Mucosal, Implantable, Transdermal, Gastroretentive DDS.pdf

Delivery system in mouth, skin, stomach

1. NDDS II
2.2.
Mucosal Drug Delivery system: Introduction, Principles of bioadhesion / mucoadhesion, concepts, advantages
and disadvantages, transmucosal permeability andformulation considerations of buccal delivery systems

2.2. Mucosal Drug Delivery system

Recent years, the drug delivery via mucosal drug delivery system has become
highly popular.

Certain drugs have lack of efficacy due to decreased bioavailability,
gastrointestinal intolerance, unpredictable and erratic absorption or pre-systemic
elimination of other potential route for administration.

Various routes for mucosal drug delivery include oral, buccal, ocular, nasal and
pulmonary routes, etc.
Typically, mucosal drug delivery systems can be classified as:
1.
Non-attached mucosal drug delivery systems:
These systems are being formulated to be absorbed through the mucosa within the
oral cavity. Examples: Sublingual tablets, Fast dissolving tablets (Melt-in-mouth or
orally disintegrating tablets), etc.
2.
Attached or immobilized mucosal drug delivery systems:
These systems are being formulated to be remained attached onto the mucosal
surface by the adhesive properties. These systems are also known as
mucoadhesive systems. Examples: Buccal drug delivery systems, rectal drug
delivery systems, vaginal drug delivery, nasal drug delivery systems systems, etc.
Different strategies have been adopted for controlled mucosal delivery are based on:
1.
Prolonging solely the duration of absorption process.
2.
Developing unidirectional delivery systems
3.
Preparing user-friendly mucosal delivery systems.
Bioadhesion:

The term ‘bioadhesive’ describes materials that bind or adhere to the biological
substrates.

‘Bioadhesive’ can be defined as a material that is capable of interacting with
biological material and being retained on them or holding them together for
extended period of time.

‘Bioadhesion’ may occur via 3 ways:
i).
Bioadhesion in-between biological layers without the involvement of artificial
materials.
ii).
Cell adhesion into the culture dishes or adhesion to a variety of substances,
such as woods, metals, and other synthetic substances.
iii).
Adhesion of artificial substances to the biological substrates like the adhesion
of hydrophilic polymers to skin or other soft tissues.
Mucoadhesive drug delivery systems:

Mucoadhesive drug delivery systems utilizes the property of
mucoadhesion/bioadhesion of certain polymers, which become adhesive on
hydration and hence, can be used for targeting a drug to the particular region of
the body for extended period of time.

The ability to maintain a delivery system at a particular location for an extended
period of time has great appeal for both local as well as systemic drug
bioavailability.

2. 
Mucoadhesive drug delivery systems facilitate the possibility of avoiding either
destruction by gastrointestinal contents or hepatic first-pass inactivation of drug.

Various mucoadhesive polymers are being used to formulate mucoadhesive drug
delivery systems. These can be broadly categorized as:
(I) Synthetic polymers:
a.
Cellulose derivatives: Methylcellulose (MC), Hydroxy ethylcellulose (HEC), Hydroxyl
propylcellulose (HPC), Hydroxy propyl methylcellulose (HPMC), Sodium carboxy
methylcellulose (NaCMC), etc.
b.
Poly (Acrylic acid) polymers: Carbomers, Polycarbophil.
c.
Poly vinyl alcohol (PVA).
(II) Natural polymers: Chitosan, gum tragacanth, sodium alginate, xanthan gum, locust
bean gum, gellan gum, etc.
Principles of bioadhesion /mucoadhesion:
For bioadhesion /mucoadhesion, 3 stages are involved:
i.
An intimate contact in-between a bioadhesive/mucoadhesive and a membrane
either from a good wetting of the bioadhesive/mucoadhesive and a membrane or
from the swelling of bioadhesive/mucoadhesive.
ii.
Penetration of the bioadhesive/mucoadhesive into the tissue takes place.
iii.
Inter penetration of the chains of bioadhesives/mucoadhesives with mucous
takes place and then, low chemical bonds can settle.
Several theories have been proposed to explain the fundamental mechanism of
bioadhesion /mucoadhesion:
i).
Wetting theory: Ability of bioadhesive/mucoadhesive polymers to spread and
develop immediate attachment with the mucous membranes.
ii).
Electronic theory: Attractive electrostatic forces in-between glycoprotein mucin
network and the bioadhesive/mucoadhesive polymers.
iii).
Adsoption theory: Surface forces (covalent bonds, ionic bonds, hydrogen
bonds, and van der Waal’s forces) resulting in chemical bonding.
iv).
Diffusion theory: Physical entanglement of mucin strands and the flexible
polymeric chain.
v).
Fracture theory: Analyses the maximum tensile stress developed during
detachment of mucoadhesive/bioadhesive drug delivery systems from the
mucosal surfaces.
Advantages:
i).
These systems allow the developing of contact in-between the dosage forms
and the mucosa (mucoadhesion/bioadhesion)
ii).
High drug concentration can be maintained at the absorptive surface for a
prolonged period.
iii).
Dosage forms can be immobilized specifically at any part of the oral mucosa,
buccal mucosa, sublingual or gingival mucosa, etc.
Disadvantages:
i).
Small mucosal surface for contact
ii).
Lack of flexibility of dosage forms
iii).
Difficult to achieve high drug release rates required for some drugs.
iv).
Extent and frequency and frequency of attachment may cause local irritation.

3. Transmucosal permeability:

The mucosal lining of the oral cavity is referred to as the oral mucosa.

The oral mucosa comprises the buccal, sublingual, gingival, palatal and labial
mucosa.

The unique environment of the transmucosal route offers its potential as an
effective route for the delivery of a variety of drugs.

Due to rich blood supply, higher bioavailability, lymphatic drainage and direct
access to systemic circulation, the transmucosal route is suitable for drugs, which
are generally susceptible to acid-hydrolysis in the gastrointestinal tract or
extensively metabolized in liver.

In addition, oral mucosa facilitates an advantage of retaining drug delivery
systems in contact with the absorptive mucosal surface for a longer period (i.e.,
mucoadhesion) and thus, optimizing the drug concentration gradient across the
mucosal membrane with the reduction of differential pathways.

Thus, the delivery of drugs through the transmucosal route has attracted
particular attention due to its potential for high patient compliance and unique
physiological features.

The drugs to be administered through the transmucosal route need to be
released from the dosage forms to the effective delivery site (e.g., buccal or
sublingual area) and pass through the mucosal layers to enter the systemic
circulation.

Certain physiological features of the transmucosal route play significant roles in
this process, including pH, enzyme activity, fluid volume and the permeability of
oral mucosa.

The secretion of saliva is also an important determinant for the performance of
transmucosal drug delivery.

The main mechanisms responsible for the penetration of various molecules
include: Simple diffusion (paracellular or transcellular), carrier-mediated diffusion,
active transport, pinocytosis or endocytosis.

However, there is little research on to what extent this phenomenon affects the
efficiency of oral transmucosal delivery from different drug delivery systems and
thus, further research needs to be conducted to better understand this effect.
Drug delivery across the oral mucosal membranes is termed transmucosal drug
delivery. It can be divided into three main categories of transmucosal drug delivery
based on the characteristics of the oral cavity:
i).
Sublingual delivery: Administration of drugs via the sublingual mucosa (the
membrane of the ventral surface of the tongue and the floor of the mouth) to
the systemic circulation.
ii).
Buccal delivery: Administration of drugs via the buccal mucosa (the lining of
the cheek) to the systemic circulation.
iii).
Local delivery: For the treatment of conditions of the oral cavity, principally
ulcers, fungal conditions and periodontal disease, gingival disease, bacterial
and fungal infections, dental stomatitis, etc.
Formulation considerations of buccal delivery systems:

Transmucosal administration of drugs accross the buccal lining is defined as
buccal drug delivery.

4. 
The mucosa of the buccal area has a large, smooth and relatively immobile
surface, which provides a large contact surface.

The large contact surface of the buccal mucosa contributes to rapid and
extensive drug absorption.

Buccal drug delivery was first introduced by Orabase in 1947, when gum
tragacanth was mixed with dental adhesive powder to supply penicillin to the
oral mucosa.

Recent years, buccal drug delivery has proven particularly useful and offers
several advantages over other drug delivery systems including:
i.
bypass of the gastrointestinal tract and hepatic portal system,
ii.
increasing the bioavailability of orally administered drugs that otherwise
undergo hepatic first-pass metabolism;
iii.
improved patient compliance due to the elimination of associated pain with
injections;
iv.
administration of drugs in unconscious or incapacitated patients;
v.
convenience of administration as compared to injections or oral medications;
vi.
sustained drug delivery; increased ease of drug administration; and
vii.
Ready termination of delivery by detaching the dosage form.

Fig. 6: Schematic diagram of buccal mucosa

Buccal drug delivery occurs in a tissue that is more permeable than skin and is
less variable between patients, resulting in lower inter-subject variability.

