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Unit-III BP 704T (Novel Drug Delivery Systems) Dr. Bijay Kumar Sahoo

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Svllabus
1. Transdermal Drug Delivery Systems: Introduction, Permeation through skin, factors
affecting permeation, permeation enhancers, basic components of TDDS, formulation
approaches
2. Gastroretentive drug delivery systems: Introduction, advantages, disadvantages, approaches

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for GRDDS Floating, high-density systems, inflatable and gastroadhesive systems and their
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applications
3. Nasopulmonary drug delivery system: Introduction to Nasal and Pulmonary routes of drug
delivery, Formulation of Inhalers (dry powder and metered dose), nasal sprays, nebulizers.
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Abbreviations:
TDDS: Transdermal drug delivery systems
SC: Stratum corneum
DMSO: Di-methylsulfoxide
PSA: Pressure Sensitive Adhesive
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GRT: Gastric retention time

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GRDDS: Gastro retentive drug delivery systems

FDDS: Floating Drug Delivery System
HPMC: Hydroxy Propyl Methyl Cellulose
DPI; Dry Power Inhalers
SCU: Spray Content Uniformity
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PDD: Pulmonary drug delivery

pMDI: Pressurized metered dose inhalers.
COPD: Chronic obstructive pulmonary disease
API: Active Pharmaceutical Ingredient
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PVP: Poly vinyl pyrrolidone

CFC: Chlorofluorocarbon
HFA:Hydrofluoroalkane

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1. Transdermal Drug Delivery Systems:
Introduction:
Transdermal drug delivery systems (TDDS), also known as "patches," are dosage forms
designed to deliver a therapeutically effective amount of drug across a patient's skin. TDD is a
painless method of delivering drugs systemically by applying a drug formulation onto intact and

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healthy skin. The drug initially penetrates through the stratum corneum and then passes through
the deeper epidermis and dermis without drug accumulation in the dermal layer. When drug
reaches the dermal layer, it becomes available for systemic absorption via the dermal
microcirculation.
Transdermal delivery provides a leading edge over injectables and oral routes by
increasing patient compliance and avoiding first pass metabolism respectively. Transdermal
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delivery not only provides controlled, constant administration of the drug, but also allows
continuous input of drugs with short biological half-lives and eliminates pulsed entry into
systemic circulation, which often causes undesirable side effects.

Advantages of TDDS
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avoids FPM
Self-
administration Convenience

Flexibility of
Alternative
termination route
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Improved
Comfortable Advantages patient
compliance

Suitable steady
infusion
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stable Cuced side

levelsblood interaction
no erects
with
gastrointestin
al fluids

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Disadvantages of TDDS:

molecular size
restriction

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(<500 Dalton)/
variation in
High Cost
barrier function
(age, site)

no rapid/
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local irritation/
pulsatile drug Disadvantages uncomfortibility
release

low drug levels Tow permeability

in blood/plasma limits
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no ionic drug
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delivery

Permeation through skin:

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To improvise the current potential of TDDS it is necessary to understand the very basic
of skin anatomy. Skin is multi-layered organ composed of many histological layers. The major
divisions of the skin, from top to bottom, are the, epidermis, the dermis and the hypodermis.
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Dermal Bulge Sebaceous Stratum corneum
epidermal

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junction gland Granular layer
Epidermis Spinous layer

Arrector
pili
Basal layer
Dermis
Cortex 03Basement
Cuticle. Medulla membrane

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Inner root. Eccrine gland
sheath
Outer root Matrix
sheath Adherens junction
Dermal papilla of Hemidesmosome
hair follicle
Fat of subcutis Desmosome
DFocal contacts
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Anatomy of Skin
Epidermis:
Stratified, squamous, keratinizing epithelium. Keratinocytes comprise the major cellular
component 90%) and are responsible for the evolution of barrier function. Keratinocytes
change their shape, size and physical properties when migrating to the skin surface.
Microscopically, the epidermis further divided into five anatomical layers with approximately
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100-150 micrometres thick, Stratum corneum (SC) forming the outer most layer of the
epidermis, exposing to the external environment. This is the most important layer to transdermal
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delivery as its composition allows it to keep water within the body and foreign substances out.
SC is large, flat, polyhedral, plate-like envelopes filled with keratin that is made up of dead cells
that have migrated up from the stratum granulosum. The SC consists of 10-15 layers of
corneocytes and varies in thickness from approximately 10-15 m in the dry state to 40 um when
they are hydrated.
Dermis:
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Dermis consists of extensive microvasculature network structures like sweat glands, hair
follicles, and the smaller blood vessels. Therefore, in order to have drug delivery via the skin, the
drug must pass through the epidermis into the dermis where it can be absorbed by capillaries into
the circulatory system. Inner and larger (90%) skin layer comprises primarily of connective
tissue and provides supports to the epidermis layer of the skin. The boundary between dermis
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and epidermis layer is called Dermal- Epidermal junction which provides a physical barrier for
the large molecules of drug and cells. It incorporates blood and lymphatic vesicles and nerve
endings. Dermis can be divided into two anatomical region; papillary dermis and reticular
dermis. Papillary is the thinner outermost portion of the dermis. Collagen and elastin fibres are
mostly vertically oriented in the papillary region and connected with the dermal-epidermal
junction.

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Hypodermis

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Subcutaneous, or hypodermis in histology, is the third layer beneath the dermis.
Subcutaneous is an elastic layer and includes a large amount of fat cells that work as a shock
absorber for blood vessels and nerve endings. The thickness of this layer is 4 to 9 mm on
average. However, the actual thickness differs from person to person and it depends on the bodyy
region.
When a molecule reaches intact skin, it contacts with the cellular debris, normal flora of
microorganisms, sebum and other materials.

