Mucoadhesive dds buccal & nasal

MUCOADHESIVE DRUG
DELIVERY SYSTEM
PREPARED BY:
K. ARSHAD AHMED KHAN
M.Pharm, (Ph.D)
Dept. of Pharmaceutics
RIPER.
1

Concept of Bioadhesion
• Bioadhesion is the state in which two materials, (at least
one of which is biological in nature), are held together for a
extended period of time by interfacial forces.
• The term bioadhesion implies attachment of drug carrier
system to specific biological location. This biological surface
can be epithelial tissue or the mucous coat on the surface
of tissue.
• If adhesive attachment is to mucous coat then
phenomenon is referred as mucoadhesion.
2

• Mucoadhesion is defined as the interaction between a
mucin surface and a synthetic or natural polymer
3

INTRODUCTION
• The MDDS uses materials that possibly combine
mucoadhesive, enzyme inhibitory & penetration
enhancer properties & improve the patient complaince.
• Hydrophilic, high mol. wt. such as peptides and large,
hydrophilic unstable proteins, oligonucleotides and
polysaccharides are best choice for MDDS.
• Depending upon the route of administration of the
mucoadhesive drugs they are different types .They are
1)Buccal delivery system 2)Sub lingual delivery system
3)Vaginal delivery system 4)Rectal delivery system
5)Nasal delivery system 6)Ocular delivery system
7)Gastro intestinal delivery system 6

Advantages
1. Ease of administration- Painless administration.
2. Termination of therapy is possible.
3. Avoids first pass metabolism.
4. Permits targeting & localization of drug at specific site
for extended period of time.
5. Significant reduction in dose can be achieved, thereby
reducing dose dependent side effects.
6. It allows local modification of tissue permeability,
inhibition of protease activity or reduction in
immunogenic response, thus selective use of
therapeutic agents like peptides proteins and ionized
species can be achieved.
7

7. Drugs which are unstable in acidic environment of
stomach or destroyed by the alkaline environment of
intestine can be given by this route.
8. Drugs which show poor bioavailability by oral route can
be administered by this route.
9. Drugs follow passive diffusion, and does not require any
activation.
10. The oral mucosa lacks prominent mucous secreting
goblet cells and therefore there is no problem of
diffusion limited mucous build up.
11. The presence of saliva ensures large amount of water for
dissolution of drug unlike in case of rectal and
transdermal route.
12. In comparison to TDDS, mucosal surfaces do not have a
stratum corneum thus, the major barrier layer is absent.
8

13. Drugs with short half life can be administered by this
method. (2-8 hrs) Eg: Nitroglycerine ( 2 hrs), Isosorbide
mononitrate ( 2-5 hrs)
14. From the formulation point of view a thin mucin film
exist on the surface of oral cavity provides opportunity to
retain delivery system in contact with mucosa for
prolonged period of time with the help of mucoadhesive
compounds.
15. The buccal membrane is sufficiently large to allow
delivery system to be placed at different sites on the
same membrane for different occasions, if the drug or
other excipients cause reversible damage or irritate
mucosa.
9

DISADVANTAGES
1. Eating and drinking may become restricted
2. There is possibility that Patient may swallow the tablet
3. The drug contained in swallowed saliva follows the per
oral route & advantages of buccal route are lost.
4. Only drug with small dose requirement can be
administered.
5. Over hydration may lead to formation of slippery surface
& structural integrity of the formulation may get
disrupted by the swelling & hydration of the bioadhesive
polymer.
6. Drug which irritate mucosa or have a bitter or
unpleasant taste or an obnoxious odor cannot be
administered by this route
10

7. Drugs which are unstable at buccal pH cannot be
administered by this route.
8. Only those drugs which are absorbed by passive
diffusion can be administered by this route
9. Relatively small absorptive surface area (0.01 sq m Vs
100 sq m for GIT)
Physiological characteristics of human mucosae
Human NASAL mucosa :- Ciliated columnar epithelium and
squamous cutaneous epithelium.
Human RECTAL mucosa :- Epithelium, lamina propria,
double layer muscularis mucosae.
Human VAGINAL mucosa :- Epithelium, lamina propria,
tunica propria, muscularis mucosae, outer fibrous layer.
11

Anatomy & Physiology of Oral Mucosa
• The oral cavity is lined by thick dense & multilayered
mucous membrane of highly vascularized nature.
• Drug penetrating into the membrane passes through
net of capillaries & arteries and reaches the systemic
circulation.
There are mainly three functional zones of oral mucosa:-
1-Masticatory mucosa-(25% of the total oral mucosa)
covers the gingiva and hard palate. Keratinized epithelium
2-Lining mucosa- (60% of the total oral mucosa)
covers the lips, cheeks, soft palate, lower surface of the
tongue and the floor of the oral cavity. Non-keratinized mucosa.
3-The specialized mucosa-(15% of the total oral mucosa) is
found on the dorsum of the tongue. high selective keratinization.
13

The oral mucosa consists of :-
1. Stratified squamous epithelium,
2. Basement membrane,
3. Lamina propria and submucosa
14

1. EPITHELIUM :-
• Measure 100 cm2.
• Protective surface layer
• Protective to deeper tissues
Important feature of oral mucosa is rapid turnover of the
cells(3 – 8 days).
15

2. Basement membrane :-
• Boundary between basal layer (epithelium) & connective
tissue (lamina propria & submucosa)
• Acts as a barrier to large molecules.
3. Lamina propria & Submucosa layer :-
• Connective tissue-- Collagen, elastic fibers, cellular
components.
• Mucus-- Secreting goblet cells / special endocrine glands
•it also carries blood capillaries & nerve fibers.
Functions of oral mucosa.
• Provide protection
• Acts as a barrier
• Provides adhesion
• Keep the mucosal membrane moist
16

SALIVA
 About 1.5 Liters of saliva is secreted daily
 Chief secretions by : Parotid, sub maxillary, sublingual
glands.
 Minor salivary glands are situated in buccal, palatal
regions.
Saliva is more important for:-
1. Drug dissolution
2. Drug permeation (across mucous membrane).
3. To hydrate oral mucosal dosage forms
4. Protective fluid for all tissues of the oral cavity
5. Continuous mineralization / demineralization of the
tooth enamel.
17

MUCUS LAYER
 Mucoadhesive inner layers called mucosa & inner
epithelial cell lining is covered with visco-elastic fluid
called mucus.
 Mucus is translucent and viscid secretion which forms a
thin continuous gel adherent to mucosal epithelial
surface.
 Composed of water and mucin.
 Thickness varies from 40 μm to 300 μm.
Composition:
Water - 95%
Glycoprotein and lipids - 0.5-5%
Mineral salts - 1%
Free proteins - 0.5-1%
18