Because of greater mucosal permeability, buccal drug delivery can also be used
to deliver larger molecules such as low molecular weight heparin.

In addition, buccal drug delivery systems could potentially be used to deliver
drugs that exhibit poor or variable bioavailability, and bioavailability will be
enhanced for drugs that undergo significant first-pass metabolism.

Because drug absorbed from the oral cavity avoids both first-pass metabolism
and enzymatic/acid degradation in the gastrointestinal tract, buccal
administration could be of value in delivering a growing number of potent peptide
and protein drug molecules.

In addition, buccal delivery of such drug molecules is a promising area for
continued research with the aim of alternative non-invasive delivery.

5. The novel type buccal dosage forms include:
i).
Buccal mucoadhesive tablets,
ii).
Buccal patches and films,
iii).
Semisolids (ointments and gels) and powders
Buccal mucoadhesive tablets: Buccal mucoadhesive tablets are dry dosage forms
that have to be moistened prior to placing in contact with buccal mucosa.
Buccal patches and films: Buccal patches and films consist of two laminates, with an
aqueous solution of the adhesive polymer being cast onto an impermeable backing
sheet, which is then cut into the required round or oval shape. These also offer
advantages over creams and ointments in that they provide a measured dose of drug to
the site. Recent years, puccal patches and films have received the greatest attention for
buccal delivery of drugs. They present a greater patient compliance compared with
tablets owing to their physical flexibility that causes only minor discomfort to the patient.
Semisolids (ointments and gels): Bioadhesive gels or ointments have less patient
acceptability than solid bioadhesive dosage forms, and most of the dosage forms are
used only for localized drug therapy within the oral cavity.
Structure and design of buccal patches:
Buccal patches are of two types on the basis of their release characteristics:
i).
Unidirectional buccal patches and
ii).
Bidirectional buccal patches
Unidirectional patches release the drug only into the mucosa, while bidirectional
patches release drug in both the mucosa and the mouth.
Buccal patches are structurally of two types:
i).
Matrix type: The buccal patch is designed in a matrix configuration contains
drug, adhesive, and additives mixed together (Fig. 7).
Fig 7: Schematic representation of the matrix-type buccal patch design
ii).
Reservoir type: The buccal patch designed in a reservoir system contains a
cavity for the drug and additives separate from the adhesive. An impermeable
backing is applied to control the direction of drug delivery; to reduce patch
deformation and disintegration while in the mouth; and to prevent drug loss.
Composition of buccal patches:
Drugs: The selection of suitable drug for the design of buccal drug delivery systems
should be based on pharmacokinetic properties of the drugs to be administered. The
drug should have following characteristics for the designing of effective buccal patches:
a)
The conventional single dose of the drug should be small.
b)
The drugs having biological half-life between 2-8 h are good candidates for
controlled drug delivery.
c)
Tmax of the drug shows wider-fluctuations or higher values when given orally.

6. d)
Through oral route drug may exhibit first pass effect or pre-systemic drug
elimination.
e)
The drug absorption should be passive when given orally.
2
f)
Buccal adhesive drug delivery systems with the size 1–3 cm
25 mg or less are preferable.
and a daily dose of
Polymers (adhesive layer): Bioadhesive polymers play a major role in the designing of
buccal patches. Bioadhesive polymers are from the most diverse class and they have
considerable benefits upon patient health care and treatment. These polymers enable
retention of dosage form at the buccal mucosal surface and thereby provide intimate
contact between the dosage form and the absorbing tissue. Drug release from a
polymeric material takes place either by the diffusion or by polymer degradation or by a
combination of the both. Polymer degradation generally takes place by the enzymes or
hydrolysis either in the form of bulk erosion or surface erosion.
An

ideal

bioadhesive

polymer

for

buccal

patches

should

have

following
characteristics:
a)
The polymer should be inert and compatible with the buccal environment.
b)
It should allow easy incorporation of drug in to the formulation.
c)
The polymer and its degradation products should be non-toxic absorbable from
the mucous layer.
d)
It should adhere quickly to moist tissue surface and should possess the site
specificity.
e)
It should form a strong non covalent bond with the mucine or epithelial surface
and should possess sufficient mechanical strength.
f)
The polymer must not decompose on storage or during the shelf life of the
dosage form.
g)
It must have high molecular weight and narrow distribution.
h)
The polymer should be easily available in the market and economical.
i)
The polymer should have good spreadability, wetting, swelling and solubility and
biodegradability properties.
j)
The pH of the polymer should be biocompatible and should possess good
viscoelastic properties.
k)
It should demonstrate local enzyme inhibition and penetration enhancement
properties.
l)
It should demonstrate acceptable shelf life.
Backing layer: Backing layer plays a major role in the attachment of buccal patches to
the mucus membrane. The materials used as backing membrane should be inert, and
impermeable to the drug and penetration enhancer. Such impermeable membrane on
buccoadhesive patches prevents the drug loss and offers better patient compliance.
The commonly used materials in backing membrane include water insoluble polymers
such as ethylcellulose, Eudrajit RL and RS, etc.
Penetration enhancer: Substances that facilitate the permeation through buccal mucosa
are referred as permeation enhancers. Selection of the appropriate permeation
enhancer and its efficacy depends on the physicochemical properties of the drug, site of
administration, nature of the vehicle and other excipients. Permeation enhancers used
for designing buccal patches must be nonirritant and have a reversible effect. The
epithelium should recover its barrier properties after the drug has been absorbed. The

7. most common classes of buccal penetration enhancers include fatty acids that act by
disrupting intercellular lipid packing, surfactants, bile salts, and alcohols.
Plasticizers: To impart appropriate plasticity of the buccal patches, suitable plasticizers
are required to add in the formulation of buccal patches. Typically, the plasticizers are
used in the concentration of 0-20 % w/w of dry polymer. Plasticizer is an important
ingredient of the film, which improves the flexibility of the film and reduces the bitterness
of the film by reducing the glass transition temperature of the film. The selection of
plasticizer depends upon the compatibility with the polymer and type of solvent
employed in the casting of film. Plasticizers should be carefully selected because
improper use of the plasticizers affects the mechanical properties of the film. Widely
used plasticizers in buccal patches and films are PEG100, 400, propylene glycol,
glycerol, castor oil etc.
Taste masking agents: Taste masking agents or taste masking methods should be used
in the formulation if the drugs have bitter taste, as the bitter drugs makes the formulation
unpalatable, especially for pediatric preparations. Thus, before incorporating the drugs
in the buccal patches, the taste needs to be masked. Various methods can be used to
improve the palatability of the formulation, such as complexation technology, salting out
technology, etc.
Mechanism of buccal absorption:
Buccal absorption leads systemic or local action via the buccal mucosa and it
occurs by passive diffusion of the non ionized species, a process governed primarily by
a concentration gradient, through the intercellular spaces of the epithelium. The passive
transport of non-ionic species across the lipid membrane of the buccal cavity is the
primary transport mechanism. The buccal mucosa has been said to be a lipoidal barrier
to the passage of drugs, as is the case with many other mucosal membrane and the
more lipophillic the drug molecule, the more readily it is absorbed.
Factors affecting buccal absorption:
The oral cavity is a complex environment for drug delivery as there are many
interdependent as well as independent factors which reduce the absorbable
concentration at the site of absorption.
1.
Membrane Factors: This involves degree of keratinization, surface area available
for absorption, mucus layer of salivary pellicle, intercellular lipids of epithelium,
basement membrane and lamina propria. In addition, the absorptive membrane
thickness, blood supply/ lymph drainage, cell renewal and enzyme content will all
contribute to reducing the rate and amount of drug entering the systemic circulation.
2.
Environmental Factors:
(a)
Saliva: The thin film of saliva coats throughout the lining of buccal mucosa and is
called salivary pellicle or film. The thickness of salivary film is 0.07 -0.10 mm. The
thickness, composition and movement of this film affect the rate of buccal absorption.
(b)
Salivary glands: The minor salivary glands are located in epithelial or deep
epithelial region of buccal mucosa. They constantly secrete mucus on surface of
buccal mucosa. Although, mucus helps to retain mucoadhesive dosage forms, it
is potential barrier to drug penetration.
Manufacturing methods of buccal patches
Manufacturing processes involved in making buccal patches, are namely solvent
casting, hot melt extrusion and direct milling.
1.
Solvent casting: In this method, all patch excipients including the drug co-
dispersed in an organic solvent and coated onto a sheet of release liner. After solvent
evaporation a thin layer of the protective backing material is laminated onto the sheet of

