GIT – Physiology and Drug

Absorption

Aulton’s Pharmaceutics: The science of dosage form design.

3rd Edition
p270-284
Drug Delivery Systems: Getting Drugs to Their
Targets in a Controlled Manner
Drug delivery refers to approaches, formulations, technologies,
and systems for transporting a pharmaceutical compound in the
body as needed to safely achieve its desired therapeutic effect.

• Mucosal routes for drug delivery

• Gastrointestinal
• Nasal
• Buccal
• Ocular
• Transdermal
• Parentral
Oral Suppository
- Pill, i.e. tablet or capsule, syrups - Vaginal (e.g., douche, pessary,
- Thin film (e.g., Listerine Pocketpaks) etc.)
- Special tablets like buccal, sublingual or orally - Rectal
disintegrating - Urethral suppositories
- Liquid solution or suspension (e.g., drink or - Nasal suppositories
syrup) - Ear cones
- Powder or liquid or solid crystals
- Natural or herbal plant, seed, or food of sorts
(e.g., marijuana such as that found in "Space Parenteral
Cake") - Intradermal (ID)
- Pastes (e.g., Toothpaste) - Subcutaneous (SC)
- Intramuscular (IM)
- Intraosseous (IO)
- Intraperitoneal (IP)
Ophthalmic - Intravenous(IV)
- Drops
- Cream Topical
- Liquid solution
- Cream, gel, liniment or balm, lotion, or ointment, etc.
- Ear drops (otic)
Inhalational - Eye drops (ophthalmic)
- Aerosol - Skin patch (transdermal)
- Inhaler - Vaginal rings
- Nebulizer - Dermal patch
- Vaporizer
Routes of drug administration
Aural (into the ear) Buccal (applied to the inside of the cheek,
between cheek and gums) Intra-arterial (into an artery) Intra-
articular (into a joint space) Intracutaneous (intradermal, into the
skin) Inhalation (into the lower airway) Intramuscular (injection into
skeletal muscle tissue) Intraosseous (into the bone marrow cavity)
Intrathecal (into the spinal canal) Intravenous (into a vein) Nasal
(into the nose/nasal passages) Ocular (into the eye) Oral (per
mouth) Per rectum (into the rectum) Per vaginam (into the vagina)
Subcutaneous (hypodermic, i.e. just beneath the skin) Sublingual
(placed under the tongue) Topical (applied to surface areas, e.g.
the skin or the surface of a wound) Transdermal (applied to the
skin for systemic absorption through it)
Examples of commonly encountered dosage
forms

Aerosols Capsules Creams Elixirs Emulsions

Gels Granules Lotions Mixtures Ointments
Ophthalmic and aural preparations Parenteral
preparations for injection Pastes Pessaries
(vaginal suppositories) Powders Skin patches
for transdermal administration Solutions
Sponges impregnated with drugs
Suppositories Suspensions Syrups Tablets
Volatile liquids and gases
 Biopharmaceutics
“Study of how physicochemical properties of drugs, dosage form
and routes of administration affect the rate and extent of drug
absorption.”

Biopharmaceutics examines the interrelationship of the

physical/chemical properties of the drug, the dosage form (drug
product) in which the drug is given, and the route of
administration on the rate and extent of systemic drug
absorption. The importance of the drug substance and the drug
formulation on absorption, and in vivo distribution of the drug to
the site of action, is described as a sequence of events that
precede elicitation of a drug's therapeutic effect.
 Gastrointestinal Drug
Delivery Systems: Oral route
Most popular & convenient route for the administration of drugs.

Easy to manufacture oral dosage forms:

• do not need to sterilise
• easy to produce in large quantities
• process can be automated

Barriers to oral delivery:

• (chemical and physical) as the GI has evolved to digest food and be selective about what isabsorbed
into the body

• Suitable for drugs that are absorbed across biologicalmembranes

This is the gross anatomy that an orally
administered dosage form is going to
Overview of the human GIT
encounter once ingested.