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Routes of skin penetration
The main route of transport for water-soluble molecules is transcellular. It involves the
passage through the cytoplasm of corneocytes and lipid arrangement of the stratum corneum9.
The pathway of transport for lipid soluble molecules is intercellular; it implicates the passage
apparently through the endogenous lipid within the stratum corneum. The transcellular and
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intercellular route is collectively known as trans-epidermal route as shown below.

TRANSEPIDERMAL ROUTE

Intercellular route Transcellular route

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Corneocyte-
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Cytoplasm - Aqeous
Plasma
Cholesterol
membrane

Intercellular
spaces
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Lipid Aqeous Ceramide Fatty acid Keratinn Minimal lipid

Triglyceride

Solute molecules may penetrate the skin through the hair follicles, sweat duct or through
the sebaceous glands. These passages are collectively known as shunt or appendageal route.
It is generally accepted that the skin appendages comprises of approximately 0.1% of fractional
area for drug permeation. Thus, the main focus is to develop pemeation strategies through the
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stratum corneum rather than through the appendages.

The main barriers to absorption are the dead cells of the SC, restricting the inward and
outward movement of drug substances and having high electrical resistance. The SC is a
heterogeneous tissue, composed of flattened keratinized cells.
The outer layers of these cells are less densely packed than those adjacent to the
underlying granular layer. Therefore, the epidermal barrier becomes more impermeable in the

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lower part and this fact has led to suggestion that a separate barrier exists at this level, the so
called SC.

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Thus as molecules move from the environment into the skin, the rate limiting barrier i.e.
the tissue that presents the greatest resistance to the movement of molecules, is the SC
Once the dosage form is applied topically, the percutaneous absorption or transdermal
permeation can be visualized as a composite of a series of steps.
a. Adsorption of a penetrant molecule onto the surface layers of SC.
b. Diffusion through SC and through viable epidermis.
Percutaneous Absorption
It is a step-wise process of penetration of substances into various layers of skin and

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permeation across the skin into systemic circulations and can be divided into three parts:
a. Penetration: the entry of a substance into a particular layer.
b. Permeation: the penetration from one layer into another, and is different both functionally and
structurally from the first layer.
c. Absorption: the uptake of a substance into systemic circulation.
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Factors affecting Permeation
The principle transport mechanism across mammalian skin is by passive diffusion
through primarily the trans-cpidermal route at steady state or through trans-appendageal route at
initially, non-steady state.
The factors that affect the permeability of the skin are classified into following three categories:
A. Physicochemical properties of the permeate molecule
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i. Partition co-efficient:
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Drug possessing both water and lipid solubility are favorably absorbed through the skin.
Transdernmal permeability co-efficient shows a linear dependence on partition co
efficient. Varying the vehicle may also alter a lipid/water partition co-efficient of a drug
molecule. The partition co-efficient of a drug molecule may be altered by chemical
modification without affecting the pharmacological activity of the drug.
ii. Molecular size: There is an inverse relationship existed between transdermal flux and
molecular weight of the molecule. The drug molecule selected as candidates for
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transdermal delivery tend to lie within narrow range of molecular weight (100-500
Dalton).
ii. Solubility / Melting point: Lipophilicity is a desired property of transdermal candidates
as lipophilic molecules tend to permeate through the skin faster than more
hydrophilic molecules. Drugs with high melting points have relatively low aqueous
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solubility at normal temperature and pressure.

iv. PH condition:
The pH mainly affects the rates of absorption of acidie and basic drugs whereas
unchanged form of drug has better penetrating capacity. Transport of ionizable species

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from aqueous solutions shows strong pH dependence. According to pHI partition
hypothesis, only the unionized form of the drugs can permeate through the lipid

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barrier in significant amounts.
B. Physicochemical properties of the drug delivery system

i. The affinity of the vehicle for the drug molecules:

It can influence the release of the drug molecule from the carrier. Solubility in the carrier
determines the release rate of the drug. The mechanism of drug release depends on whether
the drug is dissolved or suspended in the delivery/carrier system and on the interfacial

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partition co-efficient of the drug from the delivery system to skin tissue.
ii. Composition of drug delivery system:
Composition of drug delivery system may affect not only the rate of drug release but also
the permeability of the SC by means of hydration.
ii. Enhancement of transdermal permeation:
Due to the dead nature of the SC the release of the drug from the dosage form is less.
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Penetration enhancers thus can cause the physicochemical or physiological changes in SC
and increase the penetration of the drug through the skin. Various chemical substances are
found to possess such drug penetration enhancing property.

Physiological and pathological condition of the skin:

a. Skin age:
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Foetal and infant skin appears to be more permeable than mature adult skin and therefore
percutaneous absorption of topical steroids occurs more rapidly in children than in adults
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whereas, water permeation has shown to be same in adults and in children.

b. Lipid film:
The thin lipid film on skin surface is formed by the excretion of sebaceous glands and cell
lipids like sebum and epidermal cell which contain emulsifying agent may provide a
protective film to prevent the removal of natural moisturising factor from the skin and help in
maintaining the barrier function of the SC.
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c. Skin hydration:
Hydration of SC can enhance transdermal permeability. The rate of penetration study of
salicylic acid through skin with dry and hydrated corneum showed that when the tissues were
hydrated, the rate of penetration of the most water-soluble esters increased more than that of
the other esters.
d. Skin temperature:
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Raising skin temperature results in an increase in the rate of skin permeation. Rise in skin
temperature may also increase vasodilation of blood vessels, which are in contact with skin
leading to an increase in percutaneous absorption.
e. Cutaneous drug metabolism:

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After crossing the SC barrier, some of the drug reaches the general circulation in active form
and some of this in inactive form or metabolic form, because of the presence of metabolic

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enzymes present in the skin layers. It was reported that more than 95% of testosterone
absorbed was metabolized as it present through the skin.
f. Species differences:
Mammalian skin from different species display wide differences in anatomy in such
characteristics as the thickness of SC, number of sweat glands and hair follicles per unit
surface area.
g. Pathological injury to the skin:

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Injuries to the skin can cause the disturbance in the continuity of SC and leads to increase in
skin permeability.

