP6 (1 µg/antigen). NoV-specific serum IgG antibodies and their blocking activity were analyzed using vaccine-homologous and heterologous NoV VLPs. Immunization with 0.3 µg NoV VLPs alone was insufficient to induce NoV-specific immune responses, but with co-administration of 10 µg of VP6, antibodies against vaccine-derived and heterologous NoV genotypes were generated. Furthermore, corresponding adjuvant effect of VP6 was observed with 1 µg dose. Efficient uptake and presentation of VP6 by dendritic cells was demonstrated in vitro. These results show that adjuvant effect of VP6 on bivalent NoV VLP vaccine is independent of the cell source used for vaccine production. Full article
(This article belongs to the Special Issue Bioinspired Design in Drug Delivery)
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Open AccessArticle
Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but Not Female Rats
Pharmaceutics 2019, 11(5), 228; https://doi.org/10.3390/pharmaceutics11050228
Received: 26 March 2019 / Revised: 5 May 2019 / Accepted: 7 May 2019 / Published: 10 May 2019
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Abstract
It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. [...] Read more.
It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. Using a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene glycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in males but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal permeability experiments using an Ussing chamber system. The mechanism of such an effect on drug bioavailability is suggested to be due to the interaction between the excipients and the efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and protein levels were inhibited by the solubilising agents in male but not in female rats. In contrast, the non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both males and females in a non-sex-dependent manner. These findings have significant implications for the use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific modulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research is required to retract from a ‘one size fits all’ approach and to, instead, evaluate the potential impact of the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy. Full article
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Open AccessArticle
High-Throughput Dissolution/Permeation Screening—A 96-Well Two-Compartment Microplate Approach
Pharmaceutics 2019, 11(5), 227; https://doi.org/10.3390/pharmaceutics11050227
Received: 9 April 2019 / Revised: 1 May 2019 / Accepted: 7 May 2019 / Published: 10 May 2019
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Abstract
Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. [...] Read more.
Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. Freeze-drying from hydro-alcoholic solutions was used to prepare amorphous formulations. The screening approach was tested on amorphous and crystalline tadalafil formulations with and without Soluplus®. The workflow consisted of: (1) dispersion of the formulations; (2) incubation within the two-compartment plate, where a dialysis membrane separated donor (dispersed formulation) and acceptor; (3) sampling (donor and acceptor), where donor samples were centrifuged to remove non-dissolved material; and (4) quantification by UHPLC-UV. To identify optimal screening conditions, the following parameters were varied: dispersion medium (buffer/biomimetic media), acceptor medium (buffer/surfactant solutions), and incubation time (1, 3, and 6 h). Surfactants (acceptor) increased tadalafil permeation. Biomimetic medium (donor) enhanced dissolution, but not permeation, except for freeze-dried tadalafil, for which the permeated amount increased. The predictiveness was evaluated by comparing dissolution-/permeation-results with in vivo bioavailability. In general, both dissolution and permeation reflected bioavailability, whereof the latter was a better predictor. High-throughput dissolution/permeation is regarded promising for formulation screening. Full article
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Open AccessArticle
The Process–Property–Performance Relationship of Medicated Nanoparticles Prepared by Modified Coaxial Electrospraying
Pharmaceutics 2019, 11(5), 226; https://doi.org/10.3390/pharmaceutics11050226
Received: 5 April 2019 / Revised: 5 May 2019 / Accepted: 7 May 2019 / Published: 10 May 2019
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Abstract
In pharmaceutical nanotechnology, the intentional manipulation of working processes to fabricate nanoproducts with suitable properties for achieving the desired functional performances is highly sought after. The following paper aims to detail how a modified coaxial electrospraying has been developed to create ibuprofen-loaded hydroxypropyl [...] Read more.
