The Review on The
Nasal Drug Delivery
Prajapati M., Mandloi R.,
Pillai S, Birla N.
G.R.Y. Institute of Pharmacy,
Borawan, Khargone (M.P.), India
*Corresponding Author E-mail:
ABSTRACT:
Oral drug delivery is most common rout use for
the drug administration systemic effect of drug. But as per low bioavailability
of some drug compounds has try to more effective routs for systemic effect of
drug. Transmucosal rout of drug delivery (i.e. Nasal, rectal, vagina, ocular
and oral cavity). Nasal drug delivery is most useful rout for drug delivery.
Therapy through intranasal administration has been an accepted from of
treatment in the Ayurveda system of Indian Medicine Nasal cavity is well
tolerated rout. Large quantity of blood vessels in the nasal mucosa contributes
in drug absorption. Respiratory region, vestibular region, olfactory region is
part of nasal cavity. The mechanism of NDD (Nasal Drug Delivery) is depending
on two mechanisms and two processes first are Carrier mediated process and
second are Endocytic processes. NDD is novel platform, promising alternative to
injectable route for administration. Over the last few decades, transmucosal
nasal drug delivery ad a non- invasive rout has occupied an important place in
the field of drug delivery technology. The principles underlying the
development of Nasal Formulation are reviewed here. In this review, the
benefits, limitation, and absorption mechanisms of the nasal rout, as well as
finding from nasal insert-related studies are addressed.
KEYWORDS: Nasal Drug
Delivery, Transmucosal Rout, Novel Drug Delivery, Nasal Absorption, Nasal
Preparations.
INTRODUCTION:
Recent year have shown that
nasal rout can be potential route for the systemic delivery of protein/peptide
drugs as it has a considerably large absorption area (150cm2) which is highly
vascularized and has permeability similar to or higher than the small
intestinal mucosa. Nasal delivery of protein/peptide drugs also offers other
benefits such as ease of administration, noninvasive administration, rapid
onset of action, and the avoidance.
Nasal drug delivery is most
common and useful rout for well tolerated drug. Nasal rout are using for both
systemic and local drug delivery. Due to large quantity of blood vessels the
drug compound is well absorbed in this rout.[1] Ayurveda is
accepting Nasal drug delivery because of its good absorption. In latest many
drugs have been better systemic bioavailability through nasal rout than by oral
administration.[2] Nasal mucus have lack pancreatic and gastric
enzymatic activity so drug achieve faster and higher level absorbtion.[3]
The NDD is provide large surface area, high blood flow, first pass metabolism.
In Ayurveda Nasal drug delivery is finds a special place and in Ayurveda it’s
called as “Nasya Karma”.[4] Because of its ready accessibility,
nasal drug administration has been considered as an alternative route for
systemic use of drugs restricted to intravenous administration. This is
particularly important for the delivery of peptides and proteins that are
mainly administered through intravenous route because of their susceptibility
to the gastrointestinal proteases There is a growing interest in
nasal administration of vaccines, hormones, peptides and other medicinal
substances with systemic effect that are usually delivered mainly via
parenteral route. When applied into the nasal cavity medicinal substances enter
directly into the systemic circulation in a simple and painless way.[5]
1
Hepatic first pass metabolism id absent.
2
Easy administration.
3
Rapid onset action.
4
Drugs give in systemic circulation when drugs are not absorbed orally.
5
Reduced side effects.[5]
1
Nasal cavity provides smaller absorbtion surface area as compared to GIT.
2
Surfactants that are used for the chemical enhancers they dissolve the membrane
in high concentration.
3
The mechanical loss of dosage form into other parts of the respiratory track
like lungs because of improper technique of administration[6]
1
Sterility
2
Isotonicity
3
Buffer/pH adjustment
4
Minimum protein binding
5
Non irritative and nontoxic[7]
MECHANISM OF NASAL ABSORPTION:
The absorbed drug from the
nasal cavity passes through the mucus layer. It is the first step in absorption.
Small, unchanged drugs easily pass through this layer but large, charged drugs
find difficulty to cross it. The principle protein of the mucus is mucin. It
has the tendency to bind to the solutes and hinders diffusion of drug
molecules. Structural changes in the mucus layer are possible as a result of
environmental changes like change in pH, temperature. Many absorption
mechanisms were proposed earlier but only two mechanisms have been
predominantly used, such as
(a) First mechanism:
It is also known as the
paracellular transport. It involves an aqueous route of transport but slow and
passive. There is an inverse correlation between intranasal absorption and the
molecular weight of water soluble compounds. Drugs having molecular weight
greater than 1000 Daltons shows poor bioavailability.
