Drug dispensing in oral

preparation
By,

uthara menon
Ist MDS

contents
INTRODUCTION

LOCAL ORAL DRUG DELIVERY

Drawbacks of local oral drug delivery
Enhancement of trans-mucosal agent
transport of substances
MUCOADHESIVE DOSAGE FORMS
DOSAGE FORMS
ADHESIVE TABLETS, ADHESIVE PATCHES
AND FILMS, ADHESIVE SEMISOLID
SYSTEMS (GELS, OINTMENTS), ADHESIVE
LIQUID SYSTEMS (ORAL RINSE AND
SPRAYS)

INTRODUCTION

Oral mucosal diseases are among the most

common diseases affecting humans, and they
can be effectively treated by topical
therapeutic approaches, due to easy
accessibility of the oral cavity.
The oral cavity has structural, environmental,
and functional features that differ from the
skin

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

 The presence of saliva in association with

swallowing, chewing, and phonation acts to
wash away most of the drug from the site of
application, resulting in a short retention time
of the dosage forms and, consequently, low
therapeutic efficacy

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

An ideal drug administration system

should fulfil the following criteria:

It should be able to release medication in a

continuous, or at least prolonged, pattern.
It should deliver the medication in pulses that are
controllable and programmable with respect to
concentration and time.
It should provide a high efficacy of drug delivery to
minimize side effects.
It should function automatically, in order to reduce
patient burden
for self administration.
It should not impair the patients comfort taste,
sensation and
activities.
It should not
present any source of additional risk to
Drug Discovery Today Volume 13, Numbers 5/6 March

ORAL MUCOSA:
STRUCTURE AND
PERMEABILITY
FEATURES
Oral mucosa-total surface area-200cm

2 anatomical and functional layers

STRATIFIED SQUAMOUS
VASCULAR
LAYER OF
AVASCULAR EPITHELIUM
MESODERMAL
ORIGIN

NON KERATINIZED
EPITHELIUM

KERATINIZED
EPITHELIUM

(Oral Surg
Oralmucosa
Pathol Oral Radiol
The epithelium
of Oral
theMed
oral
is 2012;114:e25-

Oral cavity has 3 different types of oral

mucosa
MASTICATORY MUCOSA (i.e., gingivae and the hard palate),25%
SPECIALIZED MUCOSA (i.e., the dorsum of the tongue),15% and
LINING MUCOSA
(e.g., buccal mucosa, the floor of mouth)
60%

Most appropriate formulation reaches the deeper

layers of the oral epithelium, according to local
variations in mucosal thickness, epithelial
keratinization, and lipid composition. (barrier region)
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

The permeability of oral mucosa decreases

gradually
from the sublingual through to the buccal and
palatal mucosa
Thin and nonkeratinized

Sublingual mucosaThicker and nonkeratinized

Buccal mucosaPalatal mucosa Intermediate in thickness and keratinized

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

 Connective tissue not an effective barrier

2 sites at which mucosal barrier function
Basal complex, (immunocomplexes) and
The intercellular spaces of the superficial
epithelial layers. (penetration of polar and
nonpolar substances)
The permeability barrier of the oral mucosa is
primarily
attributable to intercellular materials derived
from the
so-called membrane-coating granules (MCGs),
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25which

Transport of substances
1.PASSIVE DIFFUSION,
the intracellular (or transcellular) pathway,and
the intercellular (or paracellular) pathway
2.CARRIER-MEDIATED ACTIVE TRANSPORT,
OR
3.ENDOCYTOSIS

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

 Nonenhanced drug delivery is based solely

on diffusion.
Hydrophilic,ionic drugs usually diffuse
through the intercellular space, while
hydrophobic are able to pass through
cellular membranes

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Resistance to penetration may be due

to
size,
lipophilia,
hydrogen bond potential,
charge, and conformation

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Areas of mucosal pathology, (erosive, ulcerated, or

hyperkeratosis lesions)
decline in mucosal barrier function
increase in the drugs ability to diffuse into the oral
mucosa
Higher permeability values of nitroso nornicotine in
leukoplakic sites and their surrounding areas than those
in normal oral mucosa

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Local oral drug delivery

Drug delivery via keratinized mucosa, and
Drug delivery via nonkeratinized mucosa
1. GINGIVAL AND HARD PALATAL MUCOSA,
not a valid site for the systemic administration
but only local (direct) drug delivery in treating
oral diseases localized to the site.

