Intranasal delivery- opportunities for systemic and brain targeting
Vibhu Nagpal; R. N. Saha*
Drug Delivery & Pharmacokinetics Lab, Birla Institute of Technology
& Science, Pilani 333031, India
*Corresponding author:
Dr. Ranendra Narayan Saha, Deputy Director (Research & Education
Development),
Birla Institute of Technology and Science, Vidhya Vihar, Pilani- 333031,
India.
E-mail: rnsaha@bits-pilani.ac.in, Tel: ++91 9414082463.
ABSTRACT
Advances in pharmaceutical technology have led to development of
specialized drug delivery systems that allow drugs to be delivered through
the various alternative routes. Mucosal membranes, particularly the nasal
mucosa, offer the potential for a rapid absorption of some drugs with a
plasma profile closely replicating that from an intravenous bolus
injection. The relatively large surface area, the porous epithelial
membrane, and the extensive vascularization are factors favoring absorption
of nasally administered drugs. This is especially useful in emergency
situation with several advantages. Intranasal drug delivery can also be
exploited as a better route of entry into the systemic circulation, as well
as for direct brain targeting and is appropriate to its clinical
application. Targeting the central nervous system (CNS) by intranasal
delivery is a promising alternative for oral or parenteral administration,
and is investigated to directly target the brain, thereby increasing CNS
target and availability and the efficacy of CNS active drugs. Direct
delivery of therapeutics from the nasal cavity via the olfactory region
into the CNS, bypasses the BBB and provides a better alternative to
invasive methods of drug administration. Another application of this nasal
delivery can be targeting brain cancer through olfactory pathway by
bypassing BBB, particularly drugs having poor permeability to brian. In
addition to bypassing the BBB, the advantages of intranasal delivery
include rapid delivery to the CNS, avoidance of hepatic firstpass drug
metabolism, and elimination of the need for systemic delivery, thereby
reducing unwanted systemic side effects. Intranasal delivery also provides
painless and convenient self-administration. Although the market share for
nasal delivery may never take the number one spot enjoyed by oral
controlled release, it remains a drug delivery route with an enormous
potential for growth.
Keywords
: Intranasal delivery, Brain targeting, Nasal transmucosal delivery,
Noninvasive.
INTRODUCTION
The anatomy and physiology of the nasal passage indicate that nasal
administration has potential benefits for systemic delivery of therapeutic
drugs. The relatively large surface area, the porous epithelial membrane,
and the extensive vascularization are factors favoring absorption of
nasally administered drugs [1]. Furthermore, nasally absorbed drugs
circumvent the first-pass metabolism in the liver associated with orally
administration. Conventionally, most of the drugs are given through oral
route. But due to various limitations like stability issues in
gastrointestinal fluid, extensive biotransformation, lack of proper
biodistribution, variability of drug absorption, problems with patients
with nausea, vomiting and swallowing difficulties and to achieve quick
onset of action, there is need for alternative delivery systems. Advances
in pharmaceutical technology have led to development of sophisticated drug
systems, that allow drugs to be delivered through the skin, ocular,
transmucosal membranes (nose, buccal or bronchial) [2]. Mucosal membranes,
particularly the nasal mucosa, offer the potential for a rapid absorption
of drugs with a plasma profile closely replicating that from an intravenous
bolus injection. This is especially useful in emergency situation.
Intranasal drug delivery exploited as a better route of entry into the
systemic circulation, either because the absorption profile of the drug is
appropriate to its clinical application, e.g. a quick onset of action for
the treatment of migraine with sumatriptan and/ or for those compounds
which cannot be given orally [3].
Despite enormous advances in brain research, central nervous system
disorders remain the world's leading cause of disability, and account for
more hospitalizations and prolonged care than almost all other diseases
combined [4]. Direct delivery of therapeutics through the nasal cavity via
the olfactory region, intranasal delivery (IN) into the CNS bypasses the
BBB and provides an better alternative to invasive methods of drug
administration [5,6]. Patient compliance and risk-benefit ratio put forward
the use of this non invasive method of drug delivery over invasive methods.