(b) Second mechanism:
It involves transport through
a lipoidal route. It is also known as the transcellular process. It is
responsible for the transport of lipophilic drugs that show a rate dependency
on their lipophilicity. Drug also crosses the cell membranes by an active
transport route via carrier-mediated means.[8]
1) Lipophilicity:
On increasing lipophilicity,
the permeation of the com- pound normally increases through nasal mucosa.
Although the nasal mucosa was found to have some hydrophilic character, it
appears that these mucosa are primarily lipophilic in nature and the lipid domain
plays an important role in the barrier function of these membranes.
2) Chemical form:
The chemical form of a drug
can be important in determining absorption.
3) Buffer Capacity:
Nasal formulations are
generally administered in small volumes ranging from 25 to 200μL with 100
μL being the most common dose volume. Hence, nasal secretions may alter
the pH of the administered
dose.
4) Polymorphism:
Polymorphism is known to
affect the dissolution rate and solubility of drugs and thus their absorption
through biological membranes. It is therefore advisable to study the poly-
morphic stability and purity of drugs for nasal powders and/or suspensions.[9]
1) pH:
The pH of the formulation, as
well as that of nasal surface can affect a drug’s permeation. To avoid nasal
irritation, the pH of the nasal formulation should be adjusted to 4.5-6.5.
2) Solubility and Dissolution Rate:
For better absorption drug
should get dissolve. If particles are present, it is somewhat difficult for
absorption.
3) Viscosity:
A higher viscosity of the
formulation increases contact time between the drug and the nasal mucosa
thereby increasing the time for permeation. At the same time, highly viscous
formulations interfere with the normal functions like ciliary beating or
mucociliary clearance and thus alter the perme-ability of drugs.
Many factors affect the
systemic bioavailability of nasally administered drugs. The factors can be
attributed to the physicochemical properties of the drugs and the
characteristics of other ingredient of delivery system has been discussed in
relevant section i.e. dosage forms and type and characteristics of selected
nasal drugs delivery system. These play significant role for most of the drugs
in order to reach therapeutically effective blood levels after nasal
administration. [10]
Strategies to improve nasal
absorption:
Nasal metabolism of drugs can
be eliminated by using the enzyme inhibitors. Mainly for the formulation of
proteins and peptide molecule development enzyme inhibitors like peptidases and
proteases are used. The absorption enhancers like salts and fluidic acid
derivatives also shows enzyme inhibition activity to increase the absorption
and bioavailability of the drug. The other enzyme inhibitors commonly used for
the enzymatic activity are tripsin, aprotinin, borovaline, amastatin, bestatin
and boroleucin inhibitors.
The permeation enhancers are
mainly used for the enhancement of absorption of the active medicament.
Generally, the absorption enhancers act via one of the following
mechanisms:
·
Inhibit enzyme activity;
·
Reduce mucus viscosity or elasticity;
·
Decrease mucociliary clearance;
·
Open tight junctions; and Solubilize or stabilize the drug.
The mechanism of action of
absorption enhancer is increasing the rate at which drug passes through the
nasal mucosa. Many enhancers act by altering the structure of epithelial cells
in some way, but they should accomplish this while causing no damage or
permanent change to nasal mucosa. Alteration of properties of mucosa layer
Opening tight junctions between epithelial cells. Reversed micelle formation
between membranes Increasing the membrane fluidity.[11]
Possible Nasal drug delivery:
It is a topically use and less
toxic and good absorption into skin. That is use as locally that is cold nasal
symptoms, antihistamines.
It is an intranasal drug
administration. It provides fast and effective drug absorption as compare to
oral and parenteral administration. Cardiovascular, analgesics drugs are
administrated by this rout.
During inhalation nasal mucosa
is first site contact to inhaled antigens that for nasal vaccines are use for
respiratory infections.[12]
The NDD has four mechanisms:
1. First Mechanism It
is known as cellular rout but it is slow drug which have low molecular weight
(1000 Dalton) show low bioavailability.
2. Second Mechanism It
is known as transcellular process. It use foe lipophilic drugs and they cross
cell membrane.
3. Carrier Mediated
process active transport mechanism for di as well as L- amino acid has been
demonstrated in nasal epithelium
4. Endocytic Process
the compound that has molecular Wight high that are use [13]
1.
