Nose to Brain Delivery

A special issue of Pharmaceutics (ISSN 1999-4923).

Deadline for manuscript submissions: closed (31 January 2019) | Viewed by 124747

Special Issue Editors


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Department of Medicine, Surgery and Pharmacy, University of Sassari, Via Muroni 23/a, 07100 Sassari, Italy
Interests: drug delivery; nanomedicine; nanoparticles
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Guest Editor

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Guest Editor
Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100 Pavia, Italy
Interests: amphiphilic polymers; bioactive polysaccharides; nanoemulsions; poorly soluble drug formulations; nanoparticles; theranostic
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The blood-brain barrier (BBB) separates the central nervous system (CNS) from general circulation. Drugs targeting the brain represent a remarkable problem, owing to BBB, which does not allow most drugs to pass through it. The use of a nose-to-brain delivery route is an important and noninvasive method of drug delivery to solve this problem and bypass the BBB. Different strategies have been developed to enhance nose-to-brain drug delivery. In fact, it is well-known that an intranasal direct anatomical connection between the nasal cavity and the CNS exists, which suggests the development of nasal formulations for brain targeting of drugs. The design and preparation of nasal formulations involve the development of polymeric pharmaceutical platforms able to interact with nasal mucosa: Bioadhesion and penetration enhancement through nasal mucosa layers are the first and most important characteristics that these systems must have. The development of new nasal systems represents a great challenge in the field of controlled drug targeting and delivery.

This Special Issue has the aim of highlighting current progress in the use of the nasal route for brain targeting.

Prof. Paolo Giunchedi
Prof. Elisabetta Gavini
Prof. Maria Cristina Bonferoni
Guest Editors

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Keywords

  • Nasal route
  • Brain targeting
  • Mucoadhesion
  • Transmucosal delivery
  • Penetration enhancers
  • Nanoparticles
  • Microspheres

Published Papers (14 papers)

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Editorial

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5 pages, 196 KiB  
Editorial
Nose-to-Brain Delivery
by Paolo Giunchedi, Elisabetta Gavini and Maria Cristina Bonferoni
Pharmaceutics 2020, 12(2), 138; https://doi.org/10.3390/pharmaceutics12020138 - 6 Feb 2020
Cited by 35 | Viewed by 3891
Abstract
Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, [...] Read more.
Nose-to-brain delivery represents a big challenge. In fact there is a large number of neurological diseases that require therapies in which the drug must reach the brain, avoiding the difficulties due to the blood–brain barrier (BBB) and the problems connected with systemic administration, such as drug bioavailability and side-effects. For these reasons the development of nasal formulations able to deliver the drug directly into the brain is of increasing importance. This Editorial regards the contributions present in the Special Issue “Nose-to-Brain Delivery”. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)

