MPH101T Unit 3

Gastro-Retentive Drug Delivery Systems and Buccal Drug Delivery Systems

Class
Contents Source
No.
Principles & Fundamentals Pharmaceutics 2019, 11, 193;
1. Anatomy of stomach,
doi:10.3390/pharmaceutics11040193

factors affecting gastric Int. J. Res. Pharm. Sci., 2(1), 2011, 76-83
2 residence, Advantages and
disadvantages

K.L. Mittal, I. S. Bakshi and J. K. Narang

Theories of Bioadhesion (eds.) Bioadhesives in Drug Delivery,
3
(220–223)

Factors Affecting K.L. Mittal, I. S. Bakshi and J. K. Narang

4. Bioadhesion/Mucoadhesion (eds.) Bioadhesives in Drug Delivery,
(223–227)
Factors Affecting K.L. Mittal, I. S. Bakshi and J. K. Narang
Bioadhesion/Mucoadhesion, (eds.) Bioadhesives in Drug Delivery,
(223–227)
5
Size-increasing drug delivery
systems Expert Opin. Drug Deliv. (2006) 3(2).
219-222
Density-controlled drug Expert Opin. Drug Deliv. (2006) 3(2).
6
delivery systems 222-228
Density-controlled drug Expert Opin. Drug Deliv. (2006) 3(2).
7 delivery systems 222-228

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 Introduction, Structure of K.L. Mittal, I. S. Bakshi and J. K. Narang
8 Buccal Mucosa (eds.) Bioadhesives in Drug Delivery,
(213–220)

K.L. Mittal, I. S. Bakshi and J. K. Narang

Stages of Mucoadhesion,
(eds.) Bioadhesives in Drug Delivery,
9 theories of Mucoadhesion
(220–223)

10 Factors Affecting K.L. Mittal, I. S. Bakshi and J. K. Narang

Bioadhesion/Mucoadhesion (eds.) Bioadhesives in Drug Delivery,
(223–227)
11 Mechanism of Buccal K.L. Mittal, I. S. Bakshi and J. K. Narang
Absorption, Buccal dosage (eds.) Bioadhesives in Drug Delivery,
forms (227–231)
12 Quality Control Tests of K.L. Mittal, I. S. Bakshi and J. K. Narang
Buccal Bioadhesive Dosage (eds.) Bioadhesives in Drug Delivery,
Forms (231–236)

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Principles & Fundamentals
Gastro retentive systems can remain in the gastric region for several hours and
hence significantly prolong the gastric residence time of drugs.
Prolonged gastric retention
• improves bioavailability
• reduces drug waste and
• improves solubility
• It has applications also for local drug delivery to the stomach and
proximal small intestines.
• Gastro retention helps to provide better availability of new products
with new therapeutic possibilities and substantial benefits for patients.

Factors controlling gastric Retention of dosage forms

There are many parameters related to stomach’s anatomy and physiology that
are needed to be considered in the development of gastroretention dosage
forms.
1. Density of dosage form
Dosage forms having a density lower than that of gastric fluid experience
floating behavior and hence gastric retention.
A density of <1.0 gm/ml is required to exhibit floating property.
However, the floating tendency of the dosage form usually decreases as a
function of time, as the dosage form gets immersed into the fluid, as a result of
the development of hydrodynamic equilibrium.

2. Shape and size of the dosage form

The mean gastric residence times of non-floating dosage forms are highly
variable and greatly dependent on their size, which may be large, medium and
small units.

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In most cases, the larger the dosage form the greater will be the gastric
retention time (GRT) due to the larger size of the dosage form would not allow
this to quickly pass through the pyloric antrum into the intestine.
Ring-shaped and tetrahedron-shaped devices have a better gastric residence
time as compared with other shapes.

3. Food intake and nature of food

Food intake, the nature of the food, caloric content, and frequency of feeding
have a profound effect on the gastric retention of dosage forms.
The presence or absence of food in the stomach influences the GRT of the
dosage form.
Usually, the presence of food increases the GRT of the dosage form and
increases drug absorption by allowing it to stay at the absorption site for a
longer time.

4. Effect of gender, posture and age

Generally, females have slower gastric emptying rates than male. The effect of
posture does not have any significant difference in the mean gastric retention
time (GRT) for individuals in upright, ambulatory and supine state. In case of
elderly persons, gastric emptying is slowed down.

Potential drug candidates

1. Drugs those are locally active in the stomach e.g. misroprostol, antacids etc.
2. Drugs that have narrow absorption window GIT e.g. L-DOPA, para
aminobenzoic acid, furosemide, riboflavin etc.
3. Drugs those are unstable in the intestinal or colonic environment e.g.
captopril, ranitidine HCl, metronidazole.
4. Drugs that disturb normal colonic microbes e.g. antibiotics against
Helicobacter pylori.

