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Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmaceutical Technology, Manufacturing and Devices".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 20382

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Prof. Dr. Anita Hafner

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Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, 10000 Zagreb, Croatia
Interests: nasal drug delivery; nasal powders; spray-drying; nanoparticles; in situ gelling systems; nasal deposition
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Dear Colleagues,

Nasal drug administration offers a wide range of therapeutic options including local and systemic drug delivery, brain targeted therapy and mucosal vaccination. However, its potential has yet to be fully exploited. Widening the palette of nasally administered drugs requires development of innovative drug formulations enhancing drug availability at the action site. Namely, formulation strategy is the key response to drug solubility, permeation and stability issues as well as mucoadhesive performance. Another key aspect is consideration of efficient drug deposition in specific nasal regions of interest, which is a prerequisite for effective nasal therapy.

This special issue aims to highlight the latest strategies and innovations in development and administration of nasal drug delivery systems. We are pleased to invite you to submit your original research articles or reviews within this subject area. Research topics may include (but not limited to) the following: Development of innovative liquid and powder nasal drug delivery systems; Nanotechnology in nasal drug delivery; In vitro/ex vivo/in vivo characterization methods in nasal formulation development; Nasal deposition studies.

I look forward to receiving your contributions.

Prof. Dr. Anita Hafner
Guest Editor

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Keywords

innovative nasal drug formulations
local effect
systemic bioavailability
nose-to-brain delivery
mucoadhesion
biocompatiblity
permeability
nasal deposition
nasal delivery device

Published Papers (9 papers)

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Research

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11 pages, 3324 KiB

Open AccessArticle

Improved Olfactory Deposition of Theophylline Using a Nanotech Soft Mist Nozzle Chip

by Madeline X. Zhang, Frank Verhoeven, Pieter Ravensbergen, Stefan Kooij, Rick Geoffrion, Daniel Bonn and Cees J. M. van Rijn

Pharmaceutics 2024, 16(1), 2; https://doi.org/10.3390/pharmaceutics16010002 - 19 Dec 2023

Viewed by 1222

Abstract

Currently, nasal administration of active pharmaceutical ingredients is most commonly performed using swirl-nozzle-based pump devices or pressurized syringes. However, they lead to limited deposition in the more active regions of the nasal cavity, especially the olfactory region, which is crucial for nose-to-brain drug delivery. This research proposes to improve deposition in the olfactory region by replacing the swirl nozzle with a nanoengineered nozzle chip containing micrometer-sized holes, which generates smaller droplets of 10–50 μm travelling at a lower plume velocity. Two nanotech nozzle chips with different hole sizes were tested at different inhalation flow rates to examine the deposition patterns of theophylline, a hyposmia treatment formulation, using a nasal cavity model. A user study was also conducted and showed that the patient instructions influenced the inhalation flow rate characteristics. Targeted flow rates of between 0 and 25 L/min were used for the in vitro deposition study, yielding 21.5–31.5% olfactory coverage. In contrast, the traditional swirl nozzle provided only 10.8% coverage at a similar flow rate. This work highlights the potential of the nanotech soft mist nozzle for improved intranasal drug delivery, particularly to the olfactory region. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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11 pages, 3143 KiB

Open AccessArticle

Utility of a Novel Micro-Spraying Device for Intranasal Administration of Drug Solutions to Mice

by Naoto Suzuki, Hiroaki Tanigawa, Taiki Nagatomo, Hiroko Miyagishi, Takanori Kanazawa, Toyofumi Suzuki and Yasuhiro Kosuge

Pharmaceutics 2023, 15(11), 2553; https://doi.org/10.3390/pharmaceutics15112553 - 29 Oct 2023