Research

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14 pages, 2602 KiB  
Article
Uptake in the Central Nervous System of Geraniol Oil Encapsulated in Chitosan Oleate Following Nasal and Oral Administration
by Maria Cristina Bonferoni, Luca Ferraro, Barbara Pavan, Sarah Beggiato, Elena Cavalieri, Paolo Giunchedi and Alessandro Dalpiaz
Pharmaceutics 2019, 11(3), 106; https://doi.org/10.3390/pharmaceutics11030106 - 3 Mar 2019
Cited by 15 | Viewed by 3436
Abstract
The pharmacological activities of geraniol include anticancer and neuroprotective properties. However, its insolubility in water easily induces separation from aqueous formulations, causing administration difficulties. Here we propose new emulsified formulations of geraniol by using the amphiphilic polymer chitosan-oleate (CS-OA) as surfactant to combine [...] Read more.
The pharmacological activities of geraniol include anticancer and neuroprotective properties. However, its insolubility in water easily induces separation from aqueous formulations, causing administration difficulties. Here we propose new emulsified formulations of geraniol by using the amphiphilic polymer chitosan-oleate (CS-OA) as surfactant to combine mucoadhesive and absorption enhancer properties with stabilization effects on the oil dispersion. The formulation based on CS-OA 2% (w/w) (G-CS-OA-2.0%) showed viscosity values compatible with oral and nasal administration to rats, and mean diameter of the dispersed phase of 819 ± 104 nm. G-CS-OA-2.0% oral administration sensibly increases the geraniol bioavailability with respect to coarse emulsions obtained without CS-OA (AUC values in the bloodstream were 42,713 ± 1553 µg∙mL−1∙min and 2158 ± 82 µg∙mL−1∙min following administration of 50 mg/kg or 1 mg/kg, respectively), and enhances the aptitude of geraniol to reach the central nervous system from the bloodstream (AUC values in the cerebrospinal fluid were 7293 ± 408 µg∙mL−1∙min and 399 ± 25 µg∙mL−1∙min after oral administration of 50 mg/kg or 1 mg/kg, respectively). Moreover, relevant geraniol amounts were detected in the cerebrospinal fluid following the G-CS-OA-2% nasal administration (AUC values in the cerebrospinal fluid were 10,778 ± 477 µg∙mL−1∙min and 5571 ± 290 µg∙mL−1∙min after nasal administration of 4 mg/kg or 1 mg/kg, respectively). Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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16 pages, 5244 KiB  
Article
Formulation Strategies to Improve Nose-to-Brain Delivery of Donepezil
by Lupe Carolina Espinoza, Marcelle Silva-Abreu, Beatriz Clares, María José Rodríguez-Lagunas, Lyda Halbaut, María-Alexandra Cañas and Ana Cristina Calpena
Pharmaceutics 2019, 11(2), 64; https://doi.org/10.3390/pharmaceutics11020064 - 1 Feb 2019
Cited by 60 | Viewed by 6099
Abstract
Donepezil (DPZ) is widely used in the treatment of Alzheimer’s disease in tablet form for oral administration. The pharmacological efficacy of this drug can be enhanced by the use of intranasal administration because this route makes bypassing the blood–brain barrier (BBB) possible. The [...] Read more.
Donepezil (DPZ) is widely used in the treatment of Alzheimer’s disease in tablet form for oral administration. The pharmacological efficacy of this drug can be enhanced by the use of intranasal administration because this route makes bypassing the blood–brain barrier (BBB) possible. The aim of this study was to develop a nanoemulsion (NE) as well as a nanoemulsion with a combination of bioadhesion and penetration enhancing properties (PNE) in order to facilitate the transport of DPZ from nose-to-brain. Composition of NE was established using three pseudo-ternary diagrams and PNE was developed by incorporating Pluronic F-127 to the aqueous phase. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined for both formulations. The tolerability was evaluated by in vitro and in vivo models. DPZ-NE and DPZ-PNE were transparent, monophasic, homogeneous, and physically stable with droplets of nanometric size and spherical shape. DPZ-NE showed Newtonian behavior whereas a shear thinning (pseudoplastic) behavior was observed for DPZ-PNE. The release profile of both formulations followed a hyperbolic kinetic. The permeation and prediction parameters were significantly higher for DPZ-PNE, suggesting the use of polymers to be an effective strategy to improve the bioadhesion and penetration of the drug through nasal mucosa, which consequently increase its bioavailability. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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17 pages, 5106 KiB  