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5. Drugs that exhibit low solubility at high pH values e.g. diazepam,
chlordiazepoxide, verapamil HCl

Drugs those are unsuitable

1. Drugs that have very limited acid solubility e.g. phenytoin etc.
2. Drugs that suffer instability in the gastric environment e.g. erythromycin etc.
3. Drugs intended for selective release in the colon e.g. 5- amino salicylic acid
and corticosteroids etc.

Advantages
1. Enhanced bioavailability
The bioavailability of riboflavin GRDF is significantly enhanced in comparison to
the administration of non-GRDF polymeric formulations. There are several
different processes, related to absorption and transit of the drug in the
gastrointestinal tract, that act concomitantly to influence the magnitude of
drug absorption.

2. Sustained drug delivery/Reduced frequency of dosing

For drugs with relatively short biological half-life, sustained and slow input
from GRDF may result in improved pharmacokinetics and reduced dosing
frequency. This feature is associated with improved patient compliance and
thereby improves therapy.

3. Targeted therapy for local ailments in the upper GIT

The prolonged and sustained administration of the drug from GRDF to the
stomach may be advantageous for local therapy in the stomach and small
intestine. By this mode of administration, therapeutic drug be concentrations
may attain locally while systemic concentrations, following drug absorption
and distribution, are minimal.

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4. Reduced fluctuations of drug concentration
Continuous input of the drug following GRDF administration produces blood
drug concentrations within a narrower range compared to the immediate
release dosage forms. Thus, fluctuations in drug effects are minimized and
concentration dependent adverse effects that are associated with peak
concentrations can be prevented. This feature is of special importance for
drugs with a narrow therapeutic index.

5. Site specific drug delivery

A floating dosage form is a feasible approach especially for drugs which have
limited absorption sites in upper small intestine. The controlled, slow delivery
of drug to the stomach provides sufficient local therapeutic levels and limits
the systemic exposure to the drug. This reduces side effects that are caused by
the drug in the blood circulation.

7. Reduced counter-activity of the body

In many cases, the pharmacological response which intervenes with the
natural physiologic processes provokes a rebound activity of the body that
minimizes drug activity.
Slow input of the drug into the body was shown to minimize the counter
activity leading to higher drug efficiency.

8. Extended time over critical (effective) concentration

• For certain drugs that have non-concentration dependent
pharmacodynamics, such as Beta-lactam antibiotics,
• the clinical response is not associated with peak concentration, but rather
with the duration of time over a critical therapeutic concentration.

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9. Minimized adverse activity at the colon
• This pharmacodynamic aspect provides the rationale for GRDF
formulation for beta-lactam antibiotics that are
• absorbed only from the small intestine, and whose presence in the colon
leads to the development of microorganism’s resistance.

Disadvantages
1. Unsuitable for drugs with limited acid solubility. E.g. Phenytoin
2. Unsuitable for drugs that are unstable in acidic environment. E.g.
Erythromycin
3. Drugs that irritates or causes gastric lesions on slow release. E.g. Aspirin &
NSAID’s
4. Drugs that absorb selectively in colon. E.g. Corticosteroid
5. Drugs that absorb equally well through GIT. E.g. Isosorbide dinitrate,
Nifedipine
6. Floating drug delivery systems require high fluid level in stomach to float
and work effectively.

Approaches to increase gastric retention

1. Bioadhesive drug delivery systems
2. Size-increasing drug delivery systems
2.1 Systems unfolding in the stomach
2.2 Systems expanding due to swellable excipients
2.3 Systems expanding due to gas generation
3. Density-controlled drug delivery systems
3.1 High-density systems
3.2 Floating systems
4. Drug delivery systems combining different
concepts

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1. Bioadhesive drug delivery systems
Bioadhesion can be explained as the attachment of synthetic or natural
macromolecules to the mucus and/or epithelial surface for extended period of
time. The bond between two materials is governed by interfacial forces.
Bioadhesion is quite similar to the conventional adhesion process. The only
difference is that bioadhesion involves special characteristics of biological
organisms and surfaces.

Advantages
i. The bioadhesive drug delivery systems have been utilized to target disease
states at the mucosal surface.
ii. The use of bioadhesive drug delivery systems enables the extension of the
residence time at the site of drug absorption.
iii. More rapid commencement of action of the drug is realized owing to the
mucosal surface.
iv. The strong adhesion of the drug delivery system (DDS) with the absorptive
mucosa or biological site generates a steeper concentration gradient which
causes an enhanced drug absorption rate.
v. Some mucoadhesive polymers may modulate the absorptivity of epithelial
tissues by relaxing the tight intercellular junctions.
vi. Some mucoadhesive polymers act as inhibitors of proteolytic enzymes, thus
enhancing the stability of the active drug component.

