Lecture 17- Biopharmaceutics IV Flashcards
Comparative dissolution testing; immediate release products
- Profile similarity determination
- If both the test + reference product show >85% dissolution within 15 minutes; profiles are considered to be similar
- Calculate the f2 value;
If f2 > 50% - profiles are regarded similar + no decimal required
Significance of the similarity factor, f2 + when comparing dissolution profile results
Comparing the dissolution profiles from solid dosage forms; e.g. tablets, capsules) to establish in-vitro similarity between different test samples of the same product
Comparison used= to support a request for waiver of performing bioequivalence study
F2 value between 50-100= 2 dissolution profiles are considered similar, f2 <50= investigation should be initiated to determine the cause of apparent dissimilarity
Dissolution testing; similarity factor f2
Equation; slide 7-10
Biopharmaceutics Classification System; BCS
Factors affecting drug absorption from GI
Pharmaceutical factors;
Physiochemical factots; pKa, solubility, stability…
Patients-related factors;
Physiological factors; GI, pH…
S12
BCS
Characterises drugs into 4 classes; according to their aqueous solubility + intestinal permeability
Waiver- based on;
- high solubility- ensures drug solubility will not limit dissolution + absorption
- high permeability- ensures drug is completely absorbed during the limited transit time through the small intestine
- rapid dissolution- ensures that the gastric emptying process- rate limiting step for absorption of highly soluble + permeable drugs
In vitro- in vivo correlation
Mathematical model= describing relationship between in vitro + in vivo properties of a drug product; in vivo properties can be predicted from in vitro behaviour
In vitro property= rate/extent of drug dissolution or extent of drug release while in vivo response- plasma drug concentration/amount absorbed
BCS + its use in drug development
Allows us to predict;
- its in vivo absorption
- disposition ; transporter+ metabolism interactions
- potential for food effects- interactions
- guide our formulation stratergies
- potentially waive clinical studies
Classes 1-4; slide 18-21
Benefits of knowing BCS category
Save time + money- immediate release, orally administered drug meets criteria, FDA= grant waiver for expensive time consuming,ing bio-equivalence studies
Reduces timelines- process and reduces unnecessary drug exposure in healthy volunteers
Class of drug- influences the decision to continue/stop development
Helps pharmaceutical manufactures to avoid unnecessary human experiments + reduce cost + time
Limitations of BCS
Absorption transporters and efflux pumps= not considered
Drugs undergoing first/second pass metabolism= not factored in appropiate manner
Solubility + permeability = loosely defines
Food effects= not considered
Chances of misclassification
Examples; s24 onwards
Examples; CLASS I
Metoprolol, diltiazem + propranolol
Drugs= well absorbed, unless unstable/form insoluble complexes + undergo 1st pass metabolism
Dissolution test for IR formulations; need to verify that the drug is rapidly released from the dosage from under mild aqueous conditions
Dissolution spec of 85% dissolution of drug contained in IR in 15 mins may ensure bioequivalence
Class II
Absorption= usually slower than class I and takes place over a longer period of time
Dose of drug= determined on the basis of pharmacokinetics/ pharmacodynamic considerations and could not be altered
Examples;
- classical micronisation, stabilisation of high energy states, use of surfactants, solid dispersion, use of complexing agents…
Class III
Drug permeation is rate controlling in drug absorption, limited or no IVIVC is expected, depending on the relative rates of dissolution + intestinal transit
Exhibit a high variability in rate + extent of absorption, if dissolution is fast the variation could be attributed to GI transit, liminal contents etc
Manipulate the site/rate of exposure or perhaps by incorporating functional agents into the dosage forms to modify metabolic activity
Class IV
Poor bioavailability, usually not well absorbed over the intestinal mucosa -> high variability is expected
Drugs of this class are problematic for effective oral administration
Examples; rarely developed + marketed
- cyclosporin A, furesomide, saquinavir + taxol
Biowaiving
Approval of a drug product without having to conduct an in-vivo bioavailability/bioequivalence
More on slide 32
Advantages;
- avoiding unnecessary human experiments, simplification of time required for product approval + reducing the cost
Abbreviated new drug application
Rest of slides