Targeting the central nervous system (CNS) by intranasal delivery is a
promising alternative for oral or parenteral administration, and is
investigated to directly target the brain, thereby increasing CNS target
site bioavailability and the efficacy of CNS drugs. One of the first to
demonstrate the presence of the olfactory pathway for non-microbial and
non-viral agents was W.F. Faber, who placed Prussian blue dye in the nasal
cavity of rabbits and observed the dye in the perineural space of the
olfactory nerve and in the subarachnoid space of the brain as early as 1937
[7].
NASAL ANATOMY AND PHYSIOLOGY
Breathing and olfaction are the prime functions of the nasal cavity. The
surface of the nasal cavity is enlarged by three main regions nasal
vestibule, the respiratory region and the olfactory region (Figure 1) [8].
Figure 1
Anatomy of the nose. To the left is the lateral wall of the nasal cavity
with the olfactory region at the roof of the cavity, just below the
cribriform plate of the ethmoid bone.
The total surface of nasal cavity is about 150 cm2 of which the
respiratory epithelium covers about 130 cm2 (large inferior
turbinate) and the olfactory region about 2 cm2 to 10 cm 2 (superior turbinate). The nasal cavity is covered with a
mucous membrane which can be divided into nonolfactory and olfactory
epithelium areas [9]. The non-olfactory area includes the nasal vestibule,
which is lined with skin-like cells, and the respiratory region, which has
a typical airway epithelium. The intense blood flow in the arteriovenous
anastomosis and the large surface of the respiratory epithelium favors
transmucosal nasal drugs absorption. On the other side, drug absorption in
the olfactory region is possibly resulting in direct nose to
brain-transport through the nervus olfactorius [10].
The Respiratory Region
The nasal respiratory epithelium is described as a pseudo-stratified
ciliated columnar epithelium. This region is considered to be the major
site for drug absorption into the systemic circulation. The four main types
of cells seen in the respiratory epithelium are ciliated columnar cells,
non-ciliated columnar cells, goblet cells and basal cells (Figure 2) [11].
Figure 2: Schematic illustration of the various cell types in the nasal
respiratory epithelium.
The proportions of these four cell types vary in different regions of the
nasal cavity. In the lower turbinate area, about 15-20% of the total
numbers of cells are ciliated and 60-70% are non-ciliated epithelial cells.
The numbers of ciliated cells increase towards the nasopharynx with a
corresponding decrease in non-ciliated cells [12]. The role of the ciliated
cells is to transport mucus towards the pharynx. The high number of non
ciliated cells indicates their importance for absorption across the nasal
epithelium. Both columnar cell types have numerous microvilli (about
300–400 per cell) [13]. The presence of large number of microvilli
increased the effective surface area and enhanced absorptive capacity of
the nasal membrane.
The Olfactory Region
In humans, the olfactory region is located on the roof of the nasal cavity,
just below the cribriform plate of the ethmoid bone, which separates the
nasal cavities from the cranial cavity (Figure 1) [8]. Humans have
relatively simple nose, since the primary function is breathing, while
other mammals have more complex nose better adapted for the primary
function of olfaction. In a morphometric analysis of rodent nasal cavities,
Gross et al. [14] indicated that, in mice and rats, about 47% and 50% of
the total nasal epithelium consists of olfactory epithelium respectively.
In humans, however, the neuroepithelium covers an area of 2-10 cm 2, i.e. around 3% [15]. The olfactory epithelium composed of a
thick connective tissue, lamina propria, which contains blood vessels,
olfactory axon bundles and Bowman’s glands. Like the epithelium of the
respiratory region, the olfactory epithelium comprises pseudo-stratified
columnar cells of three principal types: olfactory receptor cells,
supporting cells and basal cells (figure 3) [16].
Figure 3
The olfactory epithelium of the nasal cavity showing the three principal
cell types [16]
The olfactory pathways have been reviewed by several authors [16,17,18].
Mathison et al. broadly classified the pathways into two possible
routes from the olfactory mucosa in the nasal cavity into the CNS along the
olfactory neurons: the olfactory nerve pathway (axonal transport) and the
olfactory epithelial pathway. Agents that are able to enter the olfactory
receptor cells, by endocytotic or pinocytotic mechanisms, could utilise the
olfactory nerve pathway and thus be transported by intracellular axonal
transport to the olfactory bulb [17]. Mouse hepatitis [19] and vesicular
stomatitis viruses [20] and agglutinin-conjugated horseradish peroxidase
[21] have been found to enter the brain by axonal transport. In the
olfactory epithelial pathway, the substance must first cross the olfactory
epithelium. The substance could be absorbed by passive diffusion through
the supporting cells or Bowman’s glands or it could be transported by a
paracellular route through the tight junctions between the supporting.