Biological
Factors:
Nasal cavity has five sections
nasal vestibule, atrium, respiratory area, olfactory region and nasopharynx
that are influence the permeability. Enzymatic barrier delivers the drug in
nasal mucosa with the presence of oxidative and conjugative.
2.
Physiological
Factors:
Nasal mucosa is high permeable
site due to high blood supply parasympathetic stimulation gives conjugation and
low blood supply sympathetic stimulation give relaxation.
3.
Nasal
Secretions:
Mucus produces approximately
1.5-2ml mucous daily. Patho logical condition, environmental conditions,
membrane permeability influence nasal secretion.
4.
Formulation:
Viscosity, pH, pharmaceutical
excipients.[10]
Suitable drug candidate for
NDD:
1
Appropriate nasal absorption properties.
2
No any nasal irritation from the drug.
3
Dose below 25 mg per dose.
4
No toxic metabolites.
5
Suitable stabilized characteristics.
Soluble: Hydroxypropyl
methylcellulose, methyl cellulose.
Insoluble: Ethylcellulose.
Polyacrylates:
Carbomers, polycarbophils.
Starch:
Maize starch, degradable
starch microspheres (DSM)
Over the counter nasal
preparation are formulated as solution, to treat the nasal symptoms of allergic
rhinitis and common cold. A simple drug solution is adequate for this purpose
as it produces better dispersion over greater surface area. The nasal residence
time of such formulation is short (3-20 min) and exhibit high inter-individual
variability. This route provides fast peak levels.[14]
Liquid dosage forms:
Nasal drops are one of the
most simple and convenient delivery systems among all formulations. The main
disadvantage of this system is the lack of dose precision.
Both solution and suspension
formulations can be formulated into nasal sprays. Due to the availability of
metered dose pumps and actuators, a nasal spray can deliver an exact dose
anywhere from 25 - 200μL. Nasal emulsions, micro emulsions Intranasal
emulsions have not been studied as extensively as other liquid nasal delivery
systems. Nasal emulsions offer the advantages for local application mainly due
to the viscosity. Semi-solid dosage forms Semi-solid systems, for example gels,
ointments and liquid systems containing polymers that gel at particular pH
changes are usually employed for designing the nasal drug delivery systems.
Nasal gels Nasal gels are thickened solutions or suspensions, of
high-viscosity. The advantages of a nasal gel include the reduction of
post-nasal dripping due to its high viscosity, reduction of the taste impact
due to reduced swallowing, reduction of anterior leakage of the formulation.
Solid dosage forms Solid dosage forms are also becoming popular for intranasal
drug delivery, although these formulations are more suitable for pulmonary drug
delivery and similar applications, since it can cover the vasculature within
the epithelium of nasal mucosa.
Nasal Suspensions and
Emulsions:
Suspensions are rarely used or
investigated as nasal drug delivery systems. Analogous to marketed aqueous
ophthalmic suspensions of the soft corticosteroid, loteprednol etabonate (e.g.
Alrex®, Bausch and Lomb Pharmaceuticals), a nasal aqueous suspension of same
drug containing microcrystalline sodium carboxymethyl cellulose for
stabilisation and retention in the nasal cavity was patented by Senju
Pharmaceuticals Inc., Osaka, Japan and was intended for the local treatment of
allergic rhinitis. Moreover, a nasal suspension for the delivery of insulin was
investigated by Ando et al. (1998). Here, soybean-derived steryl glycoside and
sterol mixtures (1%) were used as absorption enhancers and pharmacological
bioavailabilities of 6.7% and 11.3% were achieved. However, for oral drug
delivery it has been reported by several authors that emulsions were superior
to suspensions in enhancing the bioavailability of poorly soluble drugs and the
trend is similar with nasal formulations. Absorption enhancement has been
attributed to solubilisation of the drug and the lipophilic absorption
enhancers in the composition. Similarly, other low solubility compounds have
been formulated in emulsions to increase the drug solubility, e.g. diazepam and
testosterone. Klang et al., 2015 used a nano-suspension to target the brain
through the nose. Formulation as a nanosuspension facilitated bypassing of the
blood-brain barrier (BBB) for particles ranging between 1-500 nm. Moreover,
recently researchers have also reported nasal administration of nano-emulsions
for brain targeting.[15]
Solid dosage forms:
Powder dosage forms may be
developed if solution and suspension dosage forms cannot be developed, mainly
due to lack of drug stability.
