In- Situ Nasal
Gel: A Review
Nikita S. Malekar1*,
Prof. S.B. Gondkar2, Dr. R.B. Saudagar3
1Department of Quality Assurance Techniques,
R. G. Sapkal College of Pharmacy, Anjenari,
Nashik-422213, Maharashtra, India.
2Department of Pharmaceutics, R. G. Sapkal College of Pharmacy, Anjenari,
Nashik-422213, Maharashtra, India.
3Department of Pharmaceutical Chemistry, R.G.Sapkal College of Pharmacy, Anjenari,
Nashik-422213, Maharashtra, India
*Corresponding
Author E-mail: nikitamalekarresearch@gmail.com
ABSTRACT:
Nasal therapy also called “Nasya
Karma” has been recognized form of treatment in the Ayurvedic.
System of Indian Medicine. Nowadays many drugs have better systemic
bioavailability through nasal route as compared to oral administration. The
nose is also considered an attractive route for needle-free vaccination and for
systemic drug delivery, especially when rapid absorption and effect are desired.
The nasal delivery is a feasible alternative to oral or parenteral
administration for some drug because of the high permeability of the nasal
epithelium, rapid drug absorption across
this membrane and avidance of first pass metabolism.
Prolonged drug delivery can be achieved by various new dosage forms like
in-situ gel. In-situ forming polymeric formulation are drug delivery system
that is in sol form before administration in the body, but once administered,
undergoes gelation in-situ to form a gel. In-situ
nasal drug delivery system is the type of mucoadhesive
drug delivery system. Now a days in-situ gel has been used as vehicle for the
drug delivery of the drug for both local treatment and systemic effect. In-situ
nasal gel drug delivery system is advantageous over the conventional drug
delivery system like sustained and prolonged release of drug, reduced frequency
of administration, improved patient compliance and comfort.
KEYWORDS: Nasal
drug delivery, Nasal In-situ gel, Mucoadhesive Drug
Delivery System.
INTRODUCTION:
Therapy through intranasal administration has been an
accepted form of treatment in the Ayurvedic system of
Indian Medicine. In recent years many drugs have been shown to achieve better
systemic bioavailability through nasal route than by oral administration.1
The Oral administration of protein and peptide drug is not possible because
they are significantly degraded in the gastrointestinal tract or considerably
metabolized by first pass effect in the liver. Nasal route has also been
considered for the administration of vaccines. The interest in intranasal route
for therapeutic purposes arises from the anatomical, physiological and
histological characteristics of the nasal cavity, which provides rapid systemic
drug absorption and quick onset of action.2
In addition, intranasal drug delivery enables dose
reduction, rapid attainment of therapeutic blood levels, and quicker onset of
pharmacological activity.3
Nasal route has also been considered for the administration of vaccines. The interest in intranasl route for therapeutic purposes arises from the anatomical, physiological and histological characteristics of the nasal cavity, which provides rapid systemic drug absorption.4
Smart polymeric
systems represent promising means of delivering the drugs, these polymers
undergoes sol-gel transition, once administered. These systems are injectables fluids that can be introduce into body in a
minimal invasive manner prior to solidifying or gelling within the desired or
nasal cavity.[2]
In-Situ gel
formulations offers an interesting alternative for achieving systemic drug
effects of parenteral routes, which can be
convenient, which can result unacceptability, low bioavailability and passes
first pass-effect.
Majority of
products available are used for treatment of allergic rhinitis, migraine, cold,
pain etc. The various formulations given by nasal route includes nasal gel,
spray, powders etc. Thus nasal route is the promising alternative for other
drug delivery systems. 5, 6
Nasal Drug Delivery [2]
Intranasal route
is considered for the drugs that are ineffective orally and are used
chronically where rapid entry into the circulation is desired and they require
small doses. The absorption of drugs from the nasal mucosa most probably takes
place via the aqueous channels of the membrane. Therefore, as long as the drug
is in the form of solution and molecular size is small, the drug will be
absorbed rapidly via the aqueous path of membrane.The
absorption from the nasal cavity decrease.
