Prof. Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
Department of Pharmaceutics
KLE University’s College of Pharmacy
BELGAUm – 590010, Karnataka, India
Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
08/10/2010
KLECOP, Nipani
1
CONTENTS








Introduction of absorption.
Structure of the Cell Membrane.
Gastro intestinal absorption of drugs.
Mechanism of Drug absorption.
Factors affecting drug absorption
Absorption of drugs from non-per oral routes
Methods of determining absorption
References.
08/10/2010
KLECOP, Nipani
2
Introduction of Absorption

Definition :
The process of movement of unchanged
drug from the site of administration to systemic
circulation.

There always exist a correlation between the plasma
concentration of a drug & the therapeutic response &
thus, absorption can also be defined as the process of
movement of unchanged drug from the site of
administration to the site of measurement.
i.e., plasma.
08/10/2010
KLECOP, Nipani
3
Therapeutic success of a
rapidly & completely
absorbed drug.
Plasma
Minimum effective conc.
Drug
Therapeutic failure of a
slowly absorbed drug.
Conc.
Subtherapeutic level
Not only the
magnitude of drug
that comes into the
systemic circulation
but also the rate at
which it is absorbed
is important this is
clear from the figure.
Time
08/10/2010
KLECOP, Nipani
4
08/10/2010
KLECOP, Nipani
5
CELL MEMBRANE



Also called the plasma membrane, plasmalemma or
phospholipid bilayer.
The plasma membrane is a flexible yet sturdy barrier that
surrounds & contains the cytoplasm of a cell.
Cell membrane mainly consists of:
1. Lipid bilayer-phospholipid
-Cholesterol
-Glycolipids.
2. Proitens-Integral membrane proteins
-Lipid anchored proteins
-Peripheral Proteins
08/10/2010
KLECOP, Nipani
6
LIPID BILAYER
08/10/2010
KLECOP, Nipani
7
LIPID BILAYER



The basic structural framework of the plasma
membrane is the lipid bilayer.
Consists primarily of a thin layer of amphipathic
phospholipids which spontaneously arrange so that
the hydrophobic “tail” regions are shielded from the
surrounding polar fluid, causing the more hydrophilic
“head” regions to associate with the cytosolic &
extracellular faces of the resulting bilayer.
This forms a continuous, spherical lipid bilayer app.
7nm thick.
08/10/2010
KLECOP, Nipani
8
It consists of two back to back layers made up of
three types: Phospholipid, Cholesterol, Glycolipids.
1) Phospholipids :
Principal type of lipid in
membrane about 75 %.
Contains polar and non polar
region.
Polar region is hydrophilic and
non polar region is hydrophobic.
Non polar head contain two fatty
acid chain.
One chain is straight fatty acid
chain.( Saturated )
Another tail have cis double bond
and have kink in tail.
( Unsaturated )
08/10/2010
KLECOP, Nipani
9
CHOLESTEROL



Amount in membrane is 20 %.
Insert in membrane with same orientation as
phospholipids molecules.
Polar head of cholesterol is aligned with polar head of
phospholipids.
FUNCTION:
 Immobilize first few hydrocarbons groups
phospholipids molecules.
 Prevents crystallization of hydrocarbons &
phase shift in membrane
08/10/2010
KLECOP, Nipani
10
OH
08/10/2010
KLECOP, Nipani
11
08/10/2010
KLECOP, Nipani
12
GLYCOLIPIDS

Another component of membrane lipids present about 5 %.

Carbohydrate groups form polar “head”.

Fatty acids “tails” are non polar.

Present in membrane layer that faces the extracellular fluid.

This is one reason due to which bilayer is asymmetric.

FUNCTIONS:
Protective
Insulator
Site of receptor binding
08/10/2010
KLECOP, Nipani
13
08/10/2010
KLECOP, Nipani
14
COMPOSITION OF PROTEINS
PROTEINS
INTEGRAL
PROTEINS
08/10/2010
LIPID
ANCHORED
PROTEINS
KLECOP, Nipani
PERIPHERAL
PROTEINS
15
INTEGRAL PROTEINS





Also known as “Transmembrane protein”.
Have hydrophilic and hydrophobic domain.
Hydrophobic domain anchore within the cell
membrane and hydrophilic domain interacts with
external molecules.
Hydrophobic domain consists of one, multiple or
combination of α – helices and ß – sheets protein
mofits.
Ex. – Ion Channels, Proton pump, GPCR.
08/10/2010
KLECOP, Nipani
16
LIPID ANCHORED PROTEIN

Covalently bound to single or multiple lipid
molecules.

Hydrophobically inert into cell membrane & anchor
the protein.

The protein itself is not in contact with membrane.

Ex. – G Proteins.
08/10/2010
KLECOP, Nipani
17
PERIPHERAL PROTEINS

Attached to integral membrane proteins OR
associated with peripheral regions of lipid bilayer.

Have only temporary interaction with biological
membrane.

Once reacted with molecule, dissociates to carry on
its work in cytoplasm.

Ex. – Some Enzyme, Some Hormone
08/10/2010
KLECOP, Nipani
18
GASTRO INTESTINAL ABSORPTION OF DRUGS
08/10/2010
KLECOP, Nipani
19






Stomach :
The surface area for absorption of drugs is relatively small in
the stomach due to the absence of macrovilli & microvilli.
Extent of drug absorption is affected by variation in the time it
takes the stomach to empty, i.e., how long the dosage form is
able to reside in stomach.
Drugs which are acid labile must not be in contact with the
acidic environment of the stomach.
Stomach emptying applies more to the solid dosage forms
because the drug has to dissolve in the GI fluid before it is
available for absorption.
Since solubility & dissolution rate of most drugs is a function
of pH, it follows that, a delivery system carrying a drug that is
predominantly absorbed from the stomach, must stay in the
stomach for an extended period of time in order to assure
maximum dissolution & therefore to extent of absorption.
08/10/2010
KLECOP, Nipani
20

Small Intestine :

The drugs which are predominantly absorbed through the small
intestine, the transit time of a dosage form is the major
determinant of extent of absorption.

Various studies to determine transit time:

Early studies using indirect methods placed the average normal
transit time through the small intestine at about 7 hours.
These studies were based on the detection of hydrogen after an
oral dose of lactulose. (Fermentation of lactulose by colon
bacteria yields hydrogen in the breath).

08/10/2010
KLECOP, Nipani
21

Small Intestine
: suggest the transit time to be about 3 to
Newer studies

4 hours.
Use gamma scintigraphy.


Thus, if the transit time in small intestine for most
healthy adults is between 3 to 4 hours, a drug may
take about 4 to 8 hours to pass through the stomach &
small intestine during fasting state.
During the fed state, the small intestine transit time
may take about 8 to 12 hours.
08/10/2010
KLECOP, Nipani
22

Large intestine :

The major function of large intestine is to absorb
water from ingestible food residues which are
delivered to the large intestine in a fluid state, &
eliminate them from the body as semi solid feces.

Only a few drugs are absorbed in this region.
08/10/2010
KLECOP, Nipani
23
MECHANISM OF DRUG
ABSORPTION
1) Passive diffusion
2) Pore transport
3) Carrier- mediated transport
a) Facilitated diffusion
b) Active transport
4) Ionic or Electrochemical diffusion
5) Ion-pair transport
6) Endocytosis
08/10/2010
KLECOP, Nipani
24
1) PASSIVE DIFFUSION




08/10/2010
KLECOP, Nipani
Also known as non-ionic
diffusion.
It is defined as the
difference in the drug
concentration on either side
of the membrane.
Absorption of 90% of drugs.
The driving force for this
process is the concentration
or electrochemical gradient.
25

Passive diffusion is best expressed by Fick’s first
law of diffusion which states that the drug
molecules diffuse from a region of higher
concentration to one of lower concentration until
equilibrium is attained & the rate of diffusion is
directly proportional to the concentration gradient
across the membrane.
dQ
dt
=
D A Km/w
h
(CGIT – C)
Certain characteristic of passive diffusion can be
generalized.
a) Down hill transport

08/10/2010
KLECOP, Nipani
26
b) Greater the surface area & lesser the thickness of the
membrane, faster the diffusion.
c) Equilibrium is attained when the concentration on
either side of the membrane become equal.
d) Greater the membrane/ water partition coefficient of
drug, faster the absorption.
 Passive diffusion process is energy independent but
depends more or less on the square root of the
molecular size of the drugs.
 The mol. Wt. of the most drugs lie between 100 to
400 Daltons which can be effectively absorbed
passively.
08/10/2010
KLECOP, Nipani
27
2) Pore transport
Also known as convective transport, bulk flow or
filtration.
 Important in the absorption of low mol. Wt. (less than
100). Low molecular size (smaller than the diameter
of the pore) & generally water-soluble drugs through
narrow, aqueous filled channels or pores in the
membrane structure.
e.g. urea, water & sugars.
 The driving force for the passage of the drugs is the
hydrostatic or the osmotic pressure difference across
the membrane.