Functions of mucus:
• Protective : Particularly from its hydrophobicity
• Barrier : In tissue absorption of the drugs and influence
the bioavailability.
• Adhesion : Mucus has strong cohesion properties
• Lubrication :Keep mucosal membrane moist.
Routes of drug transport
1. Paracellular Route :-
Primary route for hydrophilic drugs,
Intercellular spaces is preferred route.
Disadvantage: Limited surface area
2. Transcellular Route :-
Route for lipophiollic compounds, drugs passes through lipid
rich plasma membranes of the epithelial cells.
19

Mechanism of bioadhesion
The bioadhesion is mainly depends upon nature of
bioadhesive material.
Generally it is divided into two steps-
(a)Contact stage & (b)Consolidation stage
20

(A) CONTACT STAGE:
 The first stage is characterized by the contact between
the mucoadhesive material and the mucous
membrane, with spreading and swelling of the
formulation, initiating its deep contact with the mucus
layer.
 In ocular or vaginal formulations, the delivery system
is mechanically attached over the membrane.
 In nasal route deposition is promoted by the
aerodynamics of the organ.
 In the gastrointestinal tract, peristaltic motions can
contribute to this contact.
21

(B) CONSOLIDATION STAGE:
 The mucoadhesive materials are activated by the
presence of moisture.
 Moisture plasticizers the system, allowing the
mucoadhesive molecules to break free and to link up by
weak van der Waals and hydrogen bonds.
Two theories explaining the consolidation step:
(1) Dehydration theory
(2) Diffusion theory.
(1) Dehydration theory:
• Materials that are able to readily gelify in an aqueous
environment, when placed in contact with the mucus
can cause its dehydration due to the difference of
osmotic pressure. 22

• The difference in concentration gradient draws the water
into the formulation until the osmotic balance is reached.
• This process leads to the mixture of formulation and
mucus and can thus increase contact time with the
mucous membrane.
• However, the dehydration theory is not applicable for
solid formulations or highly hydrated forms.
23

(2) Diffusion theory:
• The mucoadhesive molecules and the glycoproteins of
the mucus mutually interact by means of
interpenetration of their chains and the building of
secondary bonds.
• Molecules with hydrogen bonds building groups (–OH, –
COOH), with an anionic surface charge, high molecular
weight, flexible chains and surface-active properties,
which induct its spread spread throughout the mucus
layer, can present mucoadhesive properties.
24

THEORIES OF MUCOADHESION
1. Electronic theory
2. Wetting theory
3. Adsorption theory
4. Fracture theory
5. Diffusion theory
1. ELECTRONIC THEORY:
The bioadhesive material and the target biological material
have different electronic surface characteristics, when two
surfaces come in contact with each other, electron transfer
occurs in an attempt to balance the Fermi levels, resulting in
the formation of a double layer of electrical charge at the
interface of the bioadhesive and the biologic surface.
Mucous network may carry negative charge because of
presence of sialic acid & sulfate residue 25

2. WETTING THEORY:
 The wetting theory applies to liquid systems which
present affinity to the surface in order to spread over it.
 This affinity can be found by using measuring techniques
such as the contact angle.
 The general rule states that the lower the contact angle
then the greater the affinity.
 The contact angle should be equal or close to zero to
provide adequate spreadability.
 Spreadability coefficient (SAB) = γA+ γB - γAB
 The greater the individual surface energy of mucus and
device in relation to the interfacial energy, the greater
the adhesion work, (WA), i.e. the greater the energy
needed to separate the two phases. WA= γA + γB – γAB
26

2. WETTING THEORY:
4. FRACTURE
THEORY:
27

3. ADSORPTION THEORY:
This theory states that the bioadhesive bond formed
between an adhesive substrate and the tissue is due to the
weak van der waals forces and hydrogen bond formation.
For example, hydrogen bonds are the prevalent interfacial
forces in polymers containing carboxyl groups.
4. FRACTURE THEORY:
This theory describes the force required for the separation
of two surfaces after adhesion.
The fracture strength is equivalent adhesive strength
through the following equation. σ = (E × ɛ/L)1/2
where σ is the fracture strength, ɛ fracture energy, E young
modulus of elasticity and L the critical crack length.
28

5. DIFFUSION THEORY:
• This theory supports interpenetration & entanglement
of bioadhesive polymer chains and mucous polymer
chains.
• The bond strength increases with the increase in the
degree of the penetration.
• This penetration rate depends on the diffusion
coefficient, flexibility and nature of the mucoadhesive
chains, mobility and contact time.
• The depth of interpenetration required to produce an
efficient bioadhesive bond lies in the range 0.2-0.5 μm.
• This interpenetration depth of polymer and mucin chains
can be estimated by equation. L = (tDb)1/2
where “t” is the contact time and “Db” is the diffusion
coefficient of the mucoadhesive material in the mucus.29

Formulation design of MDDS
In MDDS contain the following functional agents-
(1) Mucoadhesive polymers
(2) Penetration enhancers
(3) Enzyme inhibitors
(1) MUCOADHESIVE POLYMERS
To promote this adherence a suitable carrier is required.
Ideal Characteristics of Mucoadhesive Polymers:
1. A mucoadhesion promotoing agent or polymer should
promote the adhering of the active pharmaceutical
ingredient to the oral mucosa.
2. The agent can have such additional properties like
swelling so as to promote the disintegration when in
contact with the saliva.
30

3. Polymer must have a high molecular weight up to
10,000 or more. This is necessary to promote the
adhesiveness between the polymer and mucus.
4. Long chain polymers-chain length must be long enough
to promote the interpenetration and it should not be too
long that diffusion becomes a problem.
5. High viscosity & spatial confirmation.
6. Highly cross linked polymers swell in presence of water
and retain their structure.
7. Flexibility of polymer chain- this promotes the
interpenetration of the polymer within the mucus
network.
8. Optimum pH – mucoadhesion is optimum at low pH
conditions
31

9. Optimum hydration- excessive hydration leads to
decreased mucoadhesive strength due to formation
of a slippery mucilage.
10. It should non toxic, economic, biocompatible
preferably biodegradable.
Classification of POLYMERS
1) Basing on source:
Semi natural polymers Cellulose derivatives
Agarose, chitosan, gelatine,
Hyaluronic acid, Various
gums (guar, xanthan, gellan,
carragenan, pectin and
sodium alginate), starch,
sulfated polysaccharides.
Thiloated CMC, HEC, HPC,
Poly(acrylic acid)-based
polymers [CP, PC, PAA,
polyacrylates],
poly(methylvinylether-co-
methacrylic acid), PVA
32

Water-soluble polymers Water-insoluble polymers
CP, HEC, HPC (water below
38.8°C), HPMC (cold water),
PAA, sodium CMC,
sodium alginate
Chitosan (soluble in dilute
aqueous acids), EC, PC
Cationic polymers Anionic polymers Non-ionic
polymers
Aminodextran,
chitosan, (DEAE)-
dextran, TMC
Chitosan-EDTA, CP, CMC,
pectin, PAA, PC, sodium
alginate, sodium CMC,
xanthan gum
eudragit
analogues
34
2) Basing on aqueous solubility:
3) Basing on charge:

Mucoadhesive polymers can also classify into following
categories
1. Traditional non-specific first-generation mucoadhesive
polymers
2. Second-generation mucoadhesive polymers.
3. Novel polymers
1. First-generation mucoadhesive polymers may be divided
into three main subsets,
a) Anionic polymers,
b) Cationic polymers,
c) Non-ionic polymers.
Of these, anionic and cationic polymers have been shown
to exhibit the greatest mucoadhesive strength.
35

a) Anionic polymers:
• Anionic polymers are the most widely employed
mucoadhesive polymers within pharmaceutical formulation
due to their high mucoadhesive functionality and low toxicity.
• PAA and NaCMC possess excellent mucoadhesive
characteristics due to the formation of strong hydrogen
bonding interactions with mucin.
• Polycarbophil (Noveon) and Carbomers (Carbopol), PAA
derivatives are mucoadhesive platforms for drug delivery to
the GI tract.
b) Cationic Polymers:
• Chitosan is the most extensively investigated within the
current scientific literature.
• Chitosan is a cationic polysaccharide, produced by the
deacetylation of chitin, the most abundant polysaccharide in
the world, next to cellulose.
36

2. Second-generation mucoadhesive polymers:
• Second-generation polymer are less susceptible to
mucus turnover rates, with some species binding
directly to specific sites of mucosal surfaces; more
accurately termed “Cytoadhesives”.
a) LECTINS
• Lectins belong to a group of structurally diverse
proteins and glycoproteins that can bind reversibly to
specific carbohydrate residues.
• After initial mucosal cell-binding, lectins can either
remain on the cell surface or in the case of receptor
mediated adhesion possibly become internalised via a
process of endocytosis.
37

b) THIOLATED POLYMERS:
• The presence of free thiol groups in the polymeric
skeleton helps in the formation of disulphide bonds with
that of the cysteine-rich sub-domains present in mucin
which can substantially improve the mucoadhesive
properties of the polymers.
E.g. poly (acrylic acid) and chitosan.
• Various thiolated polymers include chitosan–
iminothiolane, poly(acrylic acid)– cysteine, poly (acrylic
acid)– homocysteine, chitosan–thioglycolic acid,
chitosan– thioethylamidine.
c) Polyox WSR:
A class of high molecular weight polyethylene oxide
homopolymers which are hydrophilic, biocompatible and non
toxic.
38

3. Novel polymers:
a) Tomato lectin showed that it has binding selectivity to
the small intestine epithelium.
b) A new class of hydrophilic pressure sensitive adhesives
(PSA) have been developed by corium technologies.
c) PAA has been considered as a good mucoadhesive. PAA
is co-polymerised with polyethylene glycol (PEG) or
poly (vinyl pyrrolidone) (PVP) to improve these
properties.
39

40
(2) Penetration enhancers:
• These are the Substances added to pharmaceutical
formulation in order to increase the membrane
permeation rate or absorption rate of co-administered
drug.
• PE are also required when a drug has to reach the
systemic circulation to exert its action .
1. Must be non-irritant & have a reversible effect.
2. Must be safe, non toxic and non allergenic.
3. Must be pharmacologically and chemically inert.
Categories of permeation enhancers
a) Bile salts and there steroidal detergents :-
Sodium glycolate, sodium taurocholate, saponins, etc.

41
b) Surfactants:-
i. Nonionic - Polysorbate 80,sucrose ester, etc.
ii. Cationic - Cetyltrimethyl ammonium bromide.
iii. Anionic - Sodium laurylsulfate, fatty acids.
c) Other enhancers:-
Azone, salicylates, chelating agents(Sodium EDTA),
sulfoxides, Benzalkonium chloride, Dextran sulfate,
Propyleneglycol, Menthol, Phosphatidylcholine, Polysorbate-
80 etc.,
Agent Mechanism
Surfactant (SLS) Disrupting lipid molecule packing,
increasing fluidity & drug diffusion.
Non-ionic surfactant,
fatty acids & alcohols
Increase membrane fludity by solublizing
membrane components.

42
Drug Enhancer Result
Insulin Sodium
Glycocholate
Absorption only in
presence of Enhancers
Calcitonin Saponins, Bile Salts,
sugar esters, SLS
Increase pharmacological
effect
Propranolol Methanol, lauric
acid
Increases the permeation
Salicylic
acid
Azone Increases the permeation
Thyrotropin Citric acid, sodium-
5-methoxy
salicylate
Increased absorption

43
(3) Enzyme inhibitors:
These are used for inhibiting the degradation of drug by
various enzymes present in the saliva, improves buccal
absorption of drugs, particulary peptides.
Ex-Aprotinin, Bestatin, Puromycin, etc.,
 Bile salts stabilize protein drugs by different mechanism
(effecting the activity of the enzymes, altering the
conformation of the protein).
 Chemical modification of chitosan with EDTA produces
polymer conjugate chitosan –EDTA that is a very potent
inhibitor of metallopeptidases (carboxypeptidase).
 Polymers such as carbopol, polycarbophil that can
inhibit certain proteolytic enzymes (trypsin, carbo-
peptidases etc.,)

44
FACTORS AFFECTING MUCOADHESION
a. Polymer related factors
1. Molecular
weight
The mucoadhesive force increases with
molecular weight of polymer up to 10,000
and beyond this level there is no much
effect.
2. Conc. of
active
polymers
For solid dosage forms such as tablets
showed that the higher the polymer
concentration the stronger the
mucoadhesion. There is an optimum
concentration of polymer corresponding to
the best mucoadhesion.
3. Flexibility of
polymer chain
Flexibility is an important factor for
interpenetration and enlargement.

45
b. Environment related factors
1.pH pH influences the charge on the surface of
both mucus and the polymers.
2.Applied
strength
To place a solid mucoadhesive system, it is
necessary to apply a defined strength.
3. Initial
contact time
The mucoadhesive strength increases as the
initial contact time increases.
4. Swelling Swelling depends on both polymers
concentration and on presence of water.

46
c. Physiological Variables
1.Mucin turn
over
The mucin turnover is expected to limit the
residence time of the mucoadhesive on the
mucus
layers.
2.Diseased
state
Physicochemical properties of mucus are
known to change during diseased states,
such as common cold, gastric ulcers,
ulcerative colitis, cystic fibrosis, bacterial
and fungal infections of the female
reproductive tract and inflammatory
conditions of the eye.