First (about 20–25 cm long) of SI is the

duodenum (pH 6 in the duodenum to pH
7.4 in the terminal ileum)
Pancreas produces hydrolytic enzymes as
an alkaline sol. rich in bicarbonate (acts
as a buffer)
Bile produced in the liver (stored in the gall
bladder). Bile salts aid in digestion of fats.

Green duct is the bile duct that brings

secretions from the liver and pancreas into
the small intestine (6-7m long).
Jejunum
Jejunum (2.5 m) and ileum ( 2–4 m long,
and the pH is usually between 7 and 8)

Colon = ascending, traverse and

descending
 Esophagus
(NOT A SITE FOR DRUG DELIVERY)
Any oral dosage forms must pass through the oesophagus

The action of swallowing passes substances from the mouth

to the stomach

Mucus lubricates food and also protects the lower

oesophagus from the acids in the stomach. Technitium
labelled
Peristalisis is the muscular contractions that pass food
water
down the oesophagus

Dysphagia = difficulty in swallowing

Graphs
Difference in movement of solution vs particulates.
The solution (water) moves rapidly to the stomach. By 15 Fast dissolving
sec labelled water (technetium) is in the stomach.
The particulates (the delivery system), moves down in the oral DDS
peristaltic waves and takes up to 30 secs to get to the
stomach.
 Oesophageal transit times
Formulation Weight & dimensions Transit time Posture

Tablet 14 mm x 9 mm, film coated 3sec erect

14 mm x 9 mm, film coated >300 supine

Capsule Hard gelatin (Size 2), 0.59 g 10 supine

Hard gelatin (Size 2), 1.2 g 80 supine

Hard gelatin (Size 2), 0.59 g 3 erect

Hard gelatin (Size 2), 1.2 g 9 erect

As well as the particle size of the dosage form affecting the arrival time at the stomach,oesophageal transit
is also affected by the position of the patient.

Supine = lying down

This is something that needs to be considered if you are recommending a dosage form for a patient in
hospital for example.

For data with hard gelatin capsule in the erect position, the time for the lighter capsules (0.59 g) is faster
than the 1.2 g.
These numbers for erect position are pretty close and so can conclude that transit is similar in the erect
stance.
 Plasma concentrations following oral
administration of 400 mg paracetamol

Oesophageal transit can delayed and reduced Cmax

affect drug absorption 80
and bioavailability.
normal transit
60
Look at the plasma delayed transit
concentration when in a
supine position 40

Black line = patient lying 20

down
0
0 100 200 300 400 500 600 700
Time (min)
 Oesophageal adhesion & damage
Just as lying down when take medications can increase the time
taken to reach the stomach, the amount of fluid (water) taken can
influence effectiveness of an oral tablet.

The tablet is likely to stick in the oesophagus because the tablet is

dry and the mucus in the oesophagus is wet. This leads to gel
formation and adhesion. Can be hard to dislodge once formed.

Because this adhesion of the tablet to the wall of the oesophagus

and the local release of the concentrated drug at a small site, this
can damage the epithelial lining.

Drug induced ulceration most commonly occurs at the aortic

arch. Here is a slight constriction of the oesophagus in this
position. Symptoms include retrosternal pain and may cause
stricture. retro*ster*nal pain
The function of the GI tract is to digest and absorb ingested food.

Three main sections to stomach: fundus (cardiac limb), body and pyloric
antrum.
Two sphincters that control movement of substances into and out of
stomach

Main functions of stomach are to;

1. Store food
1. volume = 1.5 L
2. Daily intake of food and drink 3-4 kg
3. 5 L gastric secretions (saliva, gastric juice, pancreatic
secretions)

2. Begin acid digestion of food = pepsin. Acid secretions maintain low

stomach pH.
Antrum is more acidic because parietal cells are here and they secrete
acid.

Mucus secreted by surface mucosal cells and this protects the stomach
lining from auto-digestion by acid and pepsins.

