Nasal Mucoadhesive Drug Delivery: Background, Applications, Trends and Future Perspectives

Advanced Drug Delivery Reviews 57 (2005) 1640 – 1665
www.elsevier.com/locate/addr
Nasal mucoadhesive drug delivery: Background, applications,

trends and future perspectivesB
Michael I. Ugwoke a,1, Remigius U. Agu c, Norbert Verbeke b,*, Renaat Kinget b
a
OctoPlus Development BV, Zernikedreef 12, 2333 CL Leiden, The Netherlands
b
Laboratorium voor Farmacotechnologie en Biofarmacie, Campus Gasthuisberg O&N,
Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
c
College of Pharmacy, Dalhousie University, Halifax, NS, Canada B3H 3J5
Received 10 December 2004; accepted 12 July 2005
Available online 21 September 2005
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 pharmaceu-
tical 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.
D 2005 Elsevier B.V. All rights reserved.
Keywords: Absorption enhancer; Microparticles; Microspheres; Mucoadhesion; Mucociliary clearance; Nasal absorption; Nasal drug
delivery; Polymer
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1641
2. Biological and pharmaceutical considerations for nasal mucoadhesive drug delivery . . . . . . . . . . . . . . 1642
2.1. Nasal anatomy and physiology relevant to nasal mucoadhesive drug administration . . . . . . . . . . 1642
B
This review is part of the Advanced Drug Delivery Reviews theme issue on ‘‘Mucoadhesive Polymers: Strategies, Achievements and
Future Challenges’’, Vol. 57/11, 2005.
* Corresponding author.
E-mail address: Norbert.verbeke@pharm.kuleuven.ac.be (N. Verbeke).
1
Current affiliation: Pharmaceutical and Analytical Development Department, Solvay Pharmaceuticals BV, C.J. Houtlaan 36 (WNH 224),
1381 CP Weesp, The Netherlands.
0169-409X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.addr.2005.07.009
M.I. Ugwoke et al. / Advanced Drug Delivery Reviews 57 (2005) 1640–1665 1641
2.2. Nasal mucus secretion and mucociliary clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642

2.2.1. Mucociliary clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642
2.3. Biophysics of nasal mucus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1644
2.4. Mucus–drug interaction: relevance to nasal mucoadhesive drug delivery . . . . . . . . . . . . . . . . 1645
2.5. Mechanism of bioadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1645
2.6. Factors that influence mucoadhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1646
2.6.1. Polymer-related factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1646
2.6.2. Environment-related factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1646
2.6.3. Physiological-related factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1646
3. Mucoadhesion as a strategy to improve systemic drug delivery via the nasal route . . . . . . . . . . . . . . 1647
4. Nasal mucoadhesive delivery of pharmaceutical compounds . . . . . . . . . . . . . . . . . . . . . . . . . . 1648
4.1. Small organic molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1648
4.2. Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1651
4.3. Macromolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1652
4.3.1. Vaccines and DNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1652
4.3.2. Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1653
5. New generation polymers used on nasal drug delivery and characterization of NDD products. . . . . . . . 1654
5.1. New generation of nasal mucoadhesives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1654
5.2. Characterization of polymers for nasal drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . 1655
6. Nasal drug delivery opportunities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1659
6.1. Mucoadhesion as a fast track industrial product development . . . . . . . . . . . . . . . . . . . . . . 1659
7. Safety considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1659
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1660
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1660
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1660
1. Introduction of failure led to the conclusion that the short resi-

dence time of the formulation within the nasal cavity
Nasal drug delivery for systemic effects has been coupled to the low permeability of the latter did play
practiced since ancient times. In modern pharmaceu- significant roles. Consequently, the attention shifted
tics, the nose had been considered primarily as a to the evaluation of mucoadhesive polymers, some of
route for local drug delivery. The last 2 decades which would even demonstrate additional permea-
heralded a number of advances in pharmaceutical tion-enhancing capabilities [2,3]. The encouraging
biotechnology resulting in possibilities for large- results and the desire to overcome some new chal-
scale productions of biopharmaceuticals especially lenges stimulated the development of new genera-
proteins and peptides. The inability to administer tions of polymers based on pH or thermal
these drugs by routes other than parenteral injection responsiveness [4,5] or modified existing polymers
motivated scientists to explore other possibilities having improved bioadhesive or permeation-enhan-
such as pulmonary and nasal administration. The cing properties [6,7,8]. Even though a number of
initial enthusiasm was soon confronted with disap- challenges are still to be overcome, especially with
pointing in vivo results showing poor bioavailabil- respect to toxicity, the potential of nasal drug deliv-
ities, typically in the order of b 5–10% for large ery (NDD), including the ability to target drugs
molecules. On the other hand, very good results across the blood–brain barrier (BBB), are very high
were obtained with small organic molecules, which and continues to stimulate academic and industrial
led to the successful development of a number of research groups so that we will keep witnessing
products currently on the market [1], list of products increasing number of advanced nasal drug delivery
that is steadily increasing. Examination of the causes products.
1642 M.I. Ugwoke et al. / Advanced Drug Delivery Reviews 57 (2005) 1640–1665
2. Biological and pharmaceutical considerations more, many of these cells possess actively beating
for nasal mucoadhesive drug delivery cilia with microvilli. Each ciliated cell contains about
100 cilia, while both ciliated and nonciliated cells
2.1. Nasal anatomy and physiology relevant to nasal possess about 300 microvilli each. Table 1 further
mucoadhesive drug administration describes the structural features of different nasal
anatomical regions and their relevance in drug per-
The nasal cavity is divided into two halves by the meability [9].
nasal septum and extends posteriorly to the nasophar-
ynx, while the most anterior part of the nasal cavity, 2.2. Nasal mucus secretion and mucociliary clearance
the nasal vestibule, opens to the face through the
nostril (Fig. 1). The atrium is an intermediate region The submucosal glands, which secrete the greater
between the vestibule and the respiratory region. The quantity of nasal mucus, comprise both mucus cells,
respiratory region, the nasal conchae or turbinates, secreting the mucus gels, and serous cells, producing a
which occupies the major part of the nasal cavity, watery fluid [10]. Seromucus glands in the human nose
possesses lateral walls dividing it into 3 sections: the have been estimated to 100,000 [11]. Mucus is also
superior, middle and inferior nasal turbinates. These released from the goblet cells as mucus granules, which
folds provide the nasal cavity with a very high surface swell in the nasal fluids to contribute to the mucus
area compared to its small volume. layer. Mucus secretion is a complex mixture of many
The epithelial cells in the nasal vestibule are stra- substances and consists of about 95% water, 2% mucin,
tified, squamous and keratinized with sebaceous 1% salts, 1% of other proteins such as albumin, immu-
glands. Due to its nature, the nasal vestibule is very noglobulins, lysozyme and lactoferrin, and b 1% lipids
resistant to dehydration and can withstand noxious [12]. The production of IgA by both the adenoid tissue
environmental substances and limits permeation of and the nasal mucosa contributes significantly to the
substances. The atrium is a transitional epithelial immune protection against inhaled bacteria and viruses
region with stratified, squamous cells anteriorly and [13]. About 1.5–2 l of nasal mucus is produced daily.
pseudostratified columnar cells with microvilli pos- This mucus blanket, about 5 Am thick, consists of two
teriorly. Pseudostratified columnar epithelial cells layers, a lower sol layer and an upper gel layer. The
(Fig. 2) interspersed with goblet cells, seromucus viscosity of both layers affects ciliary beating and the
ducts, the openings of subepithelial seromucus glands efficiency of transporting the overlying mucus—the
cover the respiratory region (the turbinates). Further- mucociliary clearance (MCC).
The nasal mucus performs a number of physiolo-
gical functions. (1) It covers the mucosa, and physi-
cally and enzymatically protects it. (2) The mucus has
water-holding capacity. (3) It exhibits surface electri-
cal activity. (4) It permits efficient heat transfer. (5) It
acts as adhesive and transports particulate matter
towards the nasopharynx.
2.2.1. Mucociliary clearance

