Influence of biopharmaceutical factors on dosage form design

Question 1

What are the key steps in absorption

Takes drug in dosage form through to the drug as solute in blood

Answer 1

Disintegration
Dissolution
Permeation
Presystemic metabolism

Question 2

What is the BCS system

Answer 2

The biopharmaceutic classification system - a system which allows us to classify drugs into one of 4 classes dependent on how their absorption is affected by their rate of dissolution or their permeability

Question 3

What is the criteria for a drug with good solubility

Answer 3

Maximum dose strength will be available in 250ml or less over the pH range 1-8

Question 4

What is the criteria for good permeability

Answer 4

Over 90% absorption predicted by an established laboratory method

Question 5

What does the BCS system not consider

Answer 5

Stability (at different pH values)

Binding interactions with gut or its contents

Question 6

Detail the solubility and permeability of the different BCS classes

Answer 6

Class I : high solubility, high permeability - easy to formulate
Class II : low solubility, high permeability - maximise dissolution rate (micronised powder form)
Class III : high solubility, low permeability - maximised exposure to intestinal surface
Class IV : low solubility, low permeability - consider prodrug or different administration route

Question 7

Give examples.of a drug from each BCS class

Answer 7

Class:
1 - propranolol 
2 - ketoprofen
3 - gabapentin
4 - furosemide

Question 8

Many physicochemical factors will affect absorption. Name 4 of them

Answer 8

Size and wetability (how well the drug particle reacts with the fluid its in) of drug particles
Solubility and planning of drug molecule
Lipophilicity (logP) of drug molecules
Chemical reaction rates affecting stability

Question 9

Unionised molecules are likely to be
Hydrophilic?
Lipophilic?

Answer 9

Lipophilic - good permiation and poor dissolution

Question 10

Many biological factors will affect absorption. Name 4 of them

Answer 10

Transit times in each section of the gut (gut motility)
Local pH
Local enzymes, surfactants
Epithelial surfactants area, mucus, gut contents

Question 11

What leads to variation in biological factors

Answer 11

The individual, their health, meals, diet, fluid intake, activity

Question 12

What is the importance of pH when considering drug absorption

Answer 12

It influences
Solubility (particularly with WA/WB) - permeable vs soluble
Stability - drug may be subject to acid hydrolysis

Question 13

Why is the influence of pH on permeability rarely critical when considering drug absorption

Answer 13

The high surface area in the small intestine means there is a very steep concentration gradient established between the inner and outer gut wall meaning the small fraction of unionised drug will be uptaken almost instantly. Then the equilibrium will be re-established.

Question 14

Give the pHs in the:
Gastric fluid
Intestinal fluid

Answer 14

pH 1-3.5 (fasted), 3-7 fed

pH 5-8 (food presence doesn’t have much of an effect)

Question 15

Why is the pH in the intestine much higher than in the stomach?

Answer 15

The gastric acid is neutralised by bicarbonate ions secreted by the pancreas

Question 16

What strategies can we use to improve drug stability in gastric fluid?
5

Answer 16

Take with/after meal (higher pH in stomach)
Large particle size to delay dissolution
Convert to salt form to alter dissolution rate
Enteric coating- delays disintegration until the drug is in the intestine
Prodrug - molecule with better solubility/permeability is metabolised into the active drug after absorption

Question 16

What strategies can we use to improve drug stability in gastric fluid?
5

Answer 16

Take with/after meal (higher pH in stomach)
Large particle size to delay dissolution
Convert to salt form to alter dissolution rate
Enteric coating- delays disintegration until the drug is in the intestine
Prodrug - molecule with better solubility/permeability is metabolised into the active drug after absorption

Question 17

What is:

The minimum effective concentration
The therapeutic range
The peak concentratkon

Answer 17

The minimum concentration of drug in the blood required to have a biological effect

The plasma concentration range between the lowest and highest blood concentration (too low = subtheraputic, too high = toxic)

This is the point where there is the highest concentration of drug in the plasma. After this peak, the elimination phase starts (where elimination is occurring faster than absorption)

Question 18

How would you measure the total amount of drug in the blood

Answer 18

We measure the concentration of drug in the blood. This is because we have a good estimate of the body’s total amount of blood (~5L) and blood plasma. From this we can calculate the total amount of drug absorbed

Question 19

How do we account for Distribution Metabolism Excretion when considering the drug concentration in the blood?

Answer 19

We must perform a control measurement. This is a measurement which only accounts for the DME and is always an IV injection of the drug. The progression of the drug concentration in the blood is measured over time. This is used to compare against the orally administered drug to work out the differeng drug concentration levels between the two dosage forms. As the drug in the central compartment will have the same DME processes as the orally administered one.

We calculate drug exposure by working out the area under the curve of each dose curve which gives us the conc/time (mg.h/l)

Question 20

What is the Cmax

Answer 20

The maximum drug concentration achieved in the blood

Question 21

What is the Tmax

Answer 21

The time it takes to achieve the Cmax

Question 22

What is the mathematical definition of absolute bioavailibility

Answer 22

F = AUCoral / AUCiv

F = absolute bioavalibility
AUCoral = area under the curve for orally administered drug
AUCiv = area under the curve for iv administered drug

Question 23

State what is needed to work out the absolute bioavailability

Answer 23

Measurements of blood plasma drug concentration vs time (AUC) after extravasuclar dosing and after IV administration of the drug

Question 24

State what is needed to work out the relative bioavailability of two different oral dosage forms

Answer 24

Plasma AUC of a test dosage is compared to a standard dosage form. Both to be administered by the same extravascular route (eg oral)

Question 25

What is bioequivalence

Answer 25

Where two dosage forms show no significant difference in AUC, Tmax and Cmax
(Concentration reached is roughly the same and the time taken to reach it is roughly the same)