Permeation Enhancers:

These are compounds that promote skin permeability by altering the skin as a barrier to the flux
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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 [de/dx]
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J = The Flux, D = diffusion coefficient, C = Concentration of the diffusing species, X =

Spatial coordinate.
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The methods employed for modifying the barier 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:
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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 thee
stratum corneum.
Promoting penetration and establishing drugs reservoir in the stratum corneum.
Chemical permeation enhancers exert their effect through above modifications in the skin
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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

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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 lipidd

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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.

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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 (2100 V) and short treatment durations
(milliseconds) are most frequently employed. The technology has been successfully used to
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enhance the skin permeability of molecules with differing lipophilicity and size (i.e., small
molecules, proteins, peptides, and oligonucleotides).
lontophoresis
This method involves enhancing the permeation of a topically applied therapeutic agent
by the application of a low-level electric current, either directl to the skin or indirectly via the
dosage form. Increase in drug permeation as a result of this methodology can be attributed to
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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.
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Ultrasound
Ultrasound involves the use of ultrasonic energy to enhance the transdernmal 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.
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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
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The skin surface temperature is usually maintained at 32°C in humans by a range of

homeostatic controls.
Microneedle-based devices

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One of the first patents ever filed for a drug delivery device for the pereutaneous
administration of drugs is based on this method. These micro-needles of length 50 to 110 mm

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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

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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
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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.
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It should be non-damaging to viable cells.

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

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
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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.
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,
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Polypropylene, Polyacrylate, Polyamide, Polyurea, Polyvinyl pyrrolidone, Polymethy

Imethacrylate, Epoxy etc.
Drug:

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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

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transdermal delivery.
Physicochemical properties:
.The drug should have a molecular weight less than approximately 1000 Daltons.
The drug should have aftinity for both lipophilic and hydrophilic phases. Extrene 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-

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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
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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.
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The first approach involves the development of new polymers, which include hydrogel
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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
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polymers in order to improve drug delivery rates

5 Backings Laminates:
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
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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:

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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

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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

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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.
Formulation Approaches of TDDS:
The different formulation approaches for TDDS are discussed as follows.
1. Polymer membrane permeation controlled TDD system:
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Drug reservoir sandwiched between drug impermeable backing laminate and rate
controlling polymeric membrane. In drug reservoir compartment drug is dispersed
homogeneously in a solid polymeric matrix(e.g. polyisobutylene), suspended in a un
leachable viscous liquid medium(e.g. silicon fluid) to form a paste like suspension. Rate
controlling membrane is either a micro-porous or a nonporous polymeric membrane e.g.
ethylene-vinyl acetate copolymer. Example of this type of patch are Estraderm(twice a
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week in treatment of postmenopausal syndrome) and Duragesic (management of chronic

pain for 72 hrs)
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Impemeable backing
Drug Reservoir

Rate
controlling
membrane
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Adhesive
Membrane permeation controlled system.

The intrinsic rate of drug release from this type of drug delivery system is defined by
d/dt}-Cr/1/Pm+1/Pa. Where, Cr = Concentration of drug in the drug reservoir. Pa=
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Permeation Co-efficient of adhesive layer. Pm= Pernmeation Co-efficient of rate controlling

membrane.
For any micro porous rate controlling membrane, Pm approximately represents the sum of
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permeability co-efficient across the pores and polymerie material. Pa and Pm may be separately
defined as Pa
Pa-Ka/m.Da/ha

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Pm-Km/r.Dm/hm
Where,

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Da-Diffusion Co-efficient of an derive layer
Dm-Diffusion Co-efficient of rate controlling membrane
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Ka/m= Partition Co-efficient for interfacial partitioning of drug from rate controlling membrane
to adhesive layer
Km/r-Partition Co-efficient for interfacial partitioning of drug from reservoir to rate controlling
membrane
hm-Thickness of rate = Controlling membrane.

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Ha- Thickness of adhesive layer
2. Polymer matrix diffusion controlled TDD system:
In this the drug reservoir is prepared by homogeneously dispersing drug particles in a
hydrophilic (or) lipophilic polymer matrix. The resulting polymer matrix is then moulded into
discs with defined surface area and controlled thickness. The medicated disc is then moulded
onto an occlusive base plate in a compartment made up of a drug impermeable backing. Finally
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adhesive polymer is spread along the circumference of the film. Examples: Nitro-glycerine
releasing transdermal therapeutic system at a daily dose of 0.5g/em2 for angina pectoris.
Rate of drug release in this system is given by the equation dq/dt = {ACpDp/2t12
Where,
A- Initial drug loading dose dispersed in polymer matrix
Cp Solubility of drug in Polymer
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Dp = Diffusivity of drug in Polymer since Cp is equal to Cr.

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Drug impermeable
Occlusive base plate plastic backing
Absorbent pad

Adhesive rim
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Drug reservoir
drug polymer matrix)
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Matrix diffusion controlled Systems

3. Adhesive Dispersion Type Systems:

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This is a Simplified form of membrane Permeation-Controlled Systems. In this system, drug

and other selected excipients are directly incorporated into the adhesive solution. They are then

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mixed and casted as thin films and finally the solvent is evaporated by drying the film. The
drug reservoir (film) is the then sandwiched between the banking laminate and rate

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controlling adhesive polymer membrane.
The rate of drug release from this system is g en by, dq/dt = Cr.Ka/r .Da/ha
Where Ka/r = Partition co-efficient for interfacial partitioning of drug from reservoir layer to
adhesive layer.
Examples: Iso sorbide dinitrate -releasing TDDS 24 hr, Used in Angina Pectoris Verapamil
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releasing TDDS-24 hrs, used in Hypertension.

