Pharmaceutics

Research

18 pages, 4151 KiB

Open AccessArticle

Critical Drug Loss Induced by Silicone and Polyurethane Implantable Catheters in a Simulated Infusion Setup with Three Model Drugs

by Nicolas Tokhadzé, Philip Chennell, Bruno Pereira, Bénédicte Mailhot-Jensen and Valérie Sautou

Pharmaceutics 2021, 13(10), 1709; https://doi.org/10.3390/pharmaceutics13101709 - 16 Oct 2021

Cited by 8 | Viewed by 2756

Abstract

Silicone and polyurethane are biocompatible materials used for the manufacture of implantable catheters, but are known to induce drug loss by sorption, causing potentially important clinical consequences. Despite this, their impact on the drugs infused through them is rarely studied, or they are [...] Read more.

Silicone and polyurethane are biocompatible materials used for the manufacture of implantable catheters, but are known to induce drug loss by sorption, causing potentially important clinical consequences. Despite this, their impact on the drugs infused through them is rarely studied, or they are studied individually and not part of a complete infusion setup. The aim of this work was to experimentally investigate the drug loss that these devices can cause, on their own and within a complete infusion setup. Paracetamol, diazepam, and insulin were chosen as models to assess drug sorption. Four commonly used silicone and polyurethane catheters were studied independently and as part of two different setups composed of a syringe, an extension set, and silicone or polyurethane implantable catheter. Simulated infusion through the catheter alone or through the complete setup were tested, at flowrates of 1 mL/h and 10 mL/h. Drug concentrations were monitored by liquid chromatography, and the silicone and polyurethane materials were characterized by ATR-IR spectroscopy and Zeta surface potential measurements. The losses observed with the complete setups followed the same trend as the losses induced individually by the most sorptive device of the setup. With the complete setups, no loss of paracetamol was observed, but diazepam and insulin maximum losses were respectively of 96.4 ± 0.9% and 54.0 ± 5.6%, when using a polyurethane catheter. Overall, catheters were shown to be the cause of some extremely high drug losses that could not be countered by optimizing the extension set in the setup. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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20 pages, 3202 KiB

Open AccessArticle

Ion-Triggered In Situ Gelling Nanoemulgel as a Platform for Nose-to-Brain Delivery of Small Lipophilic Molecules

by Sreeharsha Nagaraja, Girish Meravanige Basavarajappa, Ranjith Kumar Karnati, Esam Mohamed Bakir and Swati Pund

Pharmaceutics 2021, 13(8), 1216; https://doi.org/10.3390/pharmaceutics13081216 - 6 Aug 2021

Cited by 20 | Viewed by 3441

Abstract

Background: Intranasal route offers a direct nose-to-brain delivery via olfactory and trigeminal nerves and minimizes the systemic exposure of the drug. Although reliable and non-invasive, intranasal administration of lipophilic neuroprotective agents for brain targeting is still challenging. Literature focuses on naturally-derived compounds as [...] Read more.

Background: Intranasal route offers a direct nose-to-brain delivery via olfactory and trigeminal nerves and minimizes the systemic exposure of the drug. Although reliable and non-invasive, intranasal administration of lipophilic neuroprotective agents for brain targeting is still challenging. Literature focuses on naturally-derived compounds as a promising therapeutics for chronic brain diseases. Naringin, a natural flavonoid obtained from citrus fruits possesses neuroprotective effects. By regulating multiple crucial cellular signaling pathways, naringin acts on several therapeutic targets that make it suitable for the treatment of neurodegenerative diseases like Alzheimer’s disease and making it a suitable candidate for nasal administration. However, the hydrophobicity of naringin is the primary challenge to formulate it in an aqueous system for nasal administration. Method: We designed a lipid-based nanoemulsifying drug delivery system of naringin using Acrysol K140 as an oil, Tween 80 as a surfactant and Transcutol HP as a cosolvent, to improve solubility and harness the benefits of nanosizing like improved cellular penetration. Intranasal instillations of therapeutic agents have limited efficacy due to drug washout and inadequate adherence to the nasal mucosa. Therefore, we reconstituted the naringin self-emulsifying system in a smart, biodegradable, ion-triggered in situ gelling hydrogel and optimized for desirable gel characteristics. The naringin-loaded composition was optimized and characterized for various physicochemical and rheological properties. Results: The formulation showed a mean droplet size 152.03 ± 4.6 nm with a polydispersity index <0.23. Ex vivo transmucosal permeation kinetics of the developed formulation through sheep nasal mucosa showed sustained diffusion and enhanced steady-state flux and permeability coefficient. Scanning and transmission electron microscopy revealed the spherical shape of emulsion droplets and entrapment of droplets in a gel structure. The formulation showed excellent biocompatibility as analyzed from the viability of L929 fibroblast cells and nasal mucosa histopathology after treatment. In vivo biodistribution studies revealed significantly higher drug transport and brain targeting efficiency. Conclusion: In situ gelling system with nanoemulsified naringin demonstrated a safe nasal delivery providing a new dimension to the treatment of chronic neurodegenerative diseases using small hydrophobic phytoconstituents with minimization of dose and related systemic adverse effects. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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14 pages, 2668 KiB