Advantages of Intranasal Drug Delivery [7, 8]
§ Rapid drug absorption via highly vascular
mucosa
§ Ease of administration, non-invasive
§ Improved bioavailability
§ Improved convenience and compliance
§ Self-administration
§ Avoidance first-pass metabolism
§ Rapid onset of action
§ Lower side effects
§ Convenient route when compared with parenteral route for long term therapy.
§ Bioavailability of larger drug molecules
can be improved by means of absorption
§ enhancer or other approach
Disadvantages of Intranasal Drug Delivery
§ Some drug may cause irritation to the nasal
mucosa.
§ Nasal congestion due to cold or allergies
may interfere with absorption of drug.
§ Drug delivery is expected to decrease with
increasing molecular weight.
§ The amount of drug reaches to different
regions of the brain and spinal cord varies with each agent.
§ Frequency use of this route leads to
mucosal damage.
Anatomy and Physiology of Nose:
Fig. 1 Structure of the Nose
The nasal cavity
is divided into two halves by the nasal septum and extends posterior to the nasopharynx, while the most anterior part of the nasal
cavity, the nasal vestibule, opens to the face through the nostril Breathing
and olfaction are the major function of human nose. But is also functioned as
filtration and humidification of inhaled air before reaching in lowest airway.
Nasal cavity has mucus layer and hairs, those helpful in filtration of particles
trapped in inhaled air. Additionally metabolism of endogenous substances, mucociliary clearance also functions of nose. The human
nasal cavity has a total volume of about 16-19ml and total surface area of
about 180cm2 and is divided into two nasal cavities via septum. The volume of
each cavity is approximately 7.5ml having surfaced around 75cm2. [9]
Three Distinguished Regions
1) The
Respiratory region
The respiratory
region is the largest having the highest degree of vascularity,
and is mainly responsible for systemic drug absorption.The
respiratory epithelium is composed of four types of cells namely-non ciliated,
ciliated columnar cells, basal cells, gobalt cells.
These cells facilitate active transport processes such as the exchange of water
and ions between cells and motility of cilia. (10,11)
2) The
Olfactory region
It is of about
10 cm2 in surface area and it plays a vital role in transportation of drugs to
the brain and the CSF. The olfactory region is located on the roof of the nasal
cavities, just below the cribriform plate of the ethmoid bone, which separates the nasal cavities from the
cranial Cavity.The olfactory tissue is often yellow
in colour, in contrast to the surrounding pink tissue.The olfactory epithelial layer predominantly
contains three cell types: the olfactory neural cells, the subtentacula
cells and the basal cells. [12,13]
3) The
Vestibular region
It is anterior
part of nasal cavity. Surface area is 0.6 cm2. Nasal portion is
covered by a stratified squamous keratinized
epithelial with sebaceous gland. It is located at the opening of nasal passages
and is responsible for filtering out the air borne particles. Drug absorption
is very difficult in this region but it afforded high resistance against toxic
environment. [14, 15]
Mechanism of Drug Absorption by Nasal Route
The absorbed
drugs from the nasal cavity must pass through the mucous layer. It is the first
step in absorption. Small, unchanged
drugs easily pass through this layer but large, charged drugs are difficult to
cross it. The principle protein of the mucous is mucin
has the tendency to bind to the solute, hindering diffusion. [16]
Fig. 2
Mechanism of Drug Absorption by Nasal Route
The Three Mechanisms Are As Follows:
1) First Mechanism-
Also known as paracellular transport this utilizes
the aqueous route of transport and is slow and passive. . There is an inverse log-log
correlation between intranasal absorption and the molecular weight of water
soluble compounds. The molecular weight greater than 1000 Daltons show poor bioavailability
.[15]
2) Second
Mechanism- Also known as trancellular route which utilizes the lipoidal
route for transport of lipophilic drugs.
3) Third
Mechanism-Drugs
also cross cell membrane by an active transport routevia
carrier mediated or transport through the opening of tight junction.
Factors Affecting Nasal Drug Delivery
System [1, 4]
Factors influencing absorption are related to nasal
physiology, physic chemical characteristics of drugs and formulation aspects.
1.
Biological Factors
a) Structural features.
b) Biochemical changes.
c) Physiological factors.
d) Blood flow.
e) Nasal secretions.
f) pH of the nasal cavity.
g) Mucociliary clearance and
ciliary beat frequency.
h) Pathological conditions.
i) Environmental
conditions.
j) Temperature.
k) Humidity.
