Elsevier

Advanced Drug Delivery Reviews

Volume 57, Issue 11, 3 November 2005, Pages 1640-1665
Advanced Drug Delivery Reviews

Nasal mucoadhesive drug delivery: Background, applications, trends and future perspectives

https://doi.org/10.1016/j.addr.2005.07.009Get rights and content

Abstract

Nasal drug delivery has now been recognized as a very promising route for delivery of therapeutic compounds including biopharmaceuticals. It has been demonstrated that low absorption of drugs can be countered by using absorption enhancers or increasing the drug residence time in the nasal cavity, and that some mucoadhesive polymers can serve both functions. This article reviews the background of nasal mucoadhesive drug delivery with special references to the biological and pharmaceutical considerations for nasal mucoadhesive drug administration. Applications of nasal mucoadhesives for the delivery of small organic molecules, antibiotics, proteins, vaccines and DNA are also discussed. Furthermore, new classes of functionalized mucoadhesive polymers, the characterization and safety aspects of nasal drug products as well as the opportunities presented by nasal drug delivery are extensively discussed.

Introduction

Nasal drug delivery for systemic effects has been practiced since ancient times. In modern pharmaceutics, the nose had been considered primarily as a route for local drug delivery. The last 2 decades heralded a number of advances in pharmaceutical biotechnology resulting in possibilities for large-scale productions of biopharmaceuticals especially proteins and peptides. The inability to administer these drugs by routes other than parenteral injection motivated scientists to explore other possibilities such as pulmonary and nasal administration. The initial enthusiasm was soon confronted with disappointing in vivo results showing poor bioavailabilities, typically in the order of < 5–10% for large molecules. On the other hand, very good results were obtained with small organic molecules, which led to the successful development of a number of products currently on the market [1], list of products that is steadily increasing. Examination of the causes of failure led to the conclusion that the short residence time of the formulation within the nasal cavity coupled to the low permeability of the latter did play significant roles. Consequently, the attention shifted to the evaluation of mucoadhesive polymers, some of which would even demonstrate additional permeation-enhancing capabilities [2], [3]. The encouraging results and the desire to overcome some new challenges stimulated the development of new generations of polymers based on pH or thermal responsiveness [4], [5] or modified existing polymers having improved bioadhesive or permeation-enhancing properties [6], [7], [8]. Even though a number of challenges are still to be overcome, especially with respect to toxicity, the potential of nasal drug delivery (NDD), including the ability to target drugs across the blood–brain barrier (BBB), are very high and continues to stimulate academic and industrial research groups so that we will keep witnessing increasing number of advanced nasal drug delivery products.

Section snippets

Nasal anatomy and physiology relevant to nasal mucoadhesive drug administration

The nasal cavity is divided into two halves by the nasal septum and extends posteriorly to the nasopharynx, while the most anterior part of the nasal cavity, the nasal vestibule, opens to the face through the nostril (Fig. 1). The atrium is an intermediate region between the vestibule and the respiratory region. The respiratory region, the nasal conchae or turbinates, which occupies the major part of the nasal cavity, possesses lateral walls dividing it into 3 sections: the superior, middle and

Mucoadhesion as a strategy to improve systemic drug delivery via the nasal route

Parenteral drug administration has a lot of advantages compared to the other routes of drug administration. The superiority of these routes (iv, im, sc) stems from reduced drug metabolism and degradation, higher degree of utilization of the administered dose, programmable drug dosing within the therapeutic index, etc. However, parenteral routes, especially iv injection, have some major disadvantages such as patient compliance, health hazards, higher cost of therapy due to use of highly

Nasal mucoadhesive delivery of pharmaceutical compounds

Mucoadhesives have been used to improve local and systemic delivery of therapeutic compounds. This section examines specific applications of mucoadhesive compounds with respect to nasal administration of small organic molecules, antibiotics, vaccines, DNA, proteins and other macromolecules.

New generation of nasal mucoadhesives

Initial research on nasal mucoadhesion employed polymers manufactured for other purposes in the pharmaceutical and food industries. As shown in Table 2 several different types of polymers have been employed for delivery of different types/classes of drugs. In many cases very encouraging results were obtained, to the extent that marketed products could be developed. In a lot of other cases only marginal or even no successes were obtained. Further examination of the causes of failure pointed to

Mucoadhesion as a fast track industrial product development

The advantages of administering drugs nasally compared to oral or parenteral route have been described under Section 3. Exploitation of these unique advantages could lead to a fast track product development. This is proven by the increasing number of nasally administered drugs [1] as well as companies either entirely specialized in NDD or have strong presence in NDD research.

The possibility of increased drug absorption will allow product development of nasal peptides and small proteins, while

Safety considerations

Absorption enhancement and toxicity are the key issues in the search and design of effective and safe drug formulations for the nasal route [153]. From pharmacokinetic point of view, achieving sustained release for several hours is desirable. However, toxicity of the excipients could be aggravated because of extended contact with the nasal mucosa. Ideally, mucoadhesive polymers or other excipients should be cleared from the nasal mucosa within a few hours in order not to impair the mucociliary

Conclusions

There are a lot of exciting developments in the field of NDD including mucoadhesion. Newly marketed products based on existing polymers are on the increase, while new polymers and administration devices are still being developed. There is a lot of ground for optimism with respect to benefits derivable from more fundamental research and application leading to better understanding of the subject and eventually more marketed products. A point of caution will always be the safety aspects of nasal

Acknowledgement

This work was partly sponsored by OctoPlus International Holding BV, Zernikedreef 12, 2333 CL Leiden, The Netherlands.

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    This review is part of the Advanced Drug Delivery Reviews theme issue on "Mucoadhesive Polymers: Strategies, Achievements and Future Challenges", Vol. 57/11, 2005.

    1

    Current affiliation: Pharmaceutical and Analytical Development Department, Solvay Pharmaceuticals BV, C.J. Houtlaan 36 (WNH 224), 1381 CP Weesp, The Netherlands.

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