Theories of Bioadhesion
Bonding involved in the process occurs chiefly through both physical and weak
chemical bonds. Physical or mechanical bonds result from entanglement of the
adhesive material and the extended mucus chains. In this regard, mutual
diffusion of the mucoadhesive polymer and mucin chains will result in the
maximum attachment. Chemical bonding may be classified as a primary or

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secondary type. Primary bonds are due to covalent bonding while secondary
bonds may be due to electrostatic, hydrophobic, or hydrogen bonds.
Electrostatic interactions and hydrogen bonding appear to be important as a
result of a large number of charged species e.g., hydroxyl (-OH), carboxyl (-
COOH) and amino (-NH2) groups present on the mucosal surface.
Hydrophobic bonding occurs when non-polar groups associate with each other
in an aqueous solution due to the tendency of water molecules to exclude non-
polar molecules.

Wetting Theory
It is one of the oldest and well-established theories of adhesion. This theory
best describes the adhesion of liquids or low viscosity bioadhesives to a
biological surface. The adhesion can be expressed in terms of surface and
interfacial tensions. When an interface is formed, there is a release of energy
per cm2 that can be defined as the work of adhesion. The wetting theory deals
with the contact angle and the thermodynamic work of adhesion.

Spreading of bioadhesive liquid over a typical soft tissue surface.

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Diffusion Theory
According to this theory, the polymer chains bind to the mucus and comingle
to a sufficient depth to create a semipermanent adhesive bond. There is a
close interaction of contact between the bioadhesive material and
glycoprotein (present in the mucus membrane). The polymer chains penetrate
the mucus; the exact depth to which these penetrate to achieve sufficient
bioadhesion depends on the diffusion coefficient, time of contact, and other
experimental variables.
The diffusion coefficient depends on molecular weight and decreases rapidly
as cross-link density increases. This suggests that the flexibility and chain
segment mobility of the bioadhesive polymer and mucus glycoprotein
molecules are important parameters to control inter-diffusion. During chain
interpenetration, a concentration gradient is established.
The bioadhesive polymer chain penetration depends on the diffusion
coefficient of the macromolecule and the chemical potential gradient. In the
case of cross-linked polymers, the interpenetration of large chains occurs with
great difficulty. The exact penetration depth needed for good bioadhesive
bonds is not clearly established, but it is estimated to be in the range of 0.2–
0.5 μm. The mean diffusional depth (s) of the bioadhesive polymer segments is
calculated by equation
𝒔 = √2tD
Where D is the diffusion coefficient and t is the contact time

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Interactions resulting from inter-diffusion of polymer chains of bioadhesive
system and mucus membrane.
(a) Polymer chains before diffusion, (b) contact between polymer chains and
mucin chains and (c) inter-diffusion of mucin chains and polymer chains.

Electronic Theory
According to this theory, transfer of electrons takes place when an adhesive
polymer comes in contact with a mucus glycoprotein network because of
differences in their electronic structures.
This leads to the formation of an electrical double layer at the interface.
Such a system behaves analogously to a capacitor, which is charged when two
surfaces come in contact, and discharged when they are separated.
This theory is also applicable since both the biological substrate and the
mucoadhesive material possess some electrical charges that are opposite to
each other.
Therefore, when these two materials come in contact, they transfer electrons,
which form the electrical double layer at their interface.
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The attractive force present within this newly formed electrical double layer
determines the mucoadhesive strength.

Adsorption Theory
According to this theory, after the initial contact of the two surfaces, the
materials will adhere because of the surface forces acting between the atoms
in the two surfaces.
According to this theory, after the initial contact of the two surfaces, the
mucoadhesive material will adsorb on the biological surface due to forces
acting between them.
In adsorption, the weak forces like van der Waals interaction play an important
role at the interface.
The chemical bonds include primary and secondary bonds. Primary chemical
bonds (covalent in nature) are undesirable in bioadhesion because of their high
strength that causes the formation of permanent bonds.
Secondary chemical bonds involve forces of attraction, including electrostatic
forces, van der Waals forces and hydrogen and hydrophobic bonds.

Fracture Theory
The fracture theory of adhesion is related to the separation of two surfaces
after adhesion. The fracture strength σ is directly proportional to adhesion
strength and is given by the following equation
σ = (Eε/L)1/2
Where E is Young’s modulus of elasticity, ε is the fracture energy, and L is the
critical crack length when two surfaces are separated.

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Regions that represent rupture of the mucoadhesive bond.