2.
Physicochemical Properties of Drugs
a) Molecular weight.
b) Size.
c) Solubility.
d) Lipophilicity.
e) pka and partition
coefficient.
3.
Physicochemical Properties of Formulation
a) Dosage form.
b) Viscosity.
c) pH and mucosal irritancy.
d) Osmolarity.
e) Volume of solution applied.
4. Device
Related Factors
a) Particle size of the droplet.
b) Size and pattern of disposition
Biological
Factors [27]
Physiological
factors include firstly mucociliary clearance is one of
the major factor responsible for the clearance of the drugs from the nasal
cavity and it involves combined action of mucus layer and cilia, tips of cilia
are in contact with and transport the superficial
viscoelastic mucus layer towards nasopharynx
while less viscous lower layer of mucus is relatively stationary. Secondly
broad ranges of metabolic enzymes are present in the nasal mucosa. This can
limit bioavailability of nasally administered drugs however; level of activity
of these enzymes is lower as compared to that found in GIT and liver. Moreover
pathological conditions like rhinitis, common cold can also affect absorption
of drugs from nasal cavity and pH of nasal cavity also affects permeation of
drug. A change in the pH of mucus can affect the ionization and increase or
decrease the permeation of drug depending on the nature of the drug.
Physicochemical Properties of Drugs[1]
Various physicochemical characteristics of drug can
also affect nasal absorption of the drug.
Molecular Weight and Size
Extent of the absorption of the drug depends on
molecular weight particularly for hydrophilic compounds. Nasal route is
suitable for efficient delivery of the drugs up to 1000 Daltons. Absorption
reduces significantly if the molecular weight is greater than 1000 Daltons
except with the use of penetration enhancers. It has been reported that a good
linear correlation exists between the log percentage drug absorbed nasally and
the log molecular weight of water soluble compounds suggestion the
participation of aqueous channels in the nasal absorption of water soluble
molecules. It has been reported that particle size greater than 10μm are
deposited in the nasal cavity. Particles that are 2 to 10 μm
can be retained in the lungs and particles of less than 1μm are exhaled.
Solubility and Dissolution
Drug solubility is a major factor in determining
absorption of drug through biological membranes. Particles deposited in the
nostrils or if they are cleared away from the nasal cavity, one may not observe
the absorption of the drug.
Chemical Form
The chemical form in which a drug is presented at the
nasal mucosa can be important in determining its absorption. For example,
conversion of a drug into a salt or ester form can alter its absorption.
Partition Coefficient and pKa
A quantitative relationship between the partition
coefficient and nasal absorption is constant. As per the pH partition theory,
unionized species are absorbed better compared with ionized species and same
holds true in case of nasal absorption.
Physicochemical Properties of
Formulation[4]
Drug Concentration, Dose and Dose
Volume
Drug concentration, dose and dose volume of
administration are three interrelated parameters that impact the performance of
the nasal delivery system. If the drug is increasing by increasing formulation
volume there may be a limit as to what extent nasal absorption will drain out
of the nasal cavity. The ideal dose volume range is 0.05-0.15ml with an upper
limit of 0.20ml.
Physical Form of Formulation
Nasal drug absorption depends on the physical form of
the formulation. The important parameter in formulation development is
viscosity of the formulation. Generally a more viscous formulation will provide
less efficient systemic nasal drug delivery. In nasal delivery of desmopressin, addition of the viscous agents may produce a
somewhat more sustained effect. It would seem logical that more viscous
formulations example- Gels should be more appropriate for locally acting drugs.
Formulation pH
The pH of the formulation as well as that of nasal
surface can affect drugs permeation. The pH of the nasal formulation is
important for following reasons,
a) To avoid irritation of the nasal mucosa.
b) To allow the drug to be available in unionized form
for absorption.
c) To prevent the growth of pathogenic bacteria in the
nasal passage.
d) To sustain normal physiological ciliary
movement.
Buffer Capacity
Nasal formulations are generally administered in small
volumes ranging from 25 to 200μl with 100μl being the most common
dose volume. Hence, nasal secretions may alter the pH of the administered dose.