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Drugimpermeable metallid
plastic laminate
Adhesive
Drug rservoir
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Rate controlling
adhesive layer

Adhesive Dispersion -
Type Systems

4. Microreservoir dissolution controlled TDD system:

It is considered as the hybrid system of reservoir and matrix dispersion type drug
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delivery. In this system the drug reservoir is formed by first suspending the drug solids in
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aqueous solution of water-miscible drug solubilser e.g. polyethylene glycol and than
homogeneously dispersing the drug suspension with controlled aqueous soluble lipophillic
polymer by high shear mechanical force to form thousands of un-leachable microscopic drug
reservoir.

Adhesive foam pad

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Adhesive rim

Oclusive baseplate(Alfolldisc)
Microsopic drug reservoir
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Polmer umatris
Micro reservoir type Systems

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2. Gastro-retentive drug delivery systems:
Introduction:

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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 gastrie 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

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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
lP
dosing.
Need for gastro-retention:
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
l

treat certain conditions.

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Treatment of peptic ulcers caused by H.Pylori infections.

Potential Drug Candidates for Gastro-retentive Drug Delivery Systems:
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.
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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
Ca

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.

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Disadvantages of GRDDS:
This system should be administered with plenty of water.

rm
Drugs with solubility or stability problem in GIT can't be administered.
Drugs, which undergoes first pass metabolism, are not suitable. e.g. Nifedipine.
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

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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
lP
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.
l
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Intragastric floating system

(density 1 9.cm
Low-density systems (Floating system)
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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
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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
kinetics is measured using a novel apparatus by determining the resultant weight (RW). The RW

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apparatus operates by measuring continuously the force equivalent to F (as a function of time)
that is required to maintain the submerged object.

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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,

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V=volume and
g acceleration due to gravity. lP
Swelirg ytem W Ga-qmenating

stm

Imbbiaon of GF (0, wkaed G

pevwides F
buyan
W-ve
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onany
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Mechanism of Floating Systems

Gf= gastric fluid

In case of gas generating systems, carbon dioxide is released causing the beads to float in
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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.
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b) Effervescent system.
Non-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,

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polysaccharides and matrix forming materials such as polycarbonate, polyacrylate,
polymethacrylate, polystyrene as well as bioadhesive polymers such as chitosan and carbopol).

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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 fornm, containing one or more gel-forming
hydrophilic polymers. Hydroxypropyl methyleellulose (HPMC), hydroxethyl cellulose (HEC),
hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose (NaCMC), polycarbophil,
polyacrylate, polystyrene, agar, carrageenans or alginic acid are commonly used excipients to

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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
lP
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. Mieroballoons/ Hollow microspheres:
Microballoons / holow microspheres loaded with drugs in their other polymer shelf were
l

prepared by simple solvent evaporation or solvent diffusion evaporation methods to prolong the
gastrie retention time (GRT) of the dosage form. Commonly used polymers to develop these
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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 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.
re

OO-O
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OWemulsion Rapid dirfusion of Slow diffu sionof ethanol Hollow microsphere

dichloromethane or microballoon

Microballoons

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Effervescent System

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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 systemns
(a) Intragastric floating gastrointestinal drug delivery system

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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

Flotatiom chamber

Microporous wall
lP
Drug
Reservior

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

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
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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.
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apSule

infiaatabe cham ber

ioero ibl POlymer

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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

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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

rm
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,

ha
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 the adhesive material into the crevices or
folds of the mucosa. Chemical bonds may be either covalent (primary) or ionic (secondary) in
lP
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
l

the gastric retention of dosage forms. Certain plant lectins such as tomato lectins interact
specifically with the sugar groups present in mucus.
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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
re

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 gastrie residence time. But,
Ca

effectiveness of this system in human beings was not observed and no system has been
marketed.

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rm
High-density systems

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Raft forming Systems
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
lP
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 gastrie eontents (i.e. gastric
acid) into the esophagus by acting as a barrier between the stomach and esophagus.
l
we

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.
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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
Ca

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

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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

rm
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 ofits
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

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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 antibioties that are absorbed only from the small intestine
and whose presence in the colon leads to the development of microorganism's resistance.
lP
3. Naso-pulmonary drug delivery system:
Introduction to Nasal routes of drug delivery:
Nasal route of drug delivery has been considered as a potential administration route to
l

achieve faster and higher level of drug absorption because it is permeable to more compounds
than the gastrointestinal tract due to lack of pancreatic and gastric enzymatic activity, neutral pH
we

of the nasal mucus and less dilution by gastrointestinal contents.

It is a useful delivery method for drugs that are active in low doses and show no minimal
oral bioavailability such as proteins and peptides. One of the reasons for the low degree of
absorption of peptides and proteins via the nasal route is rapid movement away from the
absorption site in the nasal cavity due to the muco-ciliary clearance mechanism.
For many years, drugs have been administered nasally for both topical and systemic action.
re

Topical administration includes the treatment of congestion, rhinitis, sinusitis and related allergic
or chronic conditions. Prominent therapeutic classes of drugs delivered are decongestants for
cold nasal symptoms and antihistamines and corticosteroids for allergic rhinitis
The intranasal administration of drugs is an effective way for the systemic availability of
drugs as compared to oral and intravascular routes of administration. It provided fast and
Ca

extended drug absorption than oral and parenteral administration. Therapeutic classes of drugs
delivered include analgesics (morphine), cardiovascular drugs as propranolol and carvedilol,
hormones such as levonorgestrel, progesterone, and insulin, anti-inílammatory agents as
indomethacin and ketorolac, and antiviral drugs (acyclovir).