After entering the lamina propria, adjacent to the olfactory neurons, the
substance could then enter the perineural space and reach the CNS [16]. By
directly targeting the brain, it has been hypothesized that IN delivery can
enhance the CNS target site bioavailability and the efficacy of CNS drugs
[22].
FACTORS AFFECTING NASAL DRUG ABSORPTION
The extent of absorption of a drug from the nasal cavity depends partly on
the size of the drug molecules, a factor that is most important for
hydrophilic compounds. It has been reported by several workers, that there
is an almost linear but inverse relationship between the molecular weight
and the bioavailability of water soluble drugs (190–70 000 Da) and dextran
of different weights (1260–45 500 Da) [23, 24]. McMartin et al.
(1987) linked the extent of absorption of compounds with their molecular
weight. The nasal route appears to be suitable for the efficient rapid
delivery of molecules of molecular weight <1000 [25]. This means that
the bioavailability of larger polypeptides like insulin will be too low
when they are administered nasally. This factor also decides that whether
drug will be or not transported along the olfactory pathway. In studies in
rats, Sakane and co-workers have demonstrated an inverse linear
relationship between the transport of compounds from the nose into the CSF
and their molecular weight [26], but directly proportion to degree of
dissociation [27] and lipophilicity [28]. These studies demonstrated the
usefulness of dextrans as molecular weight markers and confirmed the
inverse relationship between molecular size and nasal absorption for highly
water soluble compounds. In these studies, direct uptake into the CSF of
various molecular weights of dextrans labelled with fluorescein
isothiocyanate after nasal administration was dependent on molecular
weight. Dextrans with molecular weights ≤20 kDa were directly transported
to the CSF, while those weighing 40 kD were not found in the CSF.
However, formulation additives like absorption enhancers may increase the
bioavailability of these compounds, and several research groups are now
engaged in the search for suitable enhancer systems for larger molecules.
The main problem is to achieve high absorption enhancement without causing
irreversible damage to the nasal cavity, such as affecting the cell
membrane or altering the defence mechanisms in the nose. The nasally
administered drugs will normally be cleared rapidly from the nasal cavity
into the gastrointestinal tract by the mucociliary clearance system.
Therefore, the use of absorption enhancers and the design of suitable
dosage formulations, such as mucoadhesive delivery systems, is necessary to
enhance the nasal bioavailability [29, 30]. Combination of absorption
enhancer and mucoadhesive polymers such as methyl cellulose, polyacrylic
acid, sodium alginate, chitosan, hyaluronan etc. can potentially increase
the delivery of drugs, into the system as well as CNS via the olfactory
pathway [31, 32]
Lipophilic drugs like propranolol [33] and nicotine [34] are well absorbed
from the nasal cavity, providing plasma concentration-time profiles similar
to those obtained after intravenous administration. A linear relationship
between the rate constant of absorption and the log P (octanol/water) has
been demonstrated earlier with progesterone [35] in rabbits. In case of
transport through olfactory pathway, for drugs with comparatively low
lipophilicity, transport into the CSF is also dependent on the partition
coefficient. In a reported study, the concentrations of various
sulphonamides in the CSF found to be increased linearly with the partition
coefficient [28]. Similar results were reported in a study of distribution
of local anaesthetics in rats with similar chemical structures [36]. The
rank order of these local anaesthetics, according to the ratios of the area
under the concentration-time curve (AUC) values in the CSF for the two
administration routes (nasal/parenteral), correlated well with their
ranking by distribution coefficient.
The pKa of a substance and the pH in the surrounding area vehicle are the
two factors that decide the ratio of dissociated to undissociated molecules
of a drug. Several studies have shown that the amount of absorbed drug is
increased with an increase in fraction of undissociated molecules [37].