3. Deliver food in a controlled fashion to the duodenum (pyloric

sphincter)
 Fundus
Cardiac mucosa: Chief Cells:
secretes mucus Pepsinogen
Cardia
Parietal cells:
Secrete HCl

Argentaffin cells:
Secrete hormones
including
histamine, gastrin,
somatostatin

Antral pyloris: Pyloris Body

secretes mucus
Cardiac mucosa to protect oesophagus from acid secretions in stomach

Antral pyloris secretes alkaline mucus to protect duodeunum

Mucus is 95% water. An aqueous gel. Protective layer and also a mechanical barrier.
Various thickness throughout the GIT.

It contains glycoproteins called mucins. Continually replaced. Turnover time 4-5 h,

although varies along length of tract.

Body and Fundus have;

Chief cells (peptic cells): secrete pepsinogen, the precursor or active pepsin. Pepsins
are pepsidases that break down proteins and peptides at low pH. Above pH 5, pepsin
is denatured.

Parietal cells: maintain the acid secretions of the stomach between 1 and 3.5.

Argentiaffin cells: Hormone gastrin which also stimulates gastric acid secretion.
Release of gastrin is stimulated by amino acuds from the digestion of proteins and also
distension of the stomach when food is eaten.
 Gastric pH is affected by:
• Acid secretion (HCl)
• Gastric content e.g. food increases pH
• Acid-lowering drugs
• proton pump inhibitors (e.g. omeprazole)

• In the fed state, HCl secretion is increased

dramatically, but this is counterbalanced by
the buffering effects of a meal. pH increases
to 3-5 when we eat

Meal Time (min)

• Graph
• Box-whisker plots for gastric pH data pooled from
24 young healthy men and women for three 15-
min intervals before meal (M) administration and
at 5-min intervals postprandially.
• If your patient is on omeprazole that may have
implications for other medications they are
prescribed.
 Dosage forms in the stomach
• Food effects
– increases pH
disintegration
– not mixed uniformly
– interactions

The features of the stomach reflect the function and

this is the environment into which oral dosage Dissolution Lighter objects
forms will come into contact once ingested. [HA] float on gastric
contents
This includes the food itself too and the churning of
the stomach.

Disintegration and dissolution (= transfer of

molecules in the solid state into solution) of the
dosage form are the main things that go on in the
stomach

Changes in gastric pH will affect the dissolution

rate of drugs and dosage forms
Heavy objects fall
to the base of
Very little drug get absorbed in stomach greater curvature
 Gastric pH and stability
• Gastric pH will also affect drug stability
– Drug degradation occurs at pH extremes
– Most drugs are stable between pH 4 - 8
– Effects of pH on drug stability are described by pH rate profiles

Drug degradation and loss of drug effect

pH has the biggest effect on the stability of drugs in soln

Degradation rate is more rapid at very high or very low pH, but less at pH 7.0.

At high pH, where there are many OH- ions and so get base catalysis, and
and low pH there are many H+ ions, so they get acid catalysis
 Gastric pH and enteric coatings
• Gastric pH assumed by formularies = 1.0
• However, considerable variation:
– after eating pH may increase to between 3 & 5

Example
Radiolabelled enteric coated naproxen tablets given to fed subjects
five tablets disintegrated in the small intestine
approx. 1.2 hours after gastric emptying.
– one tablet disintegrated in the stomach at pH 1.1

Since gastric pH is an issue, then as a good formulator - you would use an enteric
coat.
But not quite that simple…because get between subject variability (a example) and
gastric emptying is a really important factor
 Gastric emptying
• Important parameter controlling the onset of drug
action
– because it controls the rate of arrival of the drug to the
main absorption site (Small intestine)
• Gastric emptying - the time taken for a dosage
form to pass through the stomach
• Gastric emptying is VERY important in determining
the onset of drug action from orally administered
product.
• Determines contact time between the drug and low
pH environment
– drug stability?
 Fasted pattern of motility
Gastric emptying is controlled by the migrating myoelectric complex (MMC)
Housekeeper waves are powerful peristaltic contractions which open the pyloris
and clear the stomach of any material.
These contractions occur in between meals and cleans out the stomach of
contents (hence name)
Cycle is every 2 h or until a meal
When eat a meal, the pattern of contractions changes into the FED STATE which
is continuous contractions, but emptying is delayed.
Fasted stomach is less discriminatory for dosage forms