Open AccessArticle

The Development of an In Vitro Horizontal Diffusion Cell to Monitor Nasal Powder Penetration Inline

by Péter Gieszinger, Tamás Kiss, Piroska Szabó-Révész and Rita Ambrus

Pharmaceutics 2021, 13(6), 809; https://doi.org/10.3390/pharmaceutics13060809 - 28 May 2021

Cited by 16 | Viewed by 2768

Abstract

The development of in vitro investigation models could be important using sensitive and fast methods during formulation. Intranasal applied drugs (meloxicam, lamotrigine, and levodopa) avoid the gastrointestinal tract and can achieve higher bioavailability, therefore a penetration extent is a key property. In this [...] Read more.

The development of in vitro investigation models could be important using sensitive and fast methods during formulation. Intranasal applied drugs (meloxicam, lamotrigine, and levodopa) avoid the gastrointestinal tract and can achieve higher bioavailability, therefore a penetration extent is a key property. In this study, the in vitro adaptability of a modified horizontal diffusion cell was tested by using these model active pharmaceutical ingredients (APIs). The special factors consisted of the volume of the chambers, the arrangement of the stirrers, the design of probe input for real-time analysis and decreased membrane area. Membranes were impregnated by isopropyl myristate and by using phosphate buffer to evaluate the effect of API hydrophilicity on the diffusion properties. The lipophilicity of the API was proportional to the penetration extent through isopropyl myristate-impregnated membranes compared with buffer-soaked membranes. After evaluating the arithmetic mean of standard relative deviations and the penetrated extent of APIs at 15 min, Metricel^® could be suggested for levodopa and meloxicam, and Whatman™ for lamotrigine. The modified model is suitable for inline, real-time detection, at nasal conditions, using small volumes of phases, impregnated membrane, to monitor the diffusion of the drug and to determine its concentration in the acceptor and donor phases. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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17 pages, 4020 KiB

Open AccessArticle

Impact of CNS Diseases on Drug Delivery to Brain Extracellular and Intracellular Target Sites in Human: A “WHAT-IF” Simulation Study

by Mohammed A. A. Saleh and Elizabeth C. M. de Lange

Pharmaceutics 2021, 13(1), 95; https://doi.org/10.3390/pharmaceutics13010095 - 13 Jan 2021

Cited by 14 | Viewed by 3976

Abstract

The blood–brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration–time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug [...] Read more.