47
Buccal Adhesive Dosage Forms
1. Solid dosage
forms:
2.Semisolid dosage
form:
3. Liquid dosage
form:
a) Buccal tablet: a) Bioadhesive
patch/film:
Suspensions,
Gel forming liquids.
b) Bioadhesive
microsphere:
b) Buccal gel and
ointment:
c) Bioadhesive
wafers:
c) Medicated
chewing gum:
d) Bioadhesive
lozenges:

49
1. Solid dosage forms:
a) Buccal tablet:
• The bioadhesive tablets are most preferable mucoadhesive
device in order to improve bioavailability of drugs.
• Mucoadhesive tablet can be prepared by methods such as
wet granulation and direct compression.
• In case of buccal drug delivery, the tablets are placed in
buccal pouch below the muscles of teeth.
• Mechanism of drug release is erosion.
Advantages:
1. The buccal tablet can developed for verity of drug including
insoluble to soluble, low dose to high dose, hydrophilic to
lipophilic.
2. As compared to conventional tablet, buccal tablet are flat,
small and retained at site until release is completed.

50
Disadvantages:
1. They provide little bit of discomfort to the buccal cavity
because of their solid nature.
2. lack of physical flexibility, poor patient compliance.
3. The small surface of contact with the mucosa.
4. It is difficult to obtain high release rates, which is
required for some drugs
5. The extent & frequency of contact may cause irritation
following chronic application on the buccal & sublingual
mucosa

51
b) Bioadhesive microsphere:
Microsphere is an important part in case of novel drug
delivery system.
This mucoadhesive microsphere is mainly used for purpose
of targeting to specific body cavity.
Advantages:
They provide high absorption and enhanced bioavailability
of drug due to their surface-to-volume ratio that provide
highest contact of microspheres with mucus membrane.
c) Bioadhesive wafers:
It is a newer dosage form for bioadhesive buccal delivery.
It is used at the periodontal region for the treatment of
infections related with periodontitis.

52
d) Bioadhesive lozenges:
Bioadhesive lozenges are generally used for delivery of
drugs that are antimicrobials, corticosteroids, local
anesthetics, antibiotics and anti-fungals and are used
topically in the buccal cavity.
Advantages:
Better patient compliance and easy to swallow.
Disadvantages:
The lozenge produce a high release rate of drug at initial
stage and rapidly reaches the sub-therapeutic level

53
2.Semisolid dosage form:
a) Bioadhesive patch/film:
• These are laminates consisting of an impermeable
backing layer, a drug-containing reservoir layer, a
bioadhesive surface for mucosal attachment.
• The use of an impermeable backing layer will maximize
the drug concentration gradient and prolongs adhesion.
• Backing layer control the direction of drug release,
prevent drug loss, minimize deformation and
disintegration.
• Patches or film are preferred over tablet because of their
comfort and flexibility with greater patient complaince.
• Thickness of patch is a constraint which cannot provide
control release of drug for longer period of time.

54
• In case of drug containing reservoir layer type; drug is
released in controlled manner (1-24 hr).
• Patches and film are mostly preferred for local action to
treat oral diseases. Size (1-16cm2)
• There are many methods used for formulation of patch
or films such as solvent casting method, hot melt
extrusion technique, direct milling, semisolid casting,
solid dispersion extrusion etc.

55
b) Buccal gel and ointment:
• Advantage of these over other dosage form is that they
are easily dispersion through out the mucosa.
• They do not have accurate dosing as unit dosage form
like tablet, patches or films, hence they are mostly
preferred for local action.
• Certain polymer are used such as NaCMC, xanthan,
carbopol, hyaluronic acid, HPMC, etc.,
Advantages:
local application of steroidal gel for treatment of mucosal
ulceration in order to decrease the side effects of steroids.
Disadvantages:
It has less patient acceptability than other mucoadhesive
formulation.

56
c) Medicated chewing gum:
• Medicated chewing gum contains drug which after
chewed, offer high amount of drug to prove local
action in mouth.
• The main target mucosa for drug absorption is
sublingual mucosa.
• Chewing gums formulations consist generally of a gum
base of cellulosic or acrylic polymer.
• Drug release from chewing gum formulations is
generally not as immediate as in the case for the
dissolving tablets.
• The medicated chewing gum for nicotine replacement
therapy, caffeine chewing gums are also available.

57
LIMITATIONS :
1. The drug released into the saliva disappears rapidly
from the oral cavity because of involuntary swallowing.
2. The concentration of drug in the oral cavity is always
decreasing as a result of salivary dilution.
3. The drug is not protected from the environment found
in the oral cavity.

58
3. Liquid dosage form:
• These are available in form of solution or suspension of
drug in suitable vehicle.
• There are many liquid dosage forms that are available in
market such as mouthwashes, mouth freshener, and
are generally used for local delivery of drugs.
• Wide varieties of polymers are use from that chitosan
has greatest binding capacity than other.
• Viscous liquid formulations are preferred to coat buccal
cavity either as vehicle or as protectant.

59
Design of buccoadhesive dosage forms basing on
geometry
Type I:
 In this there is a single layer containing dosage form
which provides multidirectional drug release.
 The main disadvantage of this type is that the drug loss
is high by swallowing.
Type II:
 It contains the drug loaded bioadhesive layer covered by
impermeable backing membrane.
 The backing membrane covers only the opposite side
from the site of attachment hence preventing the drug
loss from the upper surface of device.

60
Type III:
 In this type, all sides of drug loaded mucoadhesive layer
are covered by impermeable except the side that
attaches the target area.
 It is a unidirectional drug flow preventing all kinds of
unwanted drug loss.

61
Basic Components of Buccal Drug Delivery System
1. Drug substance
2. Bioadhesive polymer
3. Backing membrane
4. Plasticizers
5. Permeation enhancers

62
1) Drug substance:
The suitable drug should be selected on the basis of its
pharmacokinetic properties.
The drug should be of following characteristics:
1. The one time dose of drug should be small (≤ 25 mg).
2. The drug should be having short biological half life
ranging from 2 to 8 hrs.
3. The drugs showing first pass metabolism can be used
for buccal drug delivery for avoiding it.
4. Mol. size 75 – 100 Daltons & Mol. weight 200 – 500
5. Drugs should be hydrophilic / lipophilic in nature
6. Drug should be stable at buccal pH ( 6.4 – 7.2 )
7. Drug should be odourless.
8. Drugs which are absorbed only by passive diffusion
should be used

63
3) Backing membrane:
•Backing membrane used for the formulations should be
impermeable to drug as well as mucus in order to prevent
the unnecessary drug loss from all sides of the device.
•The materials used for preparing backing membrane should
be inert, insoluble or should have low water solubility.
•Ex: Carbopol, sodium alginate, HPMC, EC, polycarbophil
etc.,
4) Plasticizers:
•The plasticizers are used in order to improve the folding
endurance of the delivery device.
•They provide enough flexibility to the dosage form for
improving its patient acceptability and patient compliance.
•Ex: PEG-400, PEG-600, dibutyl phthalate, propylene glycol
etc.,