Article
Fabrication, Optimization, and Evaluation of Rotigotine-Loaded Chitosan Nanoparticles for Nose-To-Brain Delivery
by Angeline Shak. Tzeyung, Shadab Md, Subrat Kumar Bhattamisra, Thiagarajan Madheswaran, Nabil A. Alhakamy, Hibah M. Aldawsari and Ammu K. Radhakrishnan
Pharmaceutics 2019, 11(1), 26; https://doi.org/10.3390/pharmaceutics11010026 - 10 Jan 2019
Cited by 102 | Viewed by 6496
Abstract
The objective of the present study was to develop, optimize, and evaluate rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery. Rotigotine-loaded chitosan nanoparticles were prepared by the ionic gelation method and optimized for various parameters such as the effect of chitosan, sodium tripolyphosphate, rotigotine [...] Read more.
The objective of the present study was to develop, optimize, and evaluate rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery. Rotigotine-loaded chitosan nanoparticles were prepared by the ionic gelation method and optimized for various parameters such as the effect of chitosan, sodium tripolyphosphate, rotigotine concentration on particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency. The prepared nanoparticles were characterized using photon correlation spectroscopy, transmission electron microscopy, scanning electron microscopy, atomic force microscopy, fourier-transform infrared spectroscopy, and X-ray diffraction. The developed RNPs showed a small hydrodynamic particle size (75.37 ± 3.37 nm), small PDI (0.368 ± 0.02), satisfactory zeta potential (25.53 ± 0.45 mV), and very high entrapment efficiency (96.08 ± 0.01). The 24-h in vitro release and ex vivo nasal permeation of rotigotine from the nanoparticles were 49.45 ± 2.09% and 92.15 ± 4.74% while rotigotine solution showed corresponding values of 95.96 ± 1.79%and 58.22 ± 1.75%, respectively. The overall improvement ratio for flux and permeability coefficient were found to be 4.88 and 2.67 when compared with rotigotine solution. A histopathological study showed that the nanoparticulate formulation produced no toxicity or structural damage to nasal mucosa. Our results indicated that rotigotine-loaded chitosan nanoparticles provide an efficient carrier for nose-to-brain delivery. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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19 pages, 5330 KiB  
Article
Intranasal Delivery of Genistein-Loaded Nanoparticles as a Potential Preventive System against Neurodegenerative Disorders
by Giovanna Rassu, Elena Piera Porcu, Silvia Fancello, Antonella Obinu, Nina Senes, Grazia Galleri, Rossana Migheli, Elisabetta Gavini and Paolo Giunchedi
Pharmaceutics 2019, 11(1), 8; https://doi.org/10.3390/pharmaceutics11010008 - 29 Dec 2018
Cited by 64 | Viewed by 5329
Abstract
Genistein has been reported to have antioxidant and neuroprotective activity. Despite encouraging in vitro and in vivo results, several disadvantages such as poor water solubility, rapid metabolism, and low oral bioavailability limit the clinical application of genistein. The aim of this study was [...] Read more.
Genistein has been reported to have antioxidant and neuroprotective activity. Despite encouraging in vitro and in vivo results, several disadvantages such as poor water solubility, rapid metabolism, and low oral bioavailability limit the clinical application of genistein. The aim of this study was to design and characterize genistein-loaded chitosan nanoparticles for intranasal drug delivery, prepared by the ionic gelation technique by using sodium hexametaphosphate. Nanoparticles were characterized in vitro and their cytotoxicity was tested on PC12 cells. Genistein-loaded nanoparticles were prepared, and sodium hexametaphosphate was used as a valid alternative to well-known cross-linkers. Nanoparticle characteristics as well as their physical stability were affected by formulation composition and manufacturing. Small (mean diameters of 200–300 nm) and homogeneous nanoparticles were obtained and were able to improve genistein penetration through the nasal mucosa as compared to pure genistein. Nanoparticle dispersions showed a pH consistent with the nasal fluid and preserved PC12 cell vitality. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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23 pages, 14164 KiB  