This can affect the concentration of unionized drug available for absorption.
Therefore, an adequate formulation buffer capacity may be required to maintain pH.
Osmolarity
Drug absorption can be affected by tonicity of the
formulation. Shrinkage of the epithelial cells has been observed in the
presence of hypertonic solutions. Hypertonic saline solutions also inhibit ciliary activity. Low pH has similar effect as that of
hypertonic solutions.
Gelling/Viscofying
Agents or Gel Forming Carriers
Some formulations need to be gelled or made more
viscous to increase nasal residence time. Increasing the solution viscosity may
provide a means of prolonging the therapeutic effect of nasal preparations.
Drug carrier such as hydroxyl propyl cellulose was
effective for improving the absorption of lower molecular weight drugs but did
not produce the same effect for high molecular weight peptides
Solubilizers[6]
Aqueous solubility of a drug is always a limitation
for nasal drug delivery in solution. Conventional solvents or co-solvents such
as glycols, small quantities of alcohol, medium chain glycerides
can be used to enhance the solubility of drugs. Other options include the use
of surfactants or cyclodextrins that serve as a
biocompatible solubilizer and stabilizer in
combination with lipophilic absorption enhancers.
Preservatives[6]
Most nasal formulations are aqueous based and need
preservatives to prevent microbial growth. Parabens, benzalkonium chloride, phenyl ethyl alcohol, benzyl alcohol
are some of the commonly used preservatives in nasal formulations.
Antioxidants
Depending upon stability profile of a given drug in
the formulation chosen, it may be necessary to use antioxidants to prevent drug
degradation. Antioxidants used are sodium metabisulfite,
tocopherol.
Humectants
Adequate intranasal moisture is essential for
preventing dehydration. Therefore, humectants can be added especially in gel
based nasal products to avoid nasal irritation and are not likely to affect
drug absorption. Some common humectants used include glycerin, sorbitol, mannitol.
Absorption Enhancer[6]
When it becomes
difficult for a nasal product to achieve its required absorption profile, the
use of absorption enhancers is recommended. The selection of absorption
enhancers is based upon their acceptability by regulatory agencies and their
impact on the physiological functioning of the nose. Absorption enhancers may
be required when a drug exhibits poor membrane permeability, large molecular
size, lack of lipophilicity and enzymatic
degradation. Once a suitable enhancer is identified, its optimal concentration
should be experimentally determined. Generally, higher concentrations of
enhancers are likely to result in nasal irritation and damage to nasal mucosa.
On the other hand, lower enhancer concentrations would generally provide lower
or no improvement of absorption.
In-Situ Gelling System
a)Gel- Gel is the state which
exists between solid and liquid phase. The solid component comprises a three
dimensional network of interlinked molecules which immobilizes the liquid
- In-situ gelation is a
process of gel formation at the site of action after the phase .[16]
b)In–situ
Delivery System-Formulation
has been applied at the site. In-situ gel phenomenon based upon liquid solution
of drug formulation and converted into semi- solid mucoadhesive
key depot. It permits the drug must be delivered in a liquid form or solution
form. [17]
In-Situ gelation is a process of gel formation at the site of
application after the composition or formulation has been applied to the site.
In the field of human and animal medicine, the sites, topical application
sites, surgical sites and other agents are brought into contact with tissues or
body fluids. As a drug delivery agent, the in-situ gel has an advantage related
to the gel being formed in-situ providing sustained release of the drug. At the
same time, it permits the drug to be delivered in liquid form. This new concept
of production a gel in –situ was suggested first time in early 1980s. In-situ
means a Latin word at the place. Both natural and synthetic polymers are used
for production of in-situ gels. In-situ gel forming drug delivery system are
principle, capable of releasing drug in sustained manner maintaining relatively
plasma profiles. [18]
Principle
of Gelling System
The principle involving the In-situ gelling of nasal
formulation is that the formulation imbibe in the nasal fluid after administration and forms
gel into the nasal cavity. In the nose, the
mucous lower layer comes and goes
around the cilia, forwarding the propulsion phase, backward in the preparatory
phase, cilia extremity scrapes the upper layer of mucous penetrating it almost
0.5 mm. Ciliary
situated backwards help to remove
any obstacle if there is any interference in the propulsion phase. After
the formulation of the gel, dissolution occurs and the mucociliary
removal towards the nasopharynx occurs. [6]
Ideal Drug
Candidate [19,20]
·
Appropriate nasal
absorption properties.