8. coated release liner to form a laminate that is die-cut to form patches of the desired size
and geometry.
2.
Hot melt extrusion: In hot melt extrusion blend of pharmaceutical ingredients is
molten and then forced through an orifice to yield a more homogeneous material in
different shapes such as granules, tablets, or films. Hot melt extrusion has been used
for the manufacture of controlled release matrix tablets, pellets and granules, as well as
oral disintegrating films. However, only a hand full article has reported the use of hot
melt extrusion for manufacturing mucoadhesive buccal patches.
3.
Direct milling: In this, patches are manufactured without the use of solvents. Drug
and excipients are mechanically mixed by direct milling or by kneading, usually
without the presence of any liquids. After the mixing process, the resultant
material is rolled on a release liner until the desired thickness is achieved. The
backing material is then laminated as previously described. While there are only
minor or even no differences in patch performance between patches fabricated
by the two processes, the solvent -free process is preferred because there is no
possibility of residual solvents and no associated solvent-related health issues.
Advantages of buccal drug delivery systems
(a)
Sustained drug delivery.
(b)
Increased ease of drug administration.
(c)
Excellent accessibility.
(d)
Drug absorption through the passive diffusion.
(e)
Low enzymatic activity, suitability for drugs or excipients that mildly and
reversibly damages or irritates the mucosa, painless administration, easy drug
withdrawal, facility to include permeation.
(f)
Versatility in designing as multidirectional or unidirectional release systems for
local or systemic actions, etc.
(g)
The drug is protected from degradation due to pH and digestive enzymes of the
middle gastrointestinal tract.
(h)
Improved patient compliance.
(i)
A relatively rapid onset of action can be achieved relative to the oral route, and
the formulation can be removed if therapy is required to be discontinued.
(j)
Flexibility in physical state, shape, size and surface.
(k)
Though less permeable than the sublingual area, the buccal mucosa is well
vascularized, and drugs from the buccal systems can be rapidly absorbed into
the venous system underneath the oral mucosa.
(l)
Transmucosal delivery occurs is fewer variables between patients, resulting in
lower inter-subject variability as compared to transdermal patches.
Limitations of buccal drug delivery systems:
Depending on whether local or systemic action is required the challenges faced
while delivering drug via buccal drug delivery can be enumerated as follows:
(a)
For local action the rapid elimination of drugs due to the flushing action of
saliva or the ingestion of foods stuffs may lead to the requirement for frequent dosing.
(b)
The non-uniform distribution of drugs within saliva on release from a solid or
semisolid delivery system could mean that some areas of the oral cavity may not
receive effective levels.
(c)
For both local and systemic action, patient acceptability in terms of taste,
irritancy and ‘mouth feel’ is an issue.

9. NDDS II
2.3. Implantable Drug Delivery Systems:Introduction, advantages and disadvantages, concept of implantsand
osmotic pump.



3.1.
Implantable Drug Delivery Systems
Implantable drug delivery systems allow targeted and localized drug delivery and
may achieve a therapeutic effect with lower concentrations of drugs. As a result, they
may minimize potential side-effects of therapy, while offering the opportunity for
increased patient compliance. This type of system also has the potential to deliver drugs
which would normally be unsuitable orally, because it avoids first pass metabolism and
chemical degradation in the stomach and intestine, thus, increasing bioavailability.
An ideal implantable parenteral system should possess following properties:
1.
Environmentally stable: Implantable systems should not breakdown under the
influence of light, air, moisture, heat, etc.
2.
Biostable: Implantable systems should not undergo physicochemical degredation
when in contact with biofluids (or drugs).
3.
Biocompatible: Implantable systems should neither stimulate immune response
(otherwise the implant will be rejected) nor thrombosis and fibrosis formation.
4.
Removal: Implantable systems should be removability when required.
5.
Non-toxic or non-carcinogenic: The degradation products or leached additives
should be completely safe.
6.
Implantable systems should have minimum surface area, smooth texture and
structural characteristics similar to the tissue in which it is to be implanted to avoid
irritation.
7.
Implantable systems should release drugs at a constant predetermined rate for a
predetermined period.
Advantages:
1.
More effective and more prolonged action.
2.
Better control over drug release
3.
A significantly small dose is sufficient.
Disadvantages:
1.
Invasive therapy
2.
Chances of device failure
3.
Limited to potent drugs
4.
Biocompatibility issues
Concept of implants:
Implants for drug delivery are several types:
1.
In situ forming implants (In situ depot forming systems):
(a)
In situ precipitating implants:
These implants are formed from drug containing in a biocompatible solvent. The
polymer solution form implants after subcutaneous (s.c.) or intramuscular (i.m.) injection
and contact with aqueous body fluids via the precipitation of polymers. In situ
precipitating implants are formulated to overcome some problems associated to the
uses of biodegradable microparticles:

10. i). Requirement for the reconstitution before
injection ii). Inability to remove the dose one
injected.
iii). Relatively complicated manufacturing procedures to produce a sterile,
stable and reproducible product.
(b)
In situ microparticle implants:
This type of implants is formed to overcome the disadvantages associated with in situ
precipitating implants. These are:
i).
High injection force.
ii).
Local irritation at the injection site.
iii).
Variability in the solidification rates.
iv).
Irregular shape of the implants formed depending on the cavity into which the
implants are introduced (implanted).
v).
Undesirable high initial burst release of drugs.
vi).
Potential solvent toxicity.
These in situ implantable systems consist of internal phase (drug-containing
polymer solution or suspension) and a continuous phase (aqueous solution with a
surfactant, oil phase with viscosity enhancer and emulsifier). The two phases are
separately stored in dual -chambered syringes and mixed through a connector before
administration.
2.
Solid implants:
Solid implants are generally cylindrical monolithic devices implanted by a minor
surgical incision or injected via a large bore needle into the s.c. or i.m. tissues.
Subcutaneous (s.c.) tissue is an ideal location because of its easy access to
implantation, poor infusion, slower drug absorption and low reactivity towards
foreign materials.
In these implants, drugs may be dissolved, dispersed or embedded in a matrix of
polymers or waxes/lipids that control the releasing via dissolution and/or diffusion,
bioerosion, biodegradation, or an activation process, such as hydrolysis or osmosis.
These systems are generally prepared as implantable flexible/rigid molded or extruded
rods, spherical pellets, or compressed tablets. Polymers used are silicone,
polymethacrylates, elastomers, polycaprolactones, polylactide-co-glycolide, etc.,
whereas waxes include glyceryl monostearate. Drugs generally presented in such
implantable systems are contraceptives, naltrexone, etc.
3.
Infusion devices:
Infusion devices are intrinsically powered to release the drugs at a zero order
rate and the drug reservoir can be replenished from time to time. Depending upon the
mechanism by which these implantable pumps are power to release the drugs. These
are 3 types:
i). Osmotic pressure activated drug delivery
systems ii). Vapor pressure activated drug
delivery systems iii). Battery powered drug
delivery systems.
Osmotic pumps:
Osmotic pumps are designed mainly by a semi-permeable membrane that
surrounds a drug reservoir (Fig. 8). The membrane should have an orifice that will allow

11. drug release. Osmotic gradients will allow a steady inflow of fluid within the implant. This
process will lead to an increase in the pressure within the implant that will force drug
release trough the orifice. This design allows constant drug release (zero order
kinetics). This type of device allows a favorable release rate but the drug loading is
limited.
The historical development of osmotic systems includes seminal contributions
such as the Rose-Nelson pump, the Higuchi-Leeper pumps, the Alzet and Osmet
systems, the elementary osmotic pump, and the push-pull or GITSR system. Recent
advances include the development of
the controlled porosity osmotic pump, systems based on asymmetric membranes, and
other approaches.







Fig. 8: Osmotic pump
Osmotic agents:
Osmotic agents are used for the fabrication of the osmotic device maintain a
concentration gradient across the membrane by generating a driving force for the
uptake of water and assist in maintaining drug uniformity in the hydrated formulation.
Osmotic agents usually are ionic compounds consisting of either inorganic salts such as
sodium chloride, potassium chloride magnesium sulphate, sodium sulphate, potassium
sulphate and sodium bicarbonate.
Additionally, sugars such as glucose, sorbitol, sucrose and inorganic salts of
carbohydrates can also act as effective osmotic agents.

12. NDDS III
3.1.
Transdermal Drug Delivery Systems: Introduction, Permeation through skin,
factorsaffecting permeation, permeation enhancers, basic components of TDDS,
formulationapproaches
3.2.
Gastroretentive drug delivery systems: Introduction, advantages,
disadvantages,approaches for GRDDS – Floating, high density systems, inflatable and
gastroadhesivesystems and their applications
3.3.
Nasopulmonary drug delivery system: Introduction to Nasal and Pulmonary
routes ofdrug delivery, Formulation of Inhalers (dry powder and metered dose), nasal
sprays,nebulizers

TRANSDERMAL DRUG DELIVERY SYSTEM:

A transdermal patch is a medicated adhesive patch that is placed on the skin to
deliver a specific dose of medication through the skin and into the bloodstream.

Transdermal drug delivery offers controlled release of the drug into the patient, it
enables a steady blood level profile, resulting in reduced systemic side effects
and, sometimes, improved efficacy over other dosage forms.

TDDS are defined as self contained, discrete dosage forms which are also
known as “patches” when patches are applied to the intact skin, deliver the drug
through the skin at a controlled rate to the systemic circulation.

TDDS are dosage forms designed to deliver a therapeutically effective amount of
drug across a patient’s skin.