Article
Allogenic Fc Domain-Facilitated Uptake of IgG in Nasal Lamina Propria: Friend or Foe for Intranasal CNS Delivery?
by Simone Ladel, Johannes Flamm, Arghavan Soleimani Zadeh, Dorothea Filzwieser, Julia-Christina Walter, Patrick Schlossbauer, Ralf Kinscherf, Katharina Lischka, Harald Luksch and Katharina Schindowski
Pharmaceutics 2018, 10(3), 107; https://doi.org/10.3390/pharmaceutics10030107 - 26 Jul 2018
Cited by 23 | Viewed by 5014
Abstract
Background: The use of therapeutic antibodies for the treatment of neurological diseases is of increasing interest. Nose-to-brain drug delivery is one strategy to bypass the blood brain barrier. The neonatal Fc receptor (FcRn) plays an important role in transepithelial transcytosis of immunoglobulin G [...] Read more.
Background: The use of therapeutic antibodies for the treatment of neurological diseases is of increasing interest. Nose-to-brain drug delivery is one strategy to bypass the blood brain barrier. The neonatal Fc receptor (FcRn) plays an important role in transepithelial transcytosis of immunoglobulin G (IgG). Recently, the presence of the FcRn was observed in nasal respiratory mucosa. The aim of the present study was to determine the presence of functional FcRn in olfactory mucosa and to evaluate its role in drug delivery. Methods: Immunoreactivity and messenger RNA (mRNA) expression of FcRn was determined in ex vivo porcine olfactory mucosa. Uptake of IgG was performed in a side-by-side cell and analysed by immunofluorescence. Results: FcRn was found in epithelial and basal cells of the olfactory epithelium as well as in glands, cavernous bodies and blood vessels. Allogenic porcine IgGs were found time-dependently in the lamina propria and along axonal bundles, while only small amounts of xenogenic human IgGs were detected. Interestingly, lymphoid follicles were spared from allogenic IgGs. Conclusion: Fc-mediated transport of IgG across the nasal epithelial barrier may have significant potential for intranasal delivery, but the relevance of immune interaction in lymphoid follicles must be clarified to avoid immunogenicity. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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16 pages, 3271 KiB  
Article
Chitosan Glutamate-Coated Niosomes: A Proposal for Nose-to-Brain Delivery
by Federica Rinaldi, Patrizia N. Hanieh, Lik King Nicholas Chan, Livia Angeloni, Daniele Passeri, Marco Rossi, Julie Tzu-Wen Wang, Anna Imbriano, Maria Carafa and Carlotta Marianecci
Pharmaceutics 2018, 10(2), 38; https://doi.org/10.3390/pharmaceutics10020038 - 22 Mar 2018
Cited by 75 | Viewed by 7790
Abstract
The aim of this in vitro study is to prepare and characterize drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery to reach the brain through intranasal delivery. Mucoadhesive properties and stability testing in various environments were evaluated to [...] Read more.
The aim of this in vitro study is to prepare and characterize drug free and pentamidine loaded chitosan glutamate coated niosomes for intranasal drug delivery to reach the brain through intranasal delivery. Mucoadhesive properties and stability testing in various environments were evaluated to examine the potential of these formulations to be effective drug delivery vehicles for intranasal delivery to the brain. Samples were prepared using thin film hydration method. Changes in size and ζ-potential of coated and uncoated niosomes with and without loading of pentamidine in various conditions were assessed by dynamic light scattering (DLS), while size and morphology were also studied by atomic force microscopy (AFM). Bilayer properties and mucoadhesive behavior were investigated by fluorescence studies and DLS analyses, respectively. Changes in vesicle size and ζ-potential values were shown after addition of chitosan glutamate to niosomes, and when in contact with mucin solution. In particular, interactions with mucin were observed in both drug free and pentamidine loaded niosomes regardless of the presence of the coating. The characteristics of the proposed systems, such as pentamidine entrapment and mucin interaction, show promising results to deliver pentamidine or other possible drugs to the brain via nasal administration. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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Review