Stages of Mucoadhesion
For a better understanding of the broad concept of mucoadhesion, the process
of mucoadhesion can be differentiated into three stages:
• wetting,
• interpenetration, and
• interaction
of mucoadhesive with biological substrate.
The mucoadhesive must wet the substrate to develop an intimate contact
between the mating partners.

Factors Affecting Bioadhesion/Mucoadhesion

The factors that affect the bioadhesive/mucoadhesive
behavior of polymers are categorized as:
• polymer related factors,
• environmental factors

1. Polymer Related Factors

These can also be expressed as ‘intrinsic factors’. These refer to the structural
characteristics of the polymer that govern its fundamental properties. These
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comprise the molecular weight, cross-linking and the existence of functional
groups as well as the bioadhesive/mucoadhesive spatial conformation

1.1 Molecular Weight

High molecular weight improves the cohesiveness of the polymer and
enhances the viscosity it could generate. The interpenetration of polymer
molecules into the mucous surface varies. For polymers possessing low
molecular weight, Penetration is higher than for the polymers with high
molecular weight Entanglements are favoured in polymers with high molecular
weight. Extremely high molecular weight diminishes the flexibility of the
molecule and hence its diffusion. There is an optimal molecular weight for
each class of polymer that determines the likely bioadhesive strength. For
instance, poly(acrylic acid) has an optimal molecular weight of about 750,000,
while poly(ethylene oxide) has an optimum molecular weight close to
40,00,000.

1.2 Chain Length

An increase in the chain length of the polymer is expected to improve the
mucoadhesive characteristic of the polymer

1.3 Flexibility
If the polymer chains are flexible, then infiltration and entanglement of the
polymer chains with those of the mucosal layer are easy, thus improving the
bioadhesive characteristic. Cross-linking and hydration of the polymer affect its
elasticity. An extreme cross-linking lowers the plasticity of the polymer chains,
hence, the amount of cross-linking should be at an optimum Level.

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1.4 Cross-Linking
Cross-linking of a polymeric material, to a very large extent, dictates how
flexible it would become and the extent of its resistance to dissolution as
moisture penetrates it.
An elevation in the extent of cross-linking decreases the mobility of the
polymer as well as the actual chain length that can penetrate the mucus layer,
thus decreasing its mucoadhesive strength.

1.5 Presence of Functional Groups

For mucoadhesion to take place, the preferred polymers essentially should
possess functional groups that can form hydrogen bonds. The hydrophilic
functional groups accountable for developing hydrogen bonds are the hydroxyl
(-OH) and carboxyl (-COOH) groups. Therefore, the presence of a functional
group to form hydrogen bond affects the degree of adhesion obtainable.
The attachment of bioadhesive polymers to biological substrates implies
interpenetration. This is followed by the development of secondary non-
covalent bonding in the form of hydrogen bonds with the substrates

1.6 Concentration of Active Polymer

When the concentration of the polymer is low, the amount of penetrating
polymer chains per unit volume of the mucus is lesser and the interaction
between polymer and mucus is not very firm. A more concentrated polymer
leads to
• extended penetrating chain length and improved adhesion.
• increasing the number of functional groups accessible to form molecular
bonds and this enhances mucoadhesion.

2. Environmental Factors
Described as the external influences that affect the properties of the
bioadhesive polymers
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 • pH/charge,
• Saliva
• Salivary Gland
• Hydration,
• Mucin Turnover
• Rate of Renewal of Mucoadhesive Cells
• Disease State
• Buccal Membrane Properties

2.1 pH
pH has a significant effect on bioadhesive property of both the mucus layer as
well as the polymer. pH influences the charge on the surfaces of both mucus as
well as bioadhesive polymer. change in pH affects the ionization of functional
groups on the carbohydrate moiety and amino acid moiety of polypeptide
backbone of polymer resulting in the formation of ionized carboxyl groups.
Protonated carboxyl groups present in the polymer react with mucin molecule
rather than ionized carboxyl groups by forming numerous H-bonds. For
example, Polycarbophil shows the maximum adhesive strength at pH 3, the
adhesion strength of Polycarbophil decreases gradually as pH increases up to
5. It does not show any mucoadhesion above pH 5. At high pH polymer chains
are repelled by negatively charged mucin molecules due to ionization of
carboxyl group.

2.2 Saliva
Saliva forms 0.07-0.1 mm thick film on the membrane of buccal cavity.
The thickness and composition of this film will affect the process of
bioadhesion.

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2.3 Salivary Gland
Salivary gland present in the buccal cavity continuously secretes mucus which
forms a layer on buccal mucosa. This helps in bioadhesion but also affects the
absorption of drug into systemic circulation.