Minimal systemic uptake

low side effects and

drug interactions
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

2.SUBLINGUAL DRUG DELIVERY (which is

the systemic delivery of drugs across the
mucosa lining the floor of mouth) and
3.BUCCAL DRUG DELIVERY (mainly via the
buccal mucosa lining the cheeks, including
systemic and/or local delivery.
The sublingual mucosa is more permeable
and thinner than the buccal mucosa.
The sublingual route is generally used for the
systemic delivery of drugs in treating acute
disorders.
Buccal mucosa constitutes a preferred route
for the systemic
treatment
of Oral
chronic
(Oral Surg Oral
Med Oral Pathol
Radiol 2012;114:e25-

drawbacks
1.Rapid drug loss from the site of absorption by
salivary scavenging and mechanical stress;
2. The non-uniform distribution of drugs in
saliva on
release from delivery systems, which implies
that
certain areas of the oral cavity might not
receive
therapeutic levels of drugs;
3. Poor patient compliance because of an
unpleasant
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Enhancement of transmucosal agent transport

Permeation of drugs throughout epithelial
barriers could be promoted by penetration
enhancers utilizing different techniques,
usually subdivided into chemical or physical
methods.
increasing cell membrane fluidity,
extracting the structural intercellular and/or
intracellular lipids,
altering cellular proteins,
or altering the mucus structure
and
rheology
Senel,
S. and
Hincal, A.A. (2001) Drug permeation enhancement via buccal
route:

Chemical penetration
enhancers
Reducing the viscosity and/or elasticity of the
mucus layer, or by transiently altering the lipid
bilayer
membrane,
or
overcoming
the
enzymatic
barrier,
or
increasing
the
thermodynamic activity of the permeant.
CHELATORS
(e.g. sodium EDTA or salicylates),
SURFACTANTS (e.g. sodium dodecyl sulfate),
BILE SALTS
(e.g. sodium deoxycholate,
sodium glycocholate),
FATTY ACIDS (e.g. oleic acid, capric acid and
lauric acid) and
Nicolazzo, J.A. et al. (2005) Buccal
penetration
enhancers: how
do they
NONSURFACTANTS
(e.g.
ciclodextrins
and
really work? J. Control. Release 105, 115

Mechanical penetration
enhancers
By removing the outermost layers from
epithelium to decrease the barrier thickness, or
electrically,
for example, by application of electric fields or
by SONOPHORESIS.
SONOPHORESIS. :
Reducing, temporarily, the density of lipids in
the intercellular domain of the membrane.
a combination of micromechanical, thermic and
cavitation effects that effectively open up the
intracellular pathways, allowing substances to
Drug Discovery Today Volume 13, Numbers 5/6 March

Mucoadhesive dosage
forms

Conventional dosage : disad: physiological

removal mechanisms of the oral cavity (the
washing effect of saliva and mechanical stress)rapid decrease in concentrations to below
therapeutic levels.
Hence attached or adhesive dosage is
requiered.
ADVANTAGES
Intimate contact between the drug dosage form
and oral mucosa;
Extended retention time, without interfering
with physiological activities, such as eating,

Mucoadhesion
phenomenon

STEP 1 : Spreading, wetting, and dissolution

of mucoadhesive polymer at the interface.
STEP 2 : Mechanical or physical entanglement
between the polymer and the tissue surface
mucus layer, resulting in an interpenetration
layer.
STEP 3 :
Chemical interactions, such as
covalent and ionic bonds, hydrogen bonding,
and Van der Waals interactions.
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

 Hydrogen bonds and hydrophobic interactions

are the most desirable in developing
mucoadhesive systems, as strong primary
bonds (e.g., covalent bonds and ionic bonds)
could cause irreversible damage of the mucosal
surface.

To enhance the intrinsic mucoadhesive

properties of a polymer, new formulated buccal
dosage forms can be composed of several
different mucoadhesive polymers and novel
copolymers, rather than using single polymeric
systems
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Dosage forms
Dosage forms can be classified into the following
categories:
MONOLITHIC (or matrix) type,
The drug is uniformly dispersed or dissolved in
the polymer matrix and drug release is effected
by diffusion through the polymer network .
and
RESERVOIR (or membrane-controlled) type
A drug reservoir is entrapped between an
impermeable backing layer and a polymeric
membrane that controls the rate of drug
release. (Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

desirable attributes
high drug-loading capacity,
nonirritancy of the tissue,
good mucoadhesion,
sufficiently reduced dimension,
and physical flexibility to be acceptable (in
termsof comfort) to the patient,
tasteless, and
sustained drug delivery

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Mucoadhesive systems for oral local drug delivery

include
ADHESIVE TABLETS,
ADHESIVE PATCHES,
ADHESIVE FILMS OR PELLICLES,
ADHESIVE SEMISOLID SYSTEMS (gels,
ointments), and
ADHESIVE LIQUID SYSTEMS
(sprays,mouthwashes).