One of the functions of the upper respiratory tract
is to prevent noxious substances (allergens, bacteria,
viruses, toxins etc.) from reaching the lungs. When
such materials adhere to, or dissolve in the mucus
lining of the nasal cavity, they are transported towards
the nasopharynx for eventual discharge into the GIT.
Fig. 1. Schematic of a sagittal section of human nasal cavity
showing the nasal vestibule (A), atrium (B), respiratory region: Clearance of this mucus and the adsorbed/dissolved
inferior turbinate (C1), middle turbinate (C2) and the superior substances into the GIT is called the MCC. It consists
turbinate (C3), the olfactory region (D) and nasopharynx (E) [19]. of a coordinated interaction between the overlying
Fig. 2. Cell types of the nasal epithelium showing ciliated cell (A), non-ciliated cell (B), goblet cells (C), gel mucus layer (D), sol layer (E), basal
cell (F) and basement membrane (G) [19].
mucus layer and the methachronal wavelike move- surface. There are approximately 300 cilia per cell,
ment of the underlying cilia. Optimum physico-che- each cilia is 5–10 Am long and 0.1–0.3 Am wide and
mical properties of the mucus and movement of the beats as a frequency of about 20 Hz. Although there is
cilia are required for effective and efficient MCC. a lot on inter-individual differences in MCC rate, this
Cilia are hair-like protrusions on the epithelial cell has been estimated at 6 mm/min [14]. Maintaining
Table 1
Structural features of different sections of nasal cavity and their relative impact on permeability [9]
Region Structural features Permeability
Nasal vestibule Nasal hairs (vibrissae) Least permeable because of the presence of
Epithelial cells are stratified, squamous and keratinized cells
keratinized
Sebaceous glands present
Atrium Transepithelial region Less permeable as it has small surface area
Stratified squamous cells present anteriorly and and stratified cells are present anteriorly
pseudostratified cells with microvilli present
posteriorly
Narrowest region of nasal cavity
Respiratory region (inferior Pseudostratified ciliated columnar cells with Most permeable region because of large surface
turbinate middle turbinate microvilli (300 per cell), large surface area area and rich vasculature
superior turbinate) Receives maximum nasal secretions because of
the presence of seromucus glands, nasolacrimal
duct and goblet cells
Richly supplied with blood for heating and humidifi-
cation of inspired air, presence of paranasal sinuses
Olfactory region Specialized ciliated olfactory nerve cells for Direct access to cerebrospinal fluid
smell perception
Receives ophthalmic and maxillary divisions of
trigeminal nerve
Direct access to cerebrospinal fluid
Nasopharynx Upper part contains ciliated cells and lower part Receives nasal cavity drainage
contains squamous epithelium
optimal MCC is very important in order to prevent erties of the mucus, is found in 2 forms: soluble
respiratory tract infections. secretory mucin and membrane-bound mucin [20–
The MCC can be influenced by environmental and 23]. Mucins are heterogenous macromolecules com-
pathological conditions. Factors that can increase cili- posed of approximately 10–30% by weight of peptide
ary beat frequency (CBF) and mucus production, or core linked to oligosaccharide chains that make up 70–
decrease mucus viscosity will all lead to increase in 80% of the total weight [24–28]. Viscoelasticity is the
MCC. Environmental conditions like temperature most extensively investigated physicochemical prop-
(below or above 23 8C), inhalation of sulfur dioxide erty of mucus. This viscoelasticity depends on the
and cigarette smoke all decrease MCC [15,16]. Such mucin, water and other ions present, with small
pathological conditions like Kartagener’s syndrome, changes in, e.g., water or pH significantly altering the
Sjorgens syndrome, asthma, nasal polyposis, defective viscoelasticity [29,30]. Alteration in mucus structure
septum, rhinitis, allergy, common cold and sinusitis could lead to changes in drug diffusivity through the
alter MCC due to their effects on CBF or mucus matrix. This is especially relevant for biopharmaceuti-
rheology. Two mechanisms have been suggested to cals like proteins and polypeptides that may encounter
be involved in increased mucus secretion irrespective resistance within the network of this matrix. The pre-
of the causative factors. First, mast cell-derived sence of phospholipids (in the mucus) confers surface
mediators released in the nasal mucosa may induce active properties to it. The surface activity can have a
secretion of nasal mucus glycoproteins. Second, neuro- powerful impact on either the stability or the perme-
hormones released may cause an increase in nasal ability of compounds following emulsification in the
blood flow and increase in transudation of fluid and mucus layer. The composition and physical properties
plasma proteins [17]. All the pathological and envir- of nasal mucus secretion can be altered significantly by
onmental conditions above will ultimately alter nasal the presence of circulating inflammatory cells like
drug delivery and the performance of nasal mucoad- neutrophils and eosinophils. When these cells die and
hesive formulations, and should be taken into account decompose locally, they release DNA molecules that
during product development. The driving force for may alter the viscoelasticity of the mucus by binding
the MCC is the coordinated manner (both in phase with mucus glycoproteins or other proteins in the secre-
and frequency) at which the cilia beat, generally tion. The products released by dead inflammatory cells
called methachronal wave. This ensures directional can in turn even modulate nasal secretion [17].
transport of the mucus and entrapped materials In solution, mucus exists as large aggregates. Var-
towards the nasopharynx. Calcium ion concentration ious models have been proposed for the tertiary struc-
has been linked with ciliary beating with calcium ture of mucin. These include (1) linear flexible chain
depletion or blocking calcium activity leading to without branching, (2) models that involve cross-link-
loss of ciliary beating [18]. This has a strong implica- ing via disulfide bridges and hydrophobic bonds [31]
tion in nasal mucoadhesive drug delivery. Some and (3) random glycoprotein coils within a spherical
mucoadhesive polymers like polyacrylic acids [2] solvent domain, called the model hydrodynamic
chelate calcium ions and thereby increasing the per- model [32]. (4) According to Meyer and Silberberg
meability of the epithelium. Calcium depletion lead- [33], non-covalent forces are responsible for maintain-
ing to reduced CBF may be an additional mechanism ing the tertiary structure of mucin. Inter-carbohydrate
(synergistic) in their mucoadhesive performance in bonds together with contributions from disulfide
increasing local drug residence time. We recently bonds provide a zipper-like association between
published a detailed review on MCC discussing its mucin chains to interact and entangle. (5) A much
mechanism and the factors that might influence it simpler model is that of entangled, randomly coiled
[19]. macromolecules forming a loose network [34]. The
differences in the proposed models may point to
2.3. Biophysics of nasal mucus ultrastructural differences in mucin produced from
different glands/organs. This clearly underscores the
Mucin is the major component of mucus. This com- need for elucidating the influence of ultrastructure of
pound, primarily responsible for the viscoelastic prop- mucin on drug delivery.
2.4. Mucus–drug interaction: relevance to nasal through the mucus is absolutely important for the
mucoadhesive drug delivery development of future therapies.
A good understanding of possible forms of inter-
It is an important consideration to understand how actions can help the formulation scientists not only to
the mucus and drugs interact with each other, and avoid problems resulting from such interactions (low
even more importantly how such interactions could drug absorption) but also to exploit the situation for
influence drug absorption and activity. Such consid- the enhancement of drug transports through the
eration includes the comprehension of the diffusion mucus. Alteration of the formulation components by
coefficient of the drug through the mucus including changing pH, ionic strength, polymer, surface charge
in disease states. One may wonder whether the drug of nanoparticles and microparticles, etc., can suffi-
changes the mucus gel structure and rheology. If so, ciently alter the gel structure to the extent that
to what extent and how can the formulation scientist increased absorption can take place.
exploit these interactions to increase drug absorption?
The drug’s molecular size, the mucus mesh size and 2.5. Mechanism of bioadhesion
the interaction between the mucus gel and the drug
influence the diffusion of drugs through the mucus. Several theories have been put forward to explain
Like in all cases of diffusion, small and neutral the mechanism of polymer–mucus interactions that
molecules diffuse faster and to a greater extent lead to mucoadhesion. To start with, the sequential
through a charged matrix compared to charged and events that occur during bioadhesion include an inti-
large molecules. It should be highlighted that some mate contact between the bioadhesive polymer and
large or charged molecules have been observed to the biological tissue due to proper wetting of the
diffuse readily through the mucus [35]. Additionally, bioadhesive surface and swelling of the bioadhesive.
particulate materials, e.g., microspheres and lipo- Following this is the penetration of the bioadhesive
somes bearing drugs, have been observed to diffuse into the tissue crevices, interpenetration between the
through the mucus and reach the epithelium intact. mucoadhesive polymer chains and those of the mucus.
Therefore, a full understanding of the underlying Subsequently low chemical bonds can become opera-
factors that influence diffusion through mucus is tive [40,41].
presently lacking. The intimacy of contact between a bioadhesive
Particulate transport through the mucus is rather polymer and the biological tissue is improved when
complex and is controlled by the mucus layer as well the surface of the latter is rough. The surface roughness,
as size, charge and surface wettability of the particles. defined by the aspect ratio (d/h) of the maximum depth
Studies on particulate transport through the mucus all (d) to the maximum width (h), must be greater than 1/
demonstrated that diffusion is size dependent and 20 for good adhesion to occur [41]. For surfaces with
decreases quickly with increasing size [36–39]. For lower aspect ratios, the viscosity and wetting power of
example, Szenkuti [38] showed that polystyrene nano- the bioadhesive become the most important factors that
and microparticles can diffuse through 30–50 Am are required for satisfactory bioadhesion. For a liquid
thick rat distal colon mucus. It should be pointed bioadhesive, its wettability and spreadability on a sur-
out that experimental techniques employed have face can be ascertained from its contact angle on that
strong influence on the conclusions that could be solid surface. For solid bioadhesion, the work of adhe-
derived from these studies. Depending on the type sion is used to determine bioadhesiveness. This is the
of polymer used binding to the epithelial cells, pulsed, energy required to counter the attractive forces between
sustained or complete drug release, etc., may take two unlike molecules [42].
place before complete hydration of the microspheres Hydration of the polymer plays a very important
followed by recovery of the mucus thickness can role in bioadhesion. There is a critical degree of
occur. Although a study of all the possible and com- hydration required for optimum bioadhesion. If there
plex interactions particles and different mucus types is incomplete hydration, the active adhesion sites are
and mucosal tissues appears rather daunting, such not completely liberated and available for interaction.
undertakings to better understand particulate transport On the other hand, an excessive amount of water
weakens the adhesive bond as a result of an over- 2.6.1. Polymer-related factors