The advantages of a nasal
powder dosage form are the absence of preservative and superior stability of
the drug in the formulation. However, the suitability of the powder formulation
is dependent on the solubility, particle size, aerodynamic properties and nasal
irritancy of the active drug and/or excipients.
Several claims have been made
in favour of developing nasal formulations containing liposomes, microspheres
and nanoparticles for intranasal drug delivery. These systems can include,
besides the drug, enzymatic inhibitors, nasal absorption enhancers or/and
mucoadhesive polymers in order to improve the stability, membrane penetration
and retention time in nasal cavity.
Liposomes are phospholipids
vesicles composed by lipid bilayers enclosing one or more aqueous compartments
and wherein drugs and other substances can be included. Liposomal drug delivery
systems present various advantages such as the effective encapsulation of small
and large molecules with a wide range of hydrophilicity and pKa values. In
fact, they have been found to enhance nasal absorption of peptides such as
insulin and calcitonin by increasing their membrane penetration. This has been
attributed to the increasing nasal retention of peptides. Protection of the
entrapped peptides from enzymatic degradation and mucosal membrane disruption.
Moreover, liposomal drug
delivery systems were also reported as useful for influenza vaccine and
non-peptide drugs such as nifedipine. Liposomes can be incorporated in
different formulations. For example, Ding et al. obtained a rapid onset of
action and sustained delivery of levonorgestrel when it was intranasally
administered as a liposome suspension. Furthermore, positive results were also
found during nasal delivery of acyclovir in a liposomal gel. The use of a
liposomal gel not only promoted the prolonged contact between the drug and the
absorptive site, but also facilitated direct absorption through the nasal
mucosa. These conclusions were obtained comparing liposomal formulations and
free drug suspended in gel.[16]
Nanoparticles:
Recently, much attention has
been given to nanotechnology in many areas. Nanoparticle systems are being
investigated to improve drug delivery and intranasal drug administration.
Nanoparticles are solid colloidal particles with diameters raging from 1-1000
nm. They consist of macromolecular materials and can be therapeutically used as
adjuvant in vaccines or as drug carriers, in which the active substance is
dissolved, entrapped, encapsulated, adsorbed or chemically attached.
Nanoparticles may offer several advantages due to their small size, but only
the smallest nanoparticles penetrate the mucosal membrane by paracellular route
and in a limited quantity because the tight junctions are in the order of
3.9-8.4 Å. Controversial results are found when using nanoparticles in
intranasal drug delivery. In fact, there are few publications wherein
nanoparticle formulations don’t significantly enhance the drug transport across
the nasal cavity. The low bioavailability obtained can be due to the fact that
particles are probably taken up by M-cells in the nasal associated lymphoid
tissue and, therefore, transported into the lymphatic system and blood stream.
In contrast, other studies have suggested that nanoparticle systems may be
ideally suited for the delivery of nasal vaccines.[17]
Microsphere technology has
been widely applied in designing formulations for nasal drug delivery.
Microspheres are usually based on mucoadhesive polymers (chitosan, alginate)
which present advantages for intranasal drug delivery. Furthermore,
microspheres may also protect the drug from enzymatic metabolism and sustain
drug release, prolonging its effect. [16]
Evaluation of Nasal Drug
Formulations:
Various approaches used to
determine the drug diffusion through nasal mucosa from the formulation. The two
important methodologies to study the diffusion profile of the drug are
discussed below.
In Vitro Diffusion Studies:
The nasal diffusion cell is
fabricated in glass. The water-jacketed recipient chamber has total capacity of
60 ml and a flanged top of about 3mm; the lid has 3 opening, each for sampling,
thermometer, and a donor tube chamber. The 10 cm long donor chamber, and a
donor tube chamber has total capacity of 60 ml and a flanged top of about 3mm;
the lid has 3 openings, each for sampling, thermometer, and a donor tube
chamber the 10 cm long donor chamber tube has internal diameter of 1.13 cm. The
nasal mucosa of sheep was separated from sub layer bony tissues and stoned in
distilled water containing few drops at gentamycin injection. After the
complete removal of blood from mucosal surface, is attached to donor chamber
tube. The donor chamber tube is placed such a way that it just touches the
diffusion medium in recipient chamber. At predetermined intervals, samples (0.5
ml) from recipient chamber are with draw and transferred to amber colored
ampoules. The samples withdrawn are suitably replaced. The samples are
estimated for drug content by suitable analytical technique. Throughout the
experiment the temperature is maintained at 37˚C.
2. In Vitro Nasal
Absorption studies:
The animal models employed for
nasal absorption studies can be of two types, viz., whole animal or in vivo
model and an isolated organ perfusion or ex vivo model.
