(Topic 4)

Oral Drug Delivery & Small

Intestine

References
Aulton’s Pharmaceutics: The science of dosage form design.
3rd Edition
p16-40 (Involved in Exams)
 Functions of small intestine : Continue enzymatic
digestion & Absorb nutrients and minerals
The small intestine is divided into 3 structural parts:

1.The duodenum: is it is functionally very important as major portion of the chemical digestion takes place
init (pH = 6 to 6.5 & 20–30 cm long) It receives gastric chyme from the stomach, together with digestive
juices from the pancreas (digestive enzymes) and the liver (bile). The duodenum contains Brunner's
glands, which produce a mucus-rich alkaline secretion containing bicarbonate. Intestinal goblet cell
produced mucus. These secretions, in combination with bicarbonate from the pancreas, neutralize the
stomach acids contained in gastric chyme.
2.The jejunum : (alkaline pH: 7 to 8 & 2 to 2.5 m long), and contains the plicae circulares, and villi that
increase its surface area. The jejunum in the small intestine is the main site for the absorption of nutrients .
Products of digestion (sugars, amino acids, and fatty acids) are absorbed into the bloodstream from
enterocytes.
3.The ileum: It is about 3 m long, and contains villi similar to the jejunum. Its major function is to absorb any
nutrients that were not absorbed in the gut. However, it is particularly involved in the absorption of bile salts
and vitamins (vitamin B12). Peyer's patches appear as oval or round lymphoid follicles (similar to lymph
nodes) located in the submucosa layer of the ileum and extend into the mucosa layer.

•Most of the digestive enzymes in the small intestine are secreted by the pancreas and enter the small
intestine via the pancreatic duct.
•The three major classes of nutrients that undergo digestion are proteins, lipids (fats),
and carbohydrates.
• Important for bioavailability, Relatively rapid
• No discrimination between solids & liquids and no difference s between fast & fed state