extension of the hydrogen bonds. During hydration, The polymer molecular mass will influence its
there is a dissociation of hydrogen bonds of the poly- bioadhesion characteristics. There is a critical poly-
mer chains. The polymer–water interaction becomes mer molecular mass and cross-linking density below
greater than the polymer–polymer interaction, thereby or above which there is reduced adhesive power, and
making the polymer chains available for mucus pene- this varies with the type of polymer [53–55].
tration [43–45]. Mucoadhesion requires an adequate free chain length
Following polymer hydration intermingling for interpenetration to occur. Reducing the free chain
between chain segments of the mucoadhesive polymer length by extensive cross-linking therefore reduces
with the mucus occurs. The factors critical for this mucoadhesion [46,53].
model of mucoadhesion are the diffusion coefficient An optimum polymer concentration is required at
of the polymer, contact time and contact pressure. The the polymer–mucus interface for bioadhesion, beyond
polymer diffusion coefficient is influenced by the which few polymer chains will be available for poly-
molecular mass between cross-links, and is inversely mer–mucus interpenetration. The polymer concentra-
related to the cross-linking density [46]. Supporting tion that is required for optimum bioadhesion is
evidence for the theory of chain interpenetration was different between gels and solid bioadhesives. In the
provided by the findings that partial mucolysis with liquid state, an optimum concentration exists for each
N-acetyl-l-cysteine increased mucoadhesiveness of polymer beyond that reduced adhesion results because
polyacrylic acid by about 37% as a result of increased fewer polymer chains will be available for interpene-
chain flexibility [47]. On the other hand, cross-linking tration with the mucus. On the other hand, with solid
the mucus with glutaraldehyde reduced mucoadhesion dosage forms such as buccal tablets, increased poly-
by about 30%. mer concentration leads to increased mucoadhesive
The adsorption theory of bioadhesion proposes that power [41,52,56].
adhesion of a polymer to a biological tissue results
from: (1) primary chemical bonds that are somewhat 2.6.2. Environment-related factors
permanent and therefore undesirable in bioadhesion Polymer hydration and swelling are required for
[48]; (2) van der Waals, hydrogen, hydrophobic and initiation of mucoadhesion but excessive hydration
electrostatic forces, which form secondary chemical with inordinate swelling of the polymer reduces its
bonds [48–50]. The electronic theory proposes the adhesive strength. The swelling/hydration rate should
existence of an electrical charge double layer at the not be too rapid in order to prolong the adhesion time.
interface between the adhesive and biological tissue as On the other hand, inordinate swelling is eventually
a result of the difference in their electronic structure required to reduce polymer adhesiveness and to allow
[51]. As demonstrated by Ponchel et al. [52], bioadhe- it to detach from the biological tissue.
sion occurs due to both chemical interaction and poly- Some polymers owe their mucoadhesiveness to
mer–mucin chains interpenetration. such forces as hydrogen bonding, van der Waals,
hydrophobic and electrostatic forces. The strength of
2.6. Factors that influence mucoadhesion these forces is influenced by the environmental pH.
Consequently, for such polymers, environmental pH is
The factors that influence mucoadhesiveness of a a very important determinant of mucoadhesive
polymer include type of functional groups present, strength. This has been clearly demonstrated for poly-
polymer molecular mass, molecular mass between carbophil [47] and more recently for chitosan [6]. This
cross-links (cross-linking density), spatial orientation, has also been exploited in development of pH-sensi-
contact time with mucus, polymer concentration, tive mucoadhesive polymers (see Section 5.1 of this
environmental pH and physiological variables like review).
mucin turnover and disease conditions. These will
be further explained under the subheadings, poly- 2.6.3. Physiological-related factors
mer-related, environment-related and physiological- MCC, mucus turnover and disease states are phy-
related factors. siological factors which influence nasal mucoadhe-
sion. Mucoadhesion can slow down MCC, but with These developments are supported by the recogni-
time, mucus production reduces the mucoadhesion tion of the advantages the nose presents for drug
bond strength, allowing a recovery of MCC to normal delivery purposes. These include
clearance rates, thereby removing the mucoadhesive.
Disease conditions mentioned earlier can affect 1. A large surface area available for drug deposition
mucoadhesion due to their influence on either and absorption. The effective absorptive surface
mucus production or ciliary beating. Thus a good area of the nasal epithelium is even higher as a
understanding of the nature of mucus in these diseases result of the presence of microvilli.
is imperative in designing a good NDD system. An 2. The nasal epithelium is thin, porous (especially
abnormal mucus layer could present an unanticipated when compared to other epithelial surfaces) and
barrier to drug transport through the mucosa. Mucoad- highly vascularized. This ensures high degree of
hesive capabilities of polymers should be studied absorption and rapid transport of absorbed sub-
during product development under such disease con- stances into the systemic circulation for initiation
ditions considered relevant. of therapeutic action.
3. A porous endothelial basement membrane that
poses no restriction to transporting the drug into
3. Mucoadhesion as a strategy to improve systemic general circulation.
drug delivery via the nasal route 4. Absorbed substances are transported directly into
the systemic circulation thereby avoiding the first
Parenteral drug administration has a lot of pass metabolic effect generally experienced follow-
advantages compared to the other routes of drug ing oral drug administration.
administration. The superiority of these routes (iv, 5. In some cases, drugs can be absorbed directly into
im, sc) stems from reduced drug metabolism and the CNS after nasal administration bypassing the
degradation, higher degree of utilization of the tight blood–brain barrier.
administered dose, programmable drug dosing 6. Generally speaking, the enzymatic activity of the
within the therapeutic index, etc. However, parent- nasal epithelium is lower than that of the GIT or
eral routes, especially iv injection, have some major liver and higher bioavailability of drugs especially
disadvantages such as patient compliance, health proteins and peptides can be achieved. In addition,
hazards, higher cost of therapy due to use of highly enzyme inhibitors are more effective following
qualified healthcare workers and expensive equip- nasal than oral application because of a higher
ment/tools. Reduced cost of therapy due to degree of dilution in the latter than in the former.
increased outpatient treatment is particularly appeal- 7. Realization of pulsatile delivery of some drugs like
ing as a result of pressure from/on healthcare reim- human growth hormone, insulin, etc., is higher
bursement institutions to reduce cost. In with NDD.
comparison, extensive drug metabolism especially 8. The nose is amenable to self-medication that not
in the liver is seen after oral administration. only lowers the cost of therapy but improves
Furthermore, the bioavailability is usually much patient compliance as well. The risk of over-dosage
less than 100% with the non-parenteral routes. A is low and nasal lavage can be used to remove
very rapid rate of absorption can be achieved fol- unabsorbed excess drug.
lowing nasal application of some drugs. Frequently 9. Reformulation of existing drugs as NDD products
(depending on the physicochemical characteristics offers companies the possibility to extend the life
of the drug) this is accompanied by high bioavail- cycle of their products.
ability. This recognition of the potential of NDD
has led to an explosion of research (both funda- In spite of the above advantages and potentials of
mental and applied) in this field in the last 2 NDD, there are some major limitations to application
decades. The list of nasal drug products in the of drugs via the nose. Only a limited amount of the
market or at various stages of preclinical and clin- formulation can be administered intranasally. Appli-
ical development is ever increasing [1]. cation of large quantities will disturb the normal
functioning of the nose (olfaction and humidification polymer on (a) ciliary beat frequency (CBF) (reduced
of inspired air). It could also lead to irreproducibility CBF analogous to increased drug residence time) and
of the dosing regimen as a result of drainage of the (b) epithelial tight junctions (tight junction opening
solution or expulsion of the dose due to sneezing. analogous to more permeation) may be used in con-
The high porosity of the nasal epithelium is still not junction with an ex vivo or in vivo model to account
sufficient for absorption of all compounds especially for the level of involvement of mucoadhesion on
hydrophilic ones and large molecules like proteins. absorption enhancement [63,64].
In addition, the nasal mucosa is enzymatically active
albeit to a lesser extent compared with the GIT. The
potential toxicology or irritancy of the drug product 4. Nasal mucoadhesive delivery of pharmaceutical
is a very important point that should be thoroughly compounds
investigated. Stringent requirement is placed on the
administration device for reproducibility of deposi- Mucoadhesives have been used to improve local
tion. Drug absorption and permeability of the differ- and systemic delivery of therapeutic compounds. This
ent regions of the nasal cavity is quite different [57– section examines specific applications of mucoadhe-
59]. Also deposition posteriorly will result in faster sive compounds with respect to nasal administration
clearance by the MCC. The MCC is a very important of small organic molecules, antibiotics, vaccines,
physiological function of the nose that works DNA, proteins and other macromolecules.
strongly against NDD. However, some of these chal-
lenges can be solved to various degrees by applica- 4.1. Small organic molecules
tion of mucoadhesive polymers. Indeed, MCC can be
largely controlled (to the extent that sufficient time is Due to the rapid therapeutic action that can be
allowed for absorption to occur) by application of achieved, medications used in emergency medical
mucoadhesive polymers either in powder or liquid situations make ideal candidates for nasal drug
form. Mucoadhesion localizes the formulation within delivery. One such drug, apomorphine is the drug
the nasal cavity for extended time period and of choice for treatment of on/off-syndrome in
increases absorption which otherwise would not patients suffering from Parkinson’s disease. Aqueous
occur. solution of the compound is reasonably well
Although nasal mucoadhesion increases drug resi- absorbed following nasal administration with a rela-
dence time and possibly enhances drug absorption, tive bioavailability of 45% [65]. We further demon-
this mechanism may not work for all compounds, strated that even higher relative bioavailability
especially large molecules such as proteins. Some (98%) is possible if we limit drainage of the solu-
polymers interact with the mucus and/or the epithe- tion through the nasopharynx [66] and rapid oxida-
lium in such a way as to increase epithelial perme- tion of the aqueous solution, with a degradation
ability. This has been demonstrated in several studies half-life in plasma at 37 8C of 39 min [67]. This
with insulin [8,60,61]. Some mucoadhesive polymers was achieved by administering the drug in pow-
like chitosan and polyacrylic acids also have enzyme dered form [66]. We have demonstrated in several
inhibitory activities. Luessen et al. [62] demonstrated studies that the pharmacokinetic profiles of apomor-
that Carbopol 934P and polycarbophil can inhibit phine after nasal administration may be improved
trypsin and increase absorption of co-administered following incorporation of the compound into
peptides. Such enzyme inhibitory activity has also mucoadhesive polymers like polyacrylic acid, carbo-
been demonstrated for polymers like polycarbophil pol and carboxymethylcellulose [68,69]. These stu-
and chitosan [2]. To the best of our knowledge, no dies showed that nasal relative bioavailability of
studies reported in literature addressed the relative apomorphine powders was higher than that of solu-
contribution of mucoadhesion, tight junction opening tions and was equivalent to subcutaneous injections.
and enzyme inhibition to the overall nasal absorption Apart from increasing the mucosal contact time for
enhancement of a drug molecule. In vitro models the drug, mucoadhesive powder formulations had
capable of providing information on the effect of a the added advantage of limiting oxidation due to
aqueous environment. Although the nasal mucoad- carboxymethylcellulose in nasal dosage forms
hesive formulations prepared with Carbopol 974P increases their residence time within the nasal cavity
had better pharmacokinetic profiles than nasal solu- and provides the opportunity for sustained nasal drug
tions, the study showed that physicochemical char- delivery (Fig. 3). The study also showed that apomor-
acteristics of a drug molecule and its release from phine inhibited nasal mucociliary clearance since
the polymer matrix could affect the rate and extent migration of radioactivity administered with the exci-
of drug absorption. Therefore, incorporation of a pients was in all cases slower than that of the corre-
rapid release excipient (e.g., lactose) may be of sponding powder without apomorphine. This was also
relevance as demonstrated for apomorphine formu- confirmed by studying the influence of the drug on
lated with Carbopol 974P [68]. Apomorphine ciliary beat frequency in cultured human nasal epithe-
absorption was fastest following intranasal adminis- lial cells (Fig. 4) [71] These results highlighted the
tration of immediate release forms prepared with fact that inhibition of ciliary activity may play an
lactose compared to subcutaneous injections. The important role in increasing the residence time of
plasma drug concentration was sustained, especially nasal formulations. If no information exists on the
with CMC (15% w/w) for which it was maintained effect of a particular compound on ciliary beat fre-
within 50% of the C max for about 70 min. The quency prior to its use in mucoadhesive formulations,
clinical relevance of this is that the frequency of the mucoadhesive attributes of the excipient may be
drug administration could be reduced by as much as overestimated because of possible cilio-inhibitory
50%. effect of the drug candidate. It is therefore pertinent
In using mucoadhesive polymers for nasal drug to know the effect of a drug on ciliary beat frequency
delivery, it is pertinent to demonstrate that mucoadhe- before recommending a particular mucoadhesive
sion is the predominant mechanism responsible for polymer for formulating the compound [72].
improved drug absorption. For apomorphine, we In addition to apomorphine, other small molecular
compared the nasal clearance of preparations based weight compounds including budesonide [73], caf-
either on Carbopol 971P or lactose (control), each feine [74], ketorolac [75], metoprolol [76], midazolam
with and without the drug, or carboxymethylcellulose [77], morphine-6-glucoronate [78,79], nicotine [80],
using 99mTc-labeled colloidal albumin in rabbit nasal oxyprenolol [81], oxymetazoline [82] and pentazocine
cavity [70]. These studies confirmed that the use of [83] have been characterized for nasal administration
mucoadhesive polymers such as Carbopol 971P or with mucoadhesives.
80
70
% Radioactivity cleared
60
50
40
30
20
10
0
0 50 100 150 200 250 300 350 400
Time post insufflation (min)