08/10/2010
KLECOP, Nipani
28

The rate of absorption via pore transport depends on the
number & size of the pores, & given as follows:
dc
dt
where,
dc =
dt
N =
R =
∆C =
η =
08/10/2010
=
N. R2. A . ∆C
(η) (h)
rate of the absorption.
number of pores
radius of pores
concentration gradient
viscosity of fluid in the pores
KLECOP, Nipani
29
3) CARRIER MEDIATED
TRANSPORT MECHANISM



Involves a carrier (a component of the membrane)
which binds reversibly with the solute molecules to be
transported to yield the carrier solute complex which
transverses across the membrane to the other side
where it dissociates to yield the solute molecule
The carrier then returns to its original site to accept a
fresh molecule of solute.
There are two types of carrier mediated transport
system:
a) facilitated diffusion
b) active transport
08/10/2010
KLECOP, Nipani
30
a) Facilitated diffusion
08/10/2010
KLECOP, Nipani

This mechanism involves
the driving force is
concentration gradient.

In this system, no
expenditure of energy is
involved (down-hill
transport), therefore the
process is not inhibited by
metabolic poisons that
interfere with energy
production.
31
Limited importance in the absorption of drugs.
e.g. Such a transport system include entry of glucose
into RBCs & intestinal absorption of vitamins B1 &
B2.
 A classical example of passive facilitated diffusion is
the gastro-intestinal absorption of vitamin B12.
 An intrinsic factor (IF), a glycoprotein produced by
the gastric parietal cells, forms a complex with
vitamin B12 which is then transported across the
intestinal membrane by a carrier system.

08/10/2010
KLECOP, Nipani
32
b) Active transport




08/10/2010
KLECOP, Nipani
More important process than
facilitated diffusion.
The driving force is against
the concentration gradient or
uphill transport.
Since the process is uphill,
energy is required in the work
done by the barrier.
As the process requires
expenditure of energy, it can
be inhibited by metabolic
poisons that interfere with
energy production.
33



If drugs (especially used in cancer) have structural similarities
to such agents, they are absorbed actively.
A good example of competitive inhibition of drug absorption
via active transport is the impaired absorption of levodopa
when ingested with meals rich in proteins.
The rate of absorption by active transport can be determined
by applying the equation used for Michalies-menten kinetics:
dc = [C].(dc/dt)max
dt
Km + [C]
Where,
(dc/dt)max = maximal rate of drug absorption at high drug
concentration.
[C]
= concentration of drug available for absorption
Km
= affinity constant of drug for the barrier.
08/10/2010
KLECOP, Nipani
34
4) IONIC OR ELECTROCHEMICAL
DIFFUSION




This charge influences the permeation of drugs.
Molecular forms of solutes are unaffected by the
membrane charge & permeate faster than ionic forms.
The permeation of anions & cations is also influenced
by pH.
Thus, at a given pH, the rate of permeation may be as
follows:
Unionized molecule > anions > cations
08/10/2010
KLECOP, Nipani
35



The permeation of ionized drugs, particularly the
cationic drugs, depend on the potential difference or
electrical gradient as the driving force across the
membrane.
Once inside the membrane, the cations are attached to
negatively charged intracellular membrane, thus
giving rise to an electrical gradient.
If the same drug is moving from a higher to lower
concentration, i.e., moving down the electrical
gradient , the phenomenon is known as
electrochemical diffusion.
08/10/2010
KLECOP, Nipani
36
5) ION PAIR TRANSPORT

08/10/2010
KLECOP, Nipani
It is another
mechanism is
able to explain
the absorption of
such drugs
which ionize at
all pH condition.
37




Transport of charged molecules due to the formation
of a neutral complex with another charged molecule
carrying an opposite charge.
Drugs have low o/w partition coefficient values, yet
these penetrate the membrane by forming reversible
neutral complexes with endogenous ions.
e.g. mucin of GIT.
Such neutral complexes have both the required
lipophilicity as well as aqueous solubility for passive
diffusion.
This phenomenon is known as ion-pair transport.
08/10/2010
KLECOP, Nipani
38
6) ENDOCYTOSIS

08/10/2010
KLECOP, Nipani
It involves engulfing
extracellular materials
within a segment of
the cell membrane to
form a saccule or a
vesicle (hence also
called as corpuscular
or vesicular transport)
which is then pinched
off intracellularly.
39
In endocytosis, there are three process:

A)
Phagocytosis
B)
Pinocytosis
C)
Transcytosis
08/10/2010
KLECOP, Nipani
40
A) Phagocytosis
08/10/2010
KLECOP, Nipani
41
B) Pinocytosis

08/10/2010
KLECOP, Nipani
This process is
important in the
absorption of oil
soluble vitamins & in
the uptake of
nutrients.
42
C) Transcytosis

It is a phenomenon in which endocytic vesicle
is transferred from one extracellular
compartment to another.
08/10/2010
KLECOP, Nipani
43
Diagram Representing Absorption, Distribution, Metabolism
and Excretion
The ultimate goal is to have the drug reach the site of action in
a concentration which produces a pharmacological effect. No
matter how the drug is given (other than IV) it must pass
through a number of biological membranes before it reaches
the site of action.
08/10/2010
KLECOP, Nipani
44
Rate dependent on polarity and size.
Polarity estimated using the partition coefficient.
The greater the lipid solubility – the faster the rate of diffusion
Smaller molecules (nm/A0) penetrate more rapidly.
Highly permeable to O2, CO2, NO and H2O .
Large polar molecules – sugar, aa, phosphorylated intermediates –
poor permeability
These are essential for cell function – must be actively
transported
08/10/2010
KLECOP, Nipani
45
MOVEMENT OF SUBSTANCES ACROSS
CELL MEMBRANES
08/10/2010
KLECOP, Nipani
46
BIOLOGICAL FACTORS:





Penetration Of Drugs Through Gastro-intestinal Tract
Penetration Of Drugs Through Blood Brain Barrier
Penetration Of Drugs Through Placental Barrier
Penetration Of Drugs Through Across The Skin
Penetration Of Drugs Through The Mucous Membrane Of The
Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal And Rectal
Surfaces
PHYSIOLOGICAL FACTORS:





Gastrointestinal (Gi) Physiology
Influence Of Drug Pka And Gi Ph On Drug Absorbtion
Git Blood Flow
Gastric Emptying
Disease States
08/10/2010
KLECOP, Nipani
47
PENETRATION OF DRUGS THROUGH
GASTRO-INTESTINAL TRACT
The Git barrier that separates the lumen of the stomach and intestine
from systemic circulation and is composed of lipids, proteins and
polysaccharides.
Git mucosa is a semi permeable membrane across which various
nutrients like Carbohydrates, Amino acids, Vitamins and foreign
substances are transported and absorbed into the blood by various
mechanisms like:
1. Passive diffusion
2. Pore transport
3. Facilitated transport
4. Active transport
5. Pinocytosis
08/10/2010
KLECOP, Nipani
48
1. PASSIVE DIFFUSION



Major process for absorption of more than 90% of drugs
Diffusion follows Fick’s law:
 The drug molecules diffuse from a region of higher
concentration to a region of lower concentration till
equilibrium is attained.
 Rate of diffusion is directly proportional to the
concentration gradient across the membrane.
Factors affecting Passive diffusion:
 Diffusion coefficient of the drug
 Related to lipid solubility and molecular wt.
 Thickness and surface area of the membrane
 Size of the molecule
08/10/2010
KLECOP, Nipani
49
08/10/2010
KLECOP, Nipani
50
2. PORE TRANSPORT