The first transdermal system, Transderm SCOP was approved by FDA in 1979
for the prevention of nausea and vomiting associated with travel.

Objective of TDDSis to deliver drugs into systemic circulation into the skin
through skin at predetermined rate with minimal inter and intra patient variation.


Advantages of TDDS

13. Disadvantages of TDDS:


Skin:
The largest organ:

The skin is the largest organ of the human body which covers a surface area of
approximately 2 sq.m.

It receives about one third of the blood circulation through the body.

It serves as a permeability barrier against the transdermal absorption of various
chemical and biological agents.
Functions of Skin:

Separates the underlying blood circulation network from the outside environment

Serves as a barrier against physical, chemical and microbiological attacks.

Acts as a thermostat in maintaining body temperature.

Plays role in the regulation of blood pressure.

Protects against the penetration of UV rays.

Skin is a major factor in determining the various drug delivery aspects like permeation
and absorption of drug across the dermis.
The diffusional resistance of the skin is greatly dependent on its anatomy and
ultrastructure.
Anatomy of Skin:
The structure of human skin can be categorized into Three main layers

The epidermis

The dermis

The innermost subcutaneous fat layer (Hypodermis)

14. SCHEMATIC REPRESENTATION OF SKIN AND ITS APPENDAGES
The Epidermis:
The epidermis is a continually self-renewing, stratified squamous epithelium covering
the entire outer surface of the body and primarily composed of two parts:

The living or viable cells of the malpighian layer (viable epidermis) and

The dead cells of the stratum corneum commonly referred to as the horny layer.
Viable epidermis is further classified into four distinct layers,

Stratum lucidum

Stratum granulosu

Stratum spinosu

Stratum basale
SCHEMATIC REPRESENTATION OF ANATOMY OF EPIDERMIS
Stratum corneum:

This is the outermost layer of skin also called as horny layer.

It is the rate limiting barrier that restricts the inward and outward movement of
chemical substances.

The barrier nature of the horny layer depends on its constituents: 75-80%
proteins, 5-15% lipids, and 5-10% ondansetron material on a dry weight basis.

Stratum corneum is approximately 10 mm thick when dry but swells to several
times when fully hydrated.

It is flexible but relatively impermeable. The architecture of horny layer may be
modeled as a wall-like structure with protein bricks and lipid mortar.

It consists of horny skin cells (corneocytes) which are connected via
desmosomes (protein-rich appendages of the cell membrane).

The corneocytes are embedded in a lipid matrix which plays a significant role in
determining the permeability of substance across the skin.

15. Dermis:

Dermis just beneath the epidermis which is 3 to 5 mm thick layer

It is composed of a matrix of connective tissues, which contains blood vessels,
lymph vessels, and nerves.

Essential function in regulation of body temperature.

It also provides nutrients and oxygen to the skin, while removing toxins and
waste products.

Capillaries reach to within 0.2 mm of skin surface and provide sink conditions for
most molecules penetrating the skin barrier.

The blood supply thus keeps the dermal concentration of permeate very low, and
the resulting concentration difference across the epidermis provides the essential
driving force for transdermal permeation.

It provides a minimal barrier to the delivery of most polar drugs, although the
dermal barrier may be significant when delivering highly lipophillic molecules.
Hypodermis:

The hypodermis or subcutaneous fat tissue supports the dermis and epidermis.

It serves as a fat storage area.

This layer helps to regulate temperature, provides nutritional support and
mechanical protection.

It carries principal blood vessels and nerves to skin and may contain sensory
pressure organs.
Percutaneous absorption:

Before a topically applied drug can act either locally or systemically, it must
penetrate through stratum corneum.

Percutaneous absorption is defined as penetration of substances into various
layers of skin and permeation across the skin into systemic circulation.

Percutaneous absorption of drug molecules is of particular importance in
transdermal drug delivery system because the drug has to be absorbed to an
adequate extent and rate to achieve and maintain uniform, systemic, therapeutic
levels throughout the duration of use.

Once drug molecule cross the stratum corneal barrier, passage into deeper
dermal layers and systemic uptake occurs relatively quickly and easily.

16. SCHEMATIC REPRESENTATION OF PERCUTANEOUS PERMEATION
Permeation Enhancers:


These are compounds that promote skin permeability by altering the skin as a
barrier to the flux of a desired penetrant.

Penetration enhancers are incorporated into a formulation to improve the
diffusivity and solubility of drugs through the skin that would reversibly reduce
the barrier resistance of the skin.

Thus allows the drug to penetrate to the viable tissues and enter the systemic
circulation.

The flux J of drug across the skin can be written as J = D [dc/dx]
J = The Flux, D = diffusion coefficient, C = Concentration of the diffusing species, X
= Spatial coordinate.

The methods employed for modifying the barrier properties of the SC to
enhance the drug penetration (and absorption) through the skin can be
categorized as chemical and physical methods of enhancement.
1.
Chemical Enhancers
Chemical permeation enhancers can work by one or more of the following
three principle mechanisms:
Relaxation of the extremely ordered lipid structure of the stratum
corneum. Interacting with aqueous domain of bilayer of lipid.
Enhanced partition of the drug, by addition of co-enhancer or solvent into
the stratum corneum.

17. Promoting penetration and establishing drugs reservoir in the stratum
corneum. Chemical permeation enhancers exert their effect through above
modifications in the skin
structure. Various Chemical permeation enhancers interact with the polar head
groups through hydrogen bonding and ionic interactions. The resultant disruption of
the lipid hydration spheres and change in head group properties cause the relaxation
at the head portion. This relaxation can decrease the resistances of this lipid-enriched
domain for polar molecules. Another aspect can be an increase in the volume of the
water layer resulting in more water flow to the tissue, a process
known as solvent swelling, leading to increased cross sectional area for diffusion of
polar molecules. A portion of free water becomes available, besides the water in
structure, at the lipid interface. This process can also occur due to simple hydration.
Some of the most widely studied permeation enhancers are di-methylsulfoxide
(DMSO), di-methylacetamide (DMA), and diethyl-toluamide (DEET), propylene glycol
(PG).
The penetration enhancers, such as DMSO, urea and surfactants, can also
interact with the keratin filaments present in corneocytes which leads to disruption
within the cell thereby increasing diffusion coefficient and permeability.
2.
Physical
Enhancers:
Electroporation
The use of electro-permeabilization as a method of enhancing diffusion across
biological barriers dates back as far as 100 years. Electroporation involves the
application of highvoltage pulses to induce skin perturbation. High voltages (≥100 V)
and short treatment durations (milliseconds) are most frequently employed. The
technology has been successfully used to enhance the skin permeability of molecules
with differing lipophilicity and size (i.e., small molecules, proteins, peptides, and
oligonucleotides).
Iontophoresis
This method involves enhancing the permeation of a topically applied
therapeutic agent by the application of a low-level electric current, either directly to the
skin or indirectly via the dosage form. Increase in drug permeation as a result of this
methodology can be attributed to either one or a combination of electro-repulsion (for
charged solutes), electro-osmosis (for uncharged solutes), and electro-perturbation
(for both charged and uncharged) mechanisms.

18. Ultrasound
Ultrasound involves the use of ultrasonic energy to enhance the transdermal
delivery of solutes either simultaneously or through pretreatment, and is frequently
referred to as sonophoresis. The proposed mechanism behind the increase in skin
permeability is attributed to the formation of gaseous cavities within the intercellular
lipids on exposure to ultrasound, resulting in disruption of the stratum corneum.
Magnetophoresis
This method involves the application of a magnetic field that acts as an external
driving force to enhance the diffusion of a diamagnetic solute across the skin. Skin
exposure to a magnetic field might also induce structural alterations that could
contribute to an increase in permeability.
Thermophoresis
The skin surface temperature is usually maintained at 32°C in humans by a
range of homeostatic controls.
Microneedle-based devices
One of the first patents ever filed for a drug delivery device for the
percutaneous administration of drugs is based on this method. These micro-needles
of length 50 to 110 mm will penetrate the stratum corneum and epidermis to deliver
the drug from the reservoir.
Needleless injection
Needleless injection is reported to involve a pain-free method of administering
drugs to the skin. This method therefore avoids the issues of safety, pain, and fear
associated with the use of hypodermic needles.

Ideal properties of penetration enhancer
The ideal properties of penetration enhancers are:
It should be pharmacologically inert.
It is should be nontoxic, nonirritating, and non-allergenic to the skin.
It should produce rapid onset of action; predictable and suitable duration
of action for the drug used
Following removal of the enhancer, the stratum corneum should
immediately and fully recover its normal barrier property.
The barrier function of the skin should decrease in one direction only i.e.,
they should permit therapeutic agents into the body and efflux of
endogenous materials should not occur.
It should be chemically and physically compatible with the delivery
system. It should be non-damaging to viable cells.

19. They should be Inexpensive and cosmetically
acceptable. The Penetration enhancer used
should be economical.

Factors affecting transdermal permeation
1.
Biological factor:
1.1
Skin conditions:

The intact skin itself acts as barrier but many agents like acids, alkali cross the
barrier cells and penetrates through the skin.