In pharmaceutical nanotechnology, the intentional manipulation of working processes to fabricate nanoproducts with suitable properties for achieving the desired functional performances is highly sought after. The following paper aims to detail how a modified coaxial electrospraying has been developed to create ibuprofen-loaded hydroxypropyl methylcellulose nanoparticles for improving the drug dissolution rate. During the working processes, a key parameter, i.e., the spreading angle of atomization region (θ, °), could provide a linkage among the working process, the property of generated nanoparticles and their functional performance. Compared with the applied voltage (V, kV; D = 2713 − 82V with RθV2 = 0.9623), θ could provide a better correlation with the diameter of resultant nanoparticles (D, nm; D = 1096 − 5θ with R2 = 0.9905), suggesting a usefulness of accurately predicting the nanoparticle diameter. The drug released from the electrosprayed nanoparticles involved both erosion and diffusion mechanisms. A univariate quadratic equation between the time of releasing 95% of the loaded drug (t, min) and D (t = 38.7 + 0.097D − 4.838 × 105D2 with a R2 value of 0.9976) suggests that the nanoparticle diameter has a profound influence on the drug release performance. The clear process-property-performance relationship should be useful for optimizing the electrospraying process, and in turn for achieving the desired medicated nanoparticles. Full article
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Open AccessArticle
The Ratio of Nasal Cannula Gas Flow to Patient Inspiratory Flow on Trans-nasal Pulmonary Aerosol Delivery for Adults: An in Vitro Study
Pharmaceutics 2019, 11(5), 225; https://doi.org/10.3390/pharmaceutics11050225
Received: 4 April 2019 / Revised: 8 May 2019 / Accepted: 8 May 2019 / Published: 10 May 2019
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Abstract
Trans-nasal aerosol deposition during distressed breathing is higher than quiet breathing, and decreases as administered gas flow increases. We hypothesize that inhaled dose is related to the ratio of gas flow to patient inspiratory flow (GF:IF). An adult manikin (Laerdal) with a collecting [...] Read more.
Trans-nasal aerosol deposition during distressed breathing is higher than quiet breathing, and decreases as administered gas flow increases. We hypothesize that inhaled dose is related to the ratio of gas flow to patient inspiratory flow (GF:IF). An adult manikin (Laerdal) with a collecting filter placed at trachea was connected to a dual-chamber model lung, which was driven by a ventilator to simulate quiet and distressed breathing with different inspiratory flows. Gas flow was set at 5, 10, 20, 40 and 60 L/min. Albuterol (2.5mg in 1 mL) was nebulized by vibrating mesh nebulizer at the inlet of humidifier at 37 °C for each condition (n = 3). Drug was eluted from the filter and assayed with UV spectrophotometry (276 nm). GF:IF was the primary predictor of inhaled dose (p < 0.001). When the ratio was < 1.0, the inhaled dose was higher than ratio > 1.0 (21.8 ± 3.8% vs. 9.0 ± 3.7%, p < 0.001), and the inhaled dose was similar between quiet and distressed breathing (22.3 ± 5.0% vs. 21.3 ± 2.7%, p = 0.379). During trans-nasal aerosol delivery, GF:IF primarily affected the inhaled dose. Compared to the ratio above 1.0, the ratio below 1.0 produced a higher and more-consistent inhaled dose. Full article
(This article belongs to the Special Issue Advances in Pulmonary Drug Delivery)
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Open AccessArticle
Application of Pharmacometrics in Pharmacotherapy: Open-Source Software for Vancomycin Therapeutic Drug Management
Pharmaceutics 2019, 11(5), 224; https://doi.org/10.3390/pharmaceutics11050224
Received: 18 February 2019 / Revised: 31 March 2019 / Accepted: 30 April 2019 / Published: 9 May 2019
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Abstract
The population pharmacokinetic (PK) parameters that are implemented in therapeutic drug management (TDM) software were generally obtained from a Western population and might not be adequate for PK prediction with a Korean population. This study aimed to develop a population PK model for [...] Read more.
The population pharmacokinetic (PK) parameters that are implemented in therapeutic drug management (TDM) software were generally obtained from a Western population and might not be adequate for PK prediction with a Korean population. This study aimed to develop a population PK model for vancomycin using Korean data to improve the quality of TDM for Korean patients. A total of 220 patients (1020 observations) who received vancomycin TDM services were included in the dataset. A population PK analysis was performed using non-linear mixed effects modeling, and a covariate evaluation was conducted. A two-compartment model with first-order elimination best explained the vancomycin PK, with estimates of 2.82 L/h, 31.8 L, 11.7 L/h, and 75.4 L for CL, V1, Q, and V2, respectively. In the covariate analysis, weight correlated with the volume of the peripheral compartment, and creatinine clearance, hemodialysis, and continuous renal replacement therapy treatments contributed to the clearance of vancomycin. The results show the clear need to optimize the PK parameters used for TDM in Korean patients. Specifically, V1 should be smaller for Korean patients, and renal replacement therapies should be considered in TDM practice. This final model was successfully applied in R shiny as open-source software for Koreans. Full article
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Open AccessArticle
Concurrent Osteosarcoma Theranostic Strategy Using Contrast-Enhanced Ultrasound and Drug-Loaded Bubbles
Pharmaceutics 2019, 11(5), 223; https://doi.org/10.3390/pharmaceutics11050223
Received: 1 April 2019 / Revised: 1 May 2019 / Accepted: 6 May 2019 / Published: 8 May 2019
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Abstract
Osteosarcoma (OS) is the most common bone tumor in children and teenagers. The multidrug resistant property of OS produces a major obstacle to chemotherapy, since the effective drug dose cannot be achieved via conventional drug delivery routes without serious systemic cytotoxicity. Microbubbles in [...] Read more.