It involves the passage of ions through Aq. Pores (4-40 A0)
Low molecular weight molecules (less than 100 Daltons)
eg- urea, water, sugar are absorbed.
Also imp. In renal excretion, removal of drug from CSF
and entry
of drugs into liver.
08/10/2010
KLECOP, Nipani
51
3. FACILITATED DIFFUSION





Carrier mediated transport (downhill transport)
Faster than passive diffusion
No energy expenditure is involved
Not inhibited by metabolic poisons
Important in transport of Polar molecules and charged
ions that dissolve in water but they can not diffuse freely
across cell membranes due to the hydrophobic nature of
the phospholipids.
Eg. 1. entry of glucose into RBCs
2. intestinal absorption vitamin B1 ,B2
3. transport of amino acids thru permeases
08/10/2010
KLECOP, Nipani
52
08/10/2010
KLECOP, Nipani
53
4. ACTIVE TRANSPORT



Carrier mediated transport (uphill transport)
Energy is required in the work done by the carrier
Inhibited by metabolic poisons

Endogenous substances that are transported actively
include sodium, potassium, calcium, iron, glucose, amino
acids and vitamins like niacin, pyridoxin.

Drugs having structural similarity to such agents are
absorbed actively
Eg. 1. Pyrimidine transport system – absorption of 5 FU
and 5 BU
2. L-amino acid transport system – absorption of
methyldopa and levodopa
08/10/2010
KLECOP, Nipani
54
08/10/2010
KLECOP, Nipani
55
5. PINOCYTOSIS
Pinocytosis ("cell-drinking")

Uptake of fluid solute.

A form of endocytosis in which small particles are brought
into the cell in the form of small vesicles which
subsequently fuse with lysosomes to hydrolyze, or to break
down, the particles.

This process requires energy in the form of (ATP).

Polio vaccine and large protein molecules are absorbed by
pinocytosis
08/10/2010
KLECOP, Nipani
56
08/10/2010
KLECOP, Nipani
57
PENETRATION OF DRUGS THROUGH
BLOOD BRAIN BARRIER



A stealth of endothelial cells lining the capillaries.
It has tight junctions and lack large intra cellular pores.
Further, neural tissue covers the capillaries.

Together , they constitute the so called
BARRIER

Astrocytes : Special cells / elements of supporting tissue found at
the base of endothelial membrane.

The blood-brain barrier (BBB) is a separation of circulating
blood and cerebrospinal fluid (CSF) maintained by the choroid
plexus in the central nervous system (CNS).
08/10/2010
KLECOP, Nipani
BLOOD BRAIN
58
08/10/2010
KLECOP, Nipani
59
Since BBB is a lipoidal barrier,
It allows only the drugs having high o/w partition coefficient
to diffuse
passively where as moderately lipid soluble and
partially ionised molecules penetrate at a slow rate.
Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria
) and large or hydrophillic molecules into the CSF, while allowing the
diffusion of small hydrophobic molecules (O2, hormones, CO2). Cells of
the barrier actively transport metabolic products such as glucose across
the barrier with specific proteins.
Various approaches to promote crossing the BBB by drugs:
•
•
•
Use of Permeation enhancers such as dimethyl sulfoxide (DMSO)
Osmotic disruption of the BBB by infusing internal carotid artery
with mannitol
Use of Dihydropyridine redox system as drug carriers to the brain
( the lipid soluble dihydropyridine is linked as a carrier to the polar
drug to form a prodrug that rapidly crosses the BBB )
08/10/2010
KLECOP, Nipani
60
PENETRATION OF DRUGS THROUGH
PLACENTAL BARRIER





Placenta is the membrane separating fetal blood from the
maternal blood.
It is made up of fetal trophoblast basement membrane
and the endothelium.
Mean thickness (25 µ) in early pregnancy and reduces to (2
µ) at full term
Many drugs having mol. wt. < 1000 daltons and moderate
to high lipid solubility e.g. ethanol, sulfonamides ,
barbiturates, steroids , anticonvulsants and some
antibiotics cross the barrier by simple diffusion quite
rapidly .
Nutrients essential for fetal growth are transported by
carrier mediated processes
08/10/2010
KLECOP, Nipani
61
08/10/2010
KLECOP, Nipani
62
PENETRATION OF DRUGS THROUGH ACROSS
THE SKIN




Skin is composed of three primary layers:
the epidermis , which provides waterproofing and serves as a barrier to
infection;
the dermis , which serves as a location for the appendages of skin; and
the hypodermis (subcutaneous adipose layer).
The stratum corneum is the outermost layer of the epidermis and is composed
mainly of dead keratinised cells (from lack of oxygen and nutrients). It has a
thickness between 10 - 40 μm.
The dermis is the layer of skin beneath the epidermis. It contains the hair
follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels
and blood vessels.
Hypodermis - Its purpose is to attach the skin to underlying bone and muscle
as well as supplying it with blood vessels and nerves. The main cell types are
fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of
body fat).
08/10/2010
KLECOP, Nipani
63
08/10/2010
KLECOP, Nipani
64
ROUTES OF PENETRATION



Through follicular region
Through sweat ducts
Through unbroken stratum corneum
FACTORS IN SKIN PERMEATION
1.
2.
3.
4.
Thickness of the skin layer:
(Thickest on palms and soles & thinest on the face)
Skin condition: permeability of skin is affected by age, disease state or
injury.
Skin temp.: permeability increases with increase in temp.
Hydration state
APPROACHES TO ENHANCE SKIN PERMEATION
1.
2.
3.
4.
Innuction
Iontophoresis
Sonophoresis
Magnetophoresis
08/10/2010
KLECOP, Nipani
65
Penetration Of Drugs Through The Mucous Membrane Of
The Nose, Throat, Trachea, Buccal Cavity, Lungs ,Vaginal
And Rectal Surfaces

The barrier for the drug absorption is the capillary endothelial
membrane which is lipoidal and consists of pores .

Thus, lipid soluble drugs can easily penetrate by diffusion and smaller
drug molecules can penetrate by pore transport.
08/10/2010
KLECOP, Nipani
66
Gastrointestinal (GI) Physiology
pH
Membrane
Blood Supply
Surface Area
Transit Time
By-pass liver
BUCCAL
approx 6
thin
Good, fast
absorption with
low dose
small
Short unless
controlled
yes
ESOPHAGUS
6
Very thick, no
absorption
-
small
short
-
STOMACH
1–3
Normal
Lipophilic,acidic
and neutral drugs
good
small
30 - 40 minutes,
reduced absorption
no
DUODENUM
5–7
Normal
Mainly lipohilic
and neutral drugs
good
large
very short (6"
long)
no
SMALL
INTESTINE
6 -7
Normal
All types of drugs
good
very large 10 - 14
ft, 80 cm 2 /cm
about 3 hours
no
LARGE
INTESTINE
6.8 - 7
-
good
not very large 4 - long, up to 24 hr
5 ft
08/10/2010
KLECOP, Nipani
lower colon,
rectum yes
67
SMALL INTESTINE :
•
•
•
•
•
•
•
•
•
Major site for absorption of most drugs due to its large surface area (0.33
m2 ).
It is 7 meters in length and is approximately 2.5-3 cm in diameter.
The Folds in small intestine called as folds of kerckring, result in 3 fold
increase in surface area ( 1 m2).
These folds possess finger like projections called Villi which increase
the surface area 30 times ( 10 m2).
From the surface of villi protrude several microvilli which increase the
surface area 600 times ( 200 m2).
Blood flow is 6-10 times that of stomach.
PH Range is 5–7.5 , favourable for most drugs to remain unionised.
Peristaltic movement is slow, while transit time is long.
Permeability is high.
All these factors make intestine the best site for absorbtion of most drugs.
08/10/2010
KLECOP, Nipani
68
INFLUENCE OF DRUG pKa AND GI PH ON
DRUG ABSORBTION
Drugs
Site of absorption
Very weak acids (pKa > 8.0)
Unionized at all ph values
Absorbed along entire length of GIT
Moderately weak acids (pKa 2.5 – 7.5)
Unionized in gastric ph
Ionized in intestinal ph
Better absorbed from stomach
Strong acids (pKa <2.5)
Ionized at all ph values
Poorly absorbed from git
Very weak bases (pKa < 5)
Unionized at all ph values
Absorbed along entire length of GIT
Moderately weak bases (pKa 5 – 11 )
Ionized in gastric ph
Unionized in intestinal ph
Better absorbed from intestine
Strong bases (pKa >11)
Ionized at all ph values
Poorly Absorbed from GIT
08/10/2010
KLECOP, Nipani
69
GIT BLOOD FLOW