Advantages of nasal drug delivery

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1) Drug degradation that is observed in the gastrointestinal tract is absent.
2) Hepatic first pass metabolism is avoided.

rm
3) Rapid drug absorption and quick onset of action can be achieved.
4) The bioavailability of larger drug molecules can be improved by means of absorption
enhancer or other approach.
5) The nasal bioavailability for smaller drug molecules is good.
6) Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal drug
delivery.
7) Studies so far carried out indicate that the nasal route is an alternate to parenteral route,

ha
especially, for protein and peptide drugs.
8) Convenient for the patients, especially for those on long term therapy, when compared with
parenteral medication.
9) Drugs possessing poor stability in g.i.t. fluids are given by nasal route.
10) Polar compounds exhibiting poor oral absorption may be particularly suited for this route of
delivery
lP
Limitations
1) The histological toxicity of absorption enhancers used in nasal drug delivery system is not yet
clearly established.
2) Relatively inconvenient to patients when compared to oral delivery systems since there is a
possibility of nasal irritation.
3) Nasal cavity provides smaller absorption surface area when compared to GIT.
l

4) There is a risk of local side effects and irreversible damage of the cilia on the nasal mucosa,
both from the substance and from constituents added to the dosage form.
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5) Certain surfactants used as chemical enhancers may disrupt and even dissolve membrane in
high concentration.
6) There could be a mechanical loss of the dosage form into the other parts of the respiratory
tract like lungs because of the improper technique of administration.

Mechanism of Nasal Absorption

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The absorbed drugs from the nasal cavity must pass through the mucus layer; it is the
first step in absorption. Small, unchanged drugs easily pass through this layer but large, charged
drugs are difficult to cross it. The principle protein of the mucus is mucin, it has the tendency to
bind to the solutes, hindering diffusion. Additionally, structural changes in the mucus layer are
possible as a result of environmental changes (i.e. pH, temperature, etc.) So many absorption
mechanisms were established earlier but only two mechanisms have been predominantly used,
Ca

such as:

a) First mechanism- It involves an aqueous route of transport, which is also known as the
paracellular route but slow and passive. There is an inverse log-log correlation between

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intranasal absorption and the molecular weight of water-soluble com-pounds. The molecular
weight greater than 1000 Daltons having drugs shows poor bioavailability.

rm
b) Second mechanism- It involves transport through a lipoidal route and it is also known as the
transcellular process. It is responsible for the transport of lipophilic drugs that show a rate
dependency on their lipo-philicity. Drug also cross cell membranes by an active transport route
via carrier-mediated means or transport through the opening of tight junctions for examples:
chitosan, a natural biopolymer from shellfish, opens tight junctions between epithelial cells
to facilitate drug transport.

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Factors Influencing Nasal Drug Absorption

Several factors affect the systemic bioavailability of drugs which are administered
through the nasal route. The factors can be affecting to the physiochemical properties of the
drugs, the anatomical and physiological properties of the nasal cavity and the type and
characteristics of selected nasal drugs delivery system. These factors play key role for most of
lP
the drugs in order to reach therapeutically effective blood levels after nasal administration. The
factors influencing nasal drug absorption are described as follows.

1. Physiochemieal properties of drug.

Molecular size.
Lipophilic-hydrophilic balance.
.Enzymatic degradation in nasal cavity.
l

Stability
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Solubility
Physical state of drug
Chemical state of drug
2. Nasal Effect
Membrane permeability.
Environmental pH
Muco-ciliary clearance
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Cold, rhinitis.
Blood flow
3. Effect of drug formulation
Formulation (Concentration, pH, osmolarity)
Delivery effects
Drugs distribution and deposition.
.
Ca

Viscosity
Pharmaceutical excipients
Nasal Sprays
Most of the pharmaceutical nasal preparations on the market containing solutions,
emulsions or suspensions are delivered by metered-dose pump sprays. Nasal sprays, or nasal
mists, are used for the nasal delivery of a drug or drugs, either locally to generally alleviate

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cold or allergy symptoms such as nasal congestion or systemically, see nasal administration.
Although delivery methods vary, most nasal sprays function by instilling a fine mist into the

rm
nostril by action of a hand-operated pump mechanism. The three main types available for
local effect are: antihistamines, corticosteroids, and topical decongestants Metered- dose
pump sprays include the container, the pump with the valve and the actuator. The dose
accuracy of metered-dose pump sprays is dependent on the sur-face tension and viscosity of
the formulation. For solutions with higher viscosity, special pump and valve combinations
are on the market.
Excipients Used in Nasal Spray Formulations

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There are various types of excipients used in nasal formulations. Commonly used and
frequently added excipients are as follows

a. Buffers: Nasal secretions may alter the pH of the administrated dose, which can affect the
concentration of un-ionized drug available for absorption. Therefore, an adequate formulation
lP
buffer capacity may be required to maintain the pH in-situ. Examples of buffer used in nasal
spray sodium phosphate, Sodium citrate and citric acid.

b. Solubilizers: Aqueous solubility of drug is always a limitation for nasal drug delivery in
solution. Conventional solvents or co-solvents such as glycols, small quantities of alcohol,
Transcutol (diethylene glycol monoethyl ether), medium chain glycerides and Labrasol
(saturated polyglycolyzed C8-CI0 glyceride) can be used to enhance the solubility of drugs.
l

Other compounds can be used like, the use of surfactants or cyclodextrins such as HP-s-
Cyclodextrin that serve as a biocompatible solubilizer and stabilizer in combination with
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lipophilic absorption enhancers. In these cases, their impact on nasal irritancy should be
considered.

c. Preservatives: Most nasal formulations are aqueous based so needs preservatives to prevent
microbial growth. Parabens, phenyl ethyl alcohol, benzalkonium chloride, EDTA and benzoyl
alcohol are some of the commonly used preservatives in nasal formulations.
re

d. Antioxidants: A small quantityof antioxidants may be required to prevent drug oxidation.

