BIOPHARMACEUTICS

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General
Overview/Definitions
Biopharmaceutics - concerned with relationship between the
physicochemical properties of a drug in a dosage form and
observed therapeutic response after administration.
Biologic response
Expressed as alteration of biologic process existing before
drug was administered
Magnitude is related to drug concentration achieved at
receptor site.
The observed effect of drug from a dosage form = inherent
pharmacological activity of the drug + its ability to reach the
receptor site in appropriate concentration
Onset, intensity and duration of therapeutic effect drugs
depend on biological + dosage form factors

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General
Overview/Definitions
(Cont.)

These factors are important for: attaining desired drug

conc. in the body + sustaining concentrations for
desired length of time + drug removal after desired
effect is attained.
Biopharmaceutics affords a basic understanding of the
processes of drug absorption, distribution and
elimination + potential effects of dosage form on these
processes that can be applied to optimize therapeutic
outcome of a patient.
Dosage form of a drug exerts its major influence on the
absorption process

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Biopharmaceutics
Biopharmaceutics - the effects of dosage
form and route of administration on the
biological effect of a drug
-study of factors influencing the presence of drug
at the site of absorption and the transfer of the
dissolved drug across biomembrane(s) into the
systemic circulation.
Biopharmaceutical methods: application of
knowledge of drug release and transport across
biomembranes to obtain/predict therapeutic effect
from a product on administration to a patient.

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Factors Influencing the

time course of a drug in
plasma
The physical/chemical properties of the drug
Type of dosage form of the drug
Composition and method of manufacture of the dosage form
The size of the dose and frequency of administration of the
dosage form
Site of absorption of the administered drug
Co-administration of other drugs
Type of food taken by the patient
The disease state of the patient that may affect drug
absorption, distribution and elimination of the drug
The age of the patient.
The genetic composition of the patient

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Bioavailability: rate
& extent
Bioavailability - transfer of drug from its site of
administration into the body system; manifested by
appearance in general circulation.
Characterized by rate of transfer and the total amount
(extent) transferred

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Factors Influencing Drug

Absorption
Can be categorized into 3 factors:

Physiological factors
- Nature of the cell membrane
Semi-permeable: Permits only water, selected small
molecules and lipid-soluble molecules.
Highly charged molecules and large molecules e.g. proteins
and protein-bound drug will not cross.

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Factors Influencing Drug

Absorption
Physicochemical factors
Surface area of the drug
Crystal or amorphous form
Salt form
State of hydration
Solubility

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Factors Influencing Drug

Absorption
Dosage form factors
- The route of administration
- The inert ingredients e.g. diluents,
binders, disintegrants, suspending
agents, coating agent, etc.
-Type of dosage form e.g. tablet, capsule,
solution,suspension, suppository, etc.

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Schematic illustration of the steps involved in the appearance of

intact drug in systemic circulation following oral administration of a
tablet
STOMACH (Gastric content.
pH 1-3)

SMALL INTESTINE (Intestinal

cont. pH 5-7)

Tablet

Tablet
Disintegration

Granules

Granules
Deaggregation

Fine
particles

Fine
particles

Dissolution

Dissolution

Drug in
solution

Drug in
solution

Absorption
Intact drug
Liver
Intact Drug in systemic
Circulation

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Pharmacologic effect

Intestinal metabolism
Hepatic
Metabolism
(1st Pass Effect)

Metabolites

Urine

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Rate Limiting Steps of Absorption

Nature of Drug

Rate Limiting Step

Poor aqueous
solubility

Rate of dissolution in gastrointestinal fluid

High aqueous
solubility

Rate at which drug crosses membrane of the GIT

Dosage Design

Rate of release from the dosage form

Other factors

Rate of gastric emptying into small intestine

Rate at which drug is metabolized by the enzymes in the
intestinal mucosal cells en route into mesenteric blood
vessels

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Rate of metabolism of drug during its initial passage through

the liver (i.e. First-pass effect).
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Physiological
Factors
Affecting Oral
Absorption

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Fate of a Drug
Product

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Simplified Model of
Membrane

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Davson-Danielli Model

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Examples of
Biomembranes
Blood-brain barrier
Has effectively no pores to prevent many polar
materials (often toxic ) from entering the brain.
Smaller lipid or lipid soluble materials, such as diethyl
ether, halothane (used as general anesthetics) can
easily enter the brain.

Renal tubules
Relatively non-porous; lipid compounds or non-ionized
species (dependent of pH and pKa) are reabsorbed.

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Examples of
Biomembranes
(contd)
Blood capillaries and renal glomerular
membranes
Quite porous, allowing non-polar and polar molecules (up to
a fairly large size, just below that of albumin, (M.Wt. 69,000)
to pass through.
Especially useful in the kidneys as it allows for excretion of
polar (drug and waste compounds) substances.

Placental barrier Research!!!

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Structure of the Gastrointestinal Tract

The GIT consists of 4 anatomical regions:

Oesophagus
Stomach
Small intestine
Large intestine (colon).

The luminal surface varies throughout the tract suited for

function

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Physiology of the G.I.T.