Fig. 3. Nasal clearance of radioactivity in rabbits as a function of time (mean F S.E.M) after i.n. administration of 99mTc labeled lactose with
(o, n = 6) and without (., n = 6) apomorphine, Carbopol 971P with ( R , n = 5) and without ( S , n = 6) apomorphine and CMC/apomorphine
(4, n = 5). The curves demonstrate the mucoadhesive capabilities of Carbopol 971P and CMC, and the fact that apomorphine inhibits mucociliary
clearance but does not abolish it [70].
Fig. 4. Top panel: effects of different concentrations of apomorphine HCl on CBF, showing both time- and concentration-dependent (0.1–0.05%
w/v), and reversible inhibitions of CBF after 15 min (2), and 60 min (3), compared to the control (1) and following washing (4), whereas 1.0%
(w/v) solutions caused irreversible inhibition, and 0.01% (w/v) solution, stimulation of CBF at the same measurement times. Bottom panel:
effects of different concentrations of CMC on CBF, showing time- and concentration-dependent inhibition of CBF after 15 min (2), and 60 min
(3), compared to the control (1) and following washing (4).
The efficacy of drugs (e.g., steroids, bronchodila- (P(MAA-g-EG)) loaded with budesonide resulted in
tors) targeted to the respiratory mucosa for diseases relatively quick absorption (T max, 45 min) with
such as rhinitis and asthma generally depends on steady-state plasma concentration that lasted longer
duration of action, and thus on drug residence time than 8 h due to continuous release of the drug from
in the mucosa. For fluticasone propionate, retention the polymer [4]. This was possible because polymers
may be achieved exclusively by lipophilicity, containing carboxylic acid groups adhere strongly to
whereas for budesonide an additional possibility epithelial mucosa due to hydrogen bond interactions
may be provided by its ability to form fatty acid in environments where the pH is less than 5, and the
esters in the airway mucosa that release the active carboxylic acid does not dissociate. As with budeso-
drug [8] or the use of mucoadhesives. Nakamura et nide, mucoadhesive formulation of xylometazoline
al. demonstrated that bioadhesive graft copolymers was shown to exhibit significantly longer clinical
of polymethacrylic acid and polyethylene glycol effect (manometric/subjective scores) than non-
mucoadhesive product [82]. This was ascribed to the due to absorption enhancement by azone and pro-
adhesiveness of the formulation, which allowed the longed intranasal drug residence time caused by
adrenergic agonist to stay longer at the site of appli- hydroxypropyl cellulose. Using adhesion studies,
cation resulting in prolonged and more pronounced Fundueanu et al. showed that starch/cyclodextrin
effect. Morphine when given orally, the bioavailabil- microspheres are good mucoadhesive excipients for
ity is approximately 20–32%. It was demonstrated by nasal delivery of gabexate mesylate used for treating
Illum et al. that chitosan-based mucoadhesive for- allergic rhinitis [86]. Similarly, solubilization of ben-
mulation of the compound resulted in rapid absorp- zodiazepines with 14% sulfobutylether b-cyclodextrin
tion of the compound (T max of 15 min) with a containing 0.1% (w/v) hydroxypropyl methylcellulose
bioavailability of about 60% [78]. The plasma improved the nasal absorption of midazolam in human
profiles after nasal administration with chitosan volunteers [77].
were better than simple liquid formulations, but
similar to those obtained after intravenous doses. 4.2. Antibiotics
Pilot studies using the formulation for treatment of
breakthrough pain in cancer patients suggested that Many antibiotics are still exclusively administered
nasal morphine–chitosan formulation was acceptable, via parenteral routes. For those administered orally,
well tolerated and may lead to rapid onset of pain some exhibit erratic and incomplete absorption.
relief [84]. The bioavailability of another analgesic, Recently a few studies have examined the potential
ketorolac was shown to remarkably improve when of the nasal route for systemic delivery of antibiotics
administered nasally with microcrystalline cellulose using mucoadhesive polymers. In a preliminary
[75]. The authors showed that differences in bioavail- study, Lim et al. prepared and evaluated mucoadhe-
ability of the compound when formulated with differ- sive microspheres of hyaluronic acid and chitosan for
ent cellulose derivatives stem from the release rate of nasal delivery of gentamicin and other drugs [87].
the drug from the mucoadhesive preparations. The The study showed that hyaluronic acid and hyaluro-
authors pointed out that in some cases the drug may nic acid/chitosan microspheres could adhere to the
not be totally released from the polymer matrix before nasal mucus. Subsequently, the authors showed that
it was removed from nasal epithelium by mucociliary hyaluronic acid and chitosan may be employed for
clearance. Therefore, good in vitro release profiles is nasal administration of antibiotics to obtain a high
important to achieve desired in vivo bioavailability. In bioavailability and prolonged release [88]. In another
other studies, oxprenolol and metoprolol [76,81] were study, Canan et al. suggested, based on particle size,
efficiently delivered through the nasal mucosa using production yield, encapsulation efficiency, shape and
mucoadhesive formulations based on alginate and surface properties, drug–polymer interaction, muco-
gelatin/poly(acrylic acid) microspheres, respectively. adhesive property and in vitro drug release that
For oxprenolol, in vitro and in vivo experiments in hydroxypropyl methylcellulose is a good polymer
rats showed good adhesive characteristics of gelatin/ for systemic delivery of gentamicin via the nasal
poly(acrylic acid) microspheres, which were greater route [89]. Successful nasal delivery of other anti-
with increasing poly(acrylic acid) content [81]. In biotics such as vancomycin and tobramycin with
vivo studies indicated that sodium alginate micro- chitosan has been reported as well [90]. It was
spheres of metoprolol tartrate significantly improved shown that the presence of chitosan salts slow
therapeutic efficacy of metoprolol with sustained and down the release of vancomycin hydrochloride at
controlled inhibition of isoprenaline-induced tachy- pH 5.5 and pH 7.4, thus guaranteeing a sustained
cardia as compared with oral and nasal administration release at acidic and alkaline pH of drug in the nasal
of drug solution [76]. For dopamine, Ikeda et al. cavity. Studies involving nasal delivery of ciproflox-
demonstrated using beagle dogs that the bioavailabil- acin hydrochloride using hydroxypropyl methylcellu-
ity of dopamine formulated with hydroxypropyl cel- lose (HPMC), hydroxyethyl cellulose (HEC), and
lulose (2%) combined with azone (2%) was similar to methylcellulose (MC) showed that the bioavailability
intravenous injections [85]. High plasma concentra- of ciprofloxacin gel formulation prepared with
tions of the compound were maintained for up to 7 h HPMC was almost identical to that of the oral
route, but the bioavailabilities for HEC and MC were high effectiveness of the live polio vaccine when
lower than oral preparations [91]. However, inclusion given at birth [93].
of 1% (w/w) Tween 80 resulted in significant It has been severally demonstrated that both sys-
improvement in ciprofloxacin bioavailability with temic and mucosal immunity can be induced follow-
respect to the oral route. The presence of Tween ing nasal vaccination in animals and man [94–99]. A
80 in the formulation possibly facilitated the release recent review article by Lemoine et al. [100] summar-
and diffusion of the antibiotic through the cellulose ized vaccination using nasally administered micropar-
matrices. ticles. In the studies cited, various levels of immune
Although it is very interesting to deliver anti- responses were induced. Vila et al. [101] studied nasal
biotics through the nasal route, the use of mucoad- immunization with tetanus toxoid following encapsu-
hesives raises important safety concerns due to the lation and administration in the forms of PEG-coated
prolonged drug–polymer residence time in the nasal polylactic acid nanospheres, chitosan-coated polylac-
mucosa, which may lead to superinfection in the tic–glycolic acid nanospheres and chitosan nano-
respiratory tract. The increased contact time may spheres. They observed that PEG-coated nanospheres
upset the nasal normal microbial flora when broad- induced higher levels of tetanus toxoid in the blood
spectrum antibiotics are used. This may lead to compared to chitosan-coated nanospheres. On the
superinfection as documented for the gastrointest- other hand, very high IgG titers were obtained 6