Viewed by 1790

Abstract

Intranasal administration has attracted attention as a means of delivering drugs because it bypasses the blood–brain barrier. However, conventional intranasal administration of drug solutions to mice using the micropipette method (MP method) is complicated and time-consuming because it requires small doses to be administered under inhalation anesthesia. This study evaluated the effectiveness of a novel intranasal administration method using Micro FPS™, a novel micro-spraying device (the MSD method). The MSD method allowed more reliable administration of the solution to the nasal mucosa than the MP method did. The transfer of inulin, a model water-soluble macromolecule compound, to the olfactory bulb and brain (cerebrum, cerebellum, brainstem, and striatum) was similar with the two methods. It also allowed the drug to be administered in a shorter time. These results suggest that the MSD method is simpler and more rapid than the MP method for intranasal administration of drugs to mice and achieves comparable delivery of inulin to the olfactory bulb and brain. Therefore, the Micro FPS™ device is a potentially useful tool for intranasal drug administration to rodents and could facilitate the development of intranasal formulations, contributing to drug development for central nervous system diseases. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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21 pages, 4299 KiB

Open AccessArticle

Innovative Aqueous Nanoemulsion Prepared by Phase Inversion Emulsification with Exceptional Homogeneity

by Patrícia C. Pires, Mariana Fernandes, Francisca Nina, Francisco Gama, Maria F. Gomes, Lina E. Rodrigues, Sara Meirinho, Samuel Silvestre, Gilberto Alves and Adriana O. Santos

Pharmaceutics 2023, 15(7), 1878; https://doi.org/10.3390/pharmaceutics15071878 - 04 Jul 2023

Cited by 1 | Viewed by 2215

Abstract

Formulating low-solubility or low-permeability drugs is a challenge, particularly with the low administration volumes required in intranasal drug delivery. Nanoemulsions (NE) can solve both issues, but their production and physical stability can be challenging, particularly when a high proportion of lipids is necessary. Hence, the aim of the present work was to develop a NE with good solubilization capacity for lipophilic drugs like simvastatin and able to promote the absorption of drugs with low permeability like fosphenytoin. Compositions with high proportion of two lipids were screened and characterized. Surprisingly, one of the compositions did not require high energy methods for high droplet size homogeneity. To better understand formulation factors important for this feature, several related compositions were evaluated, and their relative cytotoxicity was screened. Optimized compositions contained a high proportion of propylene glycol monocaprylate NF, formed very homogenous NE using a low-energy phase inversion method, solubilized simvastatin at high drug strength, and promoted a faster intranasal absorption of the hydrophilic prodrug fosphenytoin. Hence, a new highly homogeneous NE obtained by a simple low-energy method was successfully developed, which is a potential alternative for industrial application for the solubilization and protection of lipophilic actives, as well as (co-)administration of hydrophilic molecules. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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29 pages, 1342 KiB

Open AccessArticle

Chitosan-Based Thermogelling System for Nose-to-Brain Donepezil Delivery: Optimising Formulation Properties and Nasal Deposition Profile

by Mirna Perkušić, Laura Nižić Nodilo, Ivo Ugrina, Drago Špoljarić, Cvijeta Jakobušić Brala, Ivan Pepić, Jasmina Lovrić, Maša Safundžić Kučuk, Marie Trenkel, Regina Scherließ, Dijana Zadravec, Livije Kalogjera and Anita Hafner

Pharmaceutics 2023, 15(6), 1660; https://doi.org/10.3390/pharmaceutics15061660 - 05 Jun 2023

