Lecture 3: Oral Drug delivery

Introduction:
 The factors that affect the rate and extent of absorption depends on the route
of administration.
 For ex, IV route offers direct administration of the drug into the systemic
circulation and all drugs administered becomes available into the plasma to
be distributed to the tissues.
 Oral route is the most popular route of administration of drug delivery as
around 80% of medicines are delivered orally in the form of tablets, capsules,
solutions, suspensions and emulsions.

What are the advantages of oral drug delivery?

 Patient: Convenience, not invasive, higher compliance.
 Manufacture: well established process, easy to manufacture and cheap
process.
 High surface area available for absorption.

What are the formulations of oral drug delivery?

Traditional oral delivery systems:
 Tablets
 Capsules/ Soft gelatine capsules
 Suspensions
 Emulsions

Controlled oral drug delivery

 Sustained
 Extended

What are the factors affecting oral drug bioavailability?

 The rate and extent of appearance of the drug into the systemic circulation
depends on series of process.
 Among the processes the slowest step is called rate-limiting step.
 Very poorly soluble drugs will require long time to dissolve and hence
dissolution is the rate limiting step.
 While high soluble drugs have high dissolution and the rate limiting step
could be their permeation across the intestinal membrane.
  Other potential rate limiting steps, could be the gastric emptying
(Rate at which the stomach empties the drug into the small intestine because
the small intestine is where the majority of the absorption takes place)or it
could be the rate at which the drug is metabolised (either in intestinal mucosal
cells or in liver)

Physiology of GIT:
What is GIT (Gastrointestinal tract)?
-GIT is a muscular tube extend from mouth to anus
- is 6m in length with varying diameter.
-The luminal surface (the inside space of a tubular structure such as intestine) is
very rough.

Mucus:
-Majority of GIT epithelium is covered with mucus
-it’s viscoelastic translucent gel act as protective and a mechanical barrier.
-Is removed by abrasion and the acidic or enzymatic breakdown.
-Large water content (95%)
-Another primary component is a glycoprotein called mucin (the other 5%)

Majority of GI
epithelium is covered with
mucus
- Is viscoelastic translucent gel
act as
protective layer and mechanical
What is the Oesophagus?
-is a tick muscular layer join the oral cavity to stomach
-250mm long and 20mm diameter
-Has mucus glands
-Has pH between 4-6 and rapid transit (10-14 seconds)

What does the Stomach consist of?

-Most dilated part and consist of 4 anatomical regions fundus, body, antrum and
pylorus.
- Has a capacity of 1.5l
-Under fasting conditions contain 50ml of fluids mainly gastric fluid:
- Hydrochloride acid (secreted by parietal cells) to maintain the pH of stomach
between 1-3.5

-Gastrin hormone (released by G-cells) to stimulate gastric acid and pepsinogen

secretion.
-Pepsin (secreted by gastric chief cells as an inactive zymogen called pepsinogen)
-Function as a:
- Temporary storage for food, which passes from the oesophagus to the
stomach where it is held for 2h or longer
- Mixing and breakdown of food by contraction and relaxation of the muscle
layers in the stomach.
- Digestion of food

What is the small intestine?

-is the longest (4-5 m) and most convoluted part (very complicated/ difficult)
-Has a diameter of 25-30mm
-Divided into duodenum (200-300mm length), jejunum (2m length) and ileum (3m
length)
-The surface area (~ 200 m2) of the small intestine increases enormously by
who?
- Folds of Kerckring
- Villi (finger-like projections, 0.5-1.5mm in length and 0.1mm in diameter,
contain arteriole, venule and lymphatic vessels/lacteal)
- Microvilli (around 600-1000 brush like structure cover each villus)

Barriers of oral absorption:

What are the various barriers of oral absorption?
- GIT pH
- Luminal enzymes
- Food
- Physiological disorders
- Presystemic metabolism
- Mucus and unstirred water layer

1-GIT pH:
- pH varies along GIT
- Starts with lower pH 1-3.5 for the gastric fluid which increases to 3-
7 after a meal and gets back to normal after 2-3 hours.
- Intestinal pH is higher than gastric pH due to neutralization with
bicarbonate secreted by pancreas into small intestine.

Effect of pH on drugs

- Chemical stability,
such as hydrolysis which
might result in incomplete
bioavailability ex:
erythromycin and
omeprazole
degrade rapidly at
acidic pH and need to be enteric coated.
-Rate and extent of dissolution
-Absorption characteristics of the drug according to the ionisation status

2-Luminal enzymes:
-Pepsin and Protease might cause degradation to drugs which are protein in nature
such as nucleotides.
-Lipase might affect the release of drug from fat/oil containing dosage form.
-Ester drugs are susceptible to hydrolysis by esterase enzymes in the lumen.
-Colonic bacteria secrete some enzymes that could break drugs (Sulfasalazine)

3-Food:
-Presence of food can also affect the rate and extent of absorption. Either directly or
indirectly.

4-Physiological disorders:
-GIT physiological disorders affect the absorption and hence the bioavailability of
orally administered drugs.
-Local diseases can alter (change in character or composition) the gastric pH and
hence affect the stability, the dissolution and absorption of drugs.