64
METHODS OF EVALUATION
A) In vitro/ Ex vivo methods
1. • Measurement of tensile strength
2. • Measurement of shear stress
3. • Adhesion weight method
4. • Fluorescent probe method
5. • Flow channel method
6. • Mechanical spectroscopic method
7. • Falling liquid film method
8. • Colloidal gold staining method
9. • Viscometer method
10. • Thumb method
11. • Adhesion number
12. • Electrical conductance
13. • Swelling properties
14. • In vitro drug release studies
15. • Muco retentability studies
B) In Vivo methods
1. • Use of
radioisotopes
2. • Use of gamma
scintigraphy
3. • Use of pharmaco-
scintigraphy
4. • Use of electron
paramagnetic
resonance
5. •(EPR) oximetry

65
A) In vitro/ Ex vivo methods
1. MEASUREMENT OF TENSILE STRENGTH:
• The Wilhelmy plate method is for the measurement of
the force of adhesion of bioadhesive dosage forms.
• The method involves the measurement of the dynamic
contact angle and utilizes a microtensiometer and a
microbalance.
• The CAHN dynamic contact angle analyzer is used for
this purpose.
• Wilhelmy plate method measures the bioadhesive force
between the mucosal tissue and the polymer/dosage
form attached to a metal wire and suspended into the
microtensiometer.

66
• The mucosal tissue (usually rat jejunum) is used which
placed in the tissue chamber, this chamber is raised so
as to make contact between the tissue and the test
material.
• After a certain period (7 mins for microspheres) the
stage is lowered and the force of adhesion is measured.
This apparatus measures the following parameters
a) Fracture strength:
Its defined as the force per unit area required to break the
adhesive bond.
b) Deformation to failure:
It is the distance required to move the stage before
complete separation occurs.

67
• The modified Wilhelmy plate method consists of a glass
plate which is coated with the polymer layer, suspended
from a microbalance into a beaker containing mucus.
• The work done to detach the polymer from the mucus is
found.
• This system has demerit of not involving any living tissue.

68
2. MEASUREMENT OF SHEAR STRESS:
• The measurement of the shear stress gives a direct
correlation to the adhesion strength.
• In this method two smooth, polished plexi glass boxes
were selected; one block was fixed with adhesive
araldite on a glass plate, which was fixed on leveled
table.
• To the upper block, a thread was tied and the thread
was passed down through a pulley, the length of the
thread from the pulley to the pan was 12cms.
• At the end of the thread a pan of weight 17 gms was
attached into which the weights can be added.

69
• A recent method involves the measurement of
mucoadhesion by use of a stainless steel rotating
cylinder which was coated with freshly excised porcine
intestinal mucosa to which polymer discs were attached.
• The cylinder was placed in a dissolution apparatus and
rotated at 125rpm.
• It was analysed every 30 minutes for the attachment of
the polymer discs.

70
3) ADHESION WEIGHT METHOD:
• In this method the weight of adherent particle was
determined by flowing a suspension of an ion
exchange resin particles over the inner mucosal surface
of a section of animal intestine (guinea pig).
• This method has limited value due to poor data
bioavailability.
• But it was possible to determine the effect of particle
size and charge on the adhesion with everted intestine
after 5 minutes contact.

71
4) FLUORESCENT PROBE METHOD :
• For the determination of the bioadhesive potential of
large number of polymer, the Fluorescent method is
used.
• In the technique labelling of the lipid bilayer and
memberane protein with the fluorescent probes (pyrene
and fluorescein isothiocynate) is done.
• Addition of polymers to this substrate surface of lipid
bilayer or protein causing a caused a change in the
degree of fluorescent which was proportional to the
polymer binding
• The change in fluorescence, is compared to control cells.

72
5) FLOW CHANNEL METHOD :
• This method was developed by Mikos and Peppas.
• A 2% w/w aqueous solution of bovine submaxillary
mucin, thermostatic at 37oC is filled in a glass made up
of thin channel.
• Humid air at 37oC was passed through glass channel.
• The adhesion property is calculated by placing a particle
of bioadhesive polymer on the mucin gel and its static
and dynamic behaviour is monitored at frequent
intervals using a camera.

73
7. FALLING LIQUID FILM METHOD :
• Porcine stomach, intestinal and buccal mucus and also
jejunum from rabbits can be used for study.
• The selected mucous membrane is placed in a stainless
steel cylindrical tube, which has been longitudinally cut.
• This support is placed inclined in a cylindrical cell with a
temperature controlled at 370C.
• An isotonic solution is pumped through the mucous
membrane and collected in a beaker.
• Subsequently, in the case of particulate systems, the
amount remaining on the mucous membrane can be
counted with the aid of a coulter counter.
• For semi-solid systems, the non adhered mucoadhesive
can be quantified by HPLC.

75
8) COLLOIDAL GOLD STAINING METHOD :
• The technique employed red colloidal gold particles
which were stabilized by adsorbed mucin molecules
(mucin-gold conjugates).
• Upon interaction with the mucin-gold conjugates ,
bioadhesive hydrogels developed a red colour the
surface.
• Thus the interaction between them could easily be
quantified either by the measurement of the intensity
of red colour on the hydrogel surface or by the
measurement of the decrease in concentration of the
conjugates from the absorbance changes at 525 nm.

76
9) VISCOMETRIC METHOD/ RHEOLOGICAL MEASUREMENT
OF MUCOADHESION:
• Hassan and Gallo used simple viscometer to quantify
the mucin-polymer bioadhesion bond
• The Brookefield visometer measure the mucoadhesion
force by monitoring the viscosimetric changes of the
system constituted by the mixture of the polymer
chosen and mucin.
• The main disadvantage of this method is the
breakdown of the polymer and mucin network under
continuous flow.
• oscillatory rheology is a non-destructive technique and
simultaneously measures viscosity and elastic behavior
and can be used to determine mucoadhesion

77
10) ADHESION NUMBER:
• It is the ratio of number of particles attached to the
substrate to the total number of applied particles.
• The adhesion number is typically represented by the
following equation:
Na = (N/N0) X 100
Where Na is the adhesion number
N0 is the total number of applied particles
N is the number of particles attached to the substrate
• As the adhesion strength increases, the adhesion number
also increases.

78
11) ELECTRICAL CONDUCTANCE:
• The semisolid mucoadhesive ointments are tested by
electrical conductance method using modified
rotational viscometer.
• In this method the artificial membrane in the artificial
saliva is used, the adhesion of carbopol, guar gum
cudispert, orabase, and methylcellulose is calculated.
• In the presence of adhesive the conductance is
comparatively low, as the adhesive was removed, value
increased to final value, which corresponds to the
conductance of saliva, which indicates the absence of
adhesion.