In vivo models are Rat model,
Rabbit model, monkey model and dog model.
Surgical preparation is the
same as that is for in vivo rat model. During the perfusion studies, a
funnel is placed between the nose and reservoir to minimize the loss of drug
solution. The drug solution is placed in a reservoir maintained at 37°C and is
circulated through the nasal cavity of the rat with a peristaltic pump. The
perfusion solution passes out from the nostrils (through the funnel) and runs
again into the reservoir. The drug solution in the reservoir is continuously
stirred. The amount of drug absorbed is estimated by measuring the residual
drug concentration in the perfusing solution. The drug activity due to
stability problems may be lost during the course of experiment. [10]
1
Microemulsion: microemulsion is clear, stable and it have proising approach for
intranasal delivery. The therapeutic advantages is spontaneous formation, ease
of manufacture, thermodynamic stable,
2
Nano partials: it is a colloidal system and provides sustained and drug
release. It employed for the CNS disorder.
3
Microsphere: microsphere is specialized system microsphere is use in nasal drug
are water insoluble but starch and albumin are use.[17]
Current Status of NDDSS on the
pharmaceutical market:
Considering the arising
complications associated with the discovery of new therapeutically active
molecules, many opportunities are available. They are mainly directed towards
innovative pharmaceutical products intended for intranasal administration of
well-known substances or those with a status of the gold standard in therapy.
These products feature good receptivity by patients and ease of use, and offer
real benefits. A key advantage of this approach is the data available that is
supporting the efficacy and safety of such drugs. Furthermore, for these
substances clearly defined regulatory procedures are available and a lower risk
of new product development is taken. Procedures for authorization may be
further facilitated by the availability of good regulatory status of the nasal
drug delivery platform itself, particularly in terms of quality and safety of
the excipients through the available history of their clinical application.
Opioid analgesic fentanyl is probably the best example of a drug fully exploited
in innovative drug - delivery technologies. In the late 1980s, a transdermal
patch has been launched for the treatment of chronic pain; recently a number of
fentanyl formulations have been reported, which use other routes of
administration especially for specific indications such as cancer pain. Several
transmucosal fentanyl products for oral administration are already on the
market, others are in research and development process.[18]
Future prospect of NDD:
In present the drug which is
absorbed in better way is that are good rout and drug. NDD is better system for
drug absorption. Absorption promoters and absorption modulator systems being
developed commercially by companies specializing in nasal drug delivery of
normal small molecular weight drugs and biological drugs such as peptide and
proteins. The absorption promoter systems selected for discussion in this
review are those with the most promising preclinical and/or clinical data and
sufficient toxicology data and/or company development efforts to warrant use in
marketed products i.e. CPE215® (cyclopenta decalactone (azone)) developed by
CPEX Pharma. Although several novel strategies are currently used for nasal
drug delivery using bio-and muco-adhesion strategies, the potential exists to
improve these methods using other strategies such as nanoparticles, bacterial
adhesion, altered amino acid sequence, and antibody mechanism.[19] New
technologies include improved nasal formulations; site specific release,
carrierbased systems, advanced spray formulations, atomized mist technology,
preservative free system and integrated formulation development are strictly
needed for success of drug delivery through nasal mucosa.
For success of nasal drug
delivery Researchers has to on:
Development of delivery
technologies to increase efficacy and reduce side effects by target delivery
with variations potential of the drug.
Development of new
technologies to deliver macromolecules with utilization of biotechnology and
high technology .
Development of
integrated/improved nasal formulations
Development of integrated
device development for successful delivery of therapeutics.[20]
CONCLUSION:
Nasal drug delivery is a novel
platform and it is a promising alternative to injectable route of
administration. They have a large area and highly vascularized mucosa. It has
advantage in terms of reduces systemic exposure and hence side effects and
avoiding first-pass metabolism. Bioavailability of nasal product one of the
major challenges in the nasal product development, in contrast, a huge amount
of money is investigated by pharmaceutical companies in the development of
nasal drug product, because of growing demand of nasal drug product in global
pharmaceutical market. In future, the extensive research is necessary to make
this route of delivery more efficient and popular.
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Received on 25.01.2020
Modified on 28.02.2020
Accepted on 27.03.2020 ©Asian Pharma Press All Right Reserved
Asian J. Pharm. Res. 2020; 10(2):110-116.
DOI: 10.5958/2231-5691.2020.00021.0