Unit 2 - Oral Absorption 1 Flashcards
Give examples of formulations that are taken orally
Tablets Controlled release tablets Capsules - soft - hard Suspensions Micro/nanoparticles Micro/nanoemulsions Liquids
What is the major absorption barrier to oral formulations?
Small intestine
What are the small intestine villi covered by?
Intestinal epithelial cells
- enterocytes
Which surface are microvilli found on enterocytes?
Apical surface
- the surface facing the intestinal lumen
Which parts of the body produces mucus?
Oesophageal/gastric/intestinal mucosa Nasal/olfactory mucosa Lung mucosa Buccal mucosa Genitourinary tract
What is mucus made of?
Water - up to 95% Mucin - no more than 5% Inorganic salt - about 1% Carbohydrates and lipids
What is mucin made of?
80% carbohydrate by weight
Which cells produce mucus?
Goblet cells within the epithelium
Serous cells of the submucosal tissue
How does mucin form a network?
Disulphide bonding
How does mucus change with pH?
Neutral pH - viscoelastic solution
Low pH - soft viscoelastic gel
viscosity changes
What factors affect the residence time of drug(how long the drug is there) in solution at absorption surface?
Gastric emptying
Intestinal motility
What is the major site of absorption within the small intestine?
Jejunum
Ileum
What are the advantages of sublingual and rectal delivery of drugs?
Partially avoids 1st pass
1st pass metabolism: the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemic circulation. It is the fraction of drug lost during the process of absorption
What factors affect what fraction of drug can get into a solution in the lumen of the gastrointestinal tract?
Disintegration
Dissolution
Complexation
Chemical/enzymatic degradation
What factors affect what fraction of drug passes through the mucosal barrier into the portal vein?
Membrane permeability
Metabolism
What factors affect what fraction of drug passes into the general circulation from the liver?
Metabolism liver enzyme
Biliary excretion
How might the liver effect bioavailability ?
This first pass through the liver thus may greatly reduce or increase the bioavailability of the drug.
What factors affect bioavailability?
Formulation Permeability Solubility Transit time/available absorption surface Lability - chemical - enzymatic
What is rate of bioavailability?
How fast the drug absorbed into the systemic circulation
How is the rate of bioavailability measured?
First-order absorption rate
Time to maximum drug concentration
What is the extent of bioavailability?
How much of the drug dose is absorbed into the systemic circulation
How is the extent of bioavailability assessed? (on a conc vs time curve)
Maximum drug concentration
Area under the curve (AUC) on a concentration vs time curve
- a measure of exposure
AUC is a combined function of dose available to systemic circulation and drug clearance
AUC represents total drug exposure across time
What is Lipinski’s Rule of 5?
5 parameters to suggest whether a drug will have the correct physiochemical properties
Poor ‘oral’ absorption predicted for molecules with:
> 5 H-bond donors (sum of OHs & NHs)
> 10 H-bond acceptors (sum of Ns & Os, halogens)
MW > 500
CLogP > 5 (or MLogP > 4.15)
What in-vitro permeation (studies across biological membranes for formulations) studies are carried out?
PAMPA
- permeation across artificial membranes
CACO2
- permeation through a cellular barrier
What is the Biopharmaceutics Classification System?
Permeability vs solubility chart
Class 1 - high solubility, high permeability
Class 2 - Low solubility, high permeability
Class 3 - high solubility, low permeability
Class 4 - Low solubility, low permeability
How does the stomach behave in the fasted state?
Phases defined by MMC
- migrating myoelectric complex
- bursts of smooth muscle activity
How often is the MMC repeated in a stomach’s fasted state?
Every 1.5 - 2 hours until a meal is ingested
What are the four phases in the fasted state of the stomach?
Phase I - approximately 45 - 60 mins - no to rare contractions Phase II - approximately 30 - 45 mins - intermittent contractions - increase in strength and frequency Phase III - approximately 5 - 15 mins - highest contraction strength - empties large solid particles from stomach Transition phase - approximately 20 mins
How are liquids managed in the fasted state of the stomach?
< 150 ml
- no change in gastric emptying pattern
- most liquid emptied as bolus in phase II/III
Large volumes
- convert pattern to one of fed state
- immediate and continuous emptying of liquid
How does the stomach behave in the fed state?
No phases with contraction only moderate in strength Contractions - peristaltic and systolic to diminish size of stomach - cause mixing and grinding - gastric emptying of solids is slowed - greater volume of food - solid nature - higher fat content
How is gastric emptying important in the fasted state?
Drug as particle or in solution?
Calorific value of solution?
Solution - 5 - 50 mins
Particle - 5 - 2 hours
How is gastric emptying important in the fed state?
Solid or solution induced fed state?
Calorific value?
Solution induced > 150ml - 5 mins - even for drug in particle Food induced - drug particle likely to remain distributed with solid food - emptying every 0.5 - 5 hours
How long does it take material to travel through the small intestine?
3 - 5 hours independent of food
How long does it take material to travel through the large intestine?
15 - 60 hours
+ average 24 hours
How does food change absorption of drug?
Food changes the gastro-intestinal motility to a fed state
- slows gastric emptying
Stomach contents released into intestine stimulates release of bile salts
- help absorption of fats
High fat meal
- help a very hydrophobic drug to dissolve
- more of the hydrophobic drug in solution at absorption site promotes increased extent and rate of absorption
When is delayed gastric emptying undesirable?
Rapid onset of action is needed
- made worse when absorption occurs in distal part of intestine
- takes longer to reach it as further away
Stability of drug is compromised at low pH
- stays longer in the stomach surrounded by stomach acid
Disintegration/dissolution of medicine best at higher neutral/alkaline pH
- takes longer to reach the more alkaline small intestine
How does food content affect gastric emptying and drugs?
Foods tend to decrease the rate of gastric emptying
Food forms complexes with drugs
Food may affect absorption
- high fat particularly prolongs gastric emptying time
When is delayed gastric emptying desirable?
When it is an aid to disintegration/dissolution process
Why does phenoxymethylpenicillin (penicillin V/VK) have to be taken on an empty stomach?
Exposure to acid with prolonged gastric residence leads to chemical degradation and reduced biavailability with risk of therapeutic failure
Why does saquinavir have to be taken with meals?
- food changes the gastro-intestinal motility to a Fed-state - slows gastric emptying
- stomach contents released into intestine stimulates release of bile salts that help absorption of fats
- high fat meal can help a very hydrophobic drug to dissolve
- more of the hydrophobic drug in solution at absorption site promotes increased extent and rate of absorption.
Foods tend to decrease the rate of gastric emptying
Bile acids released assist solubilisation and enhance drug dissolution
- high fat meals can also enhance extent of absorption
- Saquinavir bioavailability doubles with high fat cooked breakfast
Why do bisphosphonates have to be taken on an empty stomach?
Calcium and other cations in food can form insoluble chelates
Why do fluoroquinolones have to be taken on an empty stomach?
Form slightly soluble complexes with metal ions
- reduced bioavailability
Why does ciprofloxacin have to be taken on an empty stomach?
Casein and calcium present in milk decrease the absorption
Why does tetracycline have to be taken one hour before, or two hours after meals, and not taken with milk?
Binds calcium and iron forming insoluble chelates
- reduces bioavailability
Even a little quantity of milk containing extremely small amounts of calcium severely impair the absorption of the drug
- tea
- coffee