inal mucosa. This should be considered when months post administration of chitosan nanospheres.
selecting antibiotics to the delivered nasally using Westerink et al. [102] investigated immunization with
mucoadhesives. tetanus toxoid formulation with pluronic F127, chit-
osan or chitosan/pluronic F127, and showed that the
4.3. Macromolecules combination of chitosan and pluronic F127 was super-
ior to either polymer used alone. The major attraction
4.3.1. Vaccines and DNA of adjuvants like chitosan includes its low toxicity,
Nasal vaccination is another interesting opportu- susceptibility to biodegradation, mucoadhesive prop-
nity waiting to be exploited. Pathogenic infections in erties and drug penetration enhancement capacity
such disease states as influenza, pertussis, meningitis, across mucosal barriers [103]. The type of chitosan
measles, etc., occur primarily as a result of the formulation used (solution or powder) for the nasal
pathogens gaining access to the body via mucosal administration of the antigen may affect the efficiency
contact. Consequently these diseases are ideal candi- of the immune response and possibly the permeation
dates where nasal vaccination can be applied since of the antigens across the nasal mucosa. The ability of
neutralizing antibodies and specific cellular low molecular weight chitosans to trigger long-lasting
responses at these sites of pathogen entry can take humoral and mucosal immune responses is also an
place. Unlike human systemic immunity, which important attribute. Chitosan has been reported to
declines with age, mucosa-associated local immunity significantly enhance immune response of nasally
of experimental animals does not malfunction with administered vaccines (e.g., influenza, pertussis and
age [92]. Apart from the nose being the first point of diphtheria vaccines) via induction of serum IgG
contact with inhaled pathogens, it is rich in lymphoid responses similar to secretory IgA levels and superior
tissue, specifically nasally associated lymph tissue to what was induced by a parenteral administration of
(NALT). The route of administration is easy, cheap the vaccine [104]. In another study, chitosan displayed
and can be administered to a large population. It a significantly positive influence on the immune
eliminates the use of needles and as such risk of response obtained in mice after nasal influenza vac-
infections (especially in poor countries) with hepati- cine administration [105]. Similarly very promising
tis B, HIV, etc. There is a relatively large surface clinical phase I results were obtained with the chitosan
area through which uptake of the antigenic material influenza vaccine. Chitosan also increased the serum
can take place. Mucosal immunization may be safer IgG titer after administration of diphtheria vaccine
and more successful in young children in the pre- [105]. In an elaborate study involving 25 volunteers
sence of marternal antibodies as demonstrated by the previously vaccinated against diphtheria, it was
demonstrated that the chitosan formulation was super- mannitol in rats [113]. Co-administration of TMC
ior to non-chitosan formulations in inducing neutraliz- polymers led to enhanced absorption of [14C]-man-
ing antibody levels. The positive effect of chitosan nitol in the nasal route of rats at both pH 6.2 and
was attributed to increased residence time and open- 7.4. However, the degree of quaternization of TMC
ing of the epithelial tight junctions of the nasal epithe- played an important role in the absorption enhancing
lium [105]. For more detailed information regarding properties of this polymer, especially at pH 7.4.
nasal vaccines, the reader is referred to the recent According to the authors, the charge density on the
comprehensive review by Davis [106]. TMC molecule should reach a threshold value to
Despite the successes recorded so far regarding induce significant interactions to open the tight junc-
nasal delivery of antigens with mucoadhesives, tions between adjacent epithelial cells to increase
Alpar et al. highlighted the fact that achieving protec- paracellular transport in a neutral environment. For
tive immune responses following nasal immunization selection of a particular type of matrix for nasal
is not less important than doing so with formulations protein delivery, Witschi et al. showed (using BSA
that are both safe and commercially viable [107]. It and an in vitro cell culture model) that Carbopol gels
was shown by Park et al. that the use of in situ gelling and chitosan microparticles can be used for protein
and mucoadhesive polymer vehicles (poloxamers, delivery [110].
polycarbophil or polyethylene oxide) could effec- Insulin is one of the most widely studied pro-
tively and safely improve the nasal retention and teins with respect to nasal delivery using mucoad-
absorption of plasmid DNA [108]. The most interest- hesives. The strategies adopted to optimize the use
ing aspect of the study is that the rate and extent of of mucoadhesives for nasal delivery of insulin
nasal absorption could be controlled by choice of include preparing the formulations as micro- or
mucoadhesive polymers and their contents. Extensive nanospheres, incorporation of absorption enhancers
discussion on the application of various polymers as and combination of different polymers. Dyer et al.
adjuvants for vaccine and DNA delivery exists in showed that for chitosan, the most effective formu-
literature [104,107,109]. lation for nasal insulin absorption is a chitosan
powder delivery system, which was found to be
4.3.2. Proteins better than chitosan nanoparticles and chitosan solu-
Due to high molecular weight of proteins, rapid tion formulations, respectively [114]. According to
mucociliary clearance and enzymatic degradation, the study, nanoparticles did not improve the absorp-
low absorption of these compounds occurs following tion enhancing effect of chitosan. However, nasal
nasal administration [102]. Some mucoadhesive administration of mucoadhesive starch microspheres
polymers have been suggested to extend residence was shown to increase synergistically the effect of
time and improve uptake of large molecules across absorption enhancers (that work by interacting with
the nasal mucosa [110]. Very often non-protein high the lipid bilayer) on permeation of insulin across sheep
molecular weight compounds (e.g., mannitol, dex- nasal mucosa [115]. The synergy was attributed to
trans, cyanocobalamin) have been used as surrogates increased drug residence time, which provided the
in search of mucoadhesives for nasal administration enhancers ample time to act on the epithelial mem-
of proteins [111–113]. Such studies have yielded brane. Using different proportions of various mucoad-
useful information regarding nasal protein delivery hesives, Callens and Remon reported that following
with mucoadhesives. Garcia et al. showed that incor- nasal administration of insulin formulated with drum-
poration of cyanocobalamin into microcrystalline cel- dried waxy maize starch (DDWM) or maltodextrins
lulose, dextran microspheres, and crospovidone and Carbopol 974P, the highest absolute bioavaila-
resulted in significant improvement in bioavailability bility attained was 14.4% for a mixture consisting of
of cyanocobalamin relative to simple nasal solutions DDWM/Carbopol 974P 90/10 [116]. The study iden-
in rabbits [112]. In another study, Hamman et al. tified drug loading and lyophilization as the critical
examined the effect of the degree of quaternization parameters requiring optimization prior to applying
of mucoadhesive N-trimethyl chitosan chloride these polymers for nasal delivery of insulin. Differ-
(TMC) on nasal absorption enhancement of [14C]- ences in nasal bioavailability between the different
carriers could be explained by differences in GV (sto- lack of tissue specificity with respect to adhesion, (3)
rage modulus, elasticity) and GU (loss modulus, visc- reduced adhesion time, (4) lack of permeation
osity) values [117]. The formulation giving the highest enhancement capability, (5) interaction between
bioavailability provided also the highest GV and GU drug and polymer leading to decreased release of
values. When insulin prepared with these polymers the drug from the dosage form, increased drug
was administered to rabbits daily for 1 week, a dra- instability, etc., and (6) toxicity induced by the poly-
matic reduction in bioavailability of insulin was mer. Efforts to overcome such problems have lead
observed [118]. This was due to the high viscosity of researchers to develop new polymers, the so-called
the bioadhesive powders in the nasal mucus, which second-generation mucoadhesives, a lot of which
formed a physical barrier that limited the permeation of have been developed and tested for oral drug deliv-