It plays an imp. role in drug absorption by continuously maintaining
the conc. Gradient across the epithelial membrane

Polar molecules that are slowly absorbed show no dependence on
blood flow

The absorption of lipid soluble drugs and molecules that are small
enough to easily penetrate through Aq. pores is rapid and highly
dependent on rate of blood flow
08/10/2010
KLECOP, Nipani
70
GASTRIC EMPTYING




The process by which food leaves the stomach and enters the
duodenum.
It is a RDS in drug absorbtion.
Rapid Gastric Emptying Advisable when :
 Rapid onset of action is desired eg. Sedatives
 Dissolution occurs in the intestine eg. Enteric coated tablets
 Drugs not stable in gi fluids eg. penicillin G
 Drug is best absorbed from small intestine eg. Vitamin B12
Delay in Gastric Emptying recommended when
 Food promotes drug dissolution and absorbtion eg. Gresiofulvin
 Disintegration and dissolution is is promoted by gastric fluids
08/10/2010
KLECOP, Nipani
71
Factors affecting Gastric Emptying
Volume of Ingested As volume increases initially an increase then a
Material
decrease. Bulky material tends to empty more slowly
than liquids
Type of Meal
Gastric emptying rate:
carbohydrates > proteins > fats
Temperature of Food Increase in temperature, increase in emptying rate
Body Position
Lying on the left side decreases emptying rate and right
side promotes it
Git PH
Retarded at low stomach PH and promoted at higher
alkaline PH
Emotional state
Anxiety promotes where as depression retards it
Disease states
gastric ulcer, hypothyroidism retards it, while duodenal
ulcer, hyperthyroidism promotes it.
08/10/2010
KLECOP, Nipani
72
DISEASE STATES

CHF decreases blood flow to the Git, alters GI PH,
secretions and microbial flora.

Cirrhosis influences bioavailability mainly of drugs that
undergo considerable 1st pass metabolism eg. Propranolol