The blood–brain barrier (BBB) is equipped with unique physical and functional processes that control central nervous system (CNS) drug transport and the resulting concentration–time profiles (PK). In CNS diseases, the altered BBB and CNS pathophysiology may affect the CNS PK at the drug target sites in the brain extracellular fluid (brain_ECF) and intracellular fluid (brain_ICF) that may result in changes in CNS drug effects. Here, we used our human CNS physiologically-based PK model (LeiCNS-PK3.0) to investigate the impact of altered cerebral blood flow (CBF), tight junction paracellular pore radius (para_radius), brain_ECF volume, and pH of brain_ECF (pH_ECF) and of brain_ICF (pH_ICF) on brain_ECF and brain_ICF PK for 46 small drugs with distinct physicochemical properties. LeiCNS-PK3.0 simulations showed a drug-dependent effect of the pathophysiological changes on the rate and extent of BBB transport and on brain_ECF and brain_ICF PK. Altered para_radius, pH_ECF, and pH_ICF affected both the rate and extent of BBB drug transport, whereas changes in CBF and brain_ECF volume modestly affected the rate of BBB drug transport. While the focus is often on BBB paracellular and active transport processes, this study indicates that also changes in pH should be considered for their important implications on brain_ECF and brain_ICF target site PK. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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18 pages, 1834 KiB

Open AccessArticle

Interactions of Potential Anti-COVID-19 Compounds with Multispecific ABC and OATP Drug Transporters

by Ágnes Telbisz, Csilla Ambrus, Orsolya Mózner, Edit Szabó, György Várady, Éva Bakos, Balázs Sarkadi and Csilla Özvegy-Laczka

Pharmaceutics 2021, 13(1), 81; https://doi.org/10.3390/pharmaceutics13010081 - 9 Jan 2021

Cited by 37 | Viewed by 5079

Abstract

During the COVID-19 pandemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering, or antidiabetic agents. [...] Read more.

During the COVID-19 pandemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering, or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, in this study, we examined the interactions of the repurposed drugs with the key human multidrug transporters present in the major tissue barriers and strongly affecting the pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine; the antihelmintic ivermectin; and the proposed antiviral compounds ritonavir, lopinavir, favipiravir, and remdesivir with the ABCB1/Pgp, ABCG2/BCRP, and ABCC1/MRP1 exporters, as well as the organic anion-transporting polypeptide (OATP)2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning on the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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19 pages, 2395 KiB

Open AccessArticle

ApoE-Targeting Increases the Transfer of Solid Lipid Nanoparticles with Donepezil Cargo across a Culture Model of the Blood–Brain Barrier

by Gizem Rüya Topal, Mária Mészáros, Gergő Porkoláb, Anikó Szecskó, Tamás Ferenc Polgár, László Siklós, Mária A. Deli, Szilvia Veszelka and Asuman Bozkir

Pharmaceutics 2021, 13(1), 38; https://doi.org/10.3390/pharmaceutics13010038 - 29 Dec 2020

Cited by 67 | Viewed by 6535

Abstract

Pharmacological treatment of central nervous system (CNS) disorders is difficult, because the blood–brain barrier (BBB) restricts the penetration of many drugs into the brain. To solve this unmet therapeutic need, nanosized drug carriers are the focus of research efforts to develop drug delivery [...] Read more.

Pharmacological treatment of central nervous system (CNS) disorders is difficult, because the blood–brain barrier (BBB) restricts the penetration of many drugs into the brain. To solve this unmet therapeutic need, nanosized drug carriers are the focus of research efforts to develop drug delivery systems for the CNS. For the successful delivery of nanoparticles (NPs) to the brain, targeting ligands on their surface is necessary. Our research aim was to design a nanoscale drug delivery system for a more efficient transfer of donepezil, an anticholinergic drug in the therapy of Alzheimer’s disease across the BBB. Rhodamine B-labeled solid lipid nanoparticles with donepezil cargo were prepared and targeted with apolipoprotein E (ApoE), a ligand of BBB receptors. Nanoparticles were characterized by measurement of size, polydispersity index, zeta potential, thermal analysis, Fourier-transform infrared spectroscopy, in vitro release, and stability. Cytotoxicity of nanoparticles were investigated by metabolic assay and impedance-based cell analysis. ApoE-targeting increased the uptake of lipid nanoparticles in cultured brain endothelial cells and neurons. Furthermore, the permeability of ApoE-targeted nanoparticles across a co-culture model of the BBB was also elevated. Our data indicate that ApoE, which binds BBB receptors, can potentially be exploited for successful CNS targeting of solid lipid nanoparticles. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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19 pages, 3466 KiB