90% of food chemical digestion & absorption

Highest drug absorption site
 Type your text

Secretions into SI determine the pH

•Brunner’s glands (biocarbonate)
•Intestinal goblet cells (mucus)
• Anatomy of the small intestine - emphasize the BIG surface area as a result
of all the convolutions
• These convolutions increase the SA of the small intestine 600 times from
that of a simple tube
• Folds of Kerckring are the folds in the intestine and are well developed in the
duodenum and jejunum it is as mucosal folds in SI that greatly
increase the absorptive surface area of SI.
• Villi - fingerlike projections that extend into the lumen - responsible for
absorption, each villus (0.5 to1.6 mm) has many microvilli (0.1 to 2 µm)
projecting from the enterocytes of its epithelium which collectively form the
striated or brush border. Folds of
• Crytps are for secretion of digestive enzymes Kerckring
–Goblet cells - secrete mucus
Villus
• The enterocytes that cover the villi have a border of Microvilli described as
the brush border
• These microvilli are what increase the surface area of the small
intestine wall, making available a greater surface area
for absorption.
Enterocyte
 Blood flow in the SI
• Each villus has blood supply - makes sense if this is where a lot of absorption of
nutrients occurs.
• Well supplied with blood arteriole (=artery) and venule (vein)
• Passage of blood and the drug that it contains through the liver is termed FIRST-
• Rich blood supply in SI
PASS METABOLISM as drugs that can be metabolized by the liver are degraded
• Arteriole and venule
here
• SI  hepatic portal vein
• The first pass effect is a phenomenon of drug metabolism whereby
the concentration of a drug is greatly reduced before it reaches the systemic
circulation e.g.:
 liver  systemic
imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, pethid
ine, cimetidine, lidocaine, and nitroglycerin. • - 130% after meal
– Glucose and LC fatty
• So drugs that are absorbed in the SI may be degraded by the liver before they
acids
reach the systemic circulation
• The four primary systems that affect the first pass effect of a drug are
the enzymes of the gastrointestinal lumen, gut wall enzymes, bacterial
enzymes, and hepatic enzymes.
• Alternative routes of administration like suppository, i.v., i.m., inhalational aerosol,
transdermal and sublingual can be used to avoid the first-pass effect because
they allow drugs to be absorbed directly into the systemic circulation.
• Blood flow increases to 130% after a meal so the absorbed nutrients can be
taken away
• Increase in blood flow is stimulated by glucose and long-chain fatty acids that are
in the food that we eat  feel like a sleep after a big meal.
 Lymphatic system: A role in immune function, fatty acid
absorption, and removal of interstitial fluids
•The lymphatic system is a network of tissues and
organs that help to get rid the body of toxins, waste and
other unwanted materials. The primary function of the
lymphatic system is to transport lymph, a fluid containing
infection- fighting white blood cells, throughout the body.
The lymphatic system is a vital part of the immune
system and primarily consists of lymphatic vessels, which
are similar to the circulatory system's veins and
capillaries. The vessels are connected to lymph nodes,
where the lymph is filtered.
Hundreds of lymph nodes
in the human body. They
Multiple Interrelated Functions: are located deep inside
1. It is responsible for the removal of interstitial fluid the body, such as around
the lungs and heart
from tissues into lymph fluid, which is filtered and brought
back into the bloodstream through
the subclavian veins near the heart.
2.Edema accumulates in tissues during inflammation or
when lymph drainage is impaired.
3.It absorbs and transports fatty acids and fats
as chylomicrons from the digestive system.
4. It transports white blood cells and antigen-presenting
cells, such asdendritic cells to lymph nodes where
adaptive immune responses are often triggered.
5. Tumors can spread through lymphatic transport.
 Lymphatics in SI
• Important for absorption of fats, protein drugs and lipid
soluble drugs
• Lymphatic capillaries and lymphoid tissue (GALT)
Follicle-associated – Peyers patches (ileum)
epithelium
– M cells - important in immune system.
– Transport proteins - intact across the GI tract
•Peyer’s patches are small masses of lymphatic tissue
found throughout the ileum region of the small intestine.
Also known as aggregated lymphoid nodules, they form an
important part of the immune system by monitoring intestinal
bacteria populations and preventing the growth of
Particulate delivery vehicles
pathogenic bacteria in the intestines.
•The function of Peyer’s patches is to analyze and respond
to pathogenic microbes in the ileum. Antigens from microbes
in the gut are absorbed via endocytosis by microfold cells
lining the surface of each Peyer’s patch. These antigens are
passed on to the lymphoid tissue, where they are absorbed
by macrophages and presented to T lymphocytes and B
lymphocytes. When presented with dangerous pathogenic
antigens, lymphocytes trigger the immune response by
producing pathogen-specific antibodies; turning into
pathogen-killing cytotoxic T lymphocytes; and migrating
through lymphatic vessels to lymph nodes to alert the other
cells of the immune system.
 Lumen proteases
Routes of
X
transport X
against the X X X P glycoprotein
physical X X Brush border proteases

barrier of Tight junctions

the SI Paracelluar space
10-50 Å
epithelium X
Cytoplasmic proteases
X
X

Lymph vessel
SEROSA
a = carrier-mediated, active transport
b = endocytosis / pinocytosis
c = passive, transcellular diffusion (lipid bilayer)
d = passive, paracellular diffusion (tight junctions)
• The epithelium lining the GIT is considered to constitute the main barrier to drug absorption
• Through this barrier there are a number of potential routes for drug absorption or transport
There is also a chemical (enzymatic) barrier to the delivery of drugs to the small intestine
Proteases that break down drug molecules at 3 different places during absorption thru enterocytes
Transcellular transport involves the transportation of molecules by a cell through a cell. One classic example
is the movement of glucose from the intestinal lumen to extracellular fluid by epithelial cells.
Epithelial cells use primary and secondary active transport often in conjunction with passive diffusion through
ion channels, to produce transcellular transport across epithelial tissues. This transport can either be
absorption, transport from lumen (apical membrane surface) to blood, or secretion, transport from blood to
lumen

Paracellular transport refers to the transfer of substances across an epithelium by passing through the
intercellular space between the cells. It is in contrast to transcellular transport, where the substances
travel through the cell, passing through both the apical membrane and basolateral membrane.
The distinction has particular significance in renal physiology and intestinal physiology. Transcellular transport
often involves energy expenditure whereas paracellular transport is unmediated and passive down a
concentration gradient.