Git infections like cholera and food poisoning also result in
malabsorbtion.
08/10/2010
KLECOP, Nipani
73
PHYSIO-CHEMICAL FACTORS
 PHYSICAL FACTORS
 PHYSIO-CHEMICAL FACTORS
08/10/2010
KLECOP, Nipani
74
PHYSICAL FACTORS
1. PARTICLE SIZE
Smaller particle size, greater surface area then higher will be
dissolution rate, because dissolution is thought to take place at
the surface area of the solute( Drug).
This study is imp. for drugs that have low aqueous solubility.
Absorption of such drugs can be increased by increasing particle
size by Micronization.
 ex. Griseofulvin, active intravenously but not
effective when given orally.
08/10/2010
KLECOP, Nipani
75
1. PARTICLE SIZE
To poor soluble drug, disintegration agents and surface active
agents may be added .
• ex. Bioavailability of Phenacetin is increased by tween 80.
 Micronization also reduces the dose of some drugs
• ex. the dose of griseofulvin is reduced to one half while the dose
of spironolactone is reduced to one twentieth.
08/10/2010
KLECOP, Nipani
76
Lesser particle size is always not helpful
Ex. Micronization of Aspirin, phenobarbital,
surface area and hence lesser dissolution rate
lesser effective
Reasons:
On their surface, hydrophobic drugs absorb air and reduce
their wettability
 Particle having size below 0.1 micron reaggregate to form
large particle
 Particle having certain micro size get electrical charge which
preventing contact with wetting medium
08/10/2010
KLECOP, Nipani
77
Finally drug size reduction and subsequent increase in
surface area and dissolution rate is always not useful.
Ex. of such drugs are Penicillin G & Erythromycin
These Drugs are unstable and degrade quickly in solution.
Sometime, reduction in particle size of nitrofurantoin and
piroxicam increase gastric irritation
These problem can be overcome by Microencapsulation.
08/10/2010
KLECOP, Nipani
78
2. Crystal Form
Substance can exist either in a crystalline or amorphous form.
When substance exist in more than one crystalline form, the
different form are called polymorphs and the phenomena as
polymorphism .
Two types of Polymorphism
1) Enantiotropic polymorph ex. Sulfur
2) Monotropic polymorph ex. Glyceryl Stearates
Polymorphs have the same chemical structure but different
physical properties such as solubility, density, hardness etc.
ex. Chlormphenicol has a several crystal form, and when given
orally as a suspension, the drug concentration in the body was
found to be dependent on the percentage of β - polymorph in the
suspension. The form is more soluble and better absorbed.
08/10/2010
KLECOP, Nipani
79
One of the several form of polymorphic forms is more stable
than other. Such a stable form having low energy state and high
melting point and least aqueous solubility
The remaining polymorphs are called as metastable forms
which have high energy state, low melting point and high
aqueous solubilities.
About 40% of all organic compounds exhibit polymorphism.
Some drug exists in amorphous form which have no internal
crystal structure. Such drugs have high energy states than
crystal form hence they have greater aqueous solubility than
crystalline form.
Ex. Novobiocin, cortisone acetate.
08/10/2010
KLECOP, Nipani
80
3. Solvates And Hydrates
Many drugs associate with solvent and forms solvates
Solvent is water then it is called as hydrate
eg. Anhydrous form of caffeine and theophylline dissolve more
rapidly than hydrous form of these drugs.
Solvate form of drugs with org. solvent may dissolve fast in water
than non solvated form.
eg. Fluorocortisone
4. Complexation
This property can influence the effective drug concentration in gi
fluids. Complexation of drug and gi fluids may alter the rate
and extent of absorption
eg. Intestinal Mucin form complex with Streptomycin and
Dihydro Streptomycin.
In some cases, Poor water soluble drugs can be administered as
water soluble complexes. eg. Hydroquinone with Digoxin.
08/10/2010
KLECOP, Nipani
81
5.Adsorption
It is a physical and surface phenomena where the drug
molecules are held on the surface of some inert substances by
vanderwall’s forces.
ex. Charcoal used as an antidote; When it is co-administered with
promazine, then it reduces the rate and extent of absorption
Cholestyramine reduces the absorption of warfarin.
6.Drug Stability And Hydrolysis In GIT
Drugs undergoes various reactions due to wide spectrum of ph
and enzymatic activity of GI fluid namely acid and enzymatic
hydrolysis.
eg. T½ of Penicillin G= 1 min. at pH 1
T½ of Penicillin G= 9 min. at pH2
So it means Penicillin G is stable at less acidic pH
Erythromycin and its esters are unstable at gastric fluid (T½=Less than 2 min.)
08/10/2010
KLECOP, Nipani
82
7. Salts
 Na or K salts of weak acid dissolves rapidly than free acid.
ex. Na salts of Novobiocin shows improved bioavailability
 Certain salts also may have low solubility and dissolution rate.
ex. Al salts of weak acid and pamoate salt of weak base
8. Presence Of Surfactant
Use of wetting agent and Solubilizing agent improve the Dissolution
rate & absorption of drugs.
Ex. Tween 80 increase the rate & extent of absorption of Phenacetin.
9. Dissolution
Disintegration is the formation of dispersed granules from an
intact solid dosage form whereas the dissolution is the formation
of solvated drug molecules from the drug
08/10/2010
KLECOP, Nipani
83
SOLID DRUG
DISSOLUTION
DRUG AT ABSORPTION
SITE
ABSORPTION
DRUG IN
SYSTEMIC
CIRCULATION
08/10/2010
KLECOP, Nipani
84
NOYES AND WHITNEY’S EQUATION
dc/dt = KS(CS-C)
Where,
dc/dt = Rate constant, K = constant, S = surface area
of the dissolving solid, Cs=solubility of the drug in the
solvent, C=concentration of drug in the solvent at time t.
Constant K=D/h
Where, D is the diffusion coefficient of the dissolving
material and h is the thickness of the diffusion layer
Here, C will always negligible compared to Cs
So,
dc/dt=DSCs/h
08/10/2010
KLECOP, Nipani
85
P H Y S I C O C H E M I C A L FA C TO R S
1) pH PARTITION THEORY (Brodie) :
It explain drug absorption from GIT and its distribution across
biomembranes.
Drug(>100 daltons) transported by passive diffusion depend
upon:
 dissociation constant, pKa of the drug
 lipid solubility, K o/w
 pH at absorption site.
Most drugs are either weak acids or weak bases whose degree
of ionization is depend upon pH of biological fluid.
08/10/2010
KLECOP, Nipani
86
For a drug to be absorbed, it should be unionized and the
unionized portion should be lipid soluble.
The fraction of drug remaining unionized is a function of both
Dissociation constant (pKa) and pH of solution.
The pH partition theory is based on following assumption:
 GIT acts as a lipoidal barrier to the transport of the drug
 The rate of absorption of drug is directly proportional to its
fraction of unionised drug
 Higher the lipophilicity of the unionised degree, better the
absorption.
08/10/2010
KLECOP, Nipani
87
HENDERSON HASSELBATCH EQUATION
For acid,
pKa - pH = log[ Cu/Ci ]
For base,
pKa – pH = log[ Ci/Cu ]
Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will
have > 99%of unionized form so gets absorbed in stomach
Weak base quinine (pKa=8.5) will have very negligible
unionization in gastric pH so negligible absorption
Several prodrugs have been developed which are lipid
soluble to overcome poor oral absorption of their parent
compounds.
08/10/2010
KLECOP, Nipani
88
eg. Pivampicilin, the pivaloyloxy-methyl ester of ampicilin
is
More lipid soluble than ampicilin.
Lipid solubility is provided to a drug by its partition
coefficient between
An organic solvent and water or an aq. Buffer (same pH of
ab. Site)
E.g. Barbital has a p.c. of 0.7 its absorption is 12%
Phenobarbital ( p.c = 4.8 absorption=12%)
Secobarbital (p.c =50.7 absorption=40%)
08/10/2010
KLECOP, Nipani
89
2)DRUG SOLUBILITY
The absorption of drug requires that molecule be in solution at absorption site.
Dissolution, an important step, depends upon solubility of drug substance.
pH solubility profile:
pH environment of GIT varies from Acidic in stomach to slightly Alkaline in a
small intestine.
1)Basic drug
2)Acidic drug
08/10/2010
soluble
1) Acidic medium( stomach)
2) basic medium( intestestine)
KLECOP, Nipani
90
Improvement of solubility:
Addition of acidic or basic excipient
Ex: Solubility of Aspirin (weak acid) increased by addition
of basic excipient.
For formulation of CRD , buffering agents may be added to
slow or modify the release rate of a fast dissolving drug.
08/10/2010
KLECOP, Nipani
91
PHARMACEUTICAL FACTORS
MEANS Absorption rate depends on the dosage
Form which is administred,ingredients used, procedures
Used in formulation of dosage forms.
The availability of the drug for absorption from the
dosage forms is in order.
Solutions > Suspensions > capsules > Compressed
Tablets > Coated tablets.
08/10/2010
KLECOP, Nipani
92
SOLUTIONS
Shows maximum bioavailability and factors affecting
Absorption from solution are as follows
1. Chemical stability of drug
2. Complexation: between drug and exipients of formulation
to increase the solubility, stability.
3. Solubilization: incorporation of drug into micelles to
increase the solubility of drugs.
4. Viscosity
5. Type of solution: Whether aqueous or oily solution.
08/10/2010
KLECOP, Nipani
93
SUSPENSIONS:
It comes next after solutions with respect to bioavailability
Factors that affects absorption from suspensions are
1. Particle size and effective surface area of dispersed phase
2. Crystal form of drug: some drug can change their crystal
structure.
Eg. Sulfathiazole can change its polymorphic form, it can be
overcome by addition by adding PVP.
3. Complexation: Formation of nonabsorbable complex between
drug and other ingredients.
Eg. Promazine forms a complex with attapulgite.
08/10/2010
KLECOP, Nipani
94
4. Inclusion of surfactant
Eg. The absorption of phenacitin from suspension is increased in
presence of tween 80.
5. Viscosity of suspension
Eg. Methyl cellulose reduces the rate and absorption of
nitrofurantoin
6. Inclusion of colourants:
Eg. Brilliant blue in phenobarbitone suspension.
08/10/2010
KLECOP, Nipani
95
CAPSULES
Two types of capsule
1. Hard gelatin capsule
2. Soft gelatin capsule
08/10/2010
KLECOP, Nipani
96
HARD GELATIN CAPSULE
The rate of absorption of drugs from capsule is function
Of some factors.
1.Dissolution rate of gelatin shell.
2.The rate of penetration of GI fluids into encapsulated mass
3.The rate at which the mass disaggregates in the GI fluid
4. The rate of dissolution.
5. Effect of excipients;
a).Diluents
b).Lubricants
c). Wetting characteristics of drug
d).Packing density
08/10/2010
KLECOP, Nipani
97
SOFT GELATIN CAPSULE
SGS has a gelatin shell thicker than HGS,but shell is
Plasticized by adding glycerin,sorbitol.SGS may used
To contain non aqueous solution or liquid or semi solid.
SGC have a better bioavailability than powder filled HGC
And are equivalent to emulsions.
Eg. Quinine derivative was better absorbed from SGC
Containing drug base compared with HGC containing
HCl salts.
Grieseoflavin exhibited 88% absorption from soft gelatin
Capsules compared to HGC(30%)
08/10/2010
KLECOP, Nipani
98
TABLETS
1.Compressed tablets
2. Coated tablets
08/10/2010
KLECOP, Nipani
99
Compressed tablets
Bioavailability are more due to large reduction
in surface area.
A
Intact tablets
B
a
granules
K1
K2
primary drug particles
K3
Drug in GI fluid
K4
Drug absorbed in body
08/10/2010
KLECOP, Nipani
100
The rate constants decrease in the following order.
K3>>K2>>K1
The overall dissolution rate and bioavailability of a poor
Soluble drugs is influenced by
1.The physicochemical properties of liberated particles.
2. The nature and quantity of additives.
3. The compaction pressure and speed of compression.
4. The storage and age of tablet
08/10/2010
KLECOP, Nipani
101
1.Effect of diluents :
Na Salicylates + starch = Faster dissolution
Na salicylates + lactose=Poor dissolution.
2.Effect of Granulating agent:
Phenobarbital + Gelatin solution=Faster dissolution
Phenobarbital+PEG 6000= poor dissolution.
3.Effect of lubricants:
Magnesium stearate will retard the dissolution of aspirin tablet
Whereas SLS enhance the dissolution.
08/10/2010
KLECOP, Nipani
102
4.Effect of disintegrants:
Starch tend to swell with wetting and break apart the dosage
form. It is reported that 325mg of salicylic acid tablet were
prepared by using different concentrations (5%,10%,20%) and
max. dissolution was achieved With 20% starch.
5. Effect of colorants:
6.Effect of Compression force:
08/10/2010
KLECOP, Nipani
103
COATED TABLETS:
There are three types of coating
Sugar coating
Film coating
Enteric coating
SUGAR COATING:
Sugar,Shellac,fatty glycerides, bees wax, silicone resin
Sub coating agent: Talc,acacia,starch.
FILM COATING:
Polymers, dispersible cellulose derivatives like HPMC
CMC.
ENTERIC COATING:
Shellac, cellulose acetate phthalate etc.
08/10/2010
KLECOP, Nipani
104
Factors affecting the drug release are
1.Thickness of coating
e.g.. Quinine shows decrease in rate of absorption
if coated with cellulose acetate phthalate.
2.The amount of dusting powder:
3.Effect of ageing:
e.g. The shellac coated tablets of Para amino salicylic
acid when given after two years plasma concentration
of 6-7mg/100ml. However the tablets stored for 3½ years
showed plasma concentration of only 2mg/100ml which is
the sub therapeutic effect.
08/10/2010
KLECOP, Nipani
105
SUBLINGUAL / BUCCAL ROUTE