Open AccessArticle

Freezing Weakens the Barrier Function of Reconstructed Human Epidermis as Evidenced by Raman Spectroscopy and Percutaneous Permeation

by Yuri Dancik, Hichem Kichou, Christophe Eklouh-Molinier, Martin Soucé, Emilie Munnier, Igor Chourpa and Franck Bonnier

Pharmaceutics 2020, 12(11), 1041; https://doi.org/10.3390/pharmaceutics12111041 - 30 Oct 2020

Cited by 10 | Viewed by 2921

Abstract

The development and characterization of reconstructed human epidermis (RHE) is an active area of R&D. RHE can replace animal tissues in pharmaceutical, toxicological and cosmetic sciences, yielding scientific and ethical advantages. RHEs remain costly, however, due to consumables and time required for their [...] Read more.

The development and characterization of reconstructed human epidermis (RHE) is an active area of R&D. RHE can replace animal tissues in pharmaceutical, toxicological and cosmetic sciences, yielding scientific and ethical advantages. RHEs remain costly, however, due to consumables and time required for their culture and a short shelf-life. Storing, i.e., freezing RHE could help reduce costs but to date, little is known on the effects of freezing on the barrier function of RHE. We studied such effects using commercial EpiSkin™ RHE stored at −20, −80 and −150 °C for 1 and 10 weeks. We acquired intrinsic Raman spectra in the stratum corneum (SC) of the RHEs as well as spectra obtained following topical application of resorcinol in an aqueous solution. In parallel, we quantified the effects of freezing on the permeation kinetics of resorcinol from time-dependent permeation experiments. Principal component analyses discriminated the intrinsic SC spectra and the spectra of resorcinol-containing RHEs, in each case on the basis of the freezing conditions. Permeation of resorcinol through the frozen RHE increased 3- to 6-fold compared to fresh RHE, with the strongest effect obtained from freezing at −20 °C for 10 weeks. Due to the extensive optimization and standardization of EpiSkin™ RHE, the effects observed in our work may be expected to be more pronounced with other RHEs. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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24 pages, 7131 KiB

Open AccessArticle

Impact of Glycosylation and Species Origin on the Uptake and Permeation of IgGs through the Nasal Airway Mucosa

by Simone Ladel, Frank Maigler, Johannes Flamm, Patrick Schlossbauer, Alina Handl, Rebecca Hermann, Helena Herzog, Thomas Hummel, Boris Mizaikoff and Katharina Schindowski

Pharmaceutics 2020, 12(11), 1014; https://doi.org/10.3390/pharmaceutics12111014 - 23 Oct 2020

Cited by 15 | Viewed by 3356

Abstract

Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were [...] Read more.

Although we have recently reported the involvement of neonatal Fc receptor (FcRn) in intranasal transport, the transport mechanisms are far from being elucidated. Ex vivo porcine olfactory tissue, primary cells from porcine olfactory epithelium (OEPC) and the human cell line RPMI 2650 were used to evaluate the permeation of porcine and human IgG antibodies through the nasal mucosa. IgGs were used in their wild type and deglycosylated form to investigate the impact of glycosylation. Further, the expression of FcRn and Fc-gamma receptor (FCGR) and their interaction with IgG were analyzed. Comparable permeation rates for human and porcine IgG were observed in OEPC, which display the highest expression of FcRn. Only traces of porcine IgGs could be recovered at the basolateral compartment in ex vivo olfactory tissue, while human IgGs reached far higher levels. Deglycosylated human IgG showed significantly higher permeation in comparison to the wild type in RPMI 2650 and OEPC, but insignificantly elevated in the ex vivo model. An immunoprecipitation with porcine primary cells and tissue identified FCGR2 as a potential interaction partner in the nasal mucosa. Glycosylation sensitive receptors appear to be involved in the uptake, transport, but also degradation of therapeutic IgGs in the airway epithelial layer. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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16 pages, 3138 KiB