insulin. Using hypoglycemia as therapeutic index, ery. Even though the mechanism of adhesion is the
Wang et al. showed that intranasal administration of same at nasal or gastrointestinal tract sites, the func-
insulin with aminated gelatin significantly increased tionalization of the polymers leads to more tissue/
hypoglycemia compared with intranasal administra- organ specificity. As a result, this part of the review
tion of insulin in phosphate buffered saline. This indi- will deal primarily with the functionalized polymers
cated that aminated gelatin effectively enhanced the that have been tested for NDD, but also make rele-
nasal absorption of insulin [8]. In a related study, it was vant references to other studies.
shown that blood glucose lowering effect of glucagon The simplest formulation for nasal delivery is
nasal powder formulated with microcrystalline cellu- undoubtedly a simple solution of the drug and appro-
lose was preferred over liquid formulations because of priate polymer. Mucoadhesive polymeric solutions are
higher stability, reduction of irritation and better dis- frequently viscous and difficult to be applied intrana-
persion [119]. The relevance of gelatin microspheres, sally. Presently suitable devices are not readily avail-
microcrystalline cellulose, chitosan, paloxamer 407 able. Additionally, the energy input from such devices
(Pluronic F-12) for systemic delivery of calcitonin, required to disperse the viscous solution as nasal dro-
leuprolide [120–122], atrial natriuretic factor [123], plets is tremendous. This energy will lead to thermal
desmopressin [124,125] and tetracosactide (ACTH1- and shear degradation of a lot of drugs especially
24) [126] with respect to nasal administration have proteins and other biopharmaceuticals. Recognition
been reported [120–126]. A summary of these and of this problem has led to the development of a new
other studies is highlighted in Table 2. class of mucoadhesive polymers and testing of some
already existing polymers that are either pH or thermal
sensitive in NDD. Solutions of these polymers exhibit
5. New generation polymers used on nasal drug a low viscosity under ambient conditions but gel upon
delivery and characterization of NDD products nasal administration as a result of pH or temperature
change within the local nasal environment.
5.1. New generation of nasal mucoadhesives Nakamura et al. [4] reported very encouraging
results with bioadhesive graft copolymers of poly-
Initial research on nasal mucoadhesion employed methacrylic acid and polyethylene glycol as a powder
polymers manufactured for other purposes in the delivery system for budesonide in rabbits. The nature
pharmaceutical and food industries. As shown in of the polymer ensures that is swells at neutral or basic
Table 2 several different types of polymers have pH and de-swells in acidic environment, correspond-
been employed for delivery of different types/classes ing to deprotonation and protonation of the carboxylic
of drugs. In many cases very encouraging results acid functional groups. Following nasal administra-
were obtained, to the extent that marketed products tion, a rather prolonged plasma budesonide level, in
could be developed. In a lot of other cases only excess of 8 h with T max of 45 min, was reported.
marginal or even no successes were obtained. Chitosan-4-thio-butyl-amidine [127] chitosan thiogly-
Further examination of the causes of failure pointed colic acid [128] and cysteamine conjugates of carbox-
to issues like (1) delivery from devices and deposi- ymethylcellulose and polycarbophil [129] are some of
tion in the appropriate region of the nasal cavity, (2) these new generation polymers that are pH sensitive.
Although these particular polymers have been primar- to avoid product failure either due to a lack of antici-
ily investigated for oral drug delivery, the pH range pated performance or some toxicity. Product charac-
(pH 5–5.5) where gelation and mucoadhesion are terization should take into account (1) the intended
optimal are within the physiological pH range (pH disease condition to be treated, (2) anticipated fre-
5–6.5, [130]) of the nasal mucosa, and as such should quency of administration, (3) quantity of formulation
give positive results when applied in NDD. per administered dose, (4) toxicity following acute,
Park et al. [5] reported successful delivery of plas- subacute and chronic administration as the case may
mid DNA using the thermoresponsive polymer, be, (5) residence time after single and/or repeated
poloxamer in combination with bioadhesive polymers administrations, (6) in vivo drug release after 1 and/
polycarbophil or polyethylene oxide. Both polymers or several administrations if applicable, and (7) drug–
decreased the gelation temperature of poloxamer, sug- polymer interaction. Several in vitro methods have
gesting that this gelation temperature could be been used to characterize the mucoadhesive property
manipulated to occur at the temperature range of polymers as have been thoroughly reviewed in
obtained at the nasal mucosa. The formulation con- [140,141]. All these in vitro methods suffer from 1
taining polycarbophil and poloxamer was the best and or more disadvantages and it is therefore not possible
led to an 11-fold increase in DNA absorbed when to extrapolate any of these in vitro results to in vivo
compared to saline. In another study [131], thermo- conditions. They do provide excellent means of ana-
responsive polymers were used to successfully lyzing adhesion of a polymer or drug product under
enhance rectal absorption of acetaminophen. Apart specific or simplified conditions.
from development of the above functionalized poly- We developed a system based on modified USP
mers, the last decade has witnessed increased num- XXII rotating basket, the rotating cups (Fig. 5) to
ber of existing natural and synthetic polymers that study in vitro drug release from microspheres for
were modified to increase their mucoadhesion or nasal administration [68]. This modification con-
permeation-enhancing properties. Some of these sisted in attaching an inverted aluminum cup to a
polymers include chitosan, gelatin, alginate and poly- polycarbonate cup-holder fixed to a steel bar. The
acrylic acids [6–8]. Another emerging aspect of internal dimensions of the cup were 3.6 cm (dia-
bioadhesion is called cytoadhesion and implies direct meter) and 1.5 cm (depth). The powders were
adhesion of the material to the epithelial cell surface. weighed on a polyethylenesulfone membrane filter
Lectins are naturally-occurring glycoproteins that of 0.45 Am pore and secured firmly between an
have the ability to non-specifically adhere to and aluminum ring filter holder and the cup with clamps.
be internalized by epithelial cells as has been demon- Two grooves on the side of each filter-holder facing
strated by Naisbett and Woodley [132] and Lehr the filter were air vents allowing complete contact
[133]. Although there is a paucity of nasal studies between release medium and filter. The modification
using lectins, they have good potentials for use in of the USP rotating basket is an attempt to simulate
NDD, especially where internalization of the drug an in vivo situation whereby, in the nose, the powder
encapsulated nanoparticles is of particular impor- is not in direct contact with an excess quantity of
tance such as DNA delivery. A cause of concern fluid as in the stomach. A polyethylenesulfone mem-
with these lectins is their potential for inducing brane filter separating the donor and acceptor com-
toxicity as has been reported for lectins obtained partments allows the powders to absorb just enough
from Ricinus communis [134], Phaseolus vulgaris water for its hydration without providing an addi-
[135–137], Lycopersicon esculentum [138,139] and tional barrier to drug release. This fact was proved
Canavalia ensiformis [134]. with the rapid release of apomorphine from lyophi-
lized lactose mixture. The only limiting factors are
5.2. Characterization of polymers for nasal drug drug release from and diffusion through the gel into
delivery the release medium from the available surface area.
Other apparatus used to study in vitro release rates
Bioadhesive polymers intended for use in NDD from microcapsules for nasal administration such as
must be thoroughly characterized before use in order the paddle method [142–144] and beaker with mag-
1656
Table 2
Summary of some nasal drug delivery studies where mucoadhesive excipients were employed
Drugs Mucoadhesive excipients Dosage Animal Pharmacokinetic parameters References
forms species
M.I. Ugwoke et al. / Advanced Drug Delivery Reviews 57 (2005) 1640–1665