Nasal administration of sulphasomidine in perfusions of varying pH resulted
in more extensive transport of undissociated drug molecules into the CSF
[27]. The ratio of the drug concentration in the CSF to that in the nasal
perfusion fluid was dependent on the unionised fraction of the drug, i.e.
drug transport from the nasal cavity into the CSF conforms to the pH
partition theory.
APPLICATIONS OF NASAL DELIVERY
Topical and Systemic Bioavailability of Nasally Applied Drugs
Topical drug delivery describes the application of a drug directly on the
target organ. The term nasal drug delivery refers to topical and systemic
nasal drug delivery. For diseases of the nasal mucosa, such as infectious
rhinitis, allergic rhinitis, and nasal polyposis, the topical nasal
administration delivers drug directly to the target site [38]. Nasal
applications of topical decongestants or anti-inflammatory drugs are
therefore the most popular topical nasal drug deliveries.
Whereas, nasal drug delivery for systemic effect means transmucosal drug
delivery leading to, direct access to the systemic circulation or to the
brain. As discussed earlier, transmucosal nasal drug delivery has been
found to be suitable alternative route for drugs with poor systemic
bioavailability after oral administration. Due to the rapid therapeutic
action that can be achieved, medications used in emergency medical
situations make ideal candidates for nasal drug delivery. One such drug,
apomorphine is the drug of choice for treatment of on/off-syndrome in
patients suffering from Parkinson’s disease. Aqueous solution of the
compound is reasonably well absorbed following nasal administration with a
relative bioavailability of 45% [39]. It has been demonstrated in several
studies that the pharmacokinetic profiles of apomorphine after nasal
administration may be improved following incorporation of mucoadhesive
polymers like polyacrylic acid, carbopol and carboxymethylcellulose [40].
In using mucoadhesive polymers for nasal drug delivery, it is significant
to demonstrate that mucoadhesion is the predominant mechanism responsible
for improved drug absorption. Many antibiotics are still exclusively
administered via parenteral routes. Recently a few studies have examined
the potential of the nasal route for systemic delivery of antibiotics using
mucoadhesive polymers. In a preliminary study, Lim et al. prepared and
evaluated mucoadhesive microspheres of hyaluronic acid and chitosan for
nasal delivery of gentamicin and other drugs [41]. This study showed that
hyaluronic acid and chitosan may be employed for nasal administration of
antibiotics to obtain a high bioavailability and prolonged release. For
drugs extensively metabolized in the gastrointestinal tract or in the
liver, such as proteins, peptides and steroid hormones (estradiol,
progesterone and testosterone), nasal administration is a convenient
alternative [42, 43]. Table 1 gives an overview of compounds tested for
transmucosal nasal drug delivery.
Table 1:
Compounds Studied for System Delivery by Nasal Route
Compound
|
Indication
|
Compound
|
Indication
|
apomorphine
|
Parkinson’s disease (on-offsymptoms)
|
human growth
|
hormone growth hormone deficiency
|
buserelin
|
prostate cancer
|
insulin
|
diabetes mellitus
|
calcitonin
|
Osteoporosis
|
ketamine, norketamine
|
Analgesia
|
cobalamin
|
(vitamin B12) substitution of vitamin B12
|
L-dopa
|
Parkinson’s disease
|
desmopressin
|
diabetes insipidus centralis,
enuresis nocturna
|
melatonin
|
jet-lag
|
diazepam
|
sedation, anxiolysis, status
epilepticus
|
midazolam
|
sedation, anxiolysis, status
epilepticus
|
estradiol
|
substitution of estradiol
|
morphine
|
Analgesia
|
fentanyl
|
analgesia, postoperative pain
and agitation in children
|
progesterone
|
infertility, amenorrhea
|
sildenafil
|
erectile dysfunction
|
propranolol
|
hypertonia
|
testosterone
|
substitution of testosterone
|
|
|
4.2 Targeting to the CNS
The nose-brain pathway, as a conduit for transmission of agents into the
CNS, is an area of ongoing research. Table 2 lists drugs and drug-related
compounds that are reported to reach the CNS after nasal administration. In
one of the first studies by Sakane et al. [44], the authors
compared the uptake into the CSF after intranasal, intraduodenal and
intravenous administration of the water soluble antibiotic cephalexin in a
rat model. The plasma concentrations were similar after 15 and 30 minutes
for the three routes but the levels of the drug in the CSF were found
significantly higher at both time points after nasal administration.
