The brief discription of mucoadhesive drug delivery system. the mechanism of mucoadhesion &theories of mucoadhesion as per PCI Syllabus.

1. Mucosal Drug
Delivery
System
Akshata A .Jain
M-pharm
(Pharmaceutics)

2. Introduction, principles of Bioadhesion/
Mucoadhesion:
The concept of mucoadhesion was introduced
in the field of controlled release drug delivery
systems in the early 1980s.
The term bioadhesion implies attachment of a
drug carrier system to a specific biological
location.
The biological surface can be epithelial tissue,
or the mucous coat on the surface of a tissue.

3.  If adhesive attachment is to a mucus coat, the
phenomenon is referred to as mucoadhesion.
 Mucoadhesion keeps the delivery system
adhering to the mucus membrane.
 The mucosal layer contain the GI tract, the
urogenital tract, the ear, nose & eye.
 Mucoadhesive formulations use polymers as
the adhesive component.

5.  These polymers are often water soluble.
 When used in dry form, they attract water from
mucosal surface & this water transfer leads to a strong
interaction further increasing the retension time over
mucosal surface & leads to adhesive interactions.
 Mucoadhesive drug delivery systems may be defined
as “Drug delivery system which utilize property of
bioadhesion of certain water-soluble polymers which
becomes adhesive on hydration & hence used for
targeting a drug to a particular region of body for
extended period of time.”

6. Mechanism of Bioadhesion
 It is classified into 2-categories
1. Chemical (electronic & adsorption theories)
2. Physical (wetting, diffusion & cohesive theory) methods
 these reaction are further classified as hydrogen bonds, Van der
waals force & hydrophobic bonds which are considered as
physical interactions.
 While formation of ionic & covalent bonds are categorized as
chemical interactions.
 Ionic bonds are formed due to electrostatic interactions amongst
the polymers while covalent formed due to sharing of electrons
amongst them.

7. The mechanism of mucoadhesion is generally divided in 2-
steps
1. The contact stage
2. The consolidation stage
 The first stage is characterized by the contact between the
mucoadhesive & mucus membrane, with spreading & swelling
of the formulation, initiating its deep contact with mucus layer.
 In step second the mucoadhesive material are activated by the
presence of moisture.

9.  In consolidation step, the mucoadhesive materials
are activated by the presesnce of moisture.
 There are 2-theories consolidation
a) The diffusion theory:
 The mucoadhesive molecules & glycoproteins of the mucus mutually
interact by means of interpenetration of their chains & the building of
secondary bonds.
b) The dehydration theory :
 Materials that are able to readily dissolved in aqueous environment,
when placed in contact with the mucus can cause its dehydration due
to the difference of osmotic pressure.
 The difference in conc. Gradient draws water into the formulation until
the osmotic balance is reached.

10.  Therefore, it is the water motion that leads to the consolidation of the
adhesive bond, & not the interpretation of macromolecular chains.
 Dehydration theory is not applicable for solid formulations or highly
hydrated forms.

11. Mucoadhesion theories:
Mucoadhesion
Electronic
Adsorption
Wetting
Diffusion
Mechanical
Cohesive

12. 1. Electronic theory:
 Based on both mucoadhesive &
biological materials possess
opposing electrical charges.
 When both materials come into
contact, they transfer electrons
leading to the building of a double
electronic layer at the interface
 Where the attractive forces within
this electronic layer determines the
mucoadhesive strength.

13. 2. Adsorption theory:
 According to this theory, the
mucoadhesive device adheres to the
mucus by secondary chemical
interactions.
 Such as in van der Waals and hydrogen
bonds, electrostatic attraction or
hydrophobic interactions.
 For example, hydrogen bonds are the prevalent interfacial forces in polymers
containing carboxyl groups. Such forces have been considered the most
important in the adhesive interaction phenomenon because, although they are
individually weak, a great number of interactions can result in an intense global
adhesion.

14. 3. 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.

15. 4. Diffusion theory:
 Diffusion theory describes the interpenetration of both polymer and
mucin chains to a sufficient depth to create a semi-permanent adhesive
bond.
 It is believed that the adhesion force increases with the degree of
penetration of the polymer chains.
 This penetration rate depends on the diffusion coefficient, flexibility and
nature of the mucoadhesive chains, mobility and contact time.
 In order for diffusion to occur, it is important that the components
involved have good mutual solubility, that is, both the bioadhesive and
the mucus have similar chemical structures.
 The greater the structural similarity, the better the mucoadhesive bond.

17. 5. The Cohesive Theory:
 It proposes that the phenomena of bioadhesion are mainly due to
the intermolecular interactions amongst like-molecules.
6. Mechanical Theory:
 Mechanical theory considers adhesion to be due to the filling of
the irregularities on a rough surface by a mucoadhesive liquid.
Moreover, such roughness increases the interfacial area available
to interactions thereby aiding dissipating energy and can be
considered the most important phenomenon of the process.