Commonly used antioxidants are sodium bisulfite, butylated hydroxytoluene, sodium
metabisulfite and tocopherol. Usually, antioxidants do not affect drug absorption or cause
nasal irritation.
Ca

e. Humectants; Because of allergic and chronic diseases there can be crusts and drying of
mucous membrane. Certain preservatives/ antioxidants are also likely to cause nasal irritation
especially when used in higher quantities. Adequate intranasal moisture is essential for
preventing dehydration. Therefore, humectants can be added especially in gel-based nasal
products. Humectants avoid nasal irritation and do not affect drug absorption. Common
examples include glycerin, sorbitol and mannitol.

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f. Surfactants: Surfactant incorporation into nasal dosage forms can modify the permeability of
nasal membranes, which may facilitate the nasal absorption of drug. It also increase stability

rm
of suspension. Common examples include Polysorbet.
g. Bioadhesive polymers: Compound that is capable of interacting with biological material
through interfacial forces and being retained on such material for prolonged periods is called
as bioadhesive polymer. They are also called as mucoadhesive if biological material is mucus
membrane. The bioadhesive force of a polymer material is dependent on the nature of the
polymer, the surrounding medium (pH), swelling and physiological factors (mucin turnover,

ha
disease state). Froma safety (nasal irritancy) point of view use of a combination of carriers is
often recommended.

h. Penetration enhancer: Chemical penetration enhancers are widely used in the nasal drug
delivery.

Characterization of Nasal Spray:

lP
pH
Osmolality
.Viscosity
Impurities and Degradation Products
.Preservatives and Stabilizing Excipients Assay
Pump Delivery
l

Spray Content Uniformity (SCU)

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Spray Pattern and Plume Geometry

Droplet Size Distribution
Particle Size Distribution

Pulmonary Routes of Drug Delivery:

Introduction:
Pulmonary drug delivery (PDD) systems were recently introduced into the
re

pharmaceutical field to treat both the local and the systemic type of lung diseases. PLDD systems
are known to be able to simply deliver the drug to the required site in the body directly or to
other distant sites through the bloodstream. The lungs provide a huge surface area of alveoli
with rich capillary network, which acts as an excellent absorbing surface for administration of
drugs.
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Throughout the past several years, rapid onset of action and higher efficiency has been
responsible for the success of pulmonary delivery system for symptomatic relief in treatment of
asthma and chronic obstructive pulmonary disease (COPD). The efficacy of a treatment mostly
depends on the techniques by which the drug is delivered and optimum concentration of the
drug, above or below this range can be toxic or produce no therapeutic benefit at all. The slow
progress in the efficacy of the treatment of severe diseases, has suggested a growing need for a

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multidisciplinary approach to the delivery of therapeutic agents to targets in tissues. The efficacy
of the drug and its treatment can be achieved from the new ideas on controlling the

rm
pharmacokinetics, pharmaco-dynamics, immuneginecity, and bio-recognition. These new
strategies based on interdisciplinary approaches such as polymer science, pharmaceutical
technology, bio-conjugate chemistry, and molecular biology, are often called novel/advanced
drug delivery systems. Different drug delivery/drug targeting systems already exist and currently
under development can be efficiently used to minimize the drug degradation and loss, to prevent
harmful side effects and to increase drug bioavailability. For over 20 years, the potential benefit
of nanotechnology is appreciated by most of the researchers and it is providing vast

ha
improvements in drug delivery and drug targeting. New advancements in the drug delivery
strategies are minimizing the unwanted toxicities and improving the efficacy of the treatments.
Pulmonary delivery of drug has become an attractive target and of tremendous scientific
and biomedical interest in the health care research area as the lung is capable of absorbing
pharmaceuticals either for local deposition or for systemic delivery. The respiratory epithelial
cells have a prominent role in the regulation of airway tone and the production of airway lining
lP
fluid. In this respect, growing attention has been given to the potential of a pulmonary route as a
non-invasive administration for systemic and local delivery of therapeutic agents, because the
high permeability and large absorptive surface area of lungs, (approximately 70-140 m in adult
humans having extremely thin absorptive mucosal membrane) and good blood supply.
Advantages:
1. Pulmonary drug delivery having very negligible side effects since rest of body is not
l

exposed to drug.
2. Onset of action is very quick with pulmonary drug delivery.
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3. Degradation of drug by liver is avoided in pulmonary drug delivery.

4. The ability to nebulize viscous drug formulations for pulmonary delivery, thereby
overcoming drug solubility issues with the ability to use lipid, water or lipid/water
emulsions as drug carriers.
5. Increased drug delivery efficacy due to size-stable aerosol droplets with reduced
hygroscopic growth and evaporative shrinkage.
re

6. Liposomal drug formulations remain stable, when nebulized.

7. Ability to nebulizer protein-containing solutions.
8. Inhaled drug delivery puts drug where it is needed.
Limitations:
1. The oropharyngeal settlement may give local adverse effects.
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2. Patients may have trouble using the delivery devices correctly.

3. Various aspects affect the reproducibility of drug delivery to the lungs, including
physiological (respiratory scheme) and pharmaceutical (tool, formulation) variables. For the
systemic delivery of drugs with a small therapeutic index, such deviations may be
undesirable.