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21 pages, 960 KiB  
Review
Epilepsy Disease and Nose-to-Brain Delivery of Polymeric Nanoparticles: An Overview
by Teresa Musumeci, Angela Bonaccorso and Giovanni Puglisi
Pharmaceutics 2019, 11(3), 118; https://doi.org/10.3390/pharmaceutics11030118 - 13 Mar 2019
Cited by 86 | Viewed by 7682
Abstract
Epilepsy is the fourth most common global neurological problem, which can be considered a spectrum disorder because of its various causes, seizure types, its ability to vary in severity and the impact from person to person, as well as its range of co-existing [...] Read more.
Epilepsy is the fourth most common global neurological problem, which can be considered a spectrum disorder because of its various causes, seizure types, its ability to vary in severity and the impact from person to person, as well as its range of co-existing conditions. The approaches to drug therapy of epilepsy are directed at the control of symptoms by chronic administration of antiepileptic drugs (AEDs). These AEDs are administered orally or intravenously but alternative routes of administration are needed to overcome some important limits. Intranasal (IN) administration represents an attractive route because it is possible to reach the brain bypassing the blood brain barrier while the drug avoids first-pass metabolism. It is possible to obtain an increase in patient compliance for the easy and non-invasive route of administration. This route, however, has some drawbacks such as mucociliary clearance and the small volume that can be administered, in fact, only drugs that are efficacious at low doses can be considered. The drug also needs excellent aqueous solubility or must be able to be formulated using solubilizing agents. The use of nanomedicine formulations able to encapsulate active molecules represents a good strategy to overcome several limitations of this route and of conventional drugs. The aim of this review is to discuss the innovative application of nanomedicine for epilepsy treatment using nose-to-brain delivery with particular attention focused on polymeric nanoparticles to load drugs. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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17 pages, 1312 KiB  
Review
Nanoemulsions for “Nose-to-Brain” Drug Delivery
by Maria Cristina Bonferoni, Silvia Rossi, Giuseppina Sandri, Franca Ferrari, Elisabetta Gavini, Giovanna Rassu and Paolo Giunchedi
Pharmaceutics 2019, 11(2), 84; https://doi.org/10.3390/pharmaceutics11020084 - 17 Feb 2019
Cited by 167 | Viewed by 9583
Abstract
The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding [...] Read more.
The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding the first-pass effect and bypassing the BBB. Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity. Nanoemulsions are formulations belonging to the field of nanomedicine. They consist of emulsions (commonly oil in water) stabilized by one or more surfactants—and eventually co-surfactants—delivered in droplets of small dimensions (sizes of 100–300 nm or less) with a high surface area. A mucoadhesive polymer such as chitosan can be added to the formulation to impair rapid nasal clearance. Nanoemulsions represent promising formulations to deliver drugs directly into the brain through the intranasal route. Therefore, they can be used as a possible alternative to oral administration, avoiding problems such as low solubility in water, poor bioavailability, enzymatic degradation and slow onset of action. This review focuses the present situation in literature regarding the use of nanoemulsions for nose-to-brain targeting, with particular attention to recent publications. Nasal nanoemulsions appear to be effective, non-invasive and safe drug delivery systems to achieve brain targeting for the treatment of neurological diseases. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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16 pages, 1154 KiB  
Review
Blood-Brain Delivery Methods Using Nanotechnology
by Daniel Mihai Teleanu, Cristina Chircov, Alexandru Mihai Grumezescu, Adrian Volceanov and Raluca Ioana Teleanu
Pharmaceutics 2018, 10(4), 269; https://doi.org/10.3390/pharmaceutics10040269 - 11 Dec 2018
Cited by 192 | Viewed by 8859
Abstract
Pathologies of the brain, of which brain cancer, Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis, are some of the most prevalent, and that presently are poorly treated due to the difficulties associated with drug development, administration, and targeting to the brain. The [...] Read more.
Pathologies of the brain, of which brain cancer, Alzheimer’s disease, Parkinson’s disease, stroke, and multiple sclerosis, are some of the most prevalent, and that presently are poorly treated due to the difficulties associated with drug development, administration, and targeting to the brain. The existence of the blood-brain barrier, a selective permeability system which acts as a local gateway against circulating foreign substances, represents the key challenge for the delivery of therapeutic agents to the brain. However, the development of nanotechnology-based approaches for brain delivery, such as nanoparticles, liposomes, dendrimers, micelles, and carbon nanotubes, might be the solution for improved brain therapies. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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28 pages, 2576 KiB  
Review
Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa
by Stella Gänger and Katharina Schindowski
Pharmaceutics 2018, 10(3), 116; https://doi.org/10.3390/pharmaceutics10030116 - 3 Aug 2018
Cited by 261 | Viewed by 18801
Abstract
The blood-brain barrier and the blood-cerebrospinal fluid barrier are major obstacles in central nervous system (CNS) drug delivery, since they block most molecules from entering the brain. Alternative drug delivery routes like intraparenchymal or intrathecal are invasive methods with a remaining risk of [...] Read more.