SUBLINGUAL ROUTE: the dosage form is placed
beneath the tongue.
BUCCAL ROUTE: Dosage form is placed between
the cheek and teeth or In the cheek pouch.
Drugs administered by this route are supposed to
produce systemic drug effects, and consequently, they
must have good absorption from oral mucosa.
Oral mucosal regions are highly vascularised
therefore rapid onset of action is observed.
For Eg, anti-anginal drug Nitroglycerin.
08/10/2010
KLECOP, Nipani
106
SUBLINGUAL / BUCCAL ROUTE
Blood perfuses oral regions drains directly into the general
circulation.
 Barrier to drug absorption from these routes is epithelium of
oral mucosa.
 Passive diffusion is the major mechanism of absorption of
most drugs.
 In general, sublingual tablets are designed to dissolve
slowly to minimize possibility of swallowing the dose.
Exception include: Nitroglycerin, Isosorbide dinitrate tablets
which dissolves within minutes in buccal cavity to provide
prompt treatment of acute anginal episodes.

08/10/2010
KLECOP, Nipani
107
08/10/2010
KLECOP, Nipani
108
08/10/2010
KLECOP, Nipani
109
Factors to be considered:
Lipophilicity of drug: The lipid solubility should be
high for absorption.
1.
Salivary secretion: drug should be soluble in
buccal fluid.
2.
pH of saliva: pH of saliva is usually 6.
3.
Storage compartment: some drugs have storage
compartment in buccal mucosa. Eg, Buprenorphine
4.
Thickness of oral epithelium: Sublingual
absorption is faster than buccal, because former
region is thinner than that of buccal mucosa.
08/10/2010
KLECOP, Nipani
110
FACTORS LIMITTING DRUG
ADMINISTRATION:
1.
2.
Limited mucosal surface area.
Taste of medicament and discomfort.
EXAMPLES: Nitroglycerin, Isosorbide dinitrate,
Progesterone, Oxytocin, Fenosterol, Morphine.
08/10/2010
KLECOP, Nipani
111
RECTAL ADMINISTRATION:



Absorption across the rectal mucosa occurs by
passive diffusion.
This route of administration is useful in children, old
people and unconscious patients.
Eg., drugs that administered are: aspirin,
acetaminophen, theophylline, indomethacin,
promethazine & certain barbiturates.
08/10/2010
KLECOP, Nipani
112
PARENTERAL ROUTES:
.
08/10/2010
KLECOP, Nipani
113
INTRAVENOUS ROUTE:
Absorption phase is bypassed
(100% bioavailability)
1.Precise, accurate and almost immediate onset
of action,
2. Large quantities can be given, fairly pain free
3. Greater risk of adverse effects
a. High concentration attained rapidly
b. Risk of embolism
08/10/2010
KLECOP, Nipani
114
INTRAVENOUS ROUTE:





This route is used when a rapid clinical response is
required like treatment of epileptic seizures, acute
asthmatic and cardiac arrhythmias.
There may also be a danger of precipitation of drug in
the vein if the inj. is too rapidly. This could result in
thrombophlebitis.
This mode of administration is required with drugs
having short half lives and narrow therapeutic index.
Bioavailability is not considered by this route.
Mainly antibiotics are administered by this route.
08/10/2010
KLECOP, Nipani
115
Intra arterial injection



In this route the drugs are injected directly into the
artery.
It is mainly used for cancer chemotherapy.
It increased drug delivery to the area supplied by the
infused artery and decreased drug delivery to
systemic circulation.
08/10/2010
KLECOP, Nipani
116
INTRA MUSCULAR INJECTION



Absorption of drug from muscles is rapid and
absorption rate is perfusion rate limited.
Polypeptides of less than approx 5000 gram per mole
primarily pass through capillary pathway
Greater than about 20000 g/mol are less able to
traverse capillary wall, they primarily enter blood via
lymphatic pathway.
08/10/2010
KLECOP, Nipani
117
Factors determining rate of drug absorption:
1. Vascularity to the inj. Site:
Blood flow rates to intramuscular tissues are:
Arm (deltoid) > thigh (vastus lateralis) > buttocks
(gluteus maximus).
2. Lipid solubility and ionisation of drug.
3. Molecular size of drug.
4. Volume of inj. And drug concentration.
5. pH & viscosity of inj. vehicle.
08/10/2010
KLECOP, Nipani
118
SUBCUTANOUS ROUTE:
1. Slow and constant absorption
2. Absorption is limited by blood flow, affected if
circulatory problems exist.
3. The blood supply to this is poorer than that of muscular
tissue.
4. Concurrent administration of vasoconstrictor will slow
absorption, e.g. Epinephrine.
5. The absorption is hastened by massage, application of
heat to increase blood flow and inclusion of enzyme
Hyaluronidase in drug solution.
eg. Insulin.
08/10/2010
KLECOP, Nipani
119
08/10/2010
KLECOP, Nipani
120
TOPICAL ADMINISTRATION:
• MUCOSAL MEMBRANES(eye drops, antiseptic,
sunscreen, nasal, etc.)
•SKIN
a. Dermal - rubbing in of oil or ointment
(local action)
b. Transdermal - absorption of drug through
skin (systemic action)
i. stable blood levels
ii. no first pass metabolism
iii. drug must be potent.
08/10/2010
KLECOP, Nipani
121
Skin consist of three layers :
 Epidermis
 Dermis
 Subcutaneous fat tissue
 The main route for the penetration of the drugs is
generally through epidermal layer
 Stratum corneum is the rate limiting barrier in passive
percutaneous absorption of drug.
08/10/2010
KLECOP, Nipani
122



The stratum corneum is the outermost layer of the epidermis
and is composed mainly of dead keratinized cells (from lack of
oxygen and nutrients). It has a thickness between 10 - 40 μm.
The dermis is the layer of skin beneath the epidermis. It
contains the hair follicles, sweat glands, sebaceous glands,
apocrine glands, lymphatic vessels and blood vessels.
Hypodermis - Its purpose is to attach the skin to underlying
bone and muscle as well as supplying it with blood vessels and
nerves. The main cell types are fibroblasts, macrophages and
adiposities (the hypodermis contains 50% of body fat).
08/10/2010
KLECOP, Nipani
123
08/10/2010
KLECOP, Nipani
124
OCULAR ADMINISTRATION






Eye is the most easily accessible site for topical
administration of a medication.
Topical application of drug to eyes meant for :
Mydriasis, miosis, anaesthesia, treatment of
infection, glaucoma etc.
Opthalmic solution are administered into cul-de-sac.
Barrier to intra occular penetration is cornea. It
possess both hydrophilic and lipophilic characterstics.
pH of lacrimal fluid is 7.4.
pH of lacrimal fluid influences absorption of weak
electrolyte like Pilocarpine.
08/10/2010
KLECOP, Nipani
125
OCULAR ADMINISTRATION





High pH of formulation: decrease tear flow and
Low pH of formulation: increases tear flow.
Human eye can hold around 10 microlitre of fluid.
So small volume in concentrated form increases
effectiveness.
Viscosity empartners increases bioavailability eg,
oily solutions, ointment etc.
Systemic entry of drug occur by lacrimal duct which
drains lacrimal fluid into nasal cavity.
08/10/2010
KLECOP, Nipani
126
Composition of eye

Water - 98%

Solid -1.8%


Organic element –
Protein - 0.67%, sugar - 0.65%, Nacl - 0.66%
Other mineral element sodium, potassium and
ammonia - 0.79%
08/10/2010
KLECOP, Nipani
127
08/10/2010
KLECOP, Nipani
128
Characteristics required to
optimize ocular drug delivery system

Good corneal penetration.

Prolong contact time with corneal tissue.

Simplicity of instillation for the patient.