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4. Drug absorption may be limited due to the barrier action of the mucus and the drug-mucus
interactions.

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5. Mucociliary clearance diminishes the retention time of drugs within the lungs that may affect
the pharmacological efficacy of the slowly absorbed drugs.
6. The lungs are not an easily reachable surface for drug delivery, and complex delivery devices
are required for targeted drug delivery.

Mechanisms of Respiratory Deposition:

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The respiratory tract deposition of inhaled aerosol particles is due to three principal
mechanisms: inertia impaction, Brownian diffusion and gravitational settling. A theory is
developed to predict the particle deposition and its distribution in human respiratory tract for any
breathing condition.

Once the particle enters the respiratory tract via either the nose or mouth, it may be
lP
deposited in different regions of the respiratory tract. During breathing, the airflow
undergoes several direction changes in the nasal/mouth, pharynx, larynx regions, and
airway bifurcations.
Larger particles (>0.5 um) may deposit by impaction in these regions because they could
not follow the air streamline. In fact, deposition by impaction in the oro-pharyngeal
region remains a major portion of the emitted dose for pMDI and DPI devices.
In the small airways and alveolar region, deposition by sedimentation is the major
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deposition mechanism of inhaled particles.

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Small particles (<0.2 um) may be deposited by diffusion in all regions of the respiratory
tract. Diffusion deposition is important for nano-particles <100 nm.
Interception deposition is important for elongated particles such as fibrous aerosols
when the long particle dimension is comparable with the pulmonary airway dimension.

Formulation of Inhalers:
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1. Dry power inhalers:

The dry-powder-inhalers are designed to deliver drug/excipients powder to the lungs. Dry
powder inhalers (DPIs) are devices through which a dry powder formulation of an active drug
is delivered for local or systemic effect via the pulmonary route. Dry powder inhalers are
bolus drug delivery devices that contain solid drug. suspended or dissolved in a non polar
volatile propellant or in dry powder inhaler that is fluidized when the patient inhales. These
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are commonly used to treat respiratory diseases such as asthma, bronchitis, emphysema and
COPD and have also been used in the treatment of diabetes mellitus.
The dry powder platform comprises devices that generate an aerosol directly from 1 to 5 um
size drug powder, or mixtures with excipients. Excipients used in DPI are used as carrier for

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Active Pharmaceutical Ingredient (API). Most commonly used carrier is Lactose
Monohydrate.

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Formulation of DPI mainly includes following three steps;
a. API Production
The important requirement of API in case of DPI is particle size. Particle size of drug should
be less than 5 um. It should be in the range of 2-5 um. There are various sort of mills used for
size reduction of drugs but few of them are appropriate for DPI to reduce the size in the range
of 2-5 um such as fluid-energy mills, such as the jet mill; high-peripheral-speed mills, such as
the pin-mill; and the ball mill.

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b. Formulation of API with or without carriers.
The part of carrier in DPI is enhancing the flow property of powder and also aerosol
performance of the cohesive drugs and fine lactose. After drug and carrier (s) have separately
been brought to their desired forms, they are combined in the blending process.
c. Integration of the formulation into device
After the formulation has been blended, it is filled into capsules, multi-dose blisters, or
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reservoirs for use with the inhaler device. The filling process is automated and depends on the
nature of the metering system.

The primary inhaler parts are same for all type of devices on the market and many in
development. Dry Powder Inhaler device consists of; powder formulation, dose measuring
system, powder de-agglomeration principle and mouthpiece.
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Mouthpiece

Powder de-agglomeration principle

Powder formulation

-Dose (measuring) system

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Dry powder inhalers

Currently there are two types:

Unit dose devices: In a single-unit dose device, the drug is formulated as a micronized
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drug powder and carrier system and supplied in individual gelatin capsules, which are
then embedded into the device for a single dose.
Multi dose Devices: The multi-unit dose device utilizes factory metered and sealed doses
packaged in a way that the device can hold multiple doses without having to reload.
Commonly, the packaging comprises of replaceable disks or cartridges, or strips of foil-
polymer blister packaging that may or may not be reloadable.

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2. Formulation of Pressurized Metered Dose Inhalers:

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A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication
to the lungs, in the form of a short burst of aerosolized medicine that is inhaled by the patient. It
is the most commonly used delivery system for treating asthma, chronic obstructive pulmonary
disease (COPD) and other respiratory diseases. The medication in a metered dose inhaler is most
commonly a bronchodilator, corticosteroid or a combination of both for the treatment of asthma
and COPD.

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Pressurized metered aerosols may be formulated as either solutions or suspensions of
drug in the liquefied propellant. MDIs can be formulated with the drug completely dissolved
in the formulation, rendering a solution formulation, or with the drug practically insoluble in
the formulation, rendering a suspension formulation. Compared with suspension
formulations, solution MDIs offer the benefits of homogenous formulation (i.e., patients do
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not need to shake the vial immediately prior to use and there is no concern related to
sampling homogeneity), a finer residual aerosol.
When formulating solution MDIs, the total amount of fine particle drug delivered cannot
simply be increased by increasing the drug concentration in a formulation. Many drugs are
not readily soluble in HFA propellants, which frequently limits the amount of drug that can
be dosed using MDIs. Previously, surfactants or complexation aids were used in MDIs to
increase drug solubility in CFC systems .However, many of the conventional excipients
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used in CFC formulations and approved for human use, are insoluble in HFA system.
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The method for preparing drug particles for MDI formulations needs to be selected based
on the chemical stability of the drug. Proteins, for instance, require additional care when
micronizing, due to being heat-labile and need to preserve any three-dimensional
conformation. Frequently, spray-drying with another agent i.e., sodium
carboxymethylcellulose, polyvinyl alcohol, and/or polyvinylpyrrolidone (PVP) ) is utilized for
protein drugs due to the need to preserve the three-dimensional conformation and biological
activity of the protein.
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The basic requirements for formulation of MDIs are containers, propellants, and metering
valve.
. Filling Metered Dose inhaler canister: canister is filled by liquefying the propellant at
reduced temperature or elevated pressure. In cold filling, active compound, excipients
and propellant are chilled and filling at about-60°c. additional propellant is then added
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at the same temperature and the canister sealed with the valve. In pressure filling, a
drug/propellant concentrate is produced and filled at effectively room temperature and
pressure (in fact, usually slightly chilled to below 20°c). The value is crimped on to
the canister and additional propellant is filled at elevated pressure through the valve, in

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a process known as gassing. Pressure filling most frequently employed for inhalation
aerosols.