Many solvents open the complex dense structure of horny layer Solvents like
methanol, chloroform remove lipid fraction, forming artificial shunts through which
drug molecules can pass easily.
1.2
Skin age:

Skin of adults and young ones are more permeable than the older ones.

Children shows toxic effects because of greater surface area / unit body weight.

Potent steroids, boric acid, hexachlorophene have produced severe side effects.
1.3
Blood Supply:

Changes in peripheral circulation can affect transdermal absorption.
1.4
Regional skin site:

Thickness of skin, nature of stratum and density of appendages vary site to site.

These factors affect significantly penetration.
1.5
Skin metabolism:

Skin metabolizes steroids, hormones, chemical carcinogens and some drugs.

So skin metabolism determines efficacy of drug permeated through the skin.
1.6
Species differences:

The skin thickness, density of appendages and keratinization of skin vary species
to species, so affects the penetration.
2.
Physicochemical factors:
14

2.1
Skin hydration:

In contact with water the permeability of skin increases significantly.

Hydration is most important factor increasing the permeation of skin.

So use of humectant is done in transdermal delivery.
2.2
Temperature and pH:

The permeation of drug increases ten folds with temperature variation.

The diffusion coefficient decreases as temperature falls.

Weak acids &weak bases dissociate depending on the pH and pKa values.

The proportion of unionized drug determines the drug concentration in skin.

Temperature and pH are important factors affecting drug penetration
2.3
Diffusion coefficient:

Penetration of drug depends on diffusion coefficient of drug.

At a constant temperature the diffusion coefficient of drug depends on
properties of drug, diffusion medium and interaction between them.

20. 2.4
Drug concentration:

The flux is proportional to the concentration gradient across the barrier.

Conc gradient will be higher if the conc of drug will be more across the barrier.
2.5
Partition coefficient:

The optimal partition coefficient (K) is required for good action.

Drugs with high K are not ready to leave the ipid portion of skin. Also, low K will
not be permeated.
2.6
Molecular size and shape:

Drug absorption is inversely related to molecular weight, small molecules
penetrate faster than large ones.
3.
Environmental factors:
3.1
Sunlight:

Due to Sunlight the walls of blood vessels become thinner leading to bruising
with only minor trauma in sun-exposed areas.

Also pigmentation: The most noticeable sun-induced pigment change is a freckle
or solar lentigo.
3.2
Cold Season:

Often result in itchy, dry skin.

Skin responds by increasing oil production to compensate for the weather’s
drying effects.

A good moisturizer will help ease symptoms of dry skin.

Also, drinking lots of water can keep your skin hydrated and looking radiant.
3.3
Air Pollution:

Dust can clog pores and increase bacteria on the face and surface of skin, both
of which lead to acne or spots.

This affects drug delivery through the skin.

Invisible chemical pollutants in air can interfere with skin’s natural protection,
breaking down natural skin oils that normally trap moisture in skin &keep it
supple.
3.4
Effect of Heat on Transdermal patch:

Heat induced high absorption of transdermal delivered drugs.

Patient should be advised to avoid exposing the patch application site to external
heat source like heated water bags, hot water bottles.

Even high body temperature may also increase the transdermal delivered drugs.

In this case the patch should be removed immediately.
Formulation of transdermal drug delivery system:

Basic Components of TDDS:
Transdermal drug delivery system consists of the following components.
1.
Polymer Matrix:
The Polymer controls the release of the drug from the device. Possible
useful polymers for transdermal devices are:
a.
Natural Polymers: e.g., cellulose derivatives,Zein, Gelatin, Shellac, Waxes,
Proteins, Gums and their derivatives, Natural rubber, Starch etc.

21. b.
Synthetic Elastomers: e.g., polybutadieine, Hydrin rubber, Polysiloxane,
Silicone rubber, Nitrile, Acrylonitrile, Butyl rubber, Styrenebutadieine rubber,
Neoprene etc.
c.
Synthetic Polymers: e.g., polyvinyl alcohol, Polyvinyl chloride, Polyethylene,
Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinyl pyrrolidone, Polymethy
lmethacrylate, Epoxy etc.
2.
Drug:
For successfully developing a transdermal drug delivery system, the drug should be
chosen with great care. The following are some of the desirable properties of a drug
for transdermal delivery.
Physicochemical properties:
The drug should have a molecular weight less than approximately 1000 Daltons.
The drug should have affinity for both lipophilic and hydrophilic phases. Extreme
partitioning characteristics are not conducive to successful drug delivery via the skin.
The drug should have low melting point.
Along with these properties the drug should be potent, having short half life and be non-
irritating.
3.
Permeation Enhancers:
These are compounds which promote skin permeability by altering the skin as a
barrier to the flux of a desired penetrant. Penetration enhancers are incorporated into a
formulation to improve the diffusivity and solubility of drugs through the skin that would
reversibly reduce the barrier resistance of the skin. These includes water,pyrolidones,fatty
acids and alcohols, zone and its derivatives, alcohol and glycols, essential oils,terpenes
and derivatives,sulfoxides like DMSO and their derivatives, urea and surfactant.
4 Pressure sensitive adhesives (PSA):
The fastening of all transdermal devices to the skin can be done by using a
PSA, positioned on the face of the device or in the back of the device and
extending peripherally.
The first approach involves the development of new polymers, which include
hydrogel hydrophilic polymers, and polyurethanes.
The second approach is to physically or chemically modify the chemistries of
the PSAs in current use (such as silicones, and acrylates). Physical
modification refers to the formulation of the base adhesives with some
unique additives so that, in synergy with the drug and excipients in the
system formulation, the result is enhanced drug delivery and improved skin-
adhesion properties. Chemical modification involves
chemically incorporating or grafting functional monomers to the conventional
PSA polymers in order to improve drug delivery rates
5 Backings Laminates:

22. Backings laminates are selected for appearance, flexibility and need for
occlusion. Examples of backings are polyester film, polyethylene film and
polyolefin film, and aluminum vapor coated layer. Other assiduities are the
backing additives leaching out and diffusion of drug or the compositions,
through the backing. An over emphasis on the chemical resistance often may
leads to stiffness and high occlusivity to moisture vapor and air. It causes the
TDDS to lift and may possibly irritate the skin during long-term use.
6.
Release Liner:
During storage the patch is covered by a protective liner that is removed and
discarded before the application of the patch to the skin. Since the liner is in
intimate contact with the TDDS, the liner should be chemically inert. The release
liner is composed of a base layer which may be non-occlusive (e.g. paper fabric)
or occlusive (e.g. polyethylene, polyvinylchloride) and a release coating layer
made up of silicon or Teflon. Other materials used for TDDS liners include,
polyester foil and metalized laminate that protects the patch during storage. The
liner is removed prior to use.
7.
Other Excipients:
Various solvents such as chloroform, methanol, acetone, isopropanol
and dichloromethane are used to prepare drug reservoir. In addition,
plasticizers such as di-butyl-phthalate, trietyl citrate, polyethylene glycol and
propylene glycol are added to provide plasticity to the transdermal patch.





Various components of a transdermal drug delivery system are

SCHEMATIC REPRESENTATION OF COMPONENTS OF TDDS
1.
Drug substance:
For successfully developing a TDDS, the drug should be choosen with great care. The
following are some of the desirable properties of a drug for delivery.
1.1
Physicochemical properties:

The drug should have a molecular weight less than 1000 Daltons.

The drug should have affinity for both lipophilic and hydrophilic phase.

23. 
The drug should have low melting point.

The drug should be potent, having short half-life and be non-irritating.
1.2
Biological Properties:

Drug should be very potent ,i.e. it should be effective in few mg/day

The drug should have short biological half-life.

The drug should not be irritant and non-allergic to human skin.

The drug should be stable when contact with the skin.

They should not stimulate an immune reaction to the skin.

Dose is less than 50 mg per day, and ideally less than 10 mg per day.
IDEAL PROPERTIES OF DRUG CANDIDATE FOR TDDS
Parameter Properties
Dose Less than 20mg/day
Halflife < 10 hrs
Molecular weight <400 Dalton
Melting point <200°C
Partition coefficient 1 to 4
Aqueous Solubility >1mg/mL
pH of the aqueous saturated solution 5-9
Skin Permeability Coefficient >0.5×10
-3
cm/h
Skin Reaction Non irritating and non-sensitizing
Oral Bioavailability Low
2.
Polymer matrix:

Polymers are the backbone of transdermal drug delivery system.

System fabricated as multi layered polymeric laminates in which a drug reservoir
or a drug polymer matrix is sandwiched between two polymeric layers.

an outer layer that prevents the loss of drug through the backing surface and

An inner polymeric layer that functions as an adhesive, or rate controlled memb.
2.1
Ideal properties of a polymer to be used in a transdermal system:

Molecular weight, chemical functionality of the polymer should be such that the specific
drug diffuses properly and gets released through it.