18. Mucoadhesion
theories
Chemical
Electronic Adsorption
Physical
Wetting Diffusion Cohesive

19. Advantages
High drug flux at the absorbing tissue.
Targeting & localization of the dosage form at a specific
site.
Prolongation of residence of drug in GIT.
MDDS will serve both the purposes of sustain release &
presence of dosage form at the site of absorption.
Excellent accessibility.
Low enzymatic activity & avoid of first pass metabolism.
Painless administration.

20. Disadvantages
costly drug delivery system.
If MDDS are adhere too tightly because it is undesirable to exert
too much force to remove the formulation after use, otherwise the
mucosa could be injured.
Some patient suffers unpleasent feeling.
Medications administered orally do not enter the blood stream
immediately after passage through the buccal mucosa.

21. Transmucosal permeability:
 Need for drug delivery for controlled release,for targeted & localized
drug delivery, for first pass metabolism, for avoidance of drug
degradation etc.
 It refers to the transport of material such as drugs across the oral
mucosa.
 An ideal dosage form is one which attains the desired therapeutic
conc. of drug in plasma & maintains a constant for the entire
duration of treatment.
 Several mucosal routes have been investigated over the last decades
as alternatives to oral & parenteral includes buccal, nasal, rectal,
occular, pulmonary & vaginal.

23. Buccal drug delivery system:
 Amongst the various routes of drug delivery,
oral route is perhaps the most preferred by the
patients.
 Within the oral mucosal cavity, the buccal
region offers an attractive route of
administration for systemic drug delivery.
 The mucosa has rich blood supply and it is
relatively permeable.
Considering the low patient compliance of rectal, vaginal, sublingual and nasal
drug delivery for controlled release, the buccal route of drug delivery is a good
alternative.
Drug delivery via the membranes of the oral cavity can be subdivided as
following:

24.  Sublingual delivery: Which is the administration of
drug via the sublingual mucosa to the systemic
circulation.
 Buccal delivery: Which is the administration of the
drug via the buccal mucosa to the systemic
circulation.
• Local delivery: For the treatment of conditions of the oral cavity, principally
aphthous ulcers, fungal conditions and periodontal disease.
• These oral mucosal sites differ greatly from one another in terms of
anatomy, permeability to an applied drug, and their ability to retain a delivery
system for a desired length of time.

25. Advantages of Buccal Delivery :
Ease of administration.
Termination of therapy is easy.
Permits localization of drug to the oral cavity for
a prolonged period of time.
can be administered to unconscious patients.
Offers an excellent route, for the systemic
delivery of drugs with high first pass metabolism,
thereby
Offering a greater bioavailability.
A significant reduction in dose can be achieved
thereby reducing dose related side effects

26. Disadvantages of Buccal Delivery
Relatively smaller area of adsorption.
The thickness of delivery system should be limited to a few
millimetres in order to avoid inconveniences for patient.
Part of the drug may be dissolved in the saliva and
swallowed.
Drug which irritate oral mucosa or bitter taste, or causes
allergic reactions, discoloration of teeth cannot be
formulated.
If formulation contains antimicrobial agents, that affects the
natural microbial flora of the mouth/ buccal cavity.
The patient cannot eat, drink or speak.
Drugs which are unstable at buccal pH cannot be
administered by this route.

27. CLASSIFICATION OF ORAL MUCOSAL DDS
 The various classification of the oral mucosal DDS is explained
below:
(a) Classification Based on Physiological Considerations:
Oral mucosal drug delivery is conveniently subdivided into:
 Sublingual delivery: Which is the administration of drug via the
sublingual mucosa to the systemic circulation.
 Buccal delivery: Which is the administration of the drug via the
buccal mucosa to the systemic circulation.

28.  Gingival delivery: Which is restricted to the
administration through the mucosa of the gingivae.
(b) Classification Based on the Mobility of the Oral
Mucosal DDS:
Typically, two types of systems can be described:
 Non-attached or mobile drug delivery system: That
would be physically maintained within the oral cavity in
contact with the mucosal surface by a conscious effort of
the patient.
 Attached or immobilized drug delivery system: That can
be retained on the mucosal surface.

29.  Buccal mucoadhesive dosage forms can be categorized into three types
based on their geometry:
Type I: It is a single layer device with multidirectional drug release. This
type of dosage form suffers from significant drug loss due to swallowing.
Type II: It is a device in which an impermeable backing layer is
superimposed on top of the drug loaded bioadhesive layer, creating a
double-layered device and preventing drug loss from the top surface
into the oral cavity.
Type III: It is unidirectional drug release device, from which drug loss is
minimal since the drug is released only from the side adjacent to the
buccal mucosa. This can be achieved by coating every face of the dosage
form, except the one that is in contact with the buccal mucosa.