2.4 Hydration
Hydration is also essential for forming macromolecular mesh to increase the
mobility of polymer chain into mucin. During the process of bioadhesion,
hydration should be optimum for maximum bioadhesion. Overhydration
results in the formation of slippery mucilage with no adhesion.

2.5 Mucin Turnover

Mucin is a high molecular weight, heavily glycosylated protein produced by
epithelial tissue. Mucin is the principal component of mucus or saliva.
Turnover of mucin molecules from the mucus layer is important for
bioadhesion for at least two reasons. Firstly, it results in an early removal of
bioadhesive drug delivery system from the buccal cavity, no matter how
strongly it is attached. Secondly it results in substantial amounts of soluble
mucin molecules. These molecules interact with mucoadhesive before they
have chance to interact with mucus layer, thus causing decrease in
bioadhesion.

2.6 Rate of Renewal of Mucoadhesive Cells

It also affects the bioadhesion. Increase in the rate of renewal of
mucoadhesive cells decreases the bioadhesion.

2.7 Disease State

Various disease states like common cold, gastric ulcers, ulcerative colitis, cystic
fibrosis, bacterial and fungal infection all affect the physiochemical properties
of mucus.
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2.8 Buccal Membrane Properties
Degree of keratinization, surface area of buccal cavity, mucus layer,
intercellular lipids of epithelium, basement membrane all affect the absorption
of drug. Blood supply, lymph drainage, cell renewal and enzyme content will
also affect the rate of absorption of drug.

Bioadhesive Polymers for Drug Delivery Applications

Natural Polymers
chitosan, alginates, xanthan gum, tragacanth, acacia
Synthetic Polymers
Polyacrylates, hydroxypropyl methyl cellulose (HPMC), methyl cellulose, (MC),
hydroxypropyl cellulose (HPC), and carboxy methyl cellulose (CMC).

Bioadhesive formulations
Tablets
Coupling of mucoadhesive properties to tablet has additional advantages.
Mucoadhesive tablet can be tailored to adhere to any mucosal tissue found in
GIT, thus offering the possibilities of localized as well as systemic controlled
release of drug. Carbopol 934P and sodium carboxymethylcellulose, HPMC

Bioadhesive formulations
Micro and/or Nanoparticles
Have been widely investigated for three major features:
1. Immobilization of particles on the mucosal surface by adhesion after
modification of surface properties via bioadhesive polymers.
2. Very large specific surface between the dosage forms and the oral mucosa.
3. Sustained release of entrapped drug, leading to higher absorption
Stomach-specific drug delivery system for controlled release of clarithromycin
and Amoxicillin for eradication of H.Pylori.

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Size-increasing drug delivery systems
Another approach to retain a dosage form in the stomach is by increasing its
size above the diameter of the pylorus, even in the widest state during the
housekeeper wave. Approximately, the dosage form should be >13 mm;
however, even bigger units have been observed to be emptied from the
stomach. On the other hand, the systems should also guarantee their
clearance from the stomach after predetermined time intervals, in order to
avoid accumulation following multiple administrations.
Other characteristics of an optimal size-increasing drug delivery system
include: no effect on gastric motility and emptying pattern, no other local
adverse effects (e.g., on the gastrointestinal wall), and inexpensive industrial
manufacture.
In order to facilitate swallowing, it is highly desirable to design dosage forms
with an initially small size, which, once they are in the stomach, significantly
increase in size. The expanded state should be achieved fairly quickly, in order
to prevent premature emptying through the pylorus.

A. Systems unfolding in the stomach

Several geometric shapes, such as tetrahedron, ring, cloverleaf, disk, string and
pellet/sphere, which can be packed tightly into a gelatin capsule and unfold
after dissolution of the capsule shell. These systems consist of at least one
erodible polymer (e.g., hydroxypropyl cellulose), one nonerodible polymer
(e.g., polyolefins, polyamides, polyurethanes), and a drug that is dispersed
within the polymer matrix.
The importance of the physical characteristics of this type of systems, such as
size, shape and flexibility on the resulting gastric emptying was studied in
beagle dogs. Cloverleaf, disk, string and pellet shapes were moulded from
silastic elastomer. Tetrahedron and rigid-ring shapes were fabricated from
blends of low-density polyethylene and ethylene:vinyl acetate copolymer.
Furthermore, the devices contained barium sulfate in order to monitor their
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location by X-ray. These were folded, placed within gelatin capsules and
administered to dogs. Interestingly, the tetrahedron-shaped devices remained
in the stomach for longer periods of time than the other tested shapes (of
similar size). The gastric retention of rigid rings was significantly affected by
their size. Disk- and cloverleaf-shaped systems showed only poor gastric
retention. In addition, strings and pellets were eliminated fairly rapidly.
Erodible tetrahedron-shaped devices consisting of rods (‘arms’; made of
poly[ortho ester]/polyethylene blends) and ‘corners’ (based on silastic
elastomer; Figure) showed prolonged gastric residence times in beagle dogs

B. Systems expanding due to swellable excipients

The significant swelling of this type of drug delivery system is generally due to
the presence of specific hydrogel formers, which drastically increase in size
following contact with aqueous media.
A gastroretentive dosage form based on a bilayer tablet consisting of a
collagen sponge, which is compressed onto a drug containing polymer layer
with controlled-release properties, was developed by Cloer and Gröning.