Osteosarcoma (OS) is the most common bone tumor in children and teenagers. The multidrug resistant property of OS produces a major obstacle to chemotherapy, since the effective drug dose cannot be achieved via conventional drug delivery routes without serious systemic cytotoxicity. Microbubbles in conjunction with ultrasound (US) has recently been shown to spatially and temporally permeabilize the cellular membrane, promoting drug penetration into tumors. Here, we investigated whether drug (doxorubicin, DOX)-loaded bubbles (DOX-bubbles) can serve as drug-loaded carriers in combination with US in order to facilitate tumor drug delivery. The proposed bubbles have a high payload capacity (efficiency of 69.4 ± 9.1%, payload of 1.4 mg/mL) for DOX. In vitro data revealed that when used in combination with US (1-MHz), these DOX-bubbles facilitate DOX entering into tumor cells. In tumor-bearing animals, DOX-bubbles + US could provide 3.7-fold suppression of tumor growth compared with the group without insonation (1.8 ± 0.9 cm3 vs. 8.5 ± 2.2 cm3) because of the acceleration of DOX-induced tumor necrosis. In the meantime, the tumor perfusion and volume can be monitored by DOX-bubbles with contrast-enhanced ultrasound imaging. Our data provide useful information in support of translating the use of theranostic US-responsive bubbles for regulated tumor drug delivery into clinical use. Full article
(This article belongs to the Special Issue Micro/Nano-Bubbles as a New Ultrasound Imaging and Drug Delivery Tool)
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Open AccessArticle
Systemic Design and Evaluation of Ticagrelor-Loaded Nanostructured Lipid Carriers for Enhancing Bioavailability and Antiplatelet Activity
Pharmaceutics 2019, 11(5), 222; https://doi.org/10.3390/pharmaceutics11050222
Received: 15 April 2019 / Revised: 3 May 2019 / Accepted: 6 May 2019 / Published: 8 May 2019
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Abstract
Ticagrelor (TGL), a P2Y12 receptor antagonist, is classified as biopharmaceutics classification system (BCS) class IV drug due to its poor solubility and permeability, resulting in low oral bioavailability. Nanostructured lipid carriers (NLC) are an efficient delivery system for the improvement of bioavailability [...] Read more.
Ticagrelor (TGL), a P2Y12 receptor antagonist, is classified as biopharmaceutics classification system (BCS) class IV drug due to its poor solubility and permeability, resulting in low oral bioavailability. Nanostructured lipid carriers (NLC) are an efficient delivery system for the improvement of bioavailability of BCS class IV drugs. Hence, we prepared TGL-loaded NLC (TGL-NLC) to enhance the oral bioavailability and antiplatelet activity of TGL with a systemic design approach. The optimized TGL-NLC with Box–Behnken design showed a small particle size of 87.6 nm and high encapsulation efficiency of 92.1%. Scanning electron microscope (SEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) were performed to investigate the characteristics of TGL-NLC. Furthermore, TGL-NLC exhibited biocompatible cytotoxicity against Caco-2 cells. Cellular uptake of TGL-NLC was 1.56-fold higher than that of raw TGL on Caco-2 cells. In pharmacokinetic study, the oral bioavailability of TGL-NLC was 254.99% higher than that of raw TGL. In addition, pharmacodynamic study demonstrated that the antiplatelet activity of TGL-NLC was superior to that of raw TGL, based on enhanced bioavailability of TGL-NLC. These results suggest that TGL-NLC can be applied for efficient oral absorption and antiplatelet activity of TGL. Full article
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Open AccessArticle
Thermally-Responsive Loading and Release of Elastin-Like Polypeptides from Contact Lenses
Pharmaceutics 2019, 11(5), 221; https://doi.org/10.3390/pharmaceutics11050221
Received: 25 March 2019 / Revised: 20 April 2019 / Accepted: 24 April 2019 / Published: 7 May 2019
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Abstract
Contact lenses are widely prescribed for vision correction, and as such they are an attractive platform for drug delivery to the anterior segment of the eye. This manuscript explores a novel strategy to drive the reversible adsorption of peptide-based therapeutics using commercially available [...] Read more.