31. DOSAGE FORMS
1.Buccal tablets
Bioadhesive tablets may be prepared using
different methods such as direct compression or wet
granulation technique.
 For delivery of drug via buccal route, the tablets
which are inserted into the buccal pouch may dissolve
or erode; therefore, they must be formulated and
compressed with sufficient pressure only to give a
hard tablet.
Bilayered and multilayered tablets are already
formulated using bioadhesive polymers and
excipients.
If necessary, the drug may be formulated in certain
physical states, such as microspheres, prior to direct
compression in order to attain some desired
properties.

32.  Disadvantages of buccal tablets may be patient acceptability
(mouth feel, taste and irritation) and the non-ubiquitous distribution
of drug within saliva for local therapy.
2. Buccal Semisolid Dosage Forms:
 These are semisolid dosage forms having the advantage of easy
dispersion throughout the oral mucosa over the other type of
dosage forms.
 Bioadhesive formulations have been used to overcome the poor
retention of gels on the buccal mucosa.
 Buccal bioadhesive semisolid dosage forms consist of finely
powdered natural or synthetic polymer dispersed in a polyethylene
or in aqueous solution like Arabase.

33. 3. Buccal Films:
 Buccal films are preferable over mucoadhesive discs and tablets
in terms of patient comfort and flexibility and they ensure more
precise drug dosing and longer residence time compared to gels
and ointments and thereby sustaining drug action.
 Buccal films also reduce pain by protecting wound surface and
increasing drug effectiveness.
4. Buccal Powders:
 Buccal bioadhesive powders are a mixture of drug and
bioadhesive polymers.
 Which are sprayed onto the buccal mucosa, the reduction in
diastolic B.P. after the adminitration buccal tablet and buccal
film of nifedipine.

35. 5. Micro Particle:
 Micro particles have more advantages than tablet.
 The physical properties of microspheres enable to make them
closely contact with a large mucosal surface.
6. Wafer:
 Wafer is a novel periodontal drug delivery system. This is used for
the treatment of microbial infection.

36. 7.Lozenges
 A slow release bioadhesive lozenge offers the potential for prolonged
drug release with improved patient compliance.
 Lozenges are used as topically within mouth including antimicrobials,
corticosteroids, local anaesthetics, antibiotics and antifungals.
 In lozenges multiple daily dosing is required because the release of
drug in oral cavity is initially high and then rapidly decline to the
subtherapeutic levels.
 The limitation of these bioadhesive lozenges is the short residence time
at the site of absorption which depends to the size and type of
formulation and since dissolve within 30 min, the total amount of the
drug that can be delivered is limited.

37. 8. Buccal Patches:
 These are flexibles which deliver the drugs straight in to systemic
circulation over mucus membrane thus by passing the first pass effect.
 Buccal patch formulations are placed in the mouth between the upper
gingivae (gums) and cheek to treat local and systemic conditions.
 Interaction with digestive food of gastrointestinal tract is avoided which
might be inappropriate for stability of many drugs.
 This is easy, painless and without discomfort, precise dosage form and
facilitates ease of removal without significant related pain.
 Moreover, it shows better constancy, patient compliance; uniform and
sustained drug release and above all easy and cheap methods of
preparation which can be done with various commonly available
biocompatible polymers.

38. Methods Of Preparation
1. Solvent casting:
Water soluble ingredients dissolved in water+ API in suitable
solvent
Mixing of both solutions
Resulting solution is cast as a film & allowed to dry
Film is coated

39. 2. Direct milling:
API & excipients are blended by direct milling
Blended mixture is rolled with the help of roller
Followed by material is laminated
Finally film is coated

40. 3. Hot melt extrusion of films:

41. Evaluation of buccal delivery systems:
1. Moisture absorption studies of buccal patches:
5% agar in distilled water
Transfer into petri dish & allowed to solidify
Six buccal patches are selected & weighed
Buccal patches were placed in dessicator overnight to remove moisture
Laminated one side with water impermeable backing membrane

42. Placed on surface of agar plate & incubated at 37ºC for 2 hrs
The patches were weighed again
% moisture absorption can be calculated by using the formula
100
*
%
ght
initialwei
ght
initialwei
t
finalweigh
sorbed
moistureab



43. 2. Swelling & Erosion studies for buccal tablets:
 Determined in phosphate buffer pH 6.6
Tablets were attached to preweighed glass supports using a
cynoacrylate adhesive sealant
The supports with tablets were immersed into the phosphate
buffer at 37ºC
At predetermined time intervals, the devices were removed from
the media