Carrier-mediated transport : movement which occurs across membranes, such as the blood-
brain barrier and the gastrointestinal mucosa.Inherent in the mechanism is a rapidly reversible reaction between
the substance being transported and components
of the membrane. The membrane component is the 'carrier'. The mechanism is also characterized by (1) being
saturable; (2) like substances being able to compete for the services of the carrier so that competitive inhibition
occurs.

Endocytosis is a form of active transport in which a cell transports molecules (such as proteins) into the cell by
engulfing them in an energy-using process.
Endocytosis and its counterpart, exocytosis, are used by all cells because most chemical substances important
to them are large polar molecules that cannot pass through the hydrophobic plasma or cell
membrane by passive means. Endocytosis includes pinocytosis (cell drinking) and phagocytosis (cell eating).
• Routes of transport against the physical barrier of the SI epithelium
• Relevant to the movement of drug in solution
• (b) Endocytosis / pinocytosis = membrane infolds to form a vacuole that
transports substances through the cell
• Most drugs cross membranes via the transcellular route, but for
Hydrophilic drugs (proteins and peptides), the main pathway is
paracellular.
• The paracellular pathway is governed by tight junctions.
• P glycoprotein = transporter proteins in the epithelium that ejects
absorbed materials back out into the gut lumen. Acts as a regulator.
• Also have to remember the diffusion of drug out of the enterocyte (red
arrow)
• Particulate absorption from the small intestine colloidal particles
• Are there any pathways in the SI for absorption of particulates?
• When you look at particulate delivery, SMALL particulates can be
absorbed from the GALT/
• Some viruses and bacteria can be absorbed through M-cells in the GALT
Drug dissolution
disintegration
dissolution

Tablet
Tablets that's made up from
Direct compression will
immediate start dissolution,
but very low rate

Drug Absorption Drug in

blood,
Granules in soln
tissues,
In vivo/vitro
lymph

Dissolution
•Tablet to granules is disintegration
Particles •Granules to particles is deaggregation
•The process in which the drug coming into solution is dissolution
•Absorption is when the dissolved drug reaches the
blood/tissue/lymph and then it can have its pharmacologic effect
Noyes-Whitney eqn

Drug
dm DA
 h (Cs C) h
particle
dt
C Cs
D

– factors affecting the dissolution rate are

given by the Noyes-Whitney equation

Often the rate limiting step

Q-Using Noyes Whitney equation, explain how certain factors affect the rate of mass transfer of solute particles into a
solvent (rate of dissolution).

Answer:
Noyes Whitney equation states that the rate of mass transfer of solute particles into the continuous phase
(rate of dissolution) is equal to Noyes-Whitney equation:
-Rate of dissolution is directly proportional to:
1-surface area of the solute particle
dm/dt = DACs/h 2-diffusion coefficient
where 3- concentration of solute particles present at the boundary layer
dm/dt = rate of mass transfer / rate of dissolution
-Rate of dissolution is indirectly proportional to:
D = diffusion coefficient 1-height of the boundary layer (lower the height the faster the rate
A= surface area of solute particles of dissolution)
Cs = concentration of solute particles at the boundary layer
h = height of the boundary layer

Noyes Whitney equation states that the rate of dissolution is directly proportional to the the surface area of the
solute particle, diffusion coefficient and the concentration of solute particles present at the boundary layer.
Simply put, the higher the value of the diffusion coefficient, the greater the surface area and the more
concentrated the solute particles at the boundary layers are, the higher the rate of dissolution. On the other
hand, according to the equation the height of the boundary layer is indirectly proportional to the rate of
dissolution, so the lower the height the faster the rate of dissolution.