T max C max Bioavailability (%)
Apomorphine Carbopol 971P Powder Rabbits 40.6 F 5.0 min 161.1 F14.5 (ng/ml) 99.98 F 9.7 (rel) [68]
Apomorphine Polycarbophil Powder Rabbits 38.8 F 3.2 min 193.1 F 23.3 (ng/ml) 105.0 F 8.6 (rel) [68]
Apomorphine Carboxymethylcellulose Powder Rabbits 21.8 F 3.1 min 165.7 F 17.1 (ng/ml) 102 F 15.6 (rel) [69]
Apomorphine Degradable starch microspheres Powder Rabbits 10.8 F 1.7 min 376.9 F 64.3 (ng/ml) 96 F 7.8 (rel) [69]
Budesonide (P(MAA-g-EG)) Powder Rabbits – – 83.9 (abs) [4]
Pentazocine Chitosan microspheres Powders Rabbits 1.5 F 0.03 h 1.85 F 0.11 (Ag/ml) 96.5 F 8.4 (abs) [83]
Dopamine Hydroxypropyl cellulose Solution Dogs 5 min c300 ng/ml c25.0 (abs) [85]
Dopamine Hydroxypropyl cellulose + azone Liquid Dogs 5 min c1800 ng/ml 100 (abs) [85]
Ketorolac tromethamine MCC, pH 5.95 Spray Rabbits 0.50 F 0 h 0.428 F 0.122(Ag/ml) 90.77 (abs) [75]
Ketorolac acid MCC, pH 3.2 Spray Rabbits 0.34 F 0.19 h 0.31 F 0.045(Ag/ml) 63.89 (abs) [75]
Ketorolac acid MCC, pH 6.0 Spray Rabbits 0.23 F 0.19 h 0.203 F 0.086(Ag/ml) 70.6 (abs) [75]
Ketorolac acid MCC Powder Rabbits 0.103 F 0.05 h 0.095 F 0.010(Ag/ml) 45 (abs) [75]
Ketorolac tromethamine MCC Powder Rabbits 0.148 F 0.045 h 0.170 F 0.131(Ag/ml) 38 (abs) [75]
Metoprolol tartrate Alginate microspheres Liquid Rabbits 240 F 0 min – 35.2 (abs) [76]
Midazolam ShEbCD/HPMC Spray Humans 0.25 F 0.04 h 54.3 F 5 ng/ml 73 (abs) [77]
Morphine hydrochloride Chitosan glutamate Spray Sheep 13.82 F 0.5 min 657.0 F 491.0 nM/l – [78]
Morphine hydrochloride Chitosan microspheres Powder Sheep 7.52 F 9 min 1010.8 F 733.4 nM/l – [78]
Morphine hydrochloride SMS + LPC Powder Sheep 10.0 F 4.1 min 1875.9 F 1125.3 nM/l – [78]
Morphine hydrochloride Chitosan glutamate Liquid Humans 16 F 7 min 97.72 F 57.2 nM/l – [78]
Morphine hydrochloride Chitosan glutamate Powder Humans 21 F 7 min 92.47 F 35.8 nM/l – [78]
Nicotine Amberlite resin Powder Sheep 34.2 F 13.9 min 118.3 F 65.8 ng/ml – [80]
Oxyprenolol Gelatin/polyacrylic Powder Rats 2.3 h 0.022 Ag/ml – [81]
microspheres
Gentamicin Hyaluronan Powder Rabbits 60 min 0.61 F 0.1 Ag/ml 23.3 F 1.3 (abs) [87,88]
Gentamicin Chitosan Powder Rabbits 30 min 1.53 F 0.3 Ag/ml 31.4 F 2.7 (abs) [87,88]
Gentamicin Hyaluronan/chitosan Powder Rabbits 60 min 1.29 F 0.3 Ag/ml 42.9 F 3.5 (abs) [87,88]
Leuprolide HPC/MCC Powder Rabbits – – 34.9 (abs) [120]
Calcitonin HPC/MCC Powder Rabbits – – 16.4 (abs) [120]
Calcitonin Chitosan free amine Liquid Rats – – 2.45 (abs) [121]
Ciprofloxacin HPMC Gel Rabbits 0.5 F 00 h 1.83 F 0.34 Ag/ml 40.21 F 6.41 (abs) [91]
Ciprofloxacin HEC Gel Rabbits 0.5 F 00 h 1.44 F 0.84 Ag/ml 19.46 F 2.7 (abs) [91]
Ciprofloxacin MC Gel Rabbits 0.5 F 00 h 1.05 F 0.49 Ag/ml 18.2 F 4.8 (abs) [91]
Ciprofloxacin HEC + Tween 80 Gel Rabbits 0.5 F 00 h 1.09 F 0.17 Ag/ml 25.39 F 2.19 (abs) [91]
Ciprofloxacin MC + Tween 80 Gel Rabbits 0.5 F 00 h 1.09 F 0.17 Ag/ml 22.3 F 5.5 (abs) [91]
FD4 HPC/MCC Powder Rabbits – – 35.4 (abs) [120]
FD4 Ethyl cellulose Powder Rats 27.0 F 6.7min 1.54 F 0.26 Ag/ml 38.0 F 3.8 (abs) [111]
Cyanocobalamin SD-MCC Powder Rabbits 15 min 72.9 ng/ml 25.0 (abs) [112]
Cyanocobalamin SD-CP Powder Rabbits 15 min 67.1 ng/ml 14.0 (abs) [112]
Cyanocobalamin SD-DM Powder Rabbits 30 min 22.3 ng/ml 7.0 (abs) [112]
Insulin Chitosan glutamate Liquid Sheep 27.5 F 14.7 min 179.1 F 65.5 AIU/ml 3.6 F 0.8 (rel) [113]
Insulin Chitosan glutamate Liquid Sheep 40.0 F 7.7 min 743.1 F 259.0 AIU/ml 17.0 F 6.6 (rel) [113]
Insulin Chitosan complex To check Sheep 11.7 F 5.2 min 66.9 F 24.1 AIU/ml 1.8 F 0.9 (rel) [113]
Insulin Chitosan nanoparticles To check Sheep 15.0 F 0.0 min 106.2 F 98.9 AIU/ml 1.3 F 0.8 (rel) [113]
Insulin DSM Powder Sheep – 97 F 31 m IU/ml 3.6 (rel) [115]
M.I. Ugwoke et al. / Advanced Drug Delivery Reviews 57 (2005) 1640–1665