Cited by 3 | Viewed by 1859

Abstract

Donepezil nasal delivery strategies are being continuously investigated for advancing therapy in Alzheimer’s disease. The aim of this study was to develop a chitosan-based, donepezil-loaded thermogelling formulation tailored to meet all the requirements for efficient nose-to-brain delivery. A statistical design of the experiments was implemented for the optimisation of the formulation and/or administration parameters, with regard to formulation viscosity, gelling and spray properties, as well as its targeted nasal deposition within the 3D-printed nasal cavity model. The optimised formulation was further characterised in terms of stability, in vitro release, in vitro biocompatibility and permeability (using Calu-3 cells), ex vivo mucoadhesion (using porcine nasal mucosa), and in vivo irritability (using slug mucosal irritation assay). The applied research design resulted in the development of a sprayable donepezil delivery platform characterised by instant gelation at 34 °C and olfactory deposition reaching a remarkably high 71.8% of the applied dose. The optimised formulation showed prolonged drug release (t_1/2 about 90 min), mucoadhesive behaviour, and reversible permeation enhancement, with a 20-fold increase in adhesion and a 1.5-fold increase in the apparent permeability coefficient in relation to the corresponding donepezil solution. The slug mucosal irritation assay demonstrated an acceptable irritability profile, indicating its potential for safe nasal delivery. It can be concluded that the developed thermogelling formulation showed great promise as an efficient donepezil brain-targeted delivery system. Furthermore, the formulation is worth investigating in vivo for final feasibility confirmation. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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21 pages, 6533 KiB

Open AccessArticle

Visualization and Estimation of Nasal Spray Delivery to Olfactory Mucosa in an Image-Based Transparent Nasal Model

by Amr Seifelnasr, Xiuhua April Si and Jinxiang Xi

Pharmaceutics 2023, 15(6), 1657; https://doi.org/10.3390/pharmaceutics15061657 - 05 Jun 2023

Cited by 4 | Viewed by 2072

Abstract

Background: Nose-to-brain (N2B) drug delivery offers unique advantages over intravenous methods; however, the delivery efficiency to the olfactory region using conventional nasal devices and protocols is low. This study proposes a new strategy to effectively deliver high doses to the olfactory region while minimizing dose variability and drug losses in other regions of the nasal cavity. Materials and Methods: The effects of delivery variables on the dosimetry of nasal sprays were systematically evaluated in a 3D-printed anatomical model that was generated from a magnetic resonance image of the nasal airway. The nasal model comprised four parts for regional dose quantification. A transparent nasal cast and fluorescent imaging were used for visualization, enabling detailed examination of the transient liquid film translocation, real-time feedback on input effect, and prompt adjustment to delivery variables, which included the head position, nozzle angle, applied dose, inhalation flow, and solution viscosity. Results: The results showed that the conventional vertex-to-floor head position was not optimal for olfactory delivery. Instead, a head position tilting 45–60° backward from the supine position gave a higher olfactory deposition and lower variability. A two-dose application (250 mg) was necessary to mobilize the liquid film that often accumulated in the front nose following the first dose administration. The presence of an inhalation flow reduced the olfactory deposition and redistributed the sprays to the middle meatus. The recommended olfactory delivery variables include a head position ranging 45–60°, a nozzle angle ranging 5–10°, two doses, and no inhalation flow. With these variables, an olfactory deposition fraction of 22.7 ± 3.7% was achieved in this study, with insignificant discrepancies in olfactory delivery between the right and left nasal passages. Conclusions: It is feasible to deliver clinically significant doses of nasal sprays to the olfactory region by leveraging an optimized combination of delivery variables. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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13 pages, 2493 KiB

Open AccessArticle

Safety in Rats of a Novel Nasal Spray Formulation for the Prevention of Airborne Viral Infections

by Mirella Tanori, Michele Pitaro, Emiliano Fratini, Eleonora Colantoni, Angela Amoresano, Simona Celentano, Barbara Chiaramonte and Mariateresa Mancuso

Pharmaceutics 2023, 15(2), 591; https://doi.org/10.3390/pharmaceutics15020591 - 09 Feb 2023

Viewed by 1627

Abstract

Hexedra+^® is a nasal spray containing hydroxypropyl methylcellulose, beta-cyclodextrin, and usnic acid. It has been developed with the aim of reducing the risk of transmission of airborne viral infections, with particular reference to influenza and COVID-19. As part of the preclinical development of the product, we carried out a study on thirty male Wistar rats divided into three study groups and treated with Hexedra+, an alternative formulation containing a double concentration of usnic acid (0.015% instead of 0.0075%) or saline solution. Products were administered at the dose of 30 μL into each nostril, three times a day for seven consecutive days by means of a micropipette. By the end of the treatment period, no significant changes were observed in body weight. Histological examination of nasal mucosa and soft organs did not show any significant difference in the three study groups. Serum transaminase level remained in the normal limit in all the animals treated. The serum level of usnic acid was measured in order to assess the absorption of the molecule through the nasal mucosa. By the end of the study period, the usnic acid serum level was negligible in all the animals treated. In conclusion, the safety profile of Hexedra+ appears favorable in the animal model studied. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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Review