·
The drug should not cause nasal irritation.
·
Low
dose. Generally, ≤ 25 mg per dose.
·
The
drug must not possess toxic nasal metabolites.
·
No offensive odours/aroma
associated with the drug.
·
The drug has aqueous
solubility to provide to the desired in a 25-150μl volume of formulation
administered per nostril.
·
Suitable stability characteristics.
Advantages
of In-situ Nasal Gel [21]
§ Prolong drug release
§ Reduced systemic side effect
§ Reduced number of application
§ Ease of administration
§ Reduced frequency of administration
§ Better patient compliance
Properties
of Nasal In-situ Gel-[22]
a) It should be low viscous.
b) It should be free flowing to allow for reproducible
administration to the nasal cavity, as droplet mist or as spray.
c) Nasal in-situ gel should have long residence time.
d) The nasal in-situ gel follows phase transition
mechanism and to stand with shear forces in the nasal cavity wall .
Approaches
of an In-situ Gelling System
The various approaches for in situ gelling system
1) Stimuli
Response In-Situ Gel System
a)Temperature induced in situ gel system
b)pH induced
in-situ gel systems
2) Osmotically Induced
In-situ Gelling System
3) Chemically Induced In-situ Gelling System
a) Ionic cross
linking
b)Enzymatic
cross linking
c)Photo-polymerization
1) Stimuli
Responsive In-Situ Gelling System
Physical or
chemical changes in response to small external changes in the environmental
condition
a)Temperature Induced In-Situ gel system
Temperature is
the most widely used stimulus in environmentally responsive polymer systems.
The change of temperature is not only relatively easy to control, but also
easily applicable both in vitro and in vivo. In this system, gelling of the
solution is triggered by change in temperature, thus sustaining the drug
release. These hydrogels are liquid at room
temperature (20–25 °C) and undergo gelation when in
contact with body fluids (35– 37 °C),due to an increase in temperature The
polymers which show temperature induced gelation are poloxamers or pluronics,
cellulose derivatives (methyl cellulose, HPMC, ethyl (hydroxylethyl)
cellulose (EHEC) and xylogluca etc. [23,24]
b) pH Induced In-Situ Gel System
Polymers
containing acidic or alkaline functional groups that respond to changes in pH
are called pH sensitive polymers.
Gelling of the solution is triggered by a change in pH.
At pH 4.4 the formulation is a free-running solution which undergoes
coagulation when the pH is raised by the body fluid to pH 7.4. The polymers
which shows pH induced gelation are cellulose acetate
phthalate (CAP)Latex, Carbomer and its derivatives
polyvinyl acetyldiethyl amino-acetate (AEA), Polymethacrilic acid (PMMA), polyethylene glycol (PEG).
2) Osmotically Induced In
–Situ Gelling System
In this method,
gelling of the solution instilled is triggered by change in the ionic strength.
It is assumed that the rate of gelation depend on the
osmotic gradient across the surface of the gel. The aqueous polymer solution
forms a clear gel in the presence of the mono or divalent cations.
The polymer which shows osmotically induced gelation are gellan gum, hyaluronic acid.[25]
3) Chemically Induced In-Situ Gelling System
The chemical
reaction which forms in situ gel system are crosslinking,
enzymatic crosslinking, and photo-polymerization.
a)Ionic Cross Linking- Certain ion sensitive polysaccharides such as carragenan, Gellan gum (Gelrite), Pectin, Sodium Alginate undergo phase transition
in presence of various ions such as K+ , Ca2+, Mg2+,Na+. These
polysaccharides fall into the class of ion-sensitive ones. For example, Alginic acid undergoes gelation
in presence of divalent/polyvalent cations e. g. Ca2+
due to the interaction.[26]
B) Enzymatic Cross Linking
In situ
formation catalyzed by natural enzymes has not been investigated widely but
seems to have some advantages over chemical and photochemical approaches. For
example, an enzymatic process operates efficiently under physiologic conditions
without need for potentially harmful chemicals such as monomers and initiators.