44. Blotted with tissue paper to remove excess water & weighed
After determination of wet weight
The tablets were dried at 40ºC until constant mass

46. 3.Study of the surface pH:
The bioadhesive buccal tablets were covered with 1ml of distilled water
Allowed to swell for 1-2 hrs at room temp.
The surface pH of the tablets or patches were measured by bringing pH
meter electrode in contact with the surface of the patch
Allowing it to equilibrate for 1 min

47. 4. Determination of the residence time:
 Ex vivo residence time was determined using a
modified USP disintegration apparatus.
 In this method, the disintegration medium composed
of 800 ml phosphate buffer of pH 6.6 maintained at 37
°C is passed through the porcine buccal tissue which
was tied to the surface of a glass slab, vertically
attached to an apparatus.
 Tablet formulation is attached to the surface of the
buccal tissue.
 The time which was taken for complete erosion or
detachment of the tablet from the mucosal surface
was recorded and considered as ex vivo residence

48. 5. Methods determining tensile strength:
 Tensile strength (the resistance of a material to breaking under tension) and
 shear strength (shear strength is the strength of a material or component against the
structural failure)
 measure the mechanical properties of the system, whereas peel strength measures the
peeling force.
 Texture profile analyzer is a commercial instrument which is used to measure the force
required to remove bioadhesive films from excised tissue in vitro.
 For this test, a piece of animal mucous membrane was taken and tested for the force
required to take away the formulation from a model membrane which consists of disc
composed of mucin.

49. Determination of tensile strength

50. 6. Peel Strength:
On a movable platform the animal skin was placed and on top of
it the bioadhesive film was placed, which was later on pulled
vertically to determine the peel strength.

51. 7. Methods determining shear stress:
 The measurement of the shear stress gives a direct correlation to the
adhesion strength.
 In a simple shear stress measurement-based method two smooth,
polished plexi glass boxes are selected;
one block is fixed with adhesive on a
glass plate, which is fixed on leveled table.
To the upper block, a thread is tied and
the thread is passed down through a
pulley, the length of the thread from the
pulley to the pan was 12 cm.
 At the end of the thread a pan of fixed
is attached.
 More weights can be added to it.

52. 8.Determination of Force of Adhesion and Bond
Strength:
 Mucoadhesive strength of the dosage form can be measured on the
modified physical balance.
 The apparatus consists of a modified double beam physical balance in
which the right pan is replaced by a glass slide with copper wire and
additional weight, to make the right-side weight equal with left side
pan.
 A Teflon® block of fixed diameter and height is fabricated with an
upward portion of 2 cm height and 1.5 cm diameter on one side.
 This is kept in beaker filled with buffer media 0.1 N HCl (pH 1.2),
which is then placed below right side of the balance. Goat or rat
stomach mucosa can be used as a model membrane and buffer media
0.1 N HCl (pH 1.2) can be used as moistening fluid.

53.  The one side of the dosage form is attached to
the glass slide of the right arm of the balance
and then the beaker is raised slowly until
contact between goat mucosa and
mucoadhesive dosage form established.
 A preload of 10 gm is placed on the slide for 5
min. (preload time) to establish adhesion
bonding between mucoadhesive dosage form
and goat or rat stomach mucosa.
 After the completion of preload time, preload
is removed from the glass slide and water is
then added in the plastic bottle in left side arm
by peristaltic pump at a constant rate of 100
drops per min.
 The addition of water is stopped when
mucoadhesive dosage form is detached from
the goat or rat stomach mucosa. The weight of
water required to detach mucoadhesive
dosage form from stomach mucosa is noted as
mucoadhesive strength in gram.

54. 9. Tests measuring mucoadhesive strength:
 In this test, the force required to remove the
formulation from a model membrane is measured,
which can be a disc composed of mucin, a piece of
animal mucous membrane, generally porcine nasal
mucus or intestinal mucus from rats.
 This test measures the force required to separate two
parallel glass slides covered with the polymer and with
a mucus film.
 This can also be done using Wilhemy's model in which a
glass plate is suspended by a microforce balance and
immersed in a sample of mucus under controlled
temperature.
 The force required to pull the plate out of the sample is
then measured under constant experimental
conditions.

55. 10. Falling Liquid Film Method:
 In this method, the chosen 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 37°C.
 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

56. 11. In vivo Methods:
 Using this method, the kinetics of drug absorption can be
measured.
 The methodology involves the swirling of a 25 ml sample
of the test solution for up to 15 minutes by human
volunteers followed by the expulsion of the solution.
 The amount of drug remaining in the expelled volume is
then determined in order to assess the amount of drug
absorbed.

57. Thank you