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Following contact with aqueous fluids, the collagen sponge expanded to a
length of 5 cm, which was assumed to be sufficient to prevent direct emptying
through the pylorus.

C. Systems expanding due to gas generation

A drug-containing, carbon dioxide-generating, expandable system surrounded
by a hydrophilic membrane. To provide an adequate control of drug release, a
system containing drug-loaded pellets with extended-release surrounded by a
polymer membrane (which expands reversibly due to the generation of carbon
dioxide following contact with gastric fluid), Usually, gas generation and
entrapment does not only increase the size of the drug delivery system but
also decreases its density, and possibly provides floating properties, thus,
presenting a combination of two principles to prolong the gastric residence
time. However, the increase in size is the dominant mechanism of gastric
retention of the systems. Size-increasing systems potentially present the
hazard of permanent retention and could lead to serious life-threatening
effects after multiple dosing. Consequently, these systems should consist of
biodegradable materials or lose integrity after a desired time period. Until this
happens, the systems should be sufficiently resistible in order to withstand the
powerful waves from the stomach. An important shortcoming of size-
increasing systems is the risk to obstruct the pylorus. A major advantage is the
independence of their performance on the filling state of the stomach.

3. Density-controlled drug delivery systems

3.1 High-density systems
As pointed out above, the density of a drug delivery system is an important
factor influencing the gastric residence time. High-density devices use their
weight as a retention mechanism. When the density of the system is larger
than that of the gastric juice, the device settles down to the bottom of the

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stomach, remaining located below the pylorus. However, so far, no successful
approach has been described for a gastroretentive system being based only on
high density. In contrast, it has been reported that such devices did not
significantly extend the gastric residence time. Floating systems have the
ability to prolong the gastric residence time, favoring the prolonged release of
active agents that are absorbed in the stomach, or retarding the residence
time in the gastrointestinal time and allowing the prolonged release into the
upper intestinal portion.
The system floats on the gastric contents, the active agent is released at the
desired rate and, after drug release, the residual system is emptied from the
gastric site.

Mechanism of floating
The gastric retention time of systems is dependent on the density and size of
the dosage form.
Dosage forms having a density lower than that of gastric fluid experience
floating behavior and hence gastric retention.
A density of < 1.0 g/ml is required to exhibit a floating property.
However, the floating tendency of the dosage form usually decreases as a
function of time, as the dosage form gets immersed into the fluid as a result of
the development of hydrodynamic equilibrium
The size of the system is an important factor affecting gastric retention.
Floating systems remain buoyant on gastric fluids and are less likely to be
expelled from the stomach, compared with the non-floating systems, which lie
in the antrum region and are propelled by peristaltic waves.
The presence or absence of food in the stomach influences the gastric
retention time of the system. The presence of food increases the retention
time and increases the absorption of the active agent by allowing it to stay at
the absorption site for a longer time.

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 Classification
Based on the mechanism of buoyancy, floating systems have been developed
using two distinct technologies:
• effervescent systems and
• non-effervescent systems.
The technology of the effervescent systems includes use of gas-generating
agents, carbonates (e.g., sodium bicarbonate) and other organic acids (e.g.,
citric acid and tartaric acid) present in the formulation to produce carbon
dioxide (CO2) gas. Carbon dioxide generation reduces the density of the
system, making it float on the gastric fluid. An alternative is the incorporation
of a matrix containing a portion of liquid, which produces gas that evaporates
at body temperature. Therefore, effervescent systems can be further classified
into gas-generating and volatile liquid/vacuum systems.

Effervescent systems
Gas-generating systems are subdivided into:
(a) Intragastric single-layer floating tablets.
They are composed of CO2-generating agents and the active agent within the
matrix tablet.
The system receives water from the gastric fluid, swells, and displays bulk
density lower than gastric fluids. In consequence, the system floats in the
stomach, unflattering the gastric emptying rate for a prolonged period.
The active agent is released at a desired rate for a prolonged period and is
expelled from the stomach

Schematic representation of the operating mechanism of an intragastric floating tablet. 23

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 (b) Intragastric bilayer floating tablets.
They are compressed tablets containing an immediate release layer and a
sustained release layer, and the operating mechanism is similar to the anterior

Schematic representation of the operating mechanism of an intragastric bilayer floating tablet.