Insulin DSM + GDC + STDHF Powder Sheep – 776 F 155 mIU/ml 31.9 (rel) [115]
Insulin DSM + STDHF Powder Sheep – 409 F 59 mIU/ml 16.5 (rel) [115]
Insulin DDWM Powder Rabbits 18.66 F 6.2 238.5 F 48.4 AIU/ml 4.461.2 abs [116]
Insulin DDWM/Carbopol 974P Powder Rabbits 28.2 F 3.7 418.6 F 73.3 AIU/ml 14.4 F 3.5 [116]
Insulin Maltodextrin DE 8/Carbopol 974 Powder Rabbits 23.5 F 2.7 314.06 F 69.1 AIU/ml 7.1 F1.6 (abs) [116]
Insulin Maltodextrin DE 22 Powder Rabbits 13.6 F 1.9 245.3 F 49.3 AIU/ml 4.5 F 1.0 (abs) [116]
Insulin Maltodextrin DE 22/Carbopol Powder Rabbits 24.7 F 4.4 366.8 F 81.5 AIU/ml 8.7 F 2.6 (abs) [116]
Insulin Maltodextrin DE 38 Powder Rabbits 14.2 F 1.8 202.2 F 43.1 AIU/ml 3.4 F 0.6 (abs) [116]
Insulin Maltodextrin DE 38/Carbopol Powder Rabbits 26.9 F 2.7 365.1 F108.4 AIU/ml 9.1 F 2.1 (abs) [116]
Glucagon MCC Powder Humans 10 min 6.94 F 1.06 mM/l – [119]
Desmopressin MCC Spray Humans 58 F 21 min 490 F 292 pg/ml – [124]
Desmopressin DSM Powder Sheep 8.3 F 3.3 min 1.74 F 0.16 ng/ml 4.7 F 0.5 (abs) [125]
Desmopressin DSM/LPC Powder Sheep 2.74 F 0.15 ng/ml 9.6 F 2.8 (abs) [125]
Mannitol TMC-12, pH 6.2 Liquid Rats – 0.05 F 0.03 (% of initial dose) – [113]
abs, absolute; C max, maximum plasma drug concentration; DDWM, drum-dried waxy maize starch; DSM, degradable starch microspheres; GDC, deoxyglycocholate; HEC,
hydroxyethyl cellulose; HPC, hydroxypropyl cellulose; HPMC, hydroxypropylmethyl cellulose; LPC, l-a-lysophosphatidylcholine; MC, methyl cellulose; MCC, microcrystalline
cellulose; (P(MAA-g-EG)), polymethacrylic acid and polyethylene glycol; rel, relative; ShEbCD, sulfobutylether h cyclodextrin; SD-CP, spray-dried crospovidone; SD-DM, spray-
dried dextran microspheres; SD-MCC, spray-dried microcrystalline cellulose; SMS, cross-linked eldexomer starch microspheres; STDHF, sodiumtaurodihydrofusidate; TMC, N-
trimethyl chitosan chloride; T max, time to attain maximum plasma concentration.
1657
00
6. Bottom view
φ3
Cupholder
Cup
Gel
Filter
Filterholder
Fig. 5. The rotating cup, a modification of the USP XXII rotating basket adapted for in vitro drug release from microparticulate formulations for
nasal administration.
netic stirrer [145–148] suffer from the limitations of These in vitro studies in no way replace in vivo
the microcapsules being dispersed directly in an studies in animals, and eventually man (see Section
excess amount of the release medium. This does 7 of this review for more information regarding tox-
not correspond with the in vivo situation encountered icological testing). The effects of multiple administra-
by microcapsules after nasal or buccal administrations on residence time and drug release are better
tion. In this system we observed a trend that drug understood under in vivo experimental settings. Inter-
loading influenced release rate in vitro as well as in action between the drug and mucoadhesive polymer
vivo but to different extents [66]. can decrease drug absorption, as was the case between
A number of methods/models have been described ciprofloxacin and calcium polycarbophil [152].
for characterizing the toxicological profiles of NDD There are some mucoadhesive polymers that are
products [149]. In vitro models, especially those based capable of resisting MCC with half-life clearance for
on tissues or cells of human origin [150] are very very long duration (Fig. 3). Application of such poly-
interesting since results relate more to human situa- mers in product development could potentially result
tions in vivo compared to studies based on tissues of in once a day administration of a product instead of 2–
other animals. This is particularly important when 4 times per day. In this case, a continuous release
considering (a) metabolic activation of nasally admi- (controlled release) will be achieved and this is pre-
nistered compounds to potentially toxic metabolites, sently technically possible. However, such a product,
(b) ciliotoxicity of some compounds that may involve which arrests MCC for such long periods, could lead
phosphorylation of specific proteins, (c) potential to local infection or inflammation after several admin-
nasal irritants that may trigger the release of autacoids. istrations. It will be highly recommended that differ-
When using in vitro human models, relevant toxicity ent toxicological scenarios be examined depending on
markers of cell injury may be identified and validated the intended use of the product. The choice between
against in vivo human data using standardized cyto- formulating a controlled release product must take a
logical, biochemical, immunological, and molecular lot more into account. In fact, only immediate and
biological approaches [151]. Some of the specific controlled release (a few hours only) should be admi-
proteins or isoforms involved in the cascades of nistered nasally. Undue interference with the MCC
events leading to toxicity are species dependent. should be avoided.
6. Nasal drug delivery opportunities drug formulations for the nasal route [153]. From
pharmacokinetic point of view, achieving sustained
6.1. Mucoadhesion as a fast track industrial product release for several hours is desirable. However, toxi-
development city of the excipients could be aggravated because of
extended contact with the nasal mucosa. Ideally,
The advantages of administering drugs nasally mucoadhesive polymers or other excipients should
compared to oral or parenteral route have been be cleared from the nasal mucosa within a few
described under Section 3. Exploitation of these hours in order not to impair the mucociliary system.
unique advantages could lead to a fast track product Most mucoadhesives act to oppose the mucociliary
development. This is proven by the increasing number transport system via prolongation of intranasal poly-
of nasally administered drugs [1] as well as companies mer–drug residence time. Depending on the intrinsic
either entirely specialized in NDD or have strong properties of a particular polymer and the drug loaded
presence in NDD research. in it, this could result in higher toxicity compared to
The possibility of increased drug absorption will simple nasal solutions or aerosols. The major toxico-
allow product development of nasal peptides and logical targets for nasally administered drugs include
small proteins, while this would not be possible with local irritation/tissue damage, epithelial/subepithelial
the oral route and eliminates the use of injections, with toxicity and ciliotoxicity. Furthermore, the relatively
its widely published limitations. The increased absorp- low mucus turnover of the nasal mucosa compared to
tion (due to high epithelial permeability/porosity) the gastrointestinal mucosa, extended mucoadhesion
together with low enzyme activity will act synergisti- could result in a fertile environment for establishment
cally towards increasing drug absorption. Controlled of opportunistic respiratory tract infections.
release can be achieved also after nasal administration. When developing mucoadhesive drug products for
A lot of the polymers used in nasal mucoadhesion have the nasal route, it is pertinent to assess the effect of
been thoroughly tested in humans for other application both the drug and excipients on these targets. Among
and most have GRAS (Generally Regarded As Safe) all the mucoadhesives used for nasal drug delivery,
status already. While this does not rule out the need to none has undergone extensive mucosal and mucocili-
perform local nasal toxicological studies, it reduces ary toxicity studies like the chitosans [154–158]. To
significantly the cost of product development thereby demonstrate the safety of trimethyl chitosans follow-
making this route of administration more appealing to ing nasal administration, Thanou et al. investigated
industrial executives. Apart from expanding product the cytotoxic and ciliotoxic effect of chitosans of
portfolio, it is an economical way of life cycle manage- different degrees of substitution (20%, 40% and
ment. Converting an boldQ drug previously adminis- 60%) using CaCO-2 and chicken trachea models,
tered parenterally to a nasal product will not only respectively [158]. No substantial cell membrane
expand/extend patent position but also decrease cost damage could be detected on the CaCO-2 cells treated
of goods and increase patient compliance. The short with N-trimethyl chitosans, while the effect on the
product development trajectory and multiplicity of dis- CBF in vitro was found to be marginal. Comparable
ease states where NDD can be applied are the other studies with excised human nasal tissues and human
advantages that need to be mentioned. The dual strat- volunteers also demonstrated the safety of this class of
egy of reducing product development time by applying mucoadhesives [157]. For the ex vivo studies, a range
existing excipients for NDD has been successfully of chitosans with different molecular weights were
applied in the development of products such as applied to freshly amputated human nasal turbinates,
RhinocortR [120]. and their effect on mucus transport rate was recorded.
The larger the molecular weight of the polymer, and
the more volume applied led to longer depression of
7. Safety considerations the mucus transport rate. The transient inhibitory
effect on turbinate mucus transport rate correlated
Absorption enhancement and toxicity are the key with the volume of chitosan solution applied and the
issues in the search and design of effective and safe molecular weight of the chitosan tested. The in vivo
study, which involved screening the effect of chitosan on the effects of the excipients on ciliary beat fre-
glutamate on saccharin clearance times, showed that a quency and/or mucociliary transport system. This is
once daily application of a 0.25% solution of the very important because the concept of nasal mucoad-
chitosan for 7 days had no effect on either saccharin hesion opposes the basic physiological system (muco-
clearance times or nasal histology as examined by ciliary clearance) that protects the respiratory system
light microscopy. from bacteria, viruses and noxious substances.
Using an in vitro human nasal cell culture system
exhibiting in vitro ciliogenesis previously validated
[72], we investigated the effect of Carbopol 971P 8. Conclusions
and carboxymethylcellulose on the ciliary beat fre-
quency (the motor for mucociliary clearance). Both There are a lot of exciting developments in the
Carbopol 971P and carboxymethylcellulose resulted field of NDD including mucoadhesion. Newly mar-
in only a mild-to-moderate cilio-inhibition, which keted products based on existing polymers are on the
was concentration dependent and partially reversible increase, while new polymers and administration
upon washing out the polymer (Fig. 4) [71]. The devices are still being developed. There is a lot of
formulations had no major detrimental effect upon ground for optimism with respect to benefits derivable
subacute intranasal administration in rabbits in vivo. from more fundamental research and application lead-
However, a mild-to-moderate nasal mucosal inflam- ing to better understanding of the subject and even-
mation was observed. Unlike carboxymethylcellu- tually more marketed products. A point of caution will
lose, Carbopol 971P caused severe inflammation, always be the safety aspects of nasal products,
though without necrosis, squamous metaplasia or although the recent developments of both in vitro
ciliary degeneration [159]. Using nasal mucosa of and in vivo models is a big boost to speeding up
rabbits and the foot mucosa of slugs, Callens et al. clinical developments and eventually time-to-market
showed that mucoadhesive formulations prepared of new products.
with drum-dried waxy maize (DDWM) starch and
Carbopol 974P (90/10) caused no major damage on
the nasal mucosa [160]. Twenty-four hours after Acknowledgement
administration to rabbits the release of marker mole-
cules (LDH, etc.) was comparable to the negative This work was partly sponsored by OctoPlus Inter-
controls. In another study, these excipients were national Holding BV, Zernikedreef 12, 2333 CL Lei-
shown to be well tolerated. Although they caused den, The Netherlands.
higher mucus production in the slugs, there were no
additional effects on body weight, histopathology or
release of proteins [161]. Adopting an in vitro References
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Advanced Drug Delivery Reviews 57 (2005) 1640 – 1665

Nasal mucoadhesive drug delivery: Background, applications,

2.2. Nasal mucus secretion and mucociliary clearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1642

1. Introduction of failure led to the conclusion that the short resi-

2.2.1. Mucociliary clearance

weakens the adhesive bond as a result of an over- 2.6.1. Polymer-related factors

Time post insufflation (min)

M.I. Ugwoke et al. / Advanced Drug Delivery Reviews 57 (2005) 1640–1665

M.I. Ugwoke et al. / Advanced Drug Delivery Reviews 57 (2005) 1640–1665

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