The blood-brain barrier and the blood-cerebrospinal fluid barrier are major obstacles in central nervous system (CNS) drug delivery, since they block most molecules from entering the brain. Alternative drug delivery routes like intraparenchymal or intrathecal are invasive methods with a remaining risk of infections. In contrast, nose-to-brain delivery is a minimally invasive drug administration pathway, which bypasses the blood-brain barrier as the drug is directed from the nasal cavity to the brain. In particular, the skull base located at the roof of the nasal cavity is in close vicinity to the CNS. This area is covered with olfactory mucosa. To design and tailor suitable formulations for nose-to-brain drug delivery, the architecture, structure and physico-chemical characteristics of the mucosa are important criteria. Hence, here we review the state-of-the-art knowledge about the characteristics of the nasal and, in particular, the olfactory mucosa needed for a rational design of intranasal formulations and dosage forms. Also, the information is suitable for the development of systemic or local intranasal drug delivery as well as for intranasal vaccinations. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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17 pages, 1020 KiB  
Review
In Situ-Based Gels for Nose to Brain Delivery for the Treatment of Neurological Diseases
by Blessing Atim Aderibigbe
Pharmaceutics 2018, 10(2), 40; https://doi.org/10.3390/pharmaceutics10020040 - 30 Mar 2018
Cited by 83 | Viewed by 16961
Abstract
In situ-based gel drug delivery systems that can bypass the blood-brain barrier, deliver the therapeutics to the desired site, reduce peripheral toxicity and control drug release kinetics have been developed. Some of the therapeutics used to treat neurological diseases suffer from poor bioavailability. [...] Read more.
In situ-based gel drug delivery systems that can bypass the blood-brain barrier, deliver the therapeutics to the desired site, reduce peripheral toxicity and control drug release kinetics have been developed. Some of the therapeutics used to treat neurological diseases suffer from poor bioavailability. Preclinical reports from several researchers have proven that the delivery of drugs to the brain via the nose-to-brain route using in situ gels holds great promise. However, safety issues on the toxicity of the nasal mucosa, transportation of the drugs to specific brain regions and determination of the required dose are factors that must be considered when designing these gels. This review will be focused on in situ-based gels that are used for the delivery of therapeutics via the nose-to-brain route, preclinical reports and challenges. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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15 pages, 341 KiB  
Review
Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?
by Alessandro Dalpiaz and Barbara Pavan
Pharmaceutics 2018, 10(2), 39; https://doi.org/10.3390/pharmaceutics10020039 - 26 Mar 2018
Cited by 27 | Viewed by 6897
Abstract
Although several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and [...] Read more.
Although several viruses can easily infect the central nervous system (CNS), antiviral drugs often show dramatic difficulties in penetrating the brain from the bloodstream since they are substrates of active efflux transporters (AETs). These transporters, located in the physiological barriers between blood and the CNS and in macrophage membranes, are able to recognize their substrates and actively efflux them into the bloodstream. The active transporters currently known to efflux antiviral drugs are P-glycoprotein (ABCB1 or P-gp or MDR1), multidrug resistance-associated proteins (ABCC1 or MRP1, ABCC4 or MRP4, ABCC5 or MRP5), and breast cancer resistance protein (ABCG2 or BCRP). Inhibitors of AETs may be considered, but their co-administration causes serious unwanted effects. Nasal administration of antiviral drugs is therefore proposed in order to overcome the aforementioned problems, but innovative devices, formulations (thermoreversible gels, polymeric micro- and nano-particles, solid lipid microparticles, nanoemulsions), absorption enhancers (chitosan, papaverine), and mucoadhesive agents (chitosan, polyvinilpyrrolidone) are required in order to selectively target the antiviral drugs and, possibly, the AET inhibitors in the CNS. Moreover, several prodrugs of antiretroviral agents can inhibit or elude the AET systems, appearing as interesting substrates for innovative nasal formulations able to target anti-Human Immunodeficiency Virus (HIV) agents into macrophages of the CNS, which are one of the most important HIV Sanctuaries of the body. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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34 pages, 4708 KiB  
Review
Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting
by Fabio Sonvico, Adryana Clementino, Francesca Buttini, Gaia Colombo, Silvia Pescina, Silvia Stanisçuaski Guterres, Adriana Raffin Pohlmann and Sara Nicoli
Pharmaceutics 2018, 10(1), 34; https://doi.org/10.3390/pharmaceutics10010034 - 15 Mar 2018
Cited by 221 | Viewed by 14077
Abstract
In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. [...] Read more.
In the field of nasal drug delivery, nose-to-brain delivery is among the most fascinating applications, directly targeting the central nervous system, bypassing the blood brain barrier. Its benefits include dose lowering and direct brain distribution of potent drugs, ultimately reducing systemic side effects. Recently, nasal administration of insulin showed promising results in clinical trials for the treatment of Alzheimer’s disease. Nanomedicines could further contribute to making nose-to-brain delivery a reality. While not disregarding the need for devices enabling a formulation deposition in the nose’s upper part, surface modification of nanomedicines appears the key strategy to optimize drug delivery from the nasal cavity to the brain. In this review, nanomedicine delivery based on particle engineering exploiting surface electrostatic charges, mucoadhesive polymers, or chemical moieties targeting the nasal epithelium will be discussed and critically evaluated in relation to nose-to-brain delivery. Full article
(This article belongs to the Special Issue Nose to Brain Delivery)
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