The polymer should be stable.

The polymer should be nontoxic

The polymer should be easily of manufactured

The polymer and its deaggration product must be non toxic or non-antagonistic to host.

Large amounts of the active agent are incorporated into it.
Natural Polymers Synthetic Elastomers Synthetic Polymers

Cellulose derivatives,
Arabino Galactan, Zein,
Gelatin, Proteins, Shellac
and Strarch
Polybutadiene,
Hydrinrubber, Polysiloxane,
Acrylonitrile, Neoprene,
Chloroprene and Silicon
rubber
Polyvinylalcohol,
Polyethylene, Polyviny
Chloride, Polyacrylates,
Polyamide, Acetal
copolymer and Polysyrene
3.
Penetration Enhancers:
These are compounds which promote the skin permeability by altering the skin as
barrier to the flux of a desired penetrate.
3.1
Ideal properties of penetration enhancers:

24. 
Controlled and reversible enhancing action

Chemical and physical compatibility with drug and other pharmaceutical excipients

Should not cause loss of body fluids, electrolytes or other endogenous materials

Non toxic, non allergic, non irritating

Pharmacological inertness

Odorless, colorless, economical and cosmetically acceptable.

4
Other excipients:

Various solvents such as chloroform, methanol, acetone, isopropananol, and
dichloromethane, are used to prepare drug reservoir.

Plasticizers such as dibutylpthalate, propylene glycol are added.
4.1
Pressure sensitive adhesive: (PSA)

PSA is a material that helps in maintaining an intimate contact between
transdermal system and the skin surface.

It should adhere with not more than applied finger pressure, be aggressively and
permanentaly tachy, exert a strong holding force.

It should be removable from the smooth surface without leaving a residue e.g.:
polyacrylamates, polyacrylates, polyisobutylene, silicone based adhesive.

The selection of an adhesive is based on the patch design and drug formulation.

PSA should be physicochemical & biocompatible & should not alter drug release.

The PSA can be positioned on the face of the device or in the back of the device
and extending peripherally.
4.2
Backing laminates:

While designing a backing layer the consideration of chemical resistance and
excipients may compatible because the prolonged contact between the backing
layer and the excipients, drug or penetration enhancer through the layer.

They should a low moisture vapour transmission rate.

They must have optimal elasticity, flexibility and tensile strength. eg: aluminium
vapour coated layer, a plastic film and heat real layer.
4.3.Release linear:

It prevents loss of drug that has migrated into adhesive layer & contamination.

It should comply with specific requirements regarding chemical inertness and
permeation to the drug, penetration enhancer and water.

Types of TDDS / Approaches in development of TDDS:
1.
Membrane permeation controlled systems / Reservoir type systems.
2.
Adhesive- dispersion type systems.
3.
Matrix diffusion- controlled systems.
4.
Microreservoir type/ microsealed dissolution controlled systems.

1.
Membrane-moderated or Permeation controlled DDS (Reservoir type)
•
Drug reservoir (homogenous dispersion of drug with polymeric matrix or suspension
of drug in un leachable viscous liquid medium such as silicone fluid) is encapsulated
within drug impermeable metallic plasticlaminate and a rate controlling polymeric
membrane(ethylene vinyl acetate co polymer).

25. •
The rate of drug release is determined by the permeability of the rate controlling
membrane.
•
A layer of adhesive polymer is applied on membrane to secure the device on skin.
•
The rate of release of drug is always maintained at constant rate & the type of release
is zero order.
□
Release rate of this TDDS depends upon the polymer composition, permeability co
efficient and thickness of the rate controlling membrane and adhesive.
□
The intrinsic rate of drug release from this TDDS is calculated by following formula.
Cr
dQ/dt = --------------------
1/Pm + 1/Pa
Cr- Conc. of drug in the reservoir compartment
Pm- Permeability co efficient of rate controlling polymeric membrane
Pa- Permeability co efficient of adhesive

Examples of this system are:
1.
Nitro glycerin releasing TDDS (Transderm Nitro / ciba, USA) for once a day
medication in angina pectoris
2.
Scopolamine releasing TDDS (Transderm-Scop/ ciba, USA) for 72 hrs, prophylaxis
of motion sickness
3.
Estradiol releasing TDDS (Estraderm/ciba) for treatment of menopausal syndrome
4.
Clonidine releasing TDDS (Catapres/Boehringer Ingelheim) for 7 day therapy of
hyper tension
5.
Prostaglandin -derivatives TDDS.
2.
Adhesive dispersion type systems
□
Drug reservoir is formulated by homogenous dispersion of drug with adhesive
polymer poly(isobutylene) or poly acrylate.
□
Then spreading of this medicated adhesive by solvent casting/ hot melt on flat sheet
of drug impermeable metallic plastic backing to form thin drug reservoir layer.
□
On top of the drug reservoir layer, thin layers of rate controlling adhesive polymer
of specific permeabilityand constant thickness are applied to produce anadhesive
dispersion- diffusion controlled TDDS
The rate of drug release in this system is defined by
Ka/r . Da
dQ/dt = ------------------ Cr
ha
Where, Ka/r- Partition co-efficient of drug bw adhesive layer and reservoir layer
Da- Diffusion co-efficient of drug in the adhesive layer
ha- Thickness of adhesive layer
Examples for this system

26. 1.
Isosorbide dinitrate -releasing TDDS for once a day medication of angina pectoris.
2.
Verapamil releasing TDDS
Alternatively, this type of TDDS can be modified to have the drug loading level varied by
increment to form gradient ofdrug reservoir along the multi laminate adhesive layers.
Ex: Nitroglycerine releasing TDDS


3.
Matrix diffusion – controlled systems
Drug reservoir of homogenous dispersion of drug with hydrophilic or lipophilic polymer
is prepared with one ofthe following methods
1.
Homogenous dispersion of finely ground drug particles with liquid polymer or highly
viscous base polymer followed by cross linking of polymer chains
2.
Homogenous mixing of drug solid with rubbery polymer at an elevated temperature
3.
Dissolving the drug and polymer in a common solvent followed by solvent
evaporation in a mould at an elevated temperature or under vacuum.
□
Medicated polymer is moulded in to medicated disc with desired surface area and
controlled thickness.
□
This medicated polymer disc is pasted on to an
occlusive base plate with impermeable plastic backing.
□
Then the adhesive polymer is spread along the circumference to form a strip of
adhesive rim around the medicated disc.
The advantage of this TDDS is absence of dose dumping as the polymer can not
rupture.

Example of this system

27. 1.Nitro glycerin releasing TDDS (Nitro-Dur and Nitro-Dur II /Key pharmaceuticals,USA)
deliver daily dose of 0.5mg/cm2 for therapy of angina pectoris.
The rate of drug release from this system is defined as
dQ / dt = {A Cp Dp / 2t}1/2
where
A- initial drug loading dose in polymer
Cp and Dp are solubility and diffusivity of drug in polymer matrix.
4.
Microreservoir type/ microsealed dissolution controlled systems.
This is combination of the reservoir and matrix diffusionsystems.
Drug reservoir
1.
Suspension of drug in aqueous solution of water soluble liquid polymer.
2.
Homogenously dispersing of drug suspension in a lipophilic polymer (silicone
elastomer).
3.
As a result discrete unleachable microscopic spheres of drug reservoir is formed
which is stabilized by cross linking.
4.
Medicated polymer is moulded in to medicated polymer discs of desired surface
area and controlled thickness.
•
Depending on property of drug and desired rate of drug release disc is coated with a
layer of bio compatiblepolymer.
•
This

medicated

polymer

disc

is

pasted

on

to

an

occlusive

base

plate

with
impermeable plastic backing.
•
Then the adhesive polymer is spread along the circumference to form a strip of
adhesive rim around the medicated disc.
Example of this system:
1.
Nitro glycerin releasing TDDS (Nitrodisc, searle, USA) deliver daily dose of
0.5mg/cm2 for once a day therapy of angina pectoris.

28. Evaluation of transdermal patches:
The transdermal patches can be characterized in terms of following parameters
1.
Physical evaluation: (Film thickness, % flatness, folding endurance, tensile strength/
shear strength.)
2.
Weight variation
3.
Drug content
4.
% moisture content
5.
% moisture uptake
6.
Adhesive evaluation:
6a. Peel adhesion test,
6b. Tack properties (thumb tack test, rolling ball tack test,quick- stick/ peel- tack test,
probe tack test)
7.
In-vitro drug release evaluation/ skin permeation studies.
8.
Skin uptake and metabolism.
9.
In-vivo evaluation.
10.
Cutaneous toxicological evaluations.

Physicochemical evaluation:

Thickness:
It is determined by microscope,screw gauge or micrometer at different points of the film.

Uniformity of weight:
Individually weighing 10 randomly selected patches and calculating the average weight.
The individual weight should not deviate significantly from the average weight.

Drug content determination:
Film is dissolved in suitable solvent in which drug is soluble. Then drug in solution is
estimated spectrophotometrically by appropriate dilution.