5- Presystemic metabolism:
- One of the major challenges that
faces the oral drugs
degradation /metabolism by
liver enzymes such as
cytochrome P450.
- After the drug absorption from stomach, small intestine and upper colon it
passes into the hepatic portal system prior to reaching the systemic
circulation.
- The liver is the first metabolic site and the last barrier for orally absorbed
drugs.
- Intensive drug metabolism might result in an ineffective drug for instance
propranolol is well absorbed but only 30% of oral dose are available to
systemic circulation because of the first pass effect. Sustained-release
propranolol is even less.
- What are the examples of other drugs susceptible to first pass effect?
Atorvastatin, lignocaine and diazepam.

6-Mucus and unstirred water layer:

- Before the drug get into the epithelial surface it has to pass across the
mucous layer and unstirred water layer.
- Unstirred water layer is around 30-100 μm in thickness and is created by the
incomplete mixing of luminal contents near the intestinal mucosal surface.

Mechanism of drug uptake:

What are the 2 main mechanism of drug absorption?
- Transcellular: divided into passive diffusion, active diffusion (carrier
mediated) and endocytosis.
- Paracellular
A-Transcellular:
1-Passive diffusion:
- For small lipophilic molecules (doesn’t require energy)
- Molecules pass from a region of high concentration(lumen) to region of low
concentration(blood)
- Passive diffusion can be prescribed by Fick’s first law of diffusion.
dC/𝑑𝑡 =𝐷𝐴/ℎ (𝐶s −𝐶𝑏)
- Examples: steroids, sex hormones (oestradiol)
- 𝑑𝐶/𝑑𝑡: rate of diffusion
- Diffusion constant(D) is inversely proportional to the drugs weight
- Area(A)of the membrane
- Cs-Cb: concentration gradient across membrane (downhill)
- h: thickness of membrane
- Cb equals zero at sink condition.
- If you increase the thickness this means you will decrease the absorption. If
you increase the area, you increase the overall absorption.

- dC/dt is the rate of diffusion

- Diffusion Constant (D) is
inversely proportional
- to the drug's weight.
- Area (A) of the membrane.
- Cs - Cb is concentration
gradient across
- membrane (downhill).
C/dt is the rate of diffusion
Diffusion Constant (D) is
inversely proportional
to the drug's weight.
Area (A) of the membrane.
Cs - Cb is concentration gradient
across
membrane (downhill).
h thickness of membran
- dC/dt is the rate of diffusion
- Diffusion Constant (D) is
inversely proportional
- to the drug's weight.
- Area (A) of the membrane.
- Cs - Cb is concentration
gradient across
- membrane (downhill).
- dC/dt is the rate of diffusion
- Diffusion Constant (D) is
inversely proportional
- to the drug's weight.
- Area (A) of the membrane.
- Cs - Cb is concentration
gradient across
- membrane (downhill).
- C/dt is the rate of diffusion
- Diffusion Constant (D) is
inversely proportional
- to the drug's weight.
- Area (A) of the membrane.
- Cs - Cb is concentration
gradient across
- membrane (downhill).
- h thickness of membrane
- C/dt is the rate of diffusion
- Diffusion Constant (D) is
inversely proportional
- to the drug's weight.
- Area (A) of the membrane.
 -C
s
- Cb is concentration gradient
across
- membrane (downhill).
- h thickness of memb dC/dt is the rate of
diffusioDiffusion Constant (D) is inversely proportiona
2-Active transport/diffusion (Carrier mediated transport) (require energy
because it’s mediated by carriers which need energy to function)
- Drug molecules form a complex with the carrier on the apical side and this
complex moves across the membrane to liberate the drug on the other side of
the membrane. The carrier becomes free and ready to transfer another drug
molecule.
- Drugs are transported against concentration gradients (i.e., from regions of
lower concentration to regions of higher concentration) and this is
facilitated by the energy generated by ATP hydrolysis.
- Unlike the passive diffusion, the rate of absorption is proportional with the
concentration only at low concentration. At high concentration the carrier
becomes saturated
- Examples amino acids, peptide like drugs such as penicillin, cephalosporins,
nucleoside like drugs (antiviral and anticancer)

3-Endocytosis:

Drugs are transported against

concentration gradients (i.e. from
regions of lower
concentration to regions of higher
concentration) and this is
facilitated by the energy
generated by ATP hydrolysis.
- Plasma membrane invaginates(infolding) and the invagination pinch off to
form membrane-bound vesicles that enclose the drug. The materials are
usually transferred to other vesicle or lysosomes and digested.
- Endocytosis is the primary mechanism of transport of macromolecules
- What are the further divisions of endocytosis?
-Pinocytosis: engulfment of the extracellular small droplets by membrane
vesicles such as fat-soluble vitamins ex:
Vitamin A, D, E and K
- Phagocytosis: engulfment
of particles larger than 500nm
- Transcytosis: vesicular
transport of macromolecules
across cells from one side to
another

B-Paracellular pathway takes place between the cells

-Drug molecules are transported through the aqueous pores between cells.
-These intracellular spaces occupy only 0.01% of the total surface area.

C-Efflux
After absorption of some of the drug’s molecules, they get expelled back into the
lumen of the gastrointestinal tract via efflux transporters such as (p-glycoprotein)
Examples: - digitoxin and paclitaxel.