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3. Nebulizers:
A device converts liquids into aerosols that can be inhaled into the lowwer
respiratory tract. Nebulizers are used in aerosol drug delivery produce a poly-disperse
aerosol where the drug delivered in the particles size range 1-5 um in diameter. Most
Nebulizers use compressed air for atomization, but some use ultrasonic energy.
Nebulizers are generally used for the treatment of cystic fibrosis, asthma, COPD and

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other respiratory diseases or disorders. There are following three main types of nebulizers
commercially available.

Jet Nebulizer: This uses compressed gas to make an aerosol (tiny particles of medication
in the air). Jet nebulizers are applicable for acute and domiciliary treatment of various
respiratory diseases, pediatric and adult medical practices. These types of nebulizers
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required 2-10 L\min withdraw medication a capillary tube from the reservoir of the
nebulizer. It may cause generate a wider range of particles which blasted into one or
more baffles (to convert larger particles to smaller particles) out of suspension and return
them to nebulizer.

For patient air way

Ambient air in
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Patient
Drug loss Interface
Mist transport hose
during exhalation
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Alr fiter

Baffle/Orifice Nebulizing
chamber

Dead
volume
in -Diaphragm
Liguid reservoir
Operating
water chanmber
Drain tube
Compressed gas source
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OSCliato

Jet Nebulizer Ultrasonic Nebulizer

Ultrasonic Nebulizer. This makes an aerosol through high-frequency vibrations. The

particles are larger than with a jet nebulizer. Ultrasonic nebulizers incorporate a
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piezoelectric erystal vibrating at high frequencies (1-3 MHz) to produce an aerosol.

Ultrasonic nebulizers work on the principle that converts electrical energy to high-
frequency vibrations using a transducer. This nebulizer generates vibrations, which are
transferred to solution surface that would create waves, and those waves produce aerosol;
we can say that these types of nebulizers are large volume nebulizers to deliver
hypertonic saline for sputum inductions.

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Mesh Nebulizer. Mesh nebulizers contain apertures or aperture plate; when we applied
force, it will generate aerosol. They force liquid medications through multiple apertures

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in a mesh or aperture plate to generate aerosol. Comparisons of mesh and ultrasonic
nebulizers demonstrated similar drug delivery in simulated ventilator-dependent patients.
Mesh nebulizers are more efficient than jet nebulizers and can provide higher drug doses
to patients. The efficieney of mesh nebulizers is affected by various factors like size of
the pore, aerosol chamber, and reservoir.

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Mesh Nebulizer

Formulating Nebulizer Fluids:

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Nebulizer fluids are formulated in water, occasionally with the addition of co-solvents
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such as Ethanol or propylene glycol and with the addition of surfactants for suspension
formulations. Because nypo-osmotic and hyper-osmotic solutions may cause
bronchoconstriction, as may high hydrogen ion concentrations, iso-osmotic solutions of pH
greater than 5 are usually employed. Stabilizers such as antioxidants and preservatives may also
be included, although these may also cause bronchospasm and for this reason sulfites in
particular are generally avoided as antioxidant in such formulations.
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Whilst most nebulizer formulations are solutions, suspensions of micronized drug are
also available for delivery from nebulizers. In general, suspensions are poorly delivered fromn
ultrasonic nebulizers, whereas with jet nebulizer the efficiency of drug delivery increases as the
size of suspended drug is decreased, with little or no release of particles when they exceed the
droplet size of the nebulizer aerosol.
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References:

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1. Ansel HC, Popovich NG and Allen LV. Pharmaceutical dosage forms and drug delivery
systems. Lea & Febiger, Philadelphia; 1990.
2. Chien YW and Banga AK. lontophoretic (transdermal) delivery of drugs: overview of
historical development. Journal of Pharmaceutical Sciences.1989, 78(5); 353-354.
3. Aulton. M. E. Pharmaceutics; The science of dosage form design, second edition,

Churchill Livingston, Harcourt publishers-2002.

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4. Jain.N.K, Controlled and novel drug delivery, first edition, CBS publishers and

distributors, New Delhi. 1997.

5. Klausner EA, Lavy E, Friedman M, Hoffman A. Expandable gastro-retentive dosage
forms. J Control Release 2003; 90: 143-62.
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6. Thorat and Santosh: Formulation and product development of nebulizer inhaler: An
overview. Ine Pharmaceut Sci Res 2016; 5: 30-35.
7. Perkins W: Performance of PARI eFlow® To the Editor. Journal of Aerosol Medicine
and Pulmonary Drug Delivery 2010; 23: 113-14.
8. Shubham Prajapati, Sanjay Saha, C. Dilip Kumar: Nebulized Drug delivery:An overview
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International Journal of Pharmaceutical Sciences and Research 2019;10(8): 3575-3582.

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9. Aijaz A.Sheikh, subhash V.Deshmane, Kailash R.Biyani: A Text Book of Novel Drug
Delivery Systems, S. Vikash and Company 2019.
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