In short, the factors that affect the rate of dissolution according to Noyes Whitney equation are:
1.the Diffusion coefficient,
2. the surface area of the solute particle,
3.the concentration of the solute particles at the boundary layer and
4.the height of the boundary layer.
Dissolution process

can be defined and quantified using the N-W eqn

It is important that you know how each of these factors affect the dissolution rate from a solid dosage
form.

dm/dt, the rate that mass is dissolved over time

Dissolution is time dependent and so a kinetic process (dm/dt)

D = diffusion co-efficient and can inc or dec by substances in the GIT that affect the viscosity of fluids
(e.g. mucus). Fed and fasted state may also change the viscosity of the contents of the GIT

A = surface area. Affected by surfactants in the gastric juice. IF they degrade the particles smaller,
then have a bigger surface area available for dissolution.

h = thickness of the diffusion layer. This is affected by the amount of gastric motility. The stirred
layer is smaller if have movement and churn of stomach contents.

C = concentration of solute in the bulk and this is affected by the drug absorption rate and the
volume of fluid in the GIT

Cs = conc. of drug in solution at the absorptive surface

IMPORTANTLY - this process of dissolution is often the rate limiting step in the absorption of drugs,
particularly if the drug has a low solubility
 Diffusion through the GI membrane
• Passive absorption in the SI via the transcellular route
• Rate of transfer of drug is dependant on the drug physiochemical
Maintains
• properties, the nature of the membrane and the drug
• concentration gradient across the membrane
sink
• The ability of the medium to dissolve the expected amount of conditions
drug is known as a “sink condition”. It is important to note that a
dissolution test should not be conducted in a volume of the medium which
would not dissolve the expected amount of the drug completely and freely

Gastrointestinal Blood
membrane "Sink Conditions-
maintaining a
Gastrointestinal volume of
dissolution media
fluid that is 5 to 10 times
greater than the
diffusion volume at the
saturation point of
partition partition the drug contained
in the drug delivery
Before our drug in soln can get into the bloodstream - it has to go though a membrane system being tested.
If we look at passive absorption through the GI membrane
When drug in solution reaches the circulation system (blood), it is carried away by circulating blood. This
maintains SINK conditions and so drives the concentration gradient down which the drug can enter the body
Fick's laws of diffusion describe diffusion and were derived by Adolf Fick.
They can be used to solve for the diffusion coefficient, D.
Fick's first law can be used to derive his second law which in turn is identical to
the diffusion equation.

Fick's first law relates the diffusive flux to the concentration under the
assumption of steady state. It postulates that the flux goes from regions of high
concentration to regions of low concentration, with a magnitude that is proportional
to the concentration gradient or in simplistic terms the concept that a solute will
move from a region of high concentration to a region of low concentration across a
concentration gradient.

Ficks’s law is similar to the Noyes-Whitney with partition co-efficients added

because we are dealing with a membrane

In this case have a membrane in the situation, diffusion of drugs is the opposite to
the movement of water as in osmosis

Fick's Laws
1.The molar flux due to diffusion is proportional to the concentration gradient.
2.The rate of change of concentration at a point in space is proportional to the
second derivative of concentration with space.
 Physiological factors influencing
passive absorption from SI
dm DA(K1Cg  K2Cb )

dt h

• Surface area (A) of the absorption site

– membrane surface -diffusion
A  dm/dt

• pH of the gastrointestinal fluids

fraction unionised  Cg   dm/dt
dm/dt is the rate of appearance of drug in the circulation
Drugs absorbed in the unionised state
Cg = conc. of drug in solution at the absorptive surface
• Intestinal motility
– affects residence time at the absorptive site
– mixing movements increase contact of drug with the
absorptive surface

• Drug stability in the GI tract

– chemical degradation
– Metabolism
• Presence of food
– stimulates GI secretions and may increase drug
degradation
– bile salt production = surfactant can solubilise drug
and increase Cs
– complexation between drug and food can reduce Cs
– Cs = concentration of drug at absorptive surface
Physicochemical factors influencing passive absorption from SI
pH changes when we eat and so the solubility of drugs in the GIT may change.
Drug exists in an equilibrium in solution
The degree of ionization depends on the pH
Ka = dissociation / ionization constant pKa = -log Ka
Henderson-Hasselbalch eqn pH = pKa + log [A-]/[HA]
& ionization affects absorption because we know that only the unionised form of the drug can be absorbed.
e.g.for an acid drug at Low pH in GIT, then will have more H+ ions and so equilibrium driven to HA, so
absorbed.
• Drug ionisation
pKa = -logKa pH = pKa + log[A-] / [HA]