Open AccessArticle

Verification of P-Glycoprotein Function at the Dermal Barrier in Diffusion Cells and Dynamic “Skin-On-A-Chip” Microfluidic Device

by Ágnes Bajza, Dorottya Kocsis, Orsolya Berezvai, András József Laki, Bence Lukács, Tímea Imre, Kristóf Iván, Pál Szabó and Franciska Erdő

Pharmaceutics 2020, 12(9), 804; https://doi.org/10.3390/pharmaceutics12090804 - 25 Aug 2020

Cited by 24 | Viewed by 3827

Abstract

The efficacy of transdermal absorption of drugs and the irritation or corrosion potential of topically applied formulations are important areas of investigation in pharmaceutical, military and cosmetic research. The aim of the present experiments is to test the role of P-glycoprotein in dermal [...] Read more.

The efficacy of transdermal absorption of drugs and the irritation or corrosion potential of topically applied formulations are important areas of investigation in pharmaceutical, military and cosmetic research. The aim of the present experiments is to test the role of P-glycoprotein in dermal drug delivery in various ex vivo and in vitro platforms, including a novel microchip technology developed by Pázmány Péter Catholic University. A further question is whether the freezing of excised skin and age have any influence on P-glycoprotein-mediated dermal drug absorption. Two P-glycoprotein substrate model drugs (quinidine and erythromycin) were investigated via topical administration in diffusion cells, a skin-on-a-chip device and transdermal microdialysis in rat skin. The transdermal absorption of both model drugs was reduced by P-glycoprotein inhibition, and both aging and freezing increased the permeability of the tissues. Based on our findings, it is concluded that the process of freezing leads to reduced function of efflux transporters, and increases the porosity of skin. P-glycoprotein has an absorptive orientation in the skin, and topical inhibitors can modify its action. The defensive role of the skin seems to be diminished in aged individuals, partly due to reduced thickness of the dermis. The novel microfluidic microchip seems to be an appropriate tool to investigate dermal drug delivery. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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11 pages, 2780 KiB

Open AccessArticle

Ionically Crosslinked Complex Gels Loaded with Oleic Acid-Containing Vesicles for Transdermal Drug Delivery

by Wing-Fu Lai, Ryan Tang and Wing-Tak Wong

Pharmaceutics 2020, 12(8), 725; https://doi.org/10.3390/pharmaceutics12080725 - 2 Aug 2020

Cited by 96 | Viewed by 4026

Abstract

Skin is an attractive site for drug administration partly because of its easy accessibility and favorable properties (e.g., less invasiveness and high patient compliance) over some other common routes of administration. Despite this, the efficiency in transdermal drug delivery has been largely limited [...] Read more.

Skin is an attractive site for drug administration partly because of its easy accessibility and favorable properties (e.g., less invasiveness and high patient compliance) over some other common routes of administration. Despite this, the efficiency in transdermal drug delivery has been largely limited by poor skin permeation. To address this problem, this study reports the generation of oleic acid-containing vesicles, which can enhance the drug delivery efficiency while showing good stability and limited skin disruption. Upon being loaded into a complex gel, along with the incorporation of the polymer blending technique, a delivery system exhibiting tunable transdermal flux of 2,3,5,4′-tetrahydroxystilbene 2-O-β-D-glucoside is reported. Taking the good biocompatibility and tunable delivery performance into account, our system warrants further development and optimization for future applications in the treatment of skin diseases. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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Review

Jump to: Research, Other

31 pages, 3980 KiB

Open AccessReview

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

by Giada Botti, Alessandro Dalpiaz and Barbara Pavan

Pharmaceutics 2021, 13(8), 1144; https://doi.org/10.3390/pharmaceutics13081144 - 27 Jul 2021

Cited by 18 | Viewed by 3888

Abstract

About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain [...] Read more.