79
12) SWELLING STUDIES:
 Buccal adhesive dosage forms were weighed
individually (w1) and separately in petridishes
containing 4 ml of phosphate buffer pH 6.6.
 At regular intervals (0.5,1,2,3,4,5,6 hours) the dosage
forms were removed from the petridishes and excess
surface water was removed using filter paper.
 The dosage form wee reweighed and swelling index (SI)
was calculated as follows,
SI = (W2-W1)/W1

80
13) IN-VITRO DRUG RELEASE:
• These are performed in phosphate buffer ph 6.6, 150
ml at 370C in a modified dissolution apparatus which
consist of a 250 ml beaker and a glass rod attached with
a grounded glass disk (2 cm diameter) as a donor tube.
• The back surface of the bioadhesive dosage form was
attached to the glass disk with an cynoacrylate
adhesive.
• The donor tube was dipped into the medium and
stirred at constant rpm 5ml aliquots were withdrawn at
preset times (1,2,3,4,5,6 hours),filtered through a 0.2
micron filter and absorbance was measured.

81
B) IN-VIVO TESTS:
• Säkkinen et al. (2006) applied gamma scintigraphy to
analyze mucoadhesion in vivo of chitosan within the
gastrointestinal tract.
• Gamma scintigraphy allows the immediate visualization
of all the formulation transit, with low exposure of the
subjects to radiation.
• The gastrointestinal transit time in animals can also be
evaluated in a non-invasive way, in which the release
systems can be formulated with opaque radioisotopes
and signals can be followed by X-rays, without affecting
normal gastrointestinal motility.
• Use of different methods may sometimes lead to
incoherence in results due to the heterogeneity of
parameters and conditions used.

82
NASAL DRUG DELIVERY SYSTEM
INTRODUCTION
Anatomy of nose:-
• The nasal cavity consists
of passage of a depth of
approximately 12-14cm.
• The nasal passage runs
from nasal vestibule to
nasopharynx.
The surface area in the
nose can be about 150cm2.

83
The nasal cavity consists
three main regions are
1. nasal vestibule,
2. olfactory region and
3. respiratory region.
The nasal cavity is covered
with a mucous membrane
which can be divided into
two areas;
1. Non-olfactory and
2. Olfactory epithelium,
In this non-olfactory area is covered with skin-like stratified squamous
epithelium cells,
where as respiratory region, covered with numerous microvilli,
resulting in a large surface area available for drug absorption and
transport

84
• The goblet cells are present in the mucus membrane
secretes the mucus to contribute to the mucus layer.
• The mucus secretion is composed of about 95% water, 2
% mucin, 1% salts, 1% of proteins such as albumin,
immunoglobulins, lysozyme and lactoferrin, and 1%
lipids.
Physiological functions of Mucus:
(1) It covers the mucosa, and physically and enzymatically
protects it.
(2) The mucus has water-holding capacity.
(3) It exhibits surface electrical activity.
(4) It permits efficient heat transfer.
(5) It acts as adhesive and transport s particulate matter
towards the nasopharynx.
(6) The mucus secretion gives immune protection against
inhaled bacteria and viruses.

85
ADVANTAGES
1) Drug degradation that is observed in the gastrointestinal
tract is absent.
2) Hepatic first pass metabolism is avoided.
3) Rapid drug absorption and quick onset of action can be
achieved.
4) The bioavailability of larger drug molecules can be
improved by means of absorption enhancer or other
approach.
5) The nasal bioavailability for smaller drug molecules is
good.

86
6) Drugs that are orally not absorbed can be delivered to
the systemic circulation by nasal drug delivery.
7) Nasal route is an alternate to parenteral route,
especially, for protein and peptide drugs.
8) Convenient for the patients, especially for those on long
term therapy, when compared with parenteral medication.
9) Drugs possessing poor stability in g.i.t. fluids are given by
nasal route.
10) Polar compounds exhibiting poor oral absorption may
be particularly suited for this route of deli-very.

87
DISADVANTAGES/ LIMITATIONS
1) The histological toxicity of absorption enhancers.
2) Relatively inconvenient to patients when compared to
oral delivery systems since there is a possibility of nasal
irritation.
3) Nasal cavity provides smaller absorption surface area
when compared to GIT.
4) There is a risk of local side effects and irreversible
damage of the cilia on the nasal mucosa, both from the
substance and from constituents added to the dosage form.
5) Certain surfactants used as chemical enhancers may
disrupt and even dissolve membrane in high concentration.
6) There could be a mechanical loss of the dosage form into
the other parts of the respiratory tract like lungs because of
the improper technique of administration.

88
MECHANISM OF NASAL ABSORPTION
The absorbed drugs from the nasal cavity must pass
through the mucus 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.
a) First mechanism-
It involves an aqueous route of transport, which is also
known as the paracellular route but slow and passive.
The drugs having molecular weight greater than 1000
daltons shows poor bioavailability.
B) Second mechanism-
It involves transport through a lipoidal route and it is also
known as the transcellular process. It is responsible for the
transport of lipophilic drugs.

89
FACTORS INFLUENCING NASAL DRUG ABSORPTION
1) Physiochemical properties of drug.
Molecular size.
Lipophilic-hydrophilic balance.
Enzymatic degradation in nasal cavity.
2) Nasal Effect
Membrane permeability.
Environmental pH
Mucociliary clearance
Cold, rhinitis.
3) Delivery Effect
Formulation (Concentration, pH, osmolarity)
Delivery effects
Drugs distribution and deposition.
Viscosity

90
STRATEGIES TO IMPROVE NASAL ABSORPTION
Various strategies used to improve the bioavailability of the
drug in the nasal mucosa which includes
1. To improve the nasal residence time
2. To enhance nasal absorption
3. To modify drug structure to change physicochemical
properties.
1. Nasal enzyme inhibitors:
For the formulation of proteins and peptide enzyme
inhibitors like peptidases and proteases are used.
Salts and fusidic acid derivatives also shows enzyme
inhibition.
The other enzyme inhibitors commonly used for the enzy-
matic activity are tripsin, aprotinin, borovaline, amas-tatin,
bestatin and boroleucin inhibitors.

91
2. Permeation enhancers
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:
1. Inhibit enzyme activity;
2. Reduce mucus viscosity or elasticity;
3. Decrease mucociliary clearance;
4. Open tight junctions; and
5. Solubilize or stabilize the drug.
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.

92
Surfactants:
Polyozyethylene-9-lauryl ether (Laureth-9), Saponin
Bile salts:
Trihydroxy salts (glycol- and taurocholate), Fusidic acid
derivatives (STDHF)
Chelators:
Salicylates, Ethylenediaminetetraacetic acid (EDTA)
Fatty acid salts:
Oleic acid, Caprylate (C8), Caprate (C10), Laurate (C12)
Phospholipids:
Lysophosphatidylcholine (lyso-PC), Di-decanoyl – PC
Glycyrrhetinic acid derivates: Carbenozolone, Glycyr-rhizinate
Cyclodextrins:
α, ß, and γ- cyclodextrins and their de-rivatives
Glycols:
n- glycofurols and n- ethylene glycols

93
3. Prodrug approach :
 The prodrug undergoes enzymatic transformation to
release the active medicament, when it crosses the
enzymatic and membrane barrier.
 The absorption of peptides like angiotensin II,
bradykinin, caulein, carnosine, enkepha-lin, vasopressin
and calcitonin are improved by pre-pared into enamine
derivatives, these agents showed absorption
enhancement with prodrug approach.

