Nasal mucoadhesive drug delivery: Background, applications, trends and future perspectives☆
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.
References (162)
- et al.
Effects of physicochemical properties and other factors on systemic nasal drug delivery
Adv. Drug Deliv. Rev.
(1998) - et al.
Effect of chitosan on epithelial permeability and structure
Int. J. Pharm.
(1999) - et al.
Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery
J. Control. Release
(1999) - et al.
Improvement in the mucoadhesive properties of alginate by the covalent attachment of cysteine
J. Control. Release
(2001) - et al.
Permeability issues in nasal drug delivery
Drug Discov. Today
(2002) - et al.
Human respiratory mucus
J. Allergy Clin. Immunol.
(1984) - et al.
The complexity of mucins
Biochimie
(1988) - et al.
Human cervical mucus: III. Isolation and characterization of rheologically active mucin
Fertil. Steril.
(1977) - et al.
Mass transport phenomena and models: theoretical concepts
J. Pharm. Sci.
(1974) - et al.
The physical properties of biogels and their permeability for macromolecular drugs and colloidal drug carriers
J. Pharm. Sci.
(2000)
Light microscopical observations on luminally administered dyes, dextrans, nanospheres and microspheres in the pre-epithelial mucus gel layer of the rat distal colon
J. Control. Release
Bioadhesive polymers as platforms for oral controlled drug delivery: II. Synthesis and evaluation of some swelling, water-insoluble bioadhesive polymers
J. Pharm. Sci.
The release of model macromolecules may be controlled by the hydrophobicity of palmitoyl glycol chitosan hydrogels
J. Control. Release
Physicochemical properties of water insoluble polymers important to mucin/epithelial adhesion
J. Control. Release
On the relationship between the electrostatic and the molecular components of the adhesion of elastic particles to a solid surface
J. Colloid Interface Sci.
Bioadhesive analysis of controlled-release systems: I. Fracture and interpenetration analysis in poly(acrylic acid-containing systems
J. Control. Release
Bioadhesive intraoral release systems: design, testing and analysis
Biomaterials
In vitro bioadhesion of Carbopol hydrogels
Int. J. Pharm.
Bioadhesive analysis of controlled-release systems: III. Bioadhesive and release behavior of metronidazole-containing poly(acrylic acid)-hydroxypropyl methylcellulose systems
Int. J. Pharm.
Bioadhesive starch microspheres and absorption enhancing agents act synergistically to enhance the nasal absorption of polypeptides
Int. J. Pharm.
Nasal absorption enhancement strategies for therapeutic peptides: an in vitro study using cultured human nasal epithelium
Int. J. Pharm.
Nasal toxicological investigations of Carbopol 971P formulation of apomorphine: effects on ciliary beat frequency of human nasal primary cell culture and in vivo on rabbit nasal mucosa
Eur. J. Pharm. Sci.
Nasal mucoadhesive delivery systems of the anti-parkinsonian drug, apomorphine: influence of drug-loading on in vitro and in vivo release in rabbits
Int. J. Pharm.
Stability of apomorphine in plasma and its determination by high-performance liquid chromatography with electrochemical detection
J. Chromatogr., B, Biomed. Sci. Appl.
Bioavailability of apomorphine following intranasal administration of mucoadhesive drug delivery systems in rabbits
Eur. J. Pharm. Sci.
Scintigraphic evaluation in rabbits of nasal drug delivery systems based on carbopol 971P and carboxymethylcellulose
J. Control. Release
Toxicological investigations of the effects carboxymethylcellulose on ciliary beat frequency of human nasal epithelial cells in primary suspension culture and in vivo on rabbit nasal mucosa
Int. J. Pharm.
Caffeine microparticles for nasal administration obtained by spray drying
Int. J. Pharm.
Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray
Int. J. Pharm.
Development of a novel nasal nicotine formulation comprising an optimal pulsatile and sustained plasma nicotine profile for smoking cessation
J. Control. Release
Pilot study of nasal morphine-chitosan for the relief of breakthrough pain in patients with cancer
J. Pain Symp. Manag.
Preparation and characterization of starch/cyclodextrin bioadhesive microspheres as platform for nasal administration of gabexate mesylate (Foys) in allergic rhinitis treatment
Biomaterials
Preparation and evaluation of the in vitro drug release properties and mucoadhesion of novel microspheres of hyaluronic acid and chitosan
J. Control. Release
Mucoadhesive microspheres containing gentamicin sulfate for nasal administration: preparation and in vitro characterization
Farmaco
New strategies for using mucosal vaccination to achieve more effective immunisation
Vaccine
Partial protection to respiratory syncytial virus (RSV) elicited in mice by intranasal immunisation using live staphylococci with surface-displayed RSV-peptides
Vaccine
Multifunctional polymers for the peroral delivery of peptide drugs
In situ gelling and mucoadhesive polymer vehicles for controlled intranasal delivery of plasmid DNA
J. Biomed. Mater. Res.
Chitosan and chitosan derivatives as absorption enhancers for peptide drugs across mucosal epithelia
Aminated gelatin as a nasal absorption enhancer for peptide drugs: evaluation of absorption enhancing effect and nasal mucosa perturbation in rats
J. Pharm. Pharmacol.
Mucociliary clearance and drug delivery via the respiratory tract
Adv. Drug Deliv. Rev.
Distribution of mucus producing elements in the respiratory tract. Difference between upper and lower airways
Eur. J. Respir. Dis.
The microbial ecology and immunology of the adenoid: implications for otitis media
Ann. N.Y. Acad. Sci.
The upper airways: I. Nasal physiology and defence of the lungs
Am. Rev. Respir. Disord.
Drug delivery to the buccal and nasal cavities, anatomical and physiological considerations
Effect of cigarette smoking on nasal mucociliary clearance and ciliary beat frequency
Thorax
The constituents of nasal secretion
Ear Nose Throat J.
The physiology of cilia and mucociliary interactions
Annu. Rev. Physiol.
The biopharmaceutical aspects of nasal mucoadhesive drug delivery
J. Pharm. Pharmacol.
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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.
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Current affiliation: Pharmaceutical and Analytical Development Department, Solvay Pharmaceuticals BV, C.J. Houtlaan 36 (WNH 224), 1381 CP Weesp, The Netherlands.