Special Issue "Nose to Brain Delivery"

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

Deadline for manuscript submissions: 30 November 2018

Special Issue Editors

Guest Editor
Prof. Paolo Giunchedi

Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy
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Interests: drug delivery; nanomedicine; nasal route
Guest Editor
Prof. Elisabetta Gavini

Department of Chemistry and Pharmacy, University of Sassari, via Muroni 23/a, 07100 Sassari, Italy
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Interests: drug delivery; nanomedicine; nasal route
Guest Editor
Prof. Maria Cristina Bonferoni

Department of Drug Sciences, University of Pavia, via Taramelli 12, 27100 Pavia, Italy
Website | E-Mail
Interests: drug delivery; nanomedicine; nanoemulsions

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

Manuscript Submission Information

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Keywords

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

Published Papers (6 papers)

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Research

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Open AccessArticle Allogenic Fc Domain-Facilitated Uptake of IgG in Nasal Lamina Propria: Friend or Foe for Intranasal CNS Delivery?
Pharmaceutics 2018, 10(3), 107; https://doi.org/10.3390/pharmaceutics10030107
Received: 24 June 2018 / Revised: 19 July 2018 / Accepted: 20 July 2018 / Published: 26 July 2018
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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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Open AccessArticle Chitosan Glutamate-Coated Niosomes: A Proposal for Nose-to-Brain Delivery
Pharmaceutics 2018, 10(2), 38; https://doi.org/10.3390/pharmaceutics10020038
Received: 25 January 2018 / Revised: 17 March 2018 / Accepted: 19 March 2018 / Published: 22 March 2018
Cited by 2 | PDF Full-text (3271 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa
Pharmaceutics 2018, 10(3), 116; https://doi.org/10.3390/pharmaceutics10030116
Received: 30 June 2018 / Revised: 25 July 2018 / Accepted: 1 August 2018 / Published: 3 August 2018
PDF Full-text (2576 KB) | HTML Full-text | XML Full-text
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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Open AccessReview In Situ-Based Gels for Nose to Brain Delivery for the Treatment of Neurological Diseases
Pharmaceutics 2018, 10(2), 40; https://doi.org/10.3390/pharmaceutics10020040
Received: 13 January 2018 / Revised: 17 February 2018 / Accepted: 22 February 2018 / Published: 30 March 2018
Cited by 2 | PDF Full-text (1020 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Nose-to-Brain Delivery of Antiviral Drugs: A Way to Overcome Their Active Efflux?
Pharmaceutics 2018, 10(2), 39; https://doi.org/10.3390/pharmaceutics10020039
Received: 21 February 2018 / Revised: 16 March 2018 / Accepted: 19 March 2018 / Published: 26 March 2018
Cited by 1 | PDF Full-text (341 KB) | HTML Full-text | XML Full-text
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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Open AccessReview Surface-Modified Nanocarriers for Nose-to-Brain Delivery: From Bioadhesion to Targeting
Pharmaceutics 2018, 10(1), 34; https://doi.org/10.3390/pharmaceutics10010034
Received: 8 February 2018 / Revised: 10 March 2018 / Accepted: 12 March 2018 / Published: 15 March 2018
Cited by 6 | PDF Full-text (4708 KB) | HTML Full-text | XML Full-text
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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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Tentative Title: Versatile mucohadesive niosomes: a deep physico-chemical characterization
Author: Maria Carafa
Abstract: The aim of this study is to prepare suitable chitosan-glutamate(CG) coated non-ionic surfactant vesicles for intranasal delivery. Different vesicles were prepared using several non-ionic surfactants, cholesterol and chitosan glutamate. The interaction between CG coated niosomes and different mucin concentrations was studied to obtain vesicles with mucoadhesive properties. The size, ζ-potential and pH of the nanocarriers were controlled during the study to be suited for nasal delivery. Furthermore, fluorimetric analysis was carried out to investigate fluidity, microviscosity, polarity of vesicle bilayer and turbidity of CGcoated niosome suspensions. The physical-chemical stability of niosome suspensions were tested at two different storage temperatures, 4ºC and room temperature, following the size and ζ-potential. Additionally, stability studies in artificial biological fluids were carried out. Morphology studies using Atomic Force Microscopy (AFM) was employed for niosomes, CG coated-niosomes and CG coated-niosomes with mucin.

Tentative Title: Nose to Brain Delivery of Polymeric Nanoparticles for Epilepsy Disease: an overview
Authors: Teresa Musumeci1, Angela Bonaccorso and Giovanni Puglisi
Abstract: Epilepsy is the 4th most common neurological problem affecting world population, which can be considered a spectrum disorder because of its several causes, seizure types, its ability to vary in severity and impact from person to person, and its range of co-existing conditions. The approaches to drug therapy of epilepsy are directed at the control of symptoms by chronic administrations of antiepileptic drugs. The AED are administered orally or intravenously but alternative routes of administration are needed to overcome the limits. Intranasal administration represents an attractive route because it is possible to reach the brain bypassing blood brain barrier and the drug avoids first pass metabolism. It is possible to obtain an increase in patient compliance for the easy and non-invasive way of administration. This route shows some drawbacks such as mucociliar clearance and the small volume that could be administrated, in fact only drugs that are efficacy 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 in order to overcome several limitations of this route and of conventional drug. The aim of this review is to describe the innovative application of nanomedicine for epilepsy treatment using nose to brain delivery.

 

 

 

 

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