Content uniformity test:
10 patches are selected and content is determined for individual patches. If 9 out of 10
patches have content between 85% to 115% of the specified value and one has content
not less than 75% to125% of the specified value, then transdermal patches pass the
test of content uniformity. But if 3 patches have content in the range of 75% to 125%,
then additional 20 patches are tested for drug content. If these 20 patches have range
from 85% to 115%, then the transdermal patches pass the test.

Moisture content:

29. The prepared films are weighed individually and kept in a desiccators containing
calcium chloride at room temperature for 24 h. The films are weighed again after a
specified interval until they show a constant weight.
% Moisture content = Initial weight – Final weight X 100
4


Moisture Uptake:
Weighed films are kept in a desiccator at room temperature for 24 h. These are then
taken out and exposed to 84% relative humidity using saturated solution of Potassium
chloride in a desiccator until a constant weight is achieved.
% moisture uptake = Final weight – Initial weight X 100

Flatness:
A patch should possess a smooth surface &should not constrict with time. This can be
demonstrated with flatness study. One strip is cut from the center& two from each side
of patches. The length of each strip is measured and variation in length is measured by
determining %constriction. Zero % constriction is equivalent to 100% flatness.
% constriction = I1 – I2 X 100
I2 = Final length of each strip I1 = Initial length of each strip

Folding Endurance:
It is determined by repeatedly folding the film at the same place until it break. The
number of times the films could be folded at the same place without breaking is folding
endurance value.

Tensile Strength:
Polymeric films are sandwiched separately by corked linear iron plates. One end of the
films is kept fixed with the help of an iron screen and other end is connected to a freely
movable thread over a pulley. The weights are added gradually to the pan attached with
hanging end of the thread. A pointer on the thread is used to measure the elongation of
the film. The weight sufficient to break film is noted.

Tack properties:
It is the ability of the polymer to adhere to substrate with little contact pressure. Tack is
dependent on molecular weight and composition of polymer as well as on the use of
tackifying resins in polymer.

Thumb tack test:
The force required to remove thumb from adhesive is a measure of tack.

Rolling ball test:
This test involves measurement of the distance that stainless steel ball travels along an
upward facing adhesive. The less tacky the adhesive, the further the ball will travel.

Quick stick (Peel tack) test:
The peel force required breaking the bond between an adhesive and substrate is
measured by pulling the tape away from the substrate at 90 at the speed of 12 inch/min.

Probe tack test:
Force required to pull a probe away from an adhesive at a fixed rate is recorded as tack.


In vitro release studies:

Transdermal patches can be in vitro evaluated in terms of Franz diffusion cell the
cell is composed of two compartments: donor and receptor.

The receptor compartment has a volume of 5-12ml & surface area of 1-5cm2.

The diffusion buffer is continuously stirred at 600rpm by a magnetic bar.

30. 
The temperature in the bulk of the solution is maintained by circulating
thermostated water through a water jacket that surrounds receptor compartment.

The drug content is analyzed, maintenance of sink condition is essential.

In vivo Studies:
In vivo evaluations are true depiction of drug performance. The variables which cannot
be

taken

into

account

during in vitro studies

can

be

fully

explored

during in
vivo studies. In vivo evaluation can be carried out using animal &human models.
Animal models:

Considerable time and resources are required to carry out human studies, so
animal studies are preferred at small scale.

The most common animal species used for evaluating TDDS are mouse, hairless
rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig etc.

Various experiments conducted leads to a conclusion that hairless animals are
preferred over hairy animals in both in vitro and in vivo experiments.

Rhesus monkey is one of most reliable models for in vivo evaluation of TDDS.
Human model

The final stage of development of a TDDS involves collection of pharmacokinetic
& pharmacodynamic data following application of the patch to human volunteers.

Clinical trials have been conducted to assess the efficacy, risk involved, side
effects, patient compliance etc.

Phase I clinical trials are conducted to determine mainly safety in volunteers

Phase II clinical trials determine short term safety & effectiveness in patients.

Phase III indicate safety &effectiveness in large number of patient population

Phase IV trials at post marketing surveillance to detect adverse drug reactions.

It require considerable resources best to assess the performance of the drug.

31. 3.2.
Gastroretentive drug delivery systems: Introduction, advantages,
disadvantages,approaches for GRDDS – Floating, high density systems, inflatable and
gastroadhesivesystems and their applications


3.2. Gastro-retentive drug delivery systems:
Introduction:
Gastro retentive drug delivery is an approach to prolong gastric
residence time, thereby targeting site-specific drug release in the upper
gastrointestinal tract (GIT) for local or systemic effects. Gastro retentive
dosage forms can remain in the gastric region for long periods and hence
significantly prolong the gastric retention time (GRT) of drugs.
Gastro-retentive drug delivery systems provide efficient means of
enhancing the bioavailability and controlled delivery of many drugs. The
concept involved in GRDDS is increasing the gastric retention time. Drugs
which require increase in bioavailability and controlled delivery can be
formulated by utilizing the novel concept GRDDS.
The popularity of this system increases day by day due to its easy
of manufacture and cost effective. Wide range of drugs can be used in
these system with improved bioavailability. The system can also be used
for targeting of drugs to particular part of the body especially in gastric
and duodenal part for the treatment of cancer and inflammation.
GRDDS serves as a valuable tool for the patients who prefer oral route with
less frequent dosing.
Need for gastro-retention:

32. Drugs that are absorbed from the proximal part of the
gastrointestinal tract (GIT). Drugs that are less soluble or that
degrade at the alkaline pH.
Drugs that are absorbed due to variable gastric emptying time.
Local or sustained drug delivery to the stomach and proximal small
intestine to treat certain conditions.
Treatment of peptic ulcers caused by H.Pylori infections.

Drugs those are locally active in the stomach.
Drugs that have narrow absorption window in
gastrointestinal tract (GIT). Drugs those are unstable in the
intestinal or colonic environment.
Drugs that disturb normal colonic microbes Drugs that exhibit low
solubility at high
pH values.
Advantages of GRDDS:
This system offers improved
bioavailability It reduces dose and
dosing frequency.
This system minimizes fluctuation of drug
concentration in blood This system helps in targeting
of drugs
Local action can be achieved in GIT. Eg.
Antacids This system reduces the side
effect.
Sustained release can be
achieved. Safest route of
administration
It is economic and can be used for wide range of drugs.

Disadvantages of GRDDS:
This system should be administered with plenty of water.
Drugs with solubility or stability problem in GIT can’t be administered.
Drugs, which undergoes first pass metabolism, are not suitable. e.g.
Nifedipine.

33. Drugs which are irritant to gastric mucosa are not suitable. E.g.
Aspirin & NSAID. Drugs that absorb equally well through GIT. E.g.
Isosorbide dinitrate, Nifidipine

Approaches for GRDDS:
Different approaches of gastro-retentive drug delivery systems are
discussed as follows:

1. Floating system or Low density system:
Floating Drug Delivery Systems (FDDS) have a bulk density lower
than gastric fluids and thus remain buoyant in the stomach for a
prolonged period of time, without affecting the gastric emptying rate and
the drug is released slowly at a desired rate from the system, results in an
increase in the gastric residence time and a better control of fluctuations
in the plasma drug concentrations and after complete release of the drug,
the residual system is emptied from the stomach.

Low-density systems (Floating system)

Floating drug delivery systems (FDDS) have a bulk density less than
gastric fluids and so remain buoyant in the stomach without affecting the
gastric emptying rate for a prolonged period of time. While the system is
floating on the gastric contents the drug is released slowly at the desired rate
from the system. After release of drug, the residual system is emptied from the
stomach. This results in an increased GRT and a better control of the
fluctuations in plasma drug concentration. However, besides a minimal gastric
content needed to allow the proper achievement of the buoyancy retention
principle, a minimal level of floating force (F) is also required to keep the
dosage form reliably buoyant on the surface of the meal. The floating force

34. kinetics is measured using a novel apparatus by determining the resultant
weight (RW). The RW
apparatus operates by measuring continuously the force equivalent to F (as a
function of time) that is required to maintain the submerged object.
The object floats better if RW is on the higher positive side.
RW or F = F buoyancy - F gravity
= (Df - Ds) gV,
Where,
RW = total vertical force,
Df = fluid density,
Ds = object density,
V = volume and
g = acceleration due to gravity.