(c) Multiple unit-type floating pills.

These systems are sustained release pills surrounded by double layers.
The inner layer consists of effervescent agents, while the outer layer is a
swellable membrane. The water from the gastric fluid swells the pills like
balloons, which float because they acquire low density. Carbon dioxide is
generated within the system

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Non-effervescent systems
Non-effervescent systems are normally composed of highly swellable cellulose-
type hydrocolloids, polysaccharides and matrix-forming material (e.g.,
polycarbonate, polyacrylate, polymethacrylate and polystyrene, as well as
bioadhesive polymer such as chitosan and Carbopol). Swelling is an important
strategy in this case. A colloidal gel barrier is a strategy to prepare non-
effervescent floating systems with gel-forming hydrocolloids. This type of
system possesses a high level of one or more gel-forming highly soluble

cellulose-type hydrocolloids as hydroxypropyl cellulose, HEC, hydroxypropyl

methyl cellulose, polysaccharides and matrix-forming polymers such as
polycarbophil, polyacrylate and polystyrene. The water from the gastric fluid
hydrates the hydrocolloids, and a colloidal gel barrier around its surface is
formed.
Hydrodynamically balanced system (HBS):
HBSs: These are single-unit dosage forms, containing one or more gel-forming
hydrophilic polymers. Hydroxypropyl methyl cellulose is the most common
used excipient, although HEC, hydroxypropyl cellulose, sodium carboxymethyl
cellulose, agar, carrageenans, or alginic acid are also used. The polymer is
mixed with the active agent and usually administered in a gelatin capsule. The
capsule rapidly dissolves in the gastric fluid, and hydration and swelling of the
surface polymers produces a floating mass. The release of the active agent is
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controlled by the formation of a hydrated boundary at the surface. Continuous
erosion of the surface allows water penetration to the inner layers,
maintaining surface hydration and buoyancy

Hydrodynamically balanced system (HBS): The gelatinous polymer barrier formation

results from hydrophilic polymer swelling; the active agent is released by diffusion and
erosion of the gel barrier.

Buccal Drug Delivery Systems

Dosage forms are administrated by different routes but the oral route has
been the most preferable route for drug delivery. The drugs undergoing first-
pass metabolism and degradation in GIT environment have stimulated the
discovery of other routes. Similarly researches are facing problems for delivery
of proteins, peptides and biotechnological products by other than parenteral
route.
Drugs having GI intolerance, unpredictable and erratic absorption, and low
bioavailability are promising candidates for buccal drug delivery.

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Following drugs have been tried by this route.
Piroxicam
Propranolol HCl
Terbutaline sulfate
Losartan potassium

Advantages of a Buccal Bioadhesive System

1. Drugs which are degraded in GIT can be given by this system.
2. Easy administration of dosage forms.
3. Prevents drugs from first-pass metabolism.
4. Increase’s bioavailability of drug.
5. Increased drug absorption due to enhanced blood supply.
6. Rapid onset of action.
7. Drugs like protein, peptides can be given by this route.
8. Improves patient compliance.
9. Easy removal of formulation if treatment is required to be
discontinued.
10. Drugs can be used for local as well as for systemic effects.
11. Drugs can be given to unconscious and trauma patients.
12. Drugs which show GI intolerance can be given by this route.
13. Drugs can be prevented from enzymatic degradation.

Disadvantages of a Buccal Bioadhesive System

1. Drugs which are unstable at buccal pH cannot be administered
2. Drugs with unpleasant or bitter taste cannot be administered
3. Drugs which irritate mucus membrane cannot be given
4. Large dose cannot be given by this route
5. Drugs having ulcergenic effect cannot be given
6. Poor patient acceptability
7. Continuous secretion of saliva leads to dilution of drug
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8. Swallowing of saliva leads to involuntary removal of dosage form. It may also
lead to chewing of dosage form
9. Inconvenience in eating and drinking
10. Drugs causing discoloration of teeth cannot be given

Ideal Characteristics of a Bioadhesive Dosage Form

It should adhere to the site of attachment for a required time.
2. Should not cause irritation or inconvenience to patient.
3. Should not interfere with regular functions such as drinking and talking.
4. Should release the drug in way for which it is meant to be (release the drug
in buccal mucosal membrane or saliva or in both).