Non irritative and comfortable form (viscous solution
should not provoke lachrymal secretion and reflex
blinking)

Appropriate rheological properties concentrations of
the viscous system.
08/10/2010
KLECOP, Nipani
129
Advantages









Increase ocular residence….. Improving
bioavailability
Prolonged drug release….. better efficacy
Less visual & systemic side effects
Increased shelf life
Exclusion of preservatives
Reduction of systemic side effects
Reduction of the number of administration
Better patient compliance
Accurate dose in the eye…. a better therapy
08/10/2010
KLECOP, Nipani
130
FACTOR INFLUENCING
PERCUTANEOUS ABSORPTION
1.
2.
3.
4.
5.
6.
7.
8.
Drug release from dosage form
Drug concentration in the formulation
Drug oil water partition coefficient.
Drug affinity to the skin tissue
Surface area
Site of application
Hydration of skin
Nature of vehicle used
08/10/2010
KLECOP, Nipani
131
FACTOR INFLUENCING
PERCUTANEOUS ABSORPTION
9. Rubbing
10. Contact period
11. Permeation enhancers
08/10/2010
KLECOP, Nipani
132
INHALATIONAL ROUTE:
1.Gaseous and volatile agents and aerosols.
2.Rapid onset of action due to rapid access to circulation
a.Large surface area
b.Thin membranes separates alveoli from
circulation
c.High blood flow
Particles larger than 20 micron and the particles impact in
the mouth and throat. Smaller than 0.5 micron and they
aren't retained.
08/10/2010
KLECOP, Nipani
133
INTRA NASAL ADMINISTRATION




Drugs generally administered by intra nasal route for
treatment of local condition such as perennial rhinitis,
allergic rhinitis and nasal decongestion etc.
Absorption of lipophilic drugs through nasal mucosa
by passive diffusion and absorption of polar drugs by
pore transport.
Rate of absorption of lipophilic drugs depend on their
molecular weight.
Drugs with molecular weight less than 400 daltons
exhibit higher rate of absorption.
08/10/2010
KLECOP, Nipani
134
cont…


Drugs with molecular weight 1000 daltons show
moderate rate of absorption.
Presently nasal route is becoming popular for
systemic delivery of peptide and proteins, this is
because of high permeability of nasal mucosa with
vasculature.
08/10/2010
KLECOP, Nipani
135
08/10/2010
KLECOP, Nipani
136
Advantages








Rapid drug absorption via highly-vascularized
mucosa
Rapid onset of action
Ease of administration, non-invasive
Avoidance of the gastrointestinal tract and first-pass
metabolism
Improved bioavailability
Lower dose/reduced side effects
Improved convenience and compliance
Self-administration.
08/10/2010
KLECOP, Nipani
137
Disadvantages

Nasal cavity provides smaller absorption surface area
when compared to GIT.

Relatively inconvenient to patients when compared to
oral delivery since there is possibility of nasal
irritation.

The histological toxicity of absorption enhancers used
in the nasal drug delivery system is not yet clearly
established.
08/10/2010
KLECOP, Nipani
138
Enhancement in absorption

Following approaches used for absorption
enhancement :Use of absorption enhancers

Increase in residence time.

Administration of drug in the form of microspheres.

Use of physiological modifying agents

08/10/2010
KLECOP, Nipani
139
Enhancement in absorption

Use of absorption enhancers:-

Absorption enhancers work by increasing the rate
at which the drug pass through the nasal mucosa.

Various enhancers used are surfactants, bile salts,
chelaters, fatty acid salts, phospholipids,
cyclodextrins, glycols etc.
08/10/2010
KLECOP, Nipani
140
Various mechanisms involved in absorption
enhancements are:
Increased drug solubility

Decreased mucosal viscosity

Decrease enzymatic degradation

Increased Paracellular transport

Increased transcellular transport
08/10/2010
KLECOP, Nipani
141
Various mechanisms involved in
absorption enhancements are:


Increase in residence time:By increasing the residence time the
increase in
the higher local drug concentration in the mucous
lining of the nasal mucosa is obtained.
Various mucoadhesive polymers like methylcellulose,
carboxy methyl cellulose or polyarcylic acid are used
for increasing the residence time.
08/10/2010
KLECOP, Nipani
142
Various mechanisms involved in
absorption enhancements are:
Use of physiological modifying agents:-

These agents are vasoactive agents and exert their
action by increasing the nasal blood flow.

The example of such agents are histamine,
leukotrienene D4, prostaglandin E1 and β-adrenergic
agents like isoprenaline and terbutaline.
08/10/2010
KLECOP, Nipani
143
Applications of nasal drug delivery
A.
Nasal delivery of organic based pharmaceuticals :-

Various organic based pharmaceuticals have been
investigated for nasal delivery which includes drug
with extensive presystemic metabolism.
E.g. Progesterone, Estradiol, Nitroglycerin,
Propranolol, etc.

08/10/2010
KLECOP, Nipani
144
Applications of nasal drug delivery
B.
Nasal delivery of peptide based drugs :-

Nasal delivery of peptides and proteins is depend
on –
The structure and size of the molecule.
Nasal residence time
Formulation variables (pH, viscosity)




E.g. calcitonin, secretin, albumins, insulin,
glucagon, etc.
08/10/2010
KLECOP, Nipani
145



PULMONARY ADMINISTRATION
The drugs may be administered for local action
of bronchioles or their systemic effects through
absorption of lungs.
Inhalation sprays and aerosols are used to
deliver the drugs to the lungs.
Larger surface area of alveoli, high
permeability of alveolar epithelium for drug
penetration, and a rich vasculature are
responsible for rapid absorption of drugs by
this route
08/10/2010
KLECOP, Nipani
146
PULMONARY ADMINISTRATION


In general particles greater than 10mm are
retained in the throat and upper airways whereas
fine particles reach the pulmonary epithelium
Drugs generally administered by this route are
bronchodilators (e.g.. Salbutamol, isoproterenol),
antiallergic (e.g.. Cromolym sodium), and
antiinflammatory (e.g.. Betamethasone,
dexamethasone).
08/10/2010
KLECOP, Nipani
147
08/10/2010
KLECOP, Nipani
148
Advantages

Smaller doses can be administered locally.

Reduce the potential incidence of adverse systemic
effect.

It used when a drug is poorly absorbed orally, e.g. Na
cromoglicate.

It is used when drug is rapidly metabolized orally,
e.g. isoprenaline
08/10/2010
KLECOP, Nipani
149
IN-VITRO METHODS

Everted small intestine sac method.

Everted sac modification.

Circulation technique.

Everted intestinal ring or slice technique.
08/10/2010
KLECOP, Nipani
150
Why in-vitro studies







Because of economical & ethical limitations of in-vivo
studies.
Simple & provide valuable information.
To assess the major factors involved in absorption.
Predict the rate & extent of drug absorption.
Procedures are of great value during screening of new
drug candidates.
Carried out outside the body.
Used to assess permeability of drug using animal
tissues.
08/10/2010
KLECOP, Nipani
151
Everted small intestine sac
technique
Isolation of rat intestine
Inverting the intestine
Filling the sac with drug free
buffer solution
Immersion of sac in Erlenmeyer
flask containing drug buffer
solution
08/10/2010
KLECOP, Nipani
Contd…
152
Flask & its contents
oxygenated & agitated at
37oC for specific period of
time
After incubation, the serosal
content is assayed for drug
content
08/10/2010
KLECOP, Nipani
153
Figure( reverted sac technique)
Serosal side
Mucosal side
(intestinal segment before eversion)
Serosal side
Buffer solution
Ligature
Mucosal side
08/10/2010
KLECOP, Nipani
(after eversion)
154
Advantages



Prolongs the viability & integrity of the
preparation after removal from the animal.
Convenience & accuracy with respect to drug
analysis.
The epithelial cells of the mucosal surface are
exposed directly to the oxygenated mucosal
fluid.
Difficulty in obtaining more than one sample
per intestinal segment
08/10/2010
KLECOP, Nipani
155
Everted sac modification

Crane & Wilson modification.

Essential features of simple sac methods are
retained.