[27]
c) Photo- Polymerization
In situ
photo-polymerization has been used in biomedical applications for over more
than decade. A solution of monomers or reactive macromere and initiator can be
injected into a tissues site and the application of electromagnetic radiation
used to form gel. Acrylate or similar polymerizable functional groups are typically used as the polymerizable groups on the individual monomers and
macromere because they rapidly undergo photo-polymerization in the presence of
suitable photo initiator. [28]
Ideal Characteristics of Polymer Used on Nasal In-situ
gel [2,29]
·
It
should be non -toxic
·
It
should be biodegradable and biocompatible.
·
It
should have Mucoadhesive properties .
·
It
should have good tolerance.
Polymer Used for the Preparation of In-Situ Gelling
System [2]
1) pH Sensitive Polymers-
§ Carbomer
§ Polyacrylic acid
§ Cellulose acetate phthalate
2) Temperature Sensitive Polymer
§ Poloxomer
§ Methyl cellulose
§ Chitosan
§ Hydroxylpropyl methyl cellulose
3) Ion Sensitive Polymer
§ Xanthum gum
§ Gellan gum
§ Sodium alginate
1) Polymers Used in pH Sensitive
In-Situ Gelling System[2]
a)Carbomer
It is high molecular weight, cross linked polyacrylic acid derivative and has a strong Mucoadhesive property. Carbopol
polymers are having very good water
sorption property. Carbopol
934 and Carbopol 981 are mostly used as gelling
agent. They swell in water upto 1000 times their
original volume and 10 times their original diameter to form a gel when exposed
to a pH environment above 4.0-6.0 because the pKa of
these polymers is 6.0 ± 0.5. If there is an addition of cellulose then it will
reduce polymer concentration and improve gelling property.
2) Temperature Sensitive Polymers[2,4]
a) Poloxamer
Poloxamer are water soluble
tri-block copolymer consisting of two polyethylene oxide and polypropylene
oxide core in an ABA configuration. Poloxamer
commercially also known as pluronic and has good
thermal setting property and increased drug residence time. It is used as
gelling agent, and solubilizing agent. Poloxamer gives colorless, transparent gel. Depending upon
the ratio and distribution of hydrophilic and hydrophobic chain several
molecular weights available, having different gelling property. [5, 31]
3) Polymers Used of Ion Sensitive
In-Situ Gelling System.
a) Sodium Alginate[2]
Sodium alginate is a salt of alginic
acid extracted from brown algae. It is a linear block polysaccharide consisting
of two type monomers β-D-Mannuronic acid and
α-L glucuronic acid residues joined by 1,4 glycosidic linkages. It is biodegradable and non-toxic and
exhibit good Mucoadhesive property due to its
carboxylic group.
b)Gellan Gum
Gellan gum (commercially available as Gelrite TM or Kelcogel TM ) is an
an ionic deacetylatedexocellular
polysaccharide secreted by Pseudomonas elodea with a tetra saccharide
repeating unit of one α-L-rhamnose, one β-D-glucuronic acid and two β-Dglucuronic
acid residues It has the tendency of gelation which
is temperature dependent or cations induced . This gelation involves the formation of double helical junction
zones followed by aggregation of the double helical segments to form a
three-dimensional network by complexation with cations and hydrogen bonding with water.35The sol-gel
transition process is induced by the presence of monovalent
or divalent ions such as Na+ and Ca2+.such as temperature and pH responsive gels,
have, on the other hand, appeared more frequently in nasal drug delivery
studies and have been shown to increase the residence time and improve drug
absorption.[31]
Cellulose
Derivative
There are many
pharmaceutical grade derivatives of cellulose widely used in different
Administration routes. Several cellulose derivatives have proved to be
effective on enhancing. The intranasal absorption of drugs, including soluble
cellulose derivatives such as Hydroxypropyl
methylcellulose, hydroxypropyl cellulose [HPC],
methylcellulose [MC], and insoluble
cellulose derivatives such as ethyl cellulose and microcrystalline cellulose
[MCC]. Using celluloses as absorption enhancer can lead to improved intranasal
absorption and increased bioavailability.[32]
Evaluation of In-Situ Gel
1)Clarity
The clarity of
formulated solution can be determined by visual inspection under and white
background.[33]
2)Viscosity
The viscosity
and rheological properties of the polymeric formulation, either in solution or
in gel made with artificial tissue fluid were determined with different