Phase I Phase II Phase III Phase IV

No activity Increasing Housekeeper Transition

contractions in wave time
stomach and SI
40 - 60 min 40 - 60 min 4 - 6 min 4 - 6 min

2 h cycle
 Sieving effect in fed-state
•In the fed state - gastric sieving influences gastric emptying.
•It is a selective process.
•Food also causes mechanical mixing and grinding of material in the stomach.
•Mixture of large and small particles in the food we ingest

Phase of emptying Phase of retropulsion

Phase of propulsion

Antrum

Rapid flow of liquids with Emptying of liquids with Retropulsion of large

suspended small particles small particles. Large particles
and delayed flow of large particles are retained
particles in the terminal
antrum
Gastric emptying of fluids or small granules
is an apparent first-order process

rate of gastric emptying  volume of material remaining in the stomach

% Remaining in the Stomach

100

There is a proportional
80
decrease
Tablets up to 11 mm diameter
60
can empty from the fed
stomach in a linear fashion
40

20

0
0 1 2 3 4 5

Time (hours)

• Size and emptying

If we compare the emptying of small particles with larger solids (red
line), they are emptied slower than the small particles.

This is a consequence of the retropulsion of large particles by the

antrum of the stomach is that large solids are emptied more slowly than
liquids
% Remaining in the Stomach

100

small particles
80
large solid

60

40

20

0
0 1 2 3 4 5
Time (hours)
 Gastric emptying is a highly variable
process
Pyloric stenosis = narrowing of the outlet
of the stomach

hunger fatty foods

anxiety high bulk (viscous) diet
body position mental depression
(lying on right side) gastric ulcers
intake of liquids pyloric stenosis
hypothyroidism
Generally, the presence of food in the lying on left side
stomach delays gastric emptying therefore tricyclic antidepressants
can delay drug absorption because it takes alcohol
longer for the drug to reach the small
intestine.
Effect of food on gastric residence time
of large, non-disintegrating
oral formulations
Large non-disintegrating tablet –
i.e. tablet is not broken up
a = empty stomach and emptied quickly
g = stomach is full and never in the empty state.
Gastric residence

Continual eating during the day

in (g), means the stomach does not enter the
fasted state, the housekeeper waves are
not generated and the tablet remains in the
stomach
a = on an empty stomach
b = after continental breakfast (2200 kJ)
c = after a breakfast + snack 2.5 h later
d = after lunch (4000 kJ)
e = after lunch + snack 2.5 h later
f = after supper
g = after breakfast + snack + lunch + snack
+ supper (@ 2.5 h intervals)

Figure 5.16. Gastric residence time of a large non-disintegrating

Unit (11 x 6 mm), density 1.4 g ml-1) with different feeding regimens.
 Gastric emptying of a multiparticulate
dosage form
Multiparticulate
system = Emptying rate is
capsule
containing small
slowed in the
granules fed-state

Dosed before
meal = fasted
state

Dosed with
meal and after
meal = fed state
 Effects of meal size and pellet density
on gastric emptying
Pellets with a light
meal cleared faster
than when
administered with a
heavy meal

The density of the

pellets alone relates
the the earlier slide
of floating or sinking
pellets.
 Drug induced effects on gastric
emptying

• adrenergic agonists (esp.-agonists

such as salbutamol) delay gastric
emptying
• tricyclic antidepressants depress
gastric emptying
• dopaminergic antagonists and
cholinergic agonists enhance gastric
motor activity
 Review this diagram
and be able to identify
processes that affect drug
availability for absorption

Florence and Attwood 1998

Physicochemical principles of
Pharmacy 3rd edition