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15 pages, 2849 KiB

Open AccessReview

Optimizing Absorption for Intranasal Delivery of Drugs Targeting the Central Nervous System Using Alkylsaccharide Permeation Enhancers

by Stuart Madden, Enrique Carrazana and Adrian L. Rabinowicz

Pharmaceutics 2023, 15(8), 2119; https://doi.org/10.3390/pharmaceutics15082119 - 10 Aug 2023

Cited by 2 | Viewed by 2456

Abstract

Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)–approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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26 pages, 9231 KiB

Open AccessReview

The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and “Nose-to-Brain”

by Stephen B. Shrewsbury

Pharmaceutics 2023, 15(6), 1720; https://doi.org/10.3390/pharmaceutics15061720 - 13 Jun 2023

Cited by 5 | Viewed by 2064

Abstract

Sino-nasal disease is appropriately treated with topical treatment, where the nasal mucosa acts as a barrier to systemic absorption. Non-invasive nasal delivery of drugs has produced some small molecule products with good bioavailability. With the recent COVID pandemic and the need for nasal mucosal immunity becoming more appreciated, more interest has become focused on the nasal cavity for vaccine delivery. In parallel, it has been recognized that drug delivery to different parts of the nose can have different results and for “nose-to-brain” delivery, deposition on the olfactory epithelium of the upper nasal space is desirable. Here the non-motile cilia and reduced mucociliary clearance lead to longer residence time that permits enhanced absorption, either into the systemic circulation or directly into the CNS. Many of the developments in nasal delivery have been to add bioadhesives and absorption/permeation enhancers, creating more complicated formulations and development pathways, but other projects have shown that the delivery device itself may allow more differential targeting of the upper nasal space without these additions and that could allow faster and more efficient programs to bring a wider range of drugs—and vaccines—to market. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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25 pages, 2376 KiB

Open AccessReview

Lipid and Polymeric Nanoparticles: Successful Strategies for Nose-to-Brain Drug Delivery in the Treatment of Depression and Anxiety Disorders

by Margarida Alberto, Ana Cláudia Paiva-Santos, Francisco Veiga and Patrícia C. Pires

Pharmaceutics 2022, 14(12), 2742; https://doi.org/10.3390/pharmaceutics14122742 - 08 Dec 2022

Cited by 10 | Viewed by 3497

Abstract

Intranasal administration has gained an increasing interest for brain drug delivery since it allows direct transport through neuronal pathways, which can be quite advantageous for central nervous system disorders, such as depression and anxiety. Nanoparticles have been studied as possible alternatives to conventional formulations, with the objective of improving drug bioavailability. The present work aimed to analyze the potential of intranasal nanoparticle administration for the treatment of depression and anxiety, using the analysis of several studies already performed. From the carried-out analysis, it was concluded that the use of nanoparticles allows the drug’s protection from enzymatic degradation, and the modulation of its components allows controlled drug release and enhanced drug permeation. Furthermore, the results of in vivo studies further verified these systems’ potential, with the drug reaching the brain faster and leading to increased bioavailability and, consequently, therapeutic effect. Hence, in general, the intranasal administration of nanoparticles leads to a faster onset of action, with increased and prolonged brain drug concentrations and, consequently, therapeutic effects, presenting high potential as an alternative to the currently available therapies for the treatment of depression and anxiety. Full article

(This article belongs to the Special Issue Challenges and Innovative Solutions in Nasal Drug Delivery: From Formulation Development to Mode of Administration)

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