Hollow muscular tube composed of 4 concentric

layers of tissues:
Mucosa (mucous membrane)
Sub-mucosa
Muscularis externa
Serosa (outermost layer).

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Physiology of the GIT :

Structure of the wall
Serosa epithelium
+ connective tissue
Muscularis externa
moves GI contents
Submucosa
Secretory tissue
Rich supply of blood
and lymphatic vessels
Network of nerve cells

Mucosa

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Physiology of the G.I.T. :

The Mucosa

Mucosa is most important for drug absorption.

- It contains the cellular membrane through which a drug
must pass in order to reach the blood (or lymph).

The mucosa is itself made of 3 layers:

Lining epithelium
Lamina propria
Muscularis mucosa

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Physiology of the G.I.T.:

The Mucous Layer
The gastrointestinal epithelium is covered by a layer of mucus.
Mucuous acts as a protective layer and a mechanical barrier.
It has a large water component (95%).
It also contains large glycoproteins (mucin)
The mucus layer ranges in thickness from 5 m to 500 m along
the length of the gastrointestinal tract, with average valves of
around 80 m.
The layer is thought to be continuous in the stomach and
duodenum

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Physiology of the
GIT:
The Oesophagus
Links the oral cavity with the stomach.
Composed of a thick muscular layer, approx.
250mm long and 20mm diameter.
Epithelial cell function is mainly protective:
simple mucus glands secret mucus into the narrow lumen to
lubricate food and protect the lower part of the oesophagus from
gastric acid.

The pH of the oesophageal lumen is usually

between 5 and 6.
The oesophageal transit of dosage form is approx.
10-14 seconds

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Physiology of the
GIT:
The Stomach
Most dilated part of the gastrointestinal tract.
Situated between the lower end of the oesophagus and
the small intestine.
Opening to the duodenum is controlled by the pyloric
sphincter.
Capacity of approx. 1.5L
Very little drug absorption occurs in the stomach due to
relatively small surface area (compared to small
intestines).

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Physiology of the
GIT:

The Stomach (contd)

Gastric secretions:
Acid secreted by parietal cells - maintains the pH of the
stomach between 1 and 3.5 in fasted state.
Hormone gastrin - potent stimulator of gastric acid
production.
Pepsin - secreted by peptic cells in the form of its precursor,
pepsinogen; peptidase which break down proteins to
peptides at low pH; above pH 5 pepsin is denatured.
Mucus - secreted by the surface mucosal cells and lines
the gastric mucosa; protects gastric mucosa from auto
digestion by the pepsin-acid combination.

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Physiology of the
GIT:
The Small Intestine
Longest (4-5m) and most convoluted part of the GIT, extending from
the pyloric sphincter (of stomach) to the ileo-caecal junction where it
joins the large intestines.
Main functions:
Digestion:
Process of enzymic degradation; begins in the stomach
and completed in the small intestine.
Absorption:
Small intestine is the region where most nutrients and other
materials are absorbed.
Divided into the duodenum (200-300mm long), the jejunum (2m
long) and the ileum (3m in length).

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GIT:

The Small Intestine

(contd)
The luminal pH of the small intestine increases to 6 -7.5
due to :
Brunners glands:
Located in the duodenum
responsible for the secretion of bicarbonate which neutralizes
the acid emptied from the stomach.

Intestinal cells:
present throughout the small intestine
secrete mucus and enzymes, such as hydrolases and
proteases

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GIT:

The Small Intestine

(contd)
The following structures are responsible for the very large
surface area of the small intestine.
Folds of Kerckring:

Submucosal folds extending circularly most of the way around the

intestine; well developed in the duodenum and jejunum

Villi:

described as fingerlike projections into the lumen

(approx. 0.5 - 1.5mm in length and 0.1mm in diameter).
Well perfused

Microvilli:

approximately 600-1000 brush-like structures (1 m in length and 0.1 m

in width) cover each villus,
provides the largest increase in the surface area.

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Structure

Increase in Surface
(relative to cylinder)

Surface Area
sq cm

simple
cylinder

3,300

Folds of
Kerckring

10,000

30

100,000

600

2,000,000

Villi

Microvilli

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Physiology of the
GIT:
The Colon
Terminal portion of GIT.
Unlike the small intestine, has no specialized villi.
However, the surface area is increased by the following

microvilli of the absorptive epithelial cells

presence of crypts
irregular folded mucosae serve to increase the surface area of the colon by
10-15 times.

Main functions are:

The absorption of sodium and chloride ions and water from the lumen
in exchange for bicarbonate and potassium ions.
Significant homeostatic role in the body.
Storage and compaction of faeces.

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Physiology of the
GIT:
The Colon (contd)

Colonized by a large number and variety of bacteria (about 1012

per gram of contents).
Bacterial mass is capable of several metabolic reaction,
including hydrolysis of fatty acids, reduction of inactive
conjugated drugs to their active form.
They degrade polysaccharide to produce short- chain fatty acids
(acetic, proprionic butyric acids); generation of gases hydrogen,
carbon dioxide and methane (lowers luminal pH to 6 - 6.5)
This increases to around 7-7.5. toward the distal parts of the
colon.

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