Because of the higher concentration in CSF after 15 minutes, Sakane et al. postulated that cephalexin was transported from the nasal
cavity to the CSF by passive diffusion, i.e. via the olfactory epithelium
pathway.
CSF drainage via the nasal route in man post mortem was
demonstrated by Löwhagen, P. et al., and a few studies showing access to
the human brain after nasal administration of drugs have been published
[45]. Functional evidence of the facilitated access of arginine-vasopressin
[46] and cholecystokinin-8 [47] into the brain by this route has been
reported by researchers. Intranasal administration of angiotensin II to
healthy volunteers showed that the drug directly influences the CNS
regulation of blood pressure [48]. It was shown that the blood pressure
profiles differed with the route (intravenous or intranasal) of
administration of angiotensin II, and that the plasma concentrations of
vasopressin were increased after intranasal but not after intravenous
angiotensin II administration. The same research group also showed that
nasal administration of insulin [49], an active fragment of
adrenocorticotrophin [50], and a corticotrophin-releasing hormone [51]
resulted in effects not seen after intravenous administration assuming a
direct deliver into the CNS of the compounds. Table 2 lists drugs and
drug-related compounds that are reported to reach the CNS after nasal
administration in different species.
Table 2:
Drugs and drug-related compounds reported to reach the CNS after nasal
administration in different animal models
Drug
|
Species
|
Sample
|
Method
|
Adenoviral
lacZ vector
|
Mouse
|
–
|
Histochemical
|
β-Alanine
(as carnosine)
|
Hamster
Mouse
|
Brain tissue
|
Autoradiography,
Biochemical analysis
Radioactivity counting
|
Albumin (labelled
with Evans blue)
|
Mouse
|
–
|
Light microscopy
Fluorescence microscopy
Electron microscopy
|
Bupivacaine
|
Rat
|
CSF
|
HPLC
|
Cephalexin
|
Rat
|
CSF
|
HPLC
|
Chlorpheniramine
|
Rat
|
CSF
|
HPLC
|
Cocaine
|
Rat
|
Brain tissue
|
HPLC
|
D4T
|
Rat
|
CSF
|
HPLC
|
Dextrans
(FITC labelled)
|
Rat
|
CSF
|
HPLC
|
Dihydroergotamine
|
Rat
|
Brain tissue
|
Radioactivity counting
|
Dopamine
|
Monkey
Mouse
|
CSF
Brain tissue
|
Radioactivity counting
Autoradiography
|
Estradiol
|
Monkey
Rabbit
|
CSF
|
Radioactivity counting
|
Fibroblast growth
factor
|
Mouse
|
–
|
Motor activity
Dopamine activity
|
L-dopa
|
Rat
|
–
|
Microdialysis
Activity in neostriatum
|
Lidocaine
|
Rat
|
CSF
|
ECV
HPLC
|
Nerve growth
factor
|
Rat
|
Brain tissue
CSF
|
ELISA
Radioactivity counting
|
Sulphonamides
|
Rat
|
CSF
|
HPLC
|
Tetracaine
|
Rat
|
CSF
|
HPLC
|
Triprolidine
|
Rat
|
CSF
|
HPLC
|
WGA-HRP
|
Mouse
Rat
Monkey
|
–
|
Histochemical
Light microscopy
Electron microscopy
|
D4T = 2’, 3’-didehydro-3’-deoxythymidine, WGA-HRP = wheat germ
agglutinin-horseradish peroxidase, FITC =fluorescein isothiocyanate, ELISA
= enzyme-linked immunosorbent assay, HPLC =high performance liquid
chromatography, ECF= extracellular fluid
New therapeutic approach for this nasal delivery is targeting brain cancer
through olfactory pathway by bypassing BBB. The blood-brain barrier is a
substantial obstacle for delivering anticancer agents to brain tumors, and
new strategies for bypassing it are greatly needed for brain-tumor therapy.
