GI tract Flashcards
benefits of using oral drug delivery
non invasive, painless, cost effective manufacturing, improved compliance (patient more likely to follow drug scheme)
problem with using oral delivery
most drug molecules dont have the physiochemical properties to be orally bioavailable/ insufficient amount of drug available at site of action
describe the biopharmaceutics classification system
class i- high permeability high solubility
class ii- high p low s
class iii- low p high s
class iv- low p low s
oral dosage form approach for a class ii drug in BCS (high p low s)
increase surface area like reduce particle size/solid dispersion, use solvents or surfactants
oral dosage form approach for a class iii drug in BCS (low p high s)
use permeability enhancers, maximise local lumenal concentration
factors that affect absorption
pKA of drug, local pH
what is the main cellular barrier to drug absorption from GI tract
gastrointestinal membrane that separates lumen of stomach and intestines from systemic circulation
what does GI tract stand for
gastrointestinal tract
what 2 assumptions does the pH partition hypothesis suggest
- GI tract acts as lipid barrier towards weak electrolyte drugs which are absorbed by passive diffusion
- GI/blood barrier is impermeable to ionised (poorly lipid soluble) forms of drugs, only lipid soluble unionised species will pass across
3 principal factors that determine drug uptake
-dissociation constant (pKa)
-pH at absorption site (affects ionisation state)
-lipid solubility of drug (based on polarity of drug)
what is the absorption of a weak electrolyte drug determined by
the extent of ionisation of drug at absorption site
what equation to use to calculate extent of ionisation of a drug in a particular environment
henderson-hasselbach of a weak acid and % ionised
what is ion trapping
in stomach acetyl salicylic acid is unionised, in blood it acetyl salicylic acid is ionised, equilibrium strongly in favour of uptake into blood
-once it enters blood it’s in a different pH environment and in its ionised form so it wont diffuse back into stomach
problem with pH partition hypothesis
only gives qualitative description and not quantitative, cant predict drug uptake, eg. can only rank a series of similar drugs in order of uptake in a limited pH range
why are there deviations from expected results from the pH partition hypothesis in experiments
-microclimate pH
-available surface area
-presence of unstirred water layer
-absorption of ionised forms of drug
how does the absorption of ionised forms of a drug cause deviations from the pH partition hypothesis
GI tract is partially impermeable to ionised drug, ionised form is absorbed through intestines at a lower rate than unionised
how does the presence of an unstirred water layer cause deviations from the pH partition hypothesis
extra barrier to drug absorption, aqueous boundary layer, drug absorption separated into 3 main steps (lumen to mucosal unstirred layer to epithelial cell)
how is an unstirred layer of water created
incomplete mixing of luminal contents near the intestinal mucosal surface
effects of having an unstirred layer of water
drug absorption separated into 3 main rate processes
- diffusion from lumen to mucosal unstirred layer (MUL)
- diffusion through MUL
- absorption through membrane to cell
if 2<3 then 2 will be rate limiting step
why is drug movement by diffusion slow in the mucosal unstirred layer
the layer is static (not moving), unionised can diffuse across lipid membrane easily but struggle to get through MUL, diffusion varies with molecular weight, larger/more hydrophobic will be more affected, rate limiting barrier for intestinal absorption of lipids
what is microclimate pH
difference between pH at cell membrane and bulk lumen pH
microclimate and lumenal pH equation to explain absorption anomalies
MpH= A+B(LpH-7)+C(LpH-7)^3
MpH=microclimate pH
LpH= lumenal pH
limitations of using the unifying hypothesis
only applies to pure drug in controlled conditions absorbed by only diffusion
other factors to consider in unifying hypothesis
other uptake mechanisms, carrier mediated transport, fat uptake pathway, ion pairing, drug stability/formulation, patient factors
importance of dissolution
only substances in molecularly dispersed forms are transported across intestinal wall and absorbed into systemic circulation
noyes whitney equation
dm/dt= DA(Cs-C)/h
dissolution rate, diffusion coefficient (higher D= lower viscosity), surface area (larger SA=faster rate
), saturation solubility in diffusion layer, conc of drug in solution (lower conc=more fluid=higher dissolution rate), thickness of diffusion layer (thicker=slower)
what is solubility and dissolution rate
solubility= capacity of solute to dissolve in a solvent
dissolution rate= rate which solute dissolves
total solubility equation
Cs=[HA]+[A-]
(sum of solubilities of unionised and ionised form of the drug)
for weak acid what is the dissolution rate proportional to
1/[H+]
for weak base what is the dissolution rate proportional to
[H+]
what do weak acids dissolve best in
alkaline medium
what do weak acids absorb best in
acid medium
what do weak bases dissolve best in
acid medium
what do weak base absorb best in
alkaline medium
what happens if you increase surface area of contact with GI fluids
dissolution rate increases
what does particle size reduction result in
increased dissolution rate if absorption of drug is dissolution rate limited
what and how does a solid dispersion prevent aggregation
-drug formulated with another small carrier drug that is readily soluble
-soluble component dissolves leaving a microcrystalline drug