About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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31 pages, 4285 KiB

Open AccessReview

New Perspectives of Gene Therapy on Polyglutamine Spinocerebellar Ataxias: From Molecular Targets to Novel Nanovectors

by Fabiola V. Borbolla-Jiménez, María Luisa Del Prado-Audelo, Bulmaro Cisneros, Isaac H. Caballero-Florán, Gerardo Leyva-Gómez and Jonathan J. Magaña

Pharmaceutics 2021, 13(7), 1018; https://doi.org/10.3390/pharmaceutics13071018 - 3 Jul 2021

Cited by 7 | Viewed by 4158

Abstract

Seven of the most frequent spinocerebellar ataxias (SCAs) are caused by a pathological expansion of a cytosine, adenine and guanine (CAG) trinucleotide repeat located in exonic regions of unrelated genes, which in turn leads to the synthesis of polyglutamine (polyQ) proteins. PolyQ proteins [...] Read more.

Seven of the most frequent spinocerebellar ataxias (SCAs) are caused by a pathological expansion of a cytosine, adenine and guanine (CAG) trinucleotide repeat located in exonic regions of unrelated genes, which in turn leads to the synthesis of polyglutamine (polyQ) proteins. PolyQ proteins are prone to aggregate and form intracellular inclusions, which alter diverse cellular pathways, including transcriptional regulation, protein clearance, calcium homeostasis and apoptosis, ultimately leading to neurodegeneration. At present, treatment for SCAs is limited to symptomatic intervention, and there is no therapeutic approach to prevent or reverse disease progression. This review provides a compilation of the experimental advances obtained in cell-based and animal models toward the development of gene therapy strategies against polyQ SCAs, providing a discussion of their potential application in clinical trials. In the second part, we describe the promising potential of nanotechnology developments to treat polyQ SCA diseases. We describe, in detail, how the design of nanoparticle (NP) systems with different physicochemical and functionalization characteristics has been approached, in order to determine their ability to evade the immune system response and to enhance brain delivery of molecular tools. In the final part of this review, the imminent application of NP-based strategies in clinical trials for the treatment of polyQ SCA diseases is discussed. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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22 pages, 1236 KiB

Open AccessReview

Modulation of Urate Transport by Drugs

by Péter Tátrai, Franciska Erdő, Gabriella Dörnyei and Péter Krajcsi

Pharmaceutics 2021, 13(6), 899; https://doi.org/10.3390/pharmaceutics13060899 - 17 Jun 2021

Cited by 16 | Viewed by 4591

Abstract

Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and [...] Read more.

Background: Serum urate (SU) levels in primates are extraordinarily high among mammals. Urate is a Janus-faced molecule that acts physiologically as a protective antioxidant but provokes inflammation and gout when it precipitates at high concentrations. Transporters play crucial roles in urate disposition, and drugs that interact with urate transporters either by intention or by accident may modulate SU levels. We examined whether in vitro transporter interaction studies may clarify and predict such effects. Methods: Transporter interaction profiles of clinically proven urate-lowering (uricosuric) and hyperuricemic drugs were compiled from the literature, and the predictive value of in vitro-derived cut-offs like C_max/IC₅₀ on the in vivo outcome (clinically relevant decrease or increase of SU) was assessed. Results: Interaction with the major reabsorptive urate transporter URAT1 appears to be dominant over interactions with secretory transporters in determining the net effect of a drug on SU levels. In vitro inhibition interpreted using the recommended cut-offs is useful at predicting the clinical outcome. Conclusions: In vitro safety assessments regarding urate transport should be done early in drug development to identify candidates at risk of causing major imbalances. Attention should be paid both to the inhibition of secretory transporters and inhibition or trans-stimulation of reabsorptive transporters, especially URAT1. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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15 pages, 473 KiB

Open AccessReview

Expression and Function of Organic Anion Transporting Polypeptides in the Human Brain: Physiological and Pharmacological Implications

by Anima M. Schäfer, Henriette E. Meyer zu Schwabedissen and Markus Grube

Pharmaceutics 2021, 13(6), 834; https://doi.org/10.3390/pharmaceutics13060834 - 4 Jun 2021

Cited by 23 | Viewed by 3721

Abstract

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters [...] Read more.