viscometer like Brookfield viscometer. [34]
3) Texture Analysis
The firmness,
consistency and cohesiveness of formulation are assessed using texture analyzer
which mainly indicates the syringability of sol so
the formulation can be easily administerd in vivo. [33,34]
4) Gel Strength
This parameter
can be evaluated using a rheometer .Depending on the
mechanism of the gelling agent used, a specified amount of gel is prepared in a
beaker, from the sol form .This gel containing beaker is raised at a certain
rate, so pushing a probe slowly through the gel. The can be measured as a
function of depth of immersion of the probe below the gel surface. [35]
5) In-vitro Drug
Release Studies
For the in situ
gel formulations to be administered by oral, ocular or rectal routes, the drug
release studies are carried out by using the plastic dialysis cell. The cell is
made up of two half cells, donor compartment and a receptor compartment. Both
half cells are separated with the help of cellulose membrane. The sol form of
the formulation is placed in the donor compartment. The assembled cell is then
shaken horizontally in an incubator. The total volume of the receptor solution
can be removed at intervals and replaced with the fresh media. This receptor
solution is analyzed for the drug release using analytical technique. For injectable in situ gels, the formulation is placed into
vials containing receptor media and placed on a shaker water bath at required
temperature and oscillations rate. Samples are withdrawn periodically and
analyzed. [36, 37]
6) Sol-Gel
Transition Temperature and Gelling Time
For in situ gel
forming systems, the sol-gel transition temperature and pH should be
determined. Gelling time is the time required for first detection of gelation of in situ
gelling system. Thermo sensitive in –situ gel should be checked for in
situ gelling at body temperature.[38, 39]
7) pH of The Gel
For determining
the pH of the formulation of nasal in situ gel, taken 1 ml quantity of each
formulation transferred into a different beaker and diluted it with distilled
water up to 25 ml and then pH of each formulation was determined by using
pH meter.[40]
Advancement in Nasal Dosage Forms
Nasal Drops
Nasal drops are
one of the most simple and convenient system developed for nasal delivery. Due
to ease of self- administration it is becoming more popular.
Nasal Sprays
Suspension
formulations can be formulated into nasal sprays. Due to the availability of
metered dose pumps and actuators, a nasal both solution and spray can deliver
an exact dose.
Nasal Powders
These
formulations are developed when there is problem with stability.
Nasal Gel
The nasal gel
showed growing interest due to reduction of post-nasal drip, high viscosity,
and reduction of taste impact due to reduced swallowing, target delivery to
mucosa for better absorption.
Nasal Inserts
Nasal inserts
are novel, bioadhesive, solid dosage forms for
prolonged systemic drug delivery via the nasal route.
CONCLUSION:
Nasal drug
delivery system has been considered as potential and favorable route of drug
delivery because it provides patient compliance, easy to administration ,bypass
first pass metabolism ,low dose required, rapid absorption , give desirable
effects. Bioavailability of nasal drug
product is one of the major challenges in the nasal product development. This
route provides future potential for several drugs through the development of
safe and efficacious formulation for simple, painless and long –term therapy.
Sustained and prolonged release of the drug, stability and biocompatibility
makes the in situ system very reliable. In the in situ gelling nasal
formulation, there is no need to remove the dosage form from the nasal cavity;
therefore this formulation will become the efficient way of the drug delivery.
In the future, the in situ gelling nasal drug delivery will continue to advance
and will represent a viable alternative to the oral and injectable
routes of administrations.
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D.Anish Kumar, G. Mohanranga Reddy, D. Saidarao.
Review Article On Nasal Drug Delivery System. International Journal of Research in Pharmaceutical and Nano Sciences, 1(1), 2012,35-44.
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Received on 08.06.2015 Modified on 20.06.2015
Accepted on 25.06.2015 ©A&V Publications All right reserved
Res. J. Pharm.
Dosage Form. and Tech. 7(4): Oct.-Dec., 2015; Page 285-293
DOI: 10.5958/0975-4377.2015.00040.3