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

a) matrix-type delivery device: the most simple

kind of delivery systems where drug is
uniformly dispersed into the polymeric matrix;
b) dosage form with an impermeable backing
layer in order to provide the unidirectional
release of drugs;
c) dosage form characterized by two layers from
which drugs could be delivered at different
release rate (fast and controlled release) and
d) a typical mucoadhesive dosage form with an
impermeable backing layer and a polymeric
matrix where drug is dispersed or dissolved

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Adhesive tablets
Buccal tablets are small, flat, and oval with an
approximate diameter of 5 to 8 mm and
thickness of about 2 mm.
In the presence of saliva, they adhere to the
mucosal surface until dissolution and/or drug
release is complete.
Adhesive buccal tablets can be applied to
different sites in the oral cavity, including the
palate and the mucosa of the cheeks.
Mucoadhesive tablets containing chlorhexidine
were designed to swell and form a gel, adhering
to the
mucosa
and controlling
drug
release
Mizrahi
B, Domb
AJ. Mucoadhesive
polymers for the
delivery
of drugs
to the
oral
cavity.
Recent
Drug Deliv Formul 2008;2:108-19
into
the
oralPatcavity

To prevent drug loss from the top surface of the

dosage form, specialized tablets with 2 layers
a drug-loaded bioadhesive layer and
an impermeable backing layer to promote
unidirectional drug absorption and to minimize
drug leakage in the oral cavity
ADVANCES : Bioadhesive tablets, in which the drug
can be released only from the surface of the tablet in
contact with the buccal mucosa and the other other
surfaces are coated with water- impermeable
hydrophobic substances.

Bilayered adhesive tablets containing nystatin have

been designed to potentially treat oral candidiasis.
Llabot JM, Manzo RH, Allemandi DA. Double-layered mucoadhesive tablets
containing nystatin. AAPS PharmSciTech 2002;3:E22

DISADVANTAGE: used only for the treatment of

localized oral lesions-due to:
The lack of the physical flexibility of the
material applied to the mucosa
A high level of patient discomfort and poor
compliance, especially in cases of long-term
therapy and/or repeated use.
The tablets should not be moved once in
position because their separation from mucosal
surface causes more rapid drug release, and
possibility of swallowing the device causes
adhesion to the mucosal surface of the
esophagus
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Adhesive patches and

films
Bioadhesive patches and films are laminates,
consisting of
a POLYMERIC DRUG-LOADED layer,
an IMPERMEABLE BACKING layer, to
promote unidirectional drug release and,,
MUCOADHESIVE COMPONENTS with or
without release retardants and additives, such
as penetration enhancers or enzyme inhibitors

Ishida M, Machida Y, Nambu N, Nagai T. New mucosal dosage form of insulin.

advantages
high flexibility, thus facilitating a long
residence/retention time,(useful in the treatment
of mild or severe diffuse oral diseases)

a high level of patient compliance and

comfort.
provide a more accurate dosing of drug
delivery, compared with other dosage forms,
such as gels and sprays.
protect the underlying diseased tissues, thus
reducing pain and increasing treatment
effectiveness.
(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Adhesive semisolid
systems (gels,
ointments)

ADVANTAGE :

Easy dispersion throughout the oral mucosa.

Form an intimate contact with the mucosal
membrane and rapidly release drug at the
absorption site.

DISADVANTAGE:
The residence time of gels is small because
body fluids, such as saliva, will quickly wash
them away from the site of action.
Narrow therapeutic window.

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

APPLICATION:
periodontitis,
recurrent aphthous stomatitis,
traumatic ulcers,
radiation- or chemotherapy- induced oral
mucositis,
chronic immunologically mediated oral
lesions,
hyposalivation, and,
recently, for the healing of wounds

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

Adhesive liquid systems

(oral rinse and sprays)
It coat the entire oral mucosa, thereby
increasing the total surface area through which
drug molecules can be absorbed.
high mucoadhesion and viscoelasticity
Treatment of several oral diseases, such as
ORAL LICHEN PLANUS and other
immunologically mediated diseases, aphthous
stomatitis, oral mucositis, hyposalivation
and potentially malignant disorders, such as
leukoplakia
Sankar
V, Hearnden V, and
Hull K,erythroplakia.
Juras DV, Greenberg MS, Kerr AR, et al. Local
drug delivery for oral mucosal diseases: challenges and opportunities

 Ideal adhesive spray:

Able to produce sprays patterns of a suitable
ovality (the symmetric oval shape of spray
particles)and particle size.
HENCE, Greater will be the ability of the
particles to cover the whole mucosa

(Oral Surg Oral Med Oral Pathol Oral Radiol 2012;114:e25-

conclusion
The relative impermeability of the oral cavity,
other variables pertaining to the oral
environment (e.g., eating and the effects of
saliva), and acceptability by the patient must
be considered in developing new dosage
forms. The development of new formulations
for topical drug delivery within the oral cavity
is a research field that should be intensively
investigated, considering the high prevalence
of oral mucosal lesions and periodontal

Thank
you