94
4. Structural modification:
The chemical modification of drug is used to modify the
physicochemical properties of a drug such as molecular size,
molecular weight, Pka and solubility are favorable to
improve the nasal absorption of drug.
Example, chemical modification of salmon calcitonin to
ecatonin (C-N bond replaces the S-S bond) showed better
bioavailability than salmon calcitonin
5. Particulate drug delivery:
Particle design is an increasingly important role in ab-
sorption enhancement.
Microspheres, nanoparticles and liposomes are all systems
which can be used as carriers to encapsulate an active drug.

95
NASAL DRUG DELIVERY SYSTEM DOSAGE FORMS
Four basic formulations must be considered,
i.e. solution, suspension, emulsion and dry powder
systems.
A.LIQUID NASAL FORMULATIONS
1. Instillation and rhinyle catheter
2. Compressed air nebulizers
3. Squeezed bottle
4. Metered-dose pump sprays
B. POWDER DOSAGE FORMS
1. Insufflators
2. Dry powder inhaler
C. PRESSURIZED MDIs
D. NASAL GELS

96
A. LIQUID NASAL FORMULATIONS
• Liquid preparations are the most widely used dosage
forms for nasal administration of drugs.
• They are mainly based on aqueous state formulations.
• Their humidifying effect is convenient and useful.
Disadvantages:
 Microbiological stability, irritation and allergic rhinitis
are the major drawbacks associated with the water-
based dosage forms
 The reduced chemical stability of the dissolved drug
substance and the short residence time of the
formulation in the nasal cavity are major
disadvantages of liquid formulations

97
1. Instillation and rhinyle catheter :
 Catheters are used to deliver the drops to a specified
region of nasal cavity easily.
 Place the formulation in the tube and kept tube one
end was positioned in the nose, and the solution was
delivered into the nasal cavity by blowing through the
other end by mouth.
 Dosing of catheters is determined by the filling prior to
administration and accuracy of the system and this is
mainly used for experimental studies only.

98
2. Compressed air nebulizers:
 Nebulizer is a device used to administer medication in
the form of a mist inhaled into the lungs.
 The common technical principal for all nebulizers, is to
either use oxygen, compressed air or ultrasonic power,
as means to break up medical solutions/ suspensions
into small aerosol droplets, for direct inhalation from
the mouthpiece of the device.
 Nebulizers accept their medicine in the form of a liquid
solution, which is often loaded into the device upon use.
Corticosteroids and Bronchodilators such as salbutamol
(Albuterol USAN) are often used, and sometimes in
combination with ipratropium.
 These target their effect to the respiratory tract, speeds
onset of action of the medicine and reduces side effects.

100
3. Squeezed bottle
 Squeezed nasal bottles are mainly used as delivery de-
vice for decongestants.
 They include a smooth plastic bottle with a simple jet
outlet. While pressing the plastic bottle the air inside the
container is pressed out of the small nozzle, thereby
atomizing a certain volume.
 Dose accuracy and deposition of liquids delivered via
squeezed nasal bottles are strongly de-pendent on the
mode of administration.
Diasadvantages:
1. Dose is hard to control, it differences between vigorously
and smoothly pressed application.
2. Contamination of the liquid by microorganisms and nasal
secretion

102
4. Metered-dose pump sprays :
 Nasal sprays, or nasal mists, are used for the nasal
delivery of a drug or drugs (antihistamines,
corticosteroids, and topical decongestants ), either
locally to generally alleviate cold or allergy symptoms.
 Metered- dose pump sprays include the container, the
pump with the valve and the actuator.
 The dose accuracy of metered-dose pump sprays is
dependent on the surface tension and viscosity of the
formulation.
 Nasal sprays function by instilling a fine mist into the
nostril by action of a hand-operated pump mechanism.

103
B. POWDER DOSAGE FORMS
Dry powders are less frequently used in nasal drug delivery.
Advantages:
1. The lack of preservatives,
2. The improved stability of the formulation,
3. A prolonged contact with the nasal mucosa.
1. Insufflators
• Insufflators are the devices to deliver the drug
substance for inhalation;
• it can be constructed by using a straw or tube which
contains the drug substance and sometimes it contains
syringe also.

104
• The achieved particle size of these systems is often
increased compared to the particle size of the
powder particles due to insufficient deaggregation
of the particles and results in a high coefficient of
variation for initial deposition areas.
• Many insufflator systems work with pre-dosed
powder doses in capsules

105
2. Dry powder inhaler
 Dry powder inhalers (DPIs) are devices through which
a dry powder formulation of an active drug is
delivered for local or systemic effect via the
pulmonary route.
 Dry powder inhalers are bolus drug delivery devices
that contain solid drug, suspended or dissolved in a
non polar volatile propellant (or) in dry powder
inhaler that is fluidized when the patient inhales.
 These are commonly used to treat respiratory
diseases such as asthma, bronchitis, emphysema and
COPD and have also been used in the treatment of
diabetes mellitus.

106
 The medication is commonly held either in a capsule for
manual loading or a proprietary form from inside the
inhaler.
 Once loaded or actuated, the operator puts the
mouthpiece of the inhaler into their mouth and takes a
deep inhalation, holding their breath for 5-10 seconds.
 The dose that can be delivered is typically less than a
few tens of milligrams in a single breath since larger
powder doses may lead to provocation of cough.

107
C. PRESSURIZED MDIs
• A metered-dose inhaler (MDI) is a device that delivers a
specific amount of medication to the lungs, in the form
of a short burst of aerosolized medicine that is inhaled
by the patient.
• It is the most commonly used delivery system for
treating asthma, chronic obstructive pulmonary disease
(COPD) and other respiratory diseases.
• The medication in a metered dose inhaler is most
commonly a bronchodilator, corticosteroid or a
combination of both.
• Other medications less commonly used but also
administered by MDI are mast cell stabilizers, such as
(cromoglicate or nedocromil).

108
Advantages :
1. portability and small size,
2. availability over a wide do-sage range per actuation,
3. dose consistency,
4. dose accuracy,
5. protection of the contents and
6. quickly ready for use.
 To use the inhaler the patient presses down on the
top of the canister, with their thumb supporting the
lower portion of the actuator.
 The propellant provides the force to generate the
aerosol cloud and is also the medium in which the
active component must be suspended or dissolved.

109
 Actuation of the device releases a single metered dose
of the formulation which contains the medication
either dissolved or suspended in the propellant.
 Breakup of the volatile propellant into droplets,
followed by rapid evaporation of these droplets, results
in the generation of an aerosol consisting of
micrometer-sized medication particles that are then
inhaled.