Intranasal delivery provides a practical, noninvasive method for delivering
therapeutic agents to the brain and could provide an alternative to
intravenous injection and convection-enhanced delivery. Recently,
anticancer agents such as methotrexate [52], 5-fluorouracil [53] and
raltitrexed [54] have been delivered to the CNS and/or CSF using intranasal
delivery. However, these chemotherapeutic agents do not discriminate
between tumor and normal tissues. Thus, the concentrations of drug required
to kill tumor cells can also lead to toxicity in normal neural tissues. To
achieve therapeutic efficacy without toxicity to normal tissues, the drugs
must preferentially target brain tumor while sparing normal tissues from
damage. Because telomerase is expressed in the vast majority of GBMs but
not in normal brain tissues [55], inhibition of telomerase provides a
therapeutic strategy for selectively targeting malignant gliomas. One group
of researchers has adminstered 3'-Fuorescein isothiocyanate (FITC) -
labeled GRN163 intranasally every 2 min as 6 μl drops into alternating
sides of the nasal cavity over 22 min. FITC-labeled GRN163 was present in
tumor cells at all time points studied, and accumulation of GRN163 peaked
at 4 h after delivery. Moreover, GRN163 delivered intranasally, daily for
12 days, significantly prolonged the median survival from 35 days in the
control group to 75.5 days in the GRN163-treated group. Thus, intranasal
delivery of GRN163 readily bypassed the blood-brain barrier, exhibited
favorable tumor uptake, and inhibited tumor growth, leading to a prolonged
lifespan for treated rats compared to controls. This delivery approach
appears to kill tumor cells selectively, and no toxic effects were noted in
normal brain tissue. These data support further development of intranasal
delivery of tumor-specific therapeutic agents for brain tumor patients [56]
Conclusion and Future perspectives
The advantages of administering drugs nasally compared to oral or
parenteral route have been described in this review. Exploitation of these
unique advantages could lead to a fast track product development. This is
proven by the increasing number of nasally administered drugs mentioned in
Table 1 & 2 as well as companies either entirely specialized in Nasal
Drug Delivery (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 this would not be possible with
the oral route and eliminates the use of injections. The increased
absorption (due to high epithelial permeability/porosity) together with low
enzyme activity will act synergistically towards increasing drug
absorption. Controlled release and targeted CNS delivery by bypassing BBB
is also the best advantage after nasal administration. Pharmaceutical
companies have looked increasingly towards drug delivery companies for help
in lifecycle management of drugs on the market and with promising yet
hard-to-deliver drugs. However, the potential for growth in this sector is
extensive, pending the successful delivery of proteins and peptides as an
alternative to parenteral delivery. Currently, many nasal drug products on
the market are indicated for the treatment of local diseases such as
allergic rhinitis, infectious rhinitis and nasal polposis. However, this is
likely to change soon. There are a number of nasally delivered,
systemically as well as CNS targeting on the market in different
therapeutic categories, with a growing number of products in the pipeline.
There are many reasons for this change, including improved patient
compliance (elimination of needles), avoidance of firstpass metabolism,
decreased dose which leads to minimum side effects and rapid onset of
action. Migraine is a key area where a nasal system (Imitrex® nasal spray,
GlaxoSmithKline) has provided rapid relief, avoidance of taking an oral
formulation while nauseated, and pain-free administration circumventing the
need for an injection. Other therapeutic areas where nasal delivery could
provide an alternative to current dosage forms are crisis situations
(seizure and heart attack), erectile dysfunction, pain management, motion
sickness and psychotropic drugs. New therapeutic area for this nasal
delivery is targeting brain tumors. Despite the development of drugs that
preferentially target tumor cells without harming normal tissues, delivery
of these drugs to brain tumors remains a major challenge because of
difficulty in penetrating the blood-brain barrier (BBB). Intranasal
delivery provides a practical, noninvasive method for delivering
therapeutic agents to the brain because of the unique anatomic connection
provided by the olfactory and trigeminal nerves. Further development of
intranasal ligand based delivery as a potential therapy for braintumor
patients and perhaps as a means for treating multifocal brain tumors and/or
pediatric brainstem tumors, which are less amenable to potentially risky
surgical procedures. As well as delivering tumor-specific agents
intranasally for the treatment of intracranial neoplasms. Although the
market share for nasal delivery may never take the number one spot enjoyed
by oral controlled release, it remains a drug delivery route with an
enormous potential for growth.
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