Influence of biopharmaceutical factors on dosage form design Flashcards
What are the key steps in absorption
Takes drug in dosage form through to the drug as solute in blood
Disintegration
Dissolution
Permeation
Presystemic metabolism
What is the BCS system
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
What is the criteria for a drug with good solubility
Maximum dose strength will be available in 250ml or less over the pH range 1-8
What is the criteria for good permeability
Over 90% absorption predicted by an established laboratory method
What does the BCS system not consider
Stability (at different pH values)
Binding interactions with gut or its contents
Detail the solubility and permeability of the different BCS classes
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
Give examples.of a drug from each BCS class
Class: 1 - propranolol 2 - ketoprofen 3 - gabapentin 4 - furosemide
Many physicochemical factors will affect absorption. Name 4 of them
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
Unionised molecules are likely to be
Hydrophilic?
Lipophilic?
Lipophilic - good permiation and poor dissolution
Many biological factors will affect absorption. Name 4 of them
Transit times in each section of the gut (gut motility)
Local pH
Local enzymes, surfactants
Epithelial surfactants area, mucus, gut contents
What leads to variation in biological factors
The individual, their health, meals, diet, fluid intake, activity
What is the importance of pH when considering drug absorption
It influences
Solubility (particularly with WA/WB) - permeable vs soluble
Stability - drug may be subject to acid hydrolysis
Why is the influence of pH on permeability rarely critical when considering drug absorption
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.
Give the pHs in the:
Gastric fluid
Intestinal fluid
pH 1-3.5 (fasted), 3-7 fed
pH 5-8 (food presence doesn’t have much of an effect)
Why is the pH in the intestine much higher than in the stomach?
The gastric acid is neutralised by bicarbonate ions secreted by the pancreas
What strategies can we use to improve drug stability in gastric fluid?
5
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
What strategies can we use to improve drug stability in gastric fluid?
5
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
What is:
The minimum effective concentration
The therapeutic range
The peak concentratkon
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)
How would you measure the total amount of drug in the blood
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
How do we account for Distribution Metabolism Excretion when considering the drug concentration in the blood?
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)
What is the Cmax
The maximum drug concentration achieved in the blood
What is the Tmax
The time it takes to achieve the Cmax
What is the mathematical definition of absolute bioavailibility
F = AUCoral / AUCiv
F = absolute bioavalibility AUCoral = area under the curve for orally administered drug AUCiv = area under the curve for iv administered drug
State what is needed to work out the absolute bioavailability
Measurements of blood plasma drug concentration vs time (AUC) after extravasuclar dosing and after IV administration of the drug
State what is needed to work out the relative bioavailability of two different oral dosage forms
Plasma AUC of a test dosage is compared to a standard dosage form. Both to be administered by the same extravascular route (eg oral)
What is bioequivalence
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)