Modification- the intestine is tied to a
cannula.
08/10/2010
KLECOP, Nipani
156
cannula
Plain buffer
Buffer solution
with drug
Water
maintained at
aerator
37o C
08/10/2010
KLECOP, Nipani
(FIG: EVERTED SAC MODIFICATION)
157
Procedure
Animal fasted for 20-24hrs
Water is allowed ad libitum
Animal killed with blow on
head or anesthetized with
ether or chloroform
Entire small intestine is
everted
08/10/2010
KLECOP, Nipani
158
Contd
Segments of 5-15cm length are cut
from specific region of the intestine
Distal ends tied & proximal end is
attached to cannula
Segments suspended in 40-100ml of
drug mucosal solution.
About 1ml/5cm length of drug free
buffer is then placed in serosal
compartment
Mucosal solution aerated
08/10/2010
KLECOP, Nipani
159
How to determine the rate
of drug transfer

The entire volume of serosal solution is
removed from the sac at each time interval
with the help of syringe & it is replaced with
fresh buffer solution.

The amount of drug that permeates the
intestinal mucosa is plotted against time to
describe the absorption profile of the drug at
any specific pH.
08/10/2010
KLECOP, Nipani
160
Advantages





A number of different solutions may be
tested with a single segment of the intestine
unlike in the sac technique.
Simple & reproducible.
It distinguishes between active & passive
absorption.
It determines the region of the small
intestine where absorption is optimal,
particularly in the case of active transport.
Also used to study the effect of pH, surface
active agents, complexation & enzymatic
reaction.
08/10/2010
KLECOP, Nipani
161
Disadvantages

The intestinal preparation is removed
from the animal as well as from its blood
supply. Under these conditions, the
permeability characteristics of the
membrane are significantly altered.

The rate of transport of drug as
determined from the everted sac
technique, may be slower than in the
intact animal.
08/10/2010
KLECOP, Nipani
162
Circulation technique





Small intestine may or may not be everted.
In this method either entire small intestine of
small lab animal or a segment is isolated.
Oxygenated buffer containing the drug is
circulated through the lumen.
Drug free buffer is also circulated on the
serosal side of the intestinal membrane &
oxygenated.
Absorption rate from the lumen to the outer
solution are determined by sampling both the
fluid circulating through the lumen.
08/10/2010
KLECOP, Nipani
163
Advantages

This is applicable to kinetic studies of
the factors affecting drug absorption.

Both surface are oxygenated.

Eversion is not necessary.
08/10/2010
KLECOP, Nipani
164
Everted intestinal ring or
slice technique
The entire small intestine(everted) is
isolated from fasted expt animal
Intestine cut wit scalpel or scissors
into ring like slices, 0.1-0.5cm length
Intestine washed with buffer & dried
by blotting with filter paper
Dried rings transferred to stoppered
flask containing buffer with drug at
37oC
08/10/2010
KLECOP, Nipani
Contd…165
Contents are continuously
agitated & aerated.
At selected time intervals, the
tissues slices are assayed for drug
content
08/10/2010
KLECOP, Nipani
166
Advantages

Simple & reproducible.

Kinetic studies can be performed.
 Process of cutting the intestine into rings may expose
highly permeable areas of cut or damage tissue to
medium.
 MAJOR DISADVANTAGE OF IN-VITRO METHODS
is that the are based on approximation &
oversimplification of the actual in-vivo conditions.
08/10/2010
KLECOP, Nipani
167
In-situ methods


Absorption from small intestine.

Perfusion technique.

Intestinal loop technique.
Absorption from the stomach.
08/10/2010
KLECOP, Nipani
168
Why in-situ studies.




In this method the animals blood supply remains
intact & thus the results of rate of absorption
determined may be more realistic than those from
in-vitro techniques.
Alternative means to in-vivo models in evaluating
the relative contribution of GI absorption to oral
bioavailability.
Act as bridge between in-vitro & in-vivo methods.
Mimic the in-vivo physiological process with
significant reduction in cost & time.
08/10/2010
KLECOP, Nipani
169
ABSORPTION FROM
SMALL INTESTINE
Adult male rats fasted for
about 16-24hrs.
Animal anesthetized, a
midline abdominal incision
is made.
isolation & cannulation of
Small intestine
08/10/2010
KLECOP, Nipani
Contd…
170
Replacement of intestine.
Incision closed & duodenal
cannula is attached to an infusion
pump
Intestine cleared off particulate
matter using drug free buffer
(1.5ml/30min)
Drug buffer solution is perfused
(1.5ml/30min)
08/10/2010
KLECOP, Nipani
Contd…
171
Samples at 10min interval
collected from ileal cannula
Samples assayed for drug
content
Relative rate of absorption
calculated
Relative rate of absorption = difference in the drug
concentration entering & leaving the intestine
08/10/2010
KLECOP, Nipani
172
Figure
08/10/2010
KLECOP, Nipani
173
Here, single or multiple intestinal loops are used for studying
absorption
Adult male rat fasted & water with held for
1-2hrs before expt.
Under anesthesia an abdominal incision is
made & small intestine exposed.
Placement of proximal ligature & distal
ligature.
Introduction of drug solution.
08/10/2010
KLECOP, Nipani
174
Contd..
Replacement of intestinal loop.
After a predetermined period of time,
animal is sacrificed.
Intestinal loop is rapidly excised &
homogenized.
The amount of drug unabsorbed is
determined.
08/10/2010
KLECOP, Nipani
175
For preparing multiple loops, the procedure is identical to
single loop preparation with a distance of approximately
one half inch left between successive loops.
Advantages

Simple & reproducible.
 Only 1 sample can be obtained from the
experimental animal.
08/10/2010
KLECOP, Nipani
176
Absorption from the stomach
Fasted adult male rats anesthetized, stomach
exposed & cardiac end ligated.
Introduction of cannula (pylorus).
Lumen washed several times with saline &
subsequently with 0.1N HCl containing 0.15M NaCl
Drug solution of known concentration is
introduced into the stomach
08/10/2010
KLECOP, Nipani
177
Contd….
After 1hr, the drug solution is removed from
the gastric pouch & assayed for drug content.
% of drug absorbed in 1hr may be
calculated.
The gastric pouch may also be homogenized
& analyzed for drug.
In-situ techniques equate absorption with loss of drug from the GI
lumen & if a drug is significantly accumulated or metabolized in gut
wall, one will get an overestimate of the amount of drug absorbed
08/10/2010
KLECOP, Nipani
178
In-vivo methods

Direct method.

Indirect method.
08/10/2010
KLECOP, Nipani
179
Why in-vivo studies

Only method to assess the importance of many
factors likeGastric emptying.
Intestinal motility.
Effect of drug on GIT.

The influence of dosage form variables on drug
absorption can also be studied.
08/10/2010
KLECOP, Nipani
180
Direct method

The drug level in blood or urine is
determined as a function of time.

Absorption studies on experimental
animals & clinical trials.

Selection of experimental animals- pigs,
dogs, rabbits, rat.
08/10/2010
KLECOP, Nipani
181
Procedure
A blank urine or blood sample is taken for the
test animal before the experiment.
Administration of test dosage form.
Blood or urine sampling.
Assay for drug content & determination of rate
& extent of drug absorption.
08/10/2010
KLECOP, Nipani
182
Indirect method

Adopted when the measurement of drug
concentration in blood or urine is difficult
or not possible.

Pharmacological response is taken as the
index of drug absorption.

LD 50 appears to be dependent on the rate
of absorption of drug & hence on the rate
of dissolution.

A plot of log dose vs. duration of response
time is plotted.
08/10/2010
KLECOP, Nipani
183
y
Log dose
d
Fka/2.303
x
Duration of response time
Where,
F= bioavailability.
Ka= the absorption rate constant.
d= threshold dose
08/10/2010
KLECOP, Nipani
184
REFERENCES
1. Biopharmaceutics & pharmacokinetics by
D.M.Brahmankar & Sunil B. Jaiswal.
2. Biopharmaceutics & pharmacokinetics by
P.L.Madan.
3. Biopharmaceutics & pharmacokinetics by
G.R.Chatwal.
4. Human anatomy & physiology by Tortora.
5. www.google.com.
08/10/2010
KLECOP, Nipani
185
Thank you
Cell No: 00919742431000
E-mail: bknanjwade@yahoo.co.in
08/10/2010
KLECOP, Nipani
186