Ka
A- + H+ HA HA

E.g. Acid drug at low GI pH

 Drug Ionization
•The GIT is lined with epithelial cells. Drugs must pass or permeate through these cells in
order to be absorbed into the circulatory system. One particular cellular barrier that may
prevent absorption of a given drug is the cell membrane.
•Cell membranes are essentially lipid bilayers which form a semipermeable membrane.
Pure lipid bilayers are generally permeable only to small, uncharged solutes. Hence,
whether or not a molecule is ionized will affect its absorption, since ionic molecules are
charged. Solubility favors charged species, and permeability favors neutral species.
•Some molecules have special exchange proteins and channels to facilitate movement from
the lumen into the circulation.
•Ions cannot passively diffuse through the GIT because the epithelial cell membrane is
made up of a phospholipid bilayer.
•The bilayer is made up of two layers of phospholipids in which the charged hydrophilic
heads face outwards and the non-charged hydrophobic fatty acid chains are in the middle of
the layer.
•The uncharged fatty acid chains repel ionized, charged molecules. Which mean the
ionized molecules cannot pass through the intestinal membrane and be absorbed.
•The Henderson-Hasselbalch equation offers a way to determine the proportion of a
substance that is ionized at a given pH. In the stomach, drugs that are weak acids (such
as aspirin) will be present mainly in their non-ionic form, and weak bases will be in their ionic
form.
•Since non-ionic species diffuse more readily through cell membranes, weak acids will have
a higher absorption in the highly acidic stomach.
•However, the reverse is true in the basic environment of the intestines- weak bases (such
as caffeine) will diffuse more readily since they will be non-ionic.
 Partition coefficient (LogP)

•A partition-coefficient (P) is the ratio of concentrations of a compound in a mixture of

two immiscible phases at equilibrium.
•This ratio is therefore a measure of the difference in solubility of the compound in
these two phases.

•The partition-coefficient generally refers to the concentration ratio of un-

ionized species of compound whereas the distribution-coefficient refers to the
concentration ratio of all species of the compound (ionized plus un-ionized).

•In experiment, both phases usually are solvents. Most commonly, one of the solvents
is water while the second is hydrophobic such as 1-octanol.
•Hence the partition coefficient measures how hydrophilic or hydrophobic a chemical
substance is.

•Partition coefficients are useful in estimating the distribution of drugs within the
body.
•Hydrophobic drugs with high octanol/water partition coefficients are mainly distributed
to hydrophobic areas such as lipid bilayers of cells. Conversely hydrophilic drugs (low
octanol/water partition coefficients) are found primarily in aqueous regions such
as blood serum.
 Physicochemical factors
influencing passive
absorption from SI
• Barbitone pKa = 7.8 &
• Thiopentone pKa = 7.6

• Lipid solubility
– LogP

• Molecular size
– For passive, paracellular absorption < 500 Da

• Example - these 2 barbiturates have similar dissociation constants, but

thiopentone is absorbed much better than barbitone
• Reason is that thiopentone is more lipid soluble
• The affinity that a drug has for the lipid biological membrane is partition
coefficient Log P
• Usually determined in octanol because it is the solvent that is most similar to
biological membranes
 Gastrointestinal tract related
issues in drug absorption
• pH environment
• Active transporters
• Gut contents (bile salts, enzymes, food)
• Fed or fasted state
• Regional blood flow
• Disease state
• Penetration enhancers
Carbohydrate digestion begins in the
mouth (Saliva- salivary gland)
After the carbohydrate food is chewed
into smaller pieces and mixed with
salivary amylase and other salivary
juices, breaking down the olysaccharides
in the carbohydrate food.
The mixture enters the stomach where it
is known as chyme.
pancreas releases the enzyme
pancreatic amylase, which breaks the
polysaccharide down into a disaccharide.

Review this diagram

and be able to identify
processes that affect drug
availability for absorption
The small intestine then produces
enzymes called lactase, sucrase and
maltase, which break down the
disaccharides into mono-saccharides,

Florence and Attwood 1998

Physicochemical principles of Pharmacy