what can microionisation of a hydrophobic drug lead to and its effects
aggregation, which leads to reduction in effective SA of drug exposed and leading to reduced dissolution rate and bioavailability
what can aggregation lead to
reduced effective surface area/dissolution rate/bioavailability, leads to changes in compaction characteristics and tablet may not break apart
what happens if drugs that are unstable in gastric fluid are exposed to more acid
leads to breakdown of drug and reduced bioavailabiltiy
3 ways to achieve reductions in effective particle size
- solid dispersions- microcrystalline drug dispersed in carrier
- solid solutions- drug in molecular form dispersed in carrier
- use of wetting agents
how can solid dispersions reduce particle size
drug is formulated with another small carrier drug, soluble component dissolves and leaves microcrystalline drug in better conditions
how can solid solutions reduce particle size
molecule of hydrophobic drug dispersed in hydrophilic polymer, as carrier dissolves the drug is left in molecular form
how can wetting agents reduce particle size
useful for hydrophobic drugs, surface of drug needs to wet easily to enable interactions to allow surface to dissolve, wetting agents help dissolution and improve bioavailabiltiy
other ways to enhance dissolution rates
salt form, polymorphism, amorphous form, solvates
precipitated drug will redissolve if
dissolve drug is absorbed, stomach fluid volume increases, contents of stomach enter intestine
how can weak acid drugs be formulated into its salt form
formulate as sodium salt, when drug dissolves sodium ions are present in diffusion layer, pH raised in diffusion layer, more alkaline conditions are more favourable for drug, easier dissolve and better absorption
most common salt forms of acidic drugs
sodium salts
most common salt forms of basic drugs
chloride salts
what is polymorphism
different crystalline forms of a drug
what is crystalline
materials where its molecules are packed in a defined order that repeats
what is amorphous form
no defined shape, no long range packing order
benefits of amorphous form compared to crystalline and a disadvantage of amorphous
amorphous- more soluble, rapidly dissolving
crystalline- less soluble, slower dissolving, unabsorbed and therapeutically ineffective
but amorphous slowly converts to more stable crystalline over time so must stabilise drug in dosage form
what are solvates
drug crystalises trapping molecules of the solvent within the lattice, if its water=hydrate
what is the absorption of drugs dependent on
availability of drug, bulk solubility, dissolution rate, degree of ionisation
what is absorption potential equation
Log(PfSV)/D
P=octanol water partition coefficient
f= fraction of nonionised drug at 6.5 pH
S=intrinsic solubility
V=volume of lumenal contents
D=dose
what does the number of absorption potential imply
negative AP= poor absorption
>1.0= nearly complete absorption
limitations of absorption potential
doesnt account for degradation in lumen/ non passive uptake mechanisms (eg. active transport)/ first pass metabolism/ paracellular routes, only indicates for absorption with no limitations of dosage formulation factors
maximum absorbable dose equation
MAD= VSKata
V=intestinal dissolution volume
S=intrinsic solubiltiy
Ka=first order permeability constant
ta=GIT absorption transit time
what is maximum absorbable dose
mathematical model to predict the max amount of drug that can be absorbed in a 6 hour time frame
why 6 hour time frame in max absorbable dose equation
stimulate small intestinal residence time
2 ways to avoid issues with acid/enzymatic hydrolysis leading to poor bioavailability and
prodrug administration, enteric coating
what is prodrug administration
pharmacologically inert chemical derivatives that can be converted in vivo to active drug molecule to exert a therapeutic effect
what problems can prodrug administration help with
chemical instability, low lipophilicity, poor aqueous solubility, poor distribution across membranes, rapid absorption when long term effect is required
what are enteric coatings
pH sensitive polymers that is insoluble in acid but dissolve in neutral/slightly alkaline environment of the gut
when are enteric coatings used
when drug is inactivated/destroyed in acid from stomach, drug is irritating to gastric mucosa, when bypass of stomach enhances drug absorption
what is the dissolution rate of enteric coating affected by
pKa of polymer, pH of medium, ionic strength of medium
if the molecular weight of enteric coating polymer is low what happens
polymer will dissolve and drug released rapidly
if the molecular weight of enteric coating polymer is high what happens
polymer will swell into a gel layer that controls drug release
limitations of solutions
acidic drugs as salt forms can precipitate in stomach, poorly water soluble acidic drugs may have better bioavailability as a well formulated suspension of free acid, hard to formulate
types of delivery systems
solutions, soft/hard capsules, coated/uncoated tablets, excipients, complexation, adsorbtoion
types of capsules
soft elastic gelatin and hard gelatin
write about soft elastic gelatin capsules
filled with any liquid, slower rate than solution due to capsule breaking down and dispersion, better bioavailability than tablet, uptake by fat absorption pathway when delivering oils/emulsions
write about hard gelatin capsules
disintegration of shell, contents should empty before all gelatin has dissolved, better than loosely packed tablets, no high compression forces, smaller particle=greater rate of absorption, use dilutent to minimise aggregation and maximise surface area