Contact lenses are widely prescribed for vision correction, and as such they are an attractive platform for drug delivery to the anterior segment of the eye. This manuscript explores a novel strategy to drive the reversible adsorption of peptide-based therapeutics using commercially available contact lenses. To accomplish this, thermo-sensitive elastin-like polypeptides (ELPs) alone or tagged with a candidate ocular therapeutic were characterized. For the first time, this manuscript demonstrates that Proclear CompatiblesTM contact lenses are a suitable platform for ELP adsorption. Two rhodamine-labelled ELPs, V96 (thermo-sensitive) and S96 (thermo-insensitive), were employed to test temperature-dependent association to the contact lenses. During long-term release into solution, ELP coacervation significantly modulated the release profile whereby more than 80% of loaded V96 retained with a terminal half-life of ~4 months, which was only 1–4 days under solubilizing conditions. A selected ocular therapeutic candidate lacritin-V96 fusion (LV96), either free or lens-bound LV96, was successfully transferred to HCE-T cells. These data suggest that ELPs may be useful to control loading or release from certain formulations of contact lenses and present a potential for this platform to deliver a biologically active peptide to the ocular surface via contact lenses. Full article
(This article belongs to the Special Issue Functional Polymers for Controlled Drug Release)
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Open AccessArticle
Octreotide Conjugates for Tumor Targeting and Imaging
Pharmaceutics 2019, 11(5), 220; https://doi.org/10.3390/pharmaceutics11050220
Received: 27 March 2019 / Revised: 2 May 2019 / Accepted: 3 May 2019 / Published: 7 May 2019
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Abstract
Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed [...] Read more.
Tumor targeting has emerged as an advantageous approach to improving the efficacy and safety of cytotoxic agents or radiolabeled ligands that do not preferentially accumulate in the tumor tissue. The somatostatin receptors (SSTRs) belong to the G-protein-coupled receptor superfamily and they are overexpressed in many neuroendocrine tumors (NETs). SSTRs can be efficiently targeted with octreotide, a cyclic octapeptide that is derived from native somatostatin. The conjugation of cargoes to octreotide represents an attractive approach for effective tumor targeting. In this study, we conjugated octreotide to cryptophycin, which is a highly cytotoxic depsipeptide, through the protease cleavable Val-Cit dipeptide linker using two different self-immolative moieties. The biological activity was investigated in vitro and the self-immolative part largely influenced the stability of the conjugates. Replacement of cryptophycin by the infrared cyanine dye Cy5.5 was exploited to elucidate the tumor targeting properties of the conjugates in vitro and in vivo. The compound efficiently and selectively internalized in cells overexpressing SSTR2 and accumulated in xenografts for a prolonged time. Our results on the in vivo properties indicate that octreotide may serve as an efficient delivery vehicle for tumor targeting. Full article
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Open AccessArticle
Penetration Efficiency of Antitumor Agents in Ovarian Cancer Spheroids: The Case of Recombinant Targeted Toxin DARPin-LoPE and the Chemotherapy Drug, Doxorubicin
Pharmaceutics 2019, 11(5), 219; https://doi.org/10.3390/pharmaceutics11050219
Received: 28 March 2019 / Revised: 26 April 2019 / Accepted: 5 May 2019 / Published: 7 May 2019
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Abstract
The efficiency of delivering a therapeutic agent into a tumor is among the crucial factors determining the prospects for its clinical use. This problem is particularly acute in the case of targeted antitumor agents since many of them are high-molecular-weight compounds. In this [...] Read more.
The efficiency of delivering a therapeutic agent into a tumor is among the crucial factors determining the prospects for its clinical use. This problem is particularly acute in the case of targeted antitumor agents since many of them are high-molecular-weight compounds. In this work, the penetration of therapeutic agents of two distinct molecular weights into the spheroids of ovarian adenocarcinoma overexpressing human epidermal growth factor receptor 2 (HER2) was studied. It was shown that the low-molecular-weight chemotherapy drug, doxorubicin (~0.5 kDa), effectively penetrates through almost the entire depth of a 300 to 400 μm spheroid, while the penetration depth of the HER2-specific recombinant targeted toxin, DARPin-LoPE (~42 kDa), is only a few surface layers of cells and does not exceed 70 μm. The low penetration of the targeted toxin into spheroid was shown along with a significant decrease in its efficiency against the three-dimensional tumor spheroid as compared with the two-dimensional monolayer culture. The approaches to increasing the accumulation of agents in the tumor are presented and prospects of their use in order to improve the effectiveness of therapy are discussed. Full article
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