110
D. NASAL GELS :
Nasal gels are high-viscosity thickened solutions or
suspensions.
Advantages:
1. The reduction of post-nasal drip due to high viscosity,
2. Reduction of taste impact due to reduced swallowing,
3. Reduction of anterior leakage of the formulation,
4. Reduction of irritation by using soothing/emollient
excipients and
5. Target delivery to mucosa for better absorption.

111
 The deposition of the gel in the nasal cavity
depends on the mode of administration,
because due to its viscosity the formulation has
poor spreading abilities.
 Without special application techniques it only
occupies a narrow distribution area in the nasal
cavity, where it is placed directly.
 Recently, the first nasal gel containing Vitamin
B12 for systemic medication has entered the
market.

112
APPLICATIONS
1. Delivery of non-peptide pharmaceuticals
2. Delivery of peptide-based pharmaceuticals
3. Delivery of Drugs to Brain through Nasal Cavity:
4. Delivery of Vaccines through Nasal Route:
5. Delivery of diagnostic drugs:

113
1. Delivery of non-peptide pharmaceuticals:
 Low molecular weight (below 1000 daltons) small
non- peptide lipophilic drugs are well absorbed
through the nasal mucosa even though absence of
permeation enhancer.
 Drugs with extensive pre-systemic metabolism, such
as progesterone, estradiol, propranolol,
nitroglycerin, sodium chromoglyate can be rapidly
absorbed through the nasal mucosa with a systemic
bioavailability of approximately 100% .

114
Non-peptide drugs being studied for nasal delivery
1) Adrenal corticosteroids
2) Sex hormonses: 17ß-estradiol, progesterone, no-rethindrone, and testosterone.
3) Vitamins: vitamin B
4) Cardiovascular drugs: hydralazine, Angiotensin II antagonist, nitroglycerine,
isosobide dinitrate, propanolol, and colifilium tosylate.
5) Autonomic nervous system:
a. Sympathomimetics: Ephedrine, epinephrine, phenylephrine,
b. Xylometazoline, dopamine and dobutamine.
c. Parasympathomimetics: nicotine, metacholine
d. Parasympatholytics: scopolamine, atropine, ipatropium
e. Prostaglandins
6) Central nervous systems stimulants: cocaine, lido-caine
7) Narcotics and antagonists: bupemorphine, nalox-ane
8) Histamine and antihistamines: disodium cromog-lycate, meclizine
9) Antimigrane drugs: dierogotamine, ergotamine, tartarate
10) Phenicillin, cephalosporins, gentamycin
11) Antivirals : Phenyl-p-guanidine benzoate, envirox-ime.
12) Inorganic compounds: Inorganis salts, colloidal gold, colloidal carbon, colloidal
silver.

115
2. Delivery of peptide-based pharmaceuticals:
• Peptides & proteins have low oral bioavai-lability
(1–2%) because of their physico-chemical instability and
susceptibility to hepato-gastrointestinal first-pass
elimination.
• Examples are insulin, calcitonin, pituitary hormones
etc.,
• To overcome this problem, absorption enhancers like
sufactants, glycosides, cyclodextrin and glycols to in-
crease the bioavailability.
• Nasal route is proving to be the best route for such
biotechnological products.

116
3. Delivery of Drugs to Brain through Nasal Cavity:
• This delivery system is beneficial in conditions like Par-
kinson’s disease, Alzheimer’s disease or pain because it
requires rapid and/or specific targeting of drugs to the
brain.
• The olfactory region located at the upper remote parts
of the nasal passages offers the potential for certain
compounds to circumvent the blood-brain barrier and
enter into the brain.
• The neurotrophic factors such as NGF, IGF-I, FGF and
ADNF have been intranasally delivered to the CNS shows
increase the bioavailability of drug in the brain.
• Studies in humans, with proteins such as AVP, CCK
analog, MSH/ACTH and insulin have revealed that they
are delivered directly to the brain from the nasal cavity.

117
4. Delivery of Vaccines through Nasal Route:
Reasons:
1) The nasal mucosa is the first site of contacts with inhaled
pathogens,
2) The nasal passages are rich in lymphoid tissue,
3) Creation of both mucosal and systemic immune
responses,
4) Low cost, patient friendly, non-injectable, safe.
 Nasal delivery of vaccines has been reported to not only
produce systemic but also local immune response.
 Delivering the vaccine to the nasal cavity stimulates the
production of local secretory Ig-A & Ig-G antibodies,
providing an additional first line of defense, which helps
to eliminate the pathogens.

118
 Recently, for the diseases like anthrax and influenza are
treated by using the nasal vaccines prepared by using
the recombinant Bacillus anthracis protective antigen
(rPA) and chitosan.
 The common diseases like measles, pertussis,
meningitis and influenza causing pathogens are mainly
enter into the body through the nasal mucosal surfaces
and hence good candidates for nasal vaccines.
 Nasally administered vaccines, especially if based on
attenuated live cells or adjuvanted by means of an
immuno-stimulator or a delivery system, can induce
both mucosal and systemic (i.e. humoral and cell-
mediated) immune responses.

119
5. Delivery of diagnostic drugs:
• The intranasal route is better for systemic release of
medicament into blood circulation, so can get quick
results with less toxicity.
• Phenolsulfonphthalein is a diagnostic agent used to
diagnose the kidney function of the patients.
• Pancreatic disorders of the diabetic patients were
diagnosed by using the ‘Secretin’.
• The secretory function of gastric acid was determined
by Pentagastrin, diagnostic agent.

120
REFERENCES:
1. F. C. Carvalho, Mucoadhesive drug delivery systems, Brazilian Journal
of Pharmaceutical Sciences vol. 46, n. 1, jan./mar., 2010, 1-17.
2. Amitava Roy, STRATEGIES OF MUCOADHESIVE DRUG DELIVERY
SYSTEM- AN UPDATE ON NASAL DRUG DELIVERY, UJPSR / 1 (2), 2015,
23-34.
3. Singh R, Sharma D, Garg R (2017) Review on Mucoadhesive Drug
Delivery System with Special Emphasis on Buccal Route: An Important
Tool in Designing of Novel Controlled Drug Delivery System for the
Effective Delivery of Pharmaceuticals. J Dev Drugs 6: 169.
4. Khan et al. MUCOADHESIVE DRUG DELIVERY SYSTEM: A REVIEW
.World Journal of Pharmacy and Pharmaceutical Sciences, Volume 5,
Issue 5, 392-405.
5. Amanpreet kaur et al: Mucoadhesive Drug Delivery System: A Review,
Int. J. Drug Dev. & Res., January-March 2013, 5 (1): 11-20.
6. M.Alagusundara et al. , Nasal drug delivery system - an overview. Int. J.
Res. Pharm. Sci. Vol-1, Issue-4, 454-465, 2010.

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