Quality Control Tests of Buccal Bioadhesive Dosage Forms

1. Moisture Absorption Test
2. Swelling and Erosion Tests
3. Tensile Strength and Elongation at Break
4. Surface pH
5. In-Vitro Bioadhesive Strength Measurement Test
6. Residence Time
7. Ex-Vivo Residence Time
8. In-Vivo Residence Time
9. Permeation Test
10.Absorption Test

1. Moisture Absorption Test

The absorption test is carried out to determine the moisture capacity of
patches and their integrity after absorption of moisture. The moisture
absorption test is carried out in agar petri plates made by dissolving 5% agar in
distilled water. For the test, six patches are selected from each batch and these
patches are kept in desiccators overnight to get rid of moisture. Each patch is
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then weighed and laminated on one side with a water impermeable backing
membrane. Patches are placed on the surface of agar plate and incubated for
2h at 37°C. The patches are weighed again.
% Moisture absorbed is calculated using the formula
%Moisture absorbed =
Final weight − Initial weight/Initial weight × 100

2. Swelling and Erosion Tests

For these tests, tablets are attached to a pre-weighed glass support with the
help of an adhesive. The support with tablets is immersed in phosphate buffer
of pH 6.6 at 37°C. At fixed time intervals tablets are removed, blotted with a
tissue paper to remove excess water and weighed.
Tablets are again weighed after drying at 40°C until constant weight.
Swelling index(%) = Ws-Wd/Wd
Erosion (% mass loss) =
Original weight dry- weight/Original weight × 100
Ws = weight of swollen tablet
Wd = weight of dry tablet

3. Tensile Strength and Elongation at Break

Tensile strength is measured by holding film strips of 60 × 10 mm between two
clamps positioned at a distance of 3 cm. A cardboard is attached to the clamp
surface to prevent cutting of film by grooves of clamp. During test, films are
pulled by the top clamp at a rate of 2.0mm/s to a distance until it breaks.
The force and elongation of the film are measured. The test is carried in six
replicates for each batch.
Tensile strength and elongation at break are determined by the following
formulas:
Tensile strength (kg.mm-2 ) =
Force at break (kg)/ Initial cross-sectional area of the sample (mm2)
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Elongation at break (%mm-2 ) =
Increase in the length (mm) X 100
original length Cross-sectional area (mm2)

4. Surface pH
The bioadhesive buccal tablets are covered with 1ml of distilled water and
allowed to swell for 1-2 h at room temperature.
The surface pH is measured by bringing the electrode to the surface of tablets
and allowing it to equilibrate for 1 min

5. In-Vitro Bioadhesive Strength Measurement Test

For this type of study, porcine buccal membrane is used as a model tissue
under simulated buccal conditions. The calculation is done by plotting data
using software package of the instrument. The area under the curve gives the
work of adhesion and peak of the curve gives force of detachment.
Modified Wilhelmy plate method
In this method, as shown in Figure, the apparatus consists of a modified
physical balance in which right pan has been replaced by a glass plate with
copper wires, to make the right side weight equal to left side pan.
A steel base is kept in a beaker filled with Krebs solution which is then placed
below the right side of the balance. Porcine buccal membrane is used as a
model tissue. It is attached over the steel base. One side of the tablet is
attached to the glass slide of the right arm of the balance and then beaker is
slowly raised to make contact between mucoadhesive tablet and buccal
membrane. A preload of 10 mg is placed on the glass slide for 5 min to
establish the desired adhesion bond between mucoadhesive tablet and buccal
membrane. After 5 min, the preload is removed and water is then added in the
left side of pan at a constant rate. The addition of water is stopped when
mucoadhesive tablet is detached from the buccal membrane. The weight of

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water required to detach mucoadhesive tablet is noted as bioadhesive
strength in grams. Buccal tablets are small, flat, oval in shape.
These are immobilized drug delivery systems. These can be formulated either
by wet granulation or by direct compression technique.
These dosage forms stick to the mucous membrane of buccal cavity after
wetting by saliva.

Modified Wilhelmy Plate Apparatus

6. Ex-Vivo Residence Time

Ex-vivo residence time is determined using the modified USP (United States
Pharmacopeia) disintegration apparatus. The fresh buccal membrane of sheep
or rabbit is tied to the surface of the glass tube, vertically attached to the
apparatus. The 800ml of phosphate buffer of pH 6.6 at 37°C is used for the
test. The tablet is attached to the membrane and the time taken for complete
detachment of tablet or erosion of tablet is recorded and considered as the ex-
vivo or in-vitro residence time.

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7. In-Vivo Residence Time
In-vivo residence time can be determined using 6-8 healthy male adult
volunteers aged between 22-28 years. The volunteers were asked to record
time of dislodging of patch by sensing it in their buccal cavity. This
measurement gives the in-vivo residence time.

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