The central nervous system (CNS) is an important pharmacological target, but it is very effectively protected by the blood–brain barrier (BBB), thereby impairing the efficacy of many potential active compounds as they are unable to cross this barrier. Among others, membranous efflux transporters like P-Glycoprotein are involved in the integrity of this barrier. In addition to these, however, uptake transporters have also been found to selectively uptake certain compounds into the CNS. These transporters are localized in the BBB as well as in neurons or in the choroid plexus. Among them, from a pharmacological point of view, representatives of the organic anion transporting polypeptides (OATPs) are of particular interest, as they mediate the cellular entry of a variety of different pharmaceutical compounds. Thus, OATPs in the BBB potentially offer the possibility of CNS targeting approaches. For these purposes, a profound understanding of the expression and localization of these transporters is crucial. This review therefore summarizes the current state of knowledge of the expression and localization of OATPs in the CNS, gives an overview of their possible physiological role, and outlines their possible pharmacological relevance using selected examples. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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22 pages, 1614 KiB

Open AccessReview

Therapeutic Potential of Mesenchymal Stem Cells and Their Products in Lung Diseases—Intravenous Administration versus Inhalation

by Eleonore Fröhlich

Pharmaceutics 2021, 13(2), 232; https://doi.org/10.3390/pharmaceutics13020232 - 7 Feb 2021

Cited by 24 | Viewed by 4600

Abstract

The number of publications studying the therapeutic use of stem cells has steadily increased since 2000. Compared to other applications, there has been little interest in the evaluation of mesenchymal stem cells (MSCs) and MSC-derived products (mostly extracellular vesicles) for the treatment of [...] Read more.

The number of publications studying the therapeutic use of stem cells has steadily increased since 2000. Compared to other applications, there has been little interest in the evaluation of mesenchymal stem cells (MSCs) and MSC-derived products (mostly extracellular vesicles) for the treatment of respiratory diseases. Due to the lack of efficient treatments for acute respiratory distress syndrome caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the action of MSCs has also been studied. This review describes mode of action and use of MSCs and MSC-derived products in the treatment of lung diseases including the respective advantages and limitations of the products. Further, issues related to standardized production are addressed. Administration by inhalation of MSCs, compared to intravenous injection, could decrease cell damage by shear stress, eliminate the barrier to reach target cells in the alveoli, prevent thrombus formation in the pulmonary vasculature and retention in filter for extracorporeal membrane oxygenation. There is more feasible to deliver extracellular vesicles than MSCs with inhalers, offering the advantage of non-invasive and repeated administration by the patient. Major obstacles for comparison of results are heterogeneity of the products, differences in the treatment protocols and small study cohorts. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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Other

Jump to: Research, Review

11 pages, 2779 KiB

Open AccessBrief Report

SZR-104, a Novel Kynurenic Acid Analogue with High Permeability through the Blood–Brain Barrier

by Kinga Molnár, Bálint Lőrinczi, Csilla Fazakas, István Szatmári, Ferenc Fülöp, Noémi Kmetykó, Róbert Berkecz, István Ilisz, István A. Krizbai, Imola Wilhelm and László Vécsei

Pharmaceutics 2021, 13(1), 61; https://doi.org/10.3390/pharmaceutics13010061 - 5 Jan 2021

Cited by 12 | Viewed by 3870

Abstract

By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood–brain barrier. One possibility to overcome this [...] Read more.

By being an antagonist of glutamate and other receptors, kynurenic acid serves as an endogenous neuroprotectant in several pathologies of the brain. Unfortunately, systemic administration of kynurenic acid is hindered by its low permeability through the blood–brain barrier. One possibility to overcome this problem is to use analogues with similar biological activity as kynurenic acid, but with an increased permeability through the blood–brain barrier. We synthesized six novel aminoalkylated amide derivatives of kynurenic acid, among which SZR-104 (N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-hydroxyquinoline-2-carboxamide) proved to have the highest permeability through an in vitro blood–brain barrier model. In addition, permeability of SZR-104 was significantly higher than that of kynurenic acid, xanthurenic acid and 39B, a quinolone derivative/xanthurenic acid analogue. Since peripherally administered SZR-104 is able to inhibit epileptiform activity in the brain, we conclude that SZR-104 is a promising kynurenic acid analogue with good penetrability into the central nervous system. Full article

(This article belongs to the Special Issue Drug Delivery across Physiological Barriers)

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