Mechanism of Floating Systems

Gf= gastric fluid

In case of gas generating systems, carbon dioxide is released causing
the beads to float in the stomach. And in case of non-effervescent systems, the
air trapped by the swollen polymer confers buoyancy to these dosage forms
Based on the mechanism of buoyancy, two different technologies have been
used in development of floating drug delivery systems. These include:
a)
Non- Effervescent system.
b)
Effervescent
system. Non-

35. Effervescent
System
The Non-effervescent FDDS is based on mechanism of swelling of
polymer or bio-adhesion to mucosal layer in GI tract. The most commonly used
excipients in non-effervescent. FDDS are gel forming or highly swellable
cellulose type hydrocolloids, hydrophilic gums,
polysaccharides and matrix forming materials such as polycarbonate,
polyacrylate, polymethacrylate, polystyrene as well as bioadhesive polymers
such as chitosan and carbopol). This system can be further divided in to the su-
types:
a.
Hydrodynamically balanced systems.
These systems contains drug with gel-forming hydrocolloids meant to remain
buoyant on the stomach content. These are single-unit dosage form, containing
one or more gel-forming hydrophilic polymers. Hydroxypropyl methylcellulose
(HPMC), hydroxethyl cellulose (HEC), hydroxypropyl cellulose (HPC), sodium
carboxymethyl cellulose (NaCMC), polycarbophil, polyacrylate, polystyrene,
agar, carrageenans or alginic acid are commonly used excipients to develop
these systems. The polymer is mixed with drugs and usually administered in
hydrodynamically balanced system capsule. The capsule shell dissolves in
contact with water and mixture swells to form a gelatinous barrier, which
imparts buoyancy to dosage form in gastric juice for a long period. Because,
continuous erosion of the surface allows water penetration to the inner layers
maintaining surface hydration and buoyancy to dosage form. Incorporation of
fatty excipients gives low density formulations reducing the erosion. Madopar
LPR, based on the system was marketed during the 1980’s. Effective drug
deliveries depend on the balance of drug loading and the effect of polymer on
its release profile several strategies have been tried and investigated to
improve efficiencies of the floating hydrodynamically balanced systems.
b.
Microballoons / Hollow microspheres:
Microballoons / hollow microspheres loaded with drugs in their other polymer
shelf were prepared by simple solvent evaporation or solvent diffusion
evaporation methods to prolong the gastric retention time (GRT) of the dosage
form. Commonly used polymers to develop these systems are polycarbonate,
cellulose acetate, calcium alginate, Eudragit S, agar and low methoxylated pectin
etc. Buoyancy and drug release from dosage form are dependent on quantity of
polymers, the plasticizer polymer ratio and the solvent used for formulation. The

36. micro-balloons floated continuously over the surface of an acidic dissolution
media containing surfactant for >12 hours. At present hollow microspheres are
considered to be one of the most promising buoyant systems because they
combine the advantages of multiple-unit system and good floating.



Microballoons
Effervescent System
A drug delivery system can be made to float in the stomach by incorporating
afloating chamber, which may be filled with vacuum, air or inert gas. The gas in
floating chamber can be introduced either by volatilization of an organic solvent
or by effervescent reaction between organic acids and bicarbonate salts . These
effervescent systems further classified into two types:
1)
Volatile liquid or vacuum containing systems.
2)
Gas generating systems.
Volatile liquid or vacuum containing systems
(a)
Intragastric floating gastrointestinal drug delivery system
This system floats in the stomach because of floatation chamber, which is
vacuum or filled with a harmless gas or air, while the drug reservoir is
encapsulated by a microporous compartment

Intragastric floating gastrointestinal drug
delivery device (b) Inflatable gastrointestinal delivery systems

37. These systems are incorporated with an inflatable chamber, which
contains liquid ether that gasifies at body temperature to inflate the chamber in
the stomach. These systems are fabricated by loading the inflatable chamber
with a drug reservoir, which can be a drug, impregnated polymeric matrix, then
encapsulated in a gelatin capsule. After oral administration, the capsule
dissolves to release the drug reservoir together with the inflatable chamber.
The inflatable chamber automatically inflates and retains the drug reservoir
compartment in the stomach. The drug is released continuously from the
reservoir into gastric fluid.








Inflation chamber
Bioadhesive Systems
Bio/mucoadhesive systems are those which bind to the gastric epithelial
cell surface or mucin and serve as a potential means of extending the Gastro
retention of drug delivery system (DDS) in the stomach by increasing the
intimacy and duration of contact of drug with the
biological membrane. A bio/muco-adhesive substance is a natural or synthetic
polymer capable of producing an adhesive interaction based on hydration–
mediated, bonding mediated or receptor mediated adhesion with a biological
membrane or mucus lining of GI mucosa. The binding of polymers to the
mucin-epithelial surface can be subdivided into three broad categories-
1.
Hydration-mediated adhesion
2.
Bonding-mediated adhesion
3.
Receptor-mediated adhesion
1.
Hydration-mediated adhesion
Certain hydrophilic polymers tend to imbibe large amount of water and
become sticky, thereby acquiring bioadhesive properties.
2.
Bonding-mediated adhesion
The adhesion of polymers to a mucus or epithelial cell surface involves
various bonding mechanisms, including physical-mechanical bonding and
chemical bonding. Physical-mechanical bonds can result from the insertion of

38. the adhesive material into the crevices or folds of the mucosa. Chemical
bonds may be either covalent (primary) or ionic (secondary) in nature.
Secondary chemical bonds consist of dispersive interactions (i.e., vander
Waals interactions) and stronger specific interactions such as hydrogen
bonds. The hydrophilic functional groups responsible for forming hydrogen
bonds are the hydroxyl and carboxylic groups.
3.
Receptor-mediated adhesion
Certain polymers can bind to specific receptor sites on the surface of cells,
thereby enhancing the gastric retention of dosage forms. Certain plant lectins
such as tomato lectins interact specifically with the sugar groups present in
mucus.

High Density Systems
These systems with a density of about 3 g/cm3 are retained in the
antrum part of the stomach and are capable of withstanding its peristaltic
movements. The only major drawbacks with such systems is that it is
technically difficult to manufacture such formulations with high amount of drug
(>50%) and to achieve a density of about 2.5 g/cm3. This approach involves
formulation of dosage forms with the density that must exceed density of
normal stomach content (~ 1.004 gm/cm3). These formulations are prepared by
coating drug on a heavy core or mixed with inert materials such as iron powder,
barium sulphate, zinc oxide and titanium oxide etc. The materials increase
density by up to 1.5- 2.4 gm/cm3. A density close to 2.5 gm/cm3 seems
necessary for significant prolongation of gastric residence time. But,
effectiveness of this system in human beings was not observed and no system
has been marketed.



High-density systems
Raft forming Systems

39. Raft forming systems have received much attention for the delivery of
antacids and drug delivery for gastrointestinal infections and disorders. The
mechanism involved in the raft formation includes the formation of viscous
cohesive gel in contact with gastric fluids, where in each portion of the liquid
swells forming a continuous layer called a raft. This raft floats on gastric fluids
because of low bulk density created by the formation of CO2. Usually, the
system contains a gel forming agent and alkaline bicarbonates or carbonates
responsible for the formation of CO2 to make the system less dense and float
on the gastric fluids. The system contains a gel forming agent (e.g. alginic
acid), sodium bicarbonate and acid neutralizer, which forms a foaming sodium
alginate gel (raft) when in contact with gastric fluids. The raft thus formed floats
on the gastric fluids and prevents the reflux of the gastric contents (i.e. gastric
acid) into the esophagus by acting as a barrier between the stomach and
esophagus.

Application of GRDDS:
Gastro-retentive drug delivery system offer several applications as follows:
1.
Bioavailability: The bioavailability of controlled release GRDDS is
significantly enhanced in comparison to the administration of non-GRDDS
controlled release polymeric
formulations . There are several different processes, related to absorptions
and transit of the drugs in the gastrointestinal tract, that act concomitantly to
influence the magnitude of drugs absorption.
2.
Site Specific Drug Delivery Systems: These systems are particularly
advantageous for drugs those are specifically absorbed form intestine e.g.
Furosemide. The controlled, slow delivery of drug to the stomach provides
sufficient local therapeutic levels and limits the systemic exposure to the
drugs. It reduces the side effects which are caused by the drugs in the
blood circulation. In addition, the prolonged gastric availability from a site
directed delivery system may also reduce the dosing frequency.
3.
Sustained Drug Delivery: In this system, dose large and passing from
pyloric opening is prohibited. New sustained release floating capsules of
nicardipine hydrochloride were developed and were evaluated in vivo.
Plasma concentration time curves shows a longer duration for
administration (16 hours) in the sustained release floating capsules as
compared

40. with conventional capsules (8 hours). Hydrodynamically balance system
(HBS) can remain in stomach for prolong periods and hence release the drug
in sustained manner for prolong period of time.
4.
Enhancement of Absorption: Drugs which are having poor bioavailability
because of site-specific absorption from the upper parts of the GIT are
potential candidates to be formulated as floating drug delivery systems,
thereby maximizing their absorption. By virtue of its floating ability these
dosage forms can be retained in the gastric region for prolong period of
that drug can be targeted with maximum absorption rate.
5.
Minimize adverse activity at the colon: Retention of the drug in the HBS
systems at the stomach minimizes the amount of drug that reaches the
colon. Thus, undersirable activities of the drug in colon may be prevented.
This pharmacodynamic aspect provides the rationale for GRDF formulation
for betalactam antibiotics that are absorbed only from the small intestine
and whose presence in the colon leads to the development of
microorganism’s resistance.