Oral Absorption Flashcards
Required process for oral absorption of monolithic dosage forms
- Drug molecules at surface dissolve to form saturated solution
- Dissolved drug molecules diffuse from high to low concentration
- Drug moecules diffuse through bulk solution (GI fluids) to the absorbing mucosa and are absorbed
- Replenishment of drug molecules in diffusion layer achieved by further dissolution
Dissolution
Solid tablet -> gradient -> bulk solution (GI fluids)
Effect of particle size
-increased surface area leads to increased dissolution rate
-break into smaller pieces to increase surface area
Rate of dissolution
-(dM/dt)
-change in amount of mass that appears in solution over time
Rate of dissolution equation (Noyes-Whitney)
dM/dt = (DS/h) (Cd-Ca)
D=diffusion coefficient (Fick’s 1st)
S= surface area
h= thickness of stationary layer
Cd = concentration of drug in donor
Ca = concentration in bulk solution
Dissolution rate is proportional to
-rate of diffusion (D)
-surface area
-difference in concentration gradient
-increase in one will increase dissolution vice versa
Dissolution rate is inversely proportional to
-h
-increase h = less steep gradient
-take more time for molecule to move
increase stirring rate
-decreases h
-increases dissolution rate
Permeability vs dissolution
diffusion across a barrier instead of an unstirred layer
Partition coefficient
must be included in permeability to account for changes in environment between insise and outside membrane
Can remove Ca if we assume sink condition
concentration in membrane is negligible compared to GI fluids
Permeability equation
dM/dt = (DSKCd/h) = PSCd
dC/dt = PSCd/V
D=diffusivity
S=surface area of boundary
K= partition coefficient (solubility inside barrier/solubilty outside)
Cd = donor (GI) concentration
h= thickness of barrier (GI cell membrane
P= (DK)/h = permeability
Factors limiting oral drug absorption
- solubility (cant get enough drug in solution)
- Dissolution (cant get drug out of tablet)
- Permeability (cant get across Gi membrane)
Solubility limited
-characteristic of drug itself
-poorly soluble drugs limited as candidates
-small Cd value
-form dissolves fast and drug permeates readily
-increasing dose doesnt increase blood levels as GI fluids are already saturated
Dissolution Limited
-drug unable to dissolve into solution from dosage form in sub-saturated fluid
-takes longer than absorption in intestines
-due to poor formulation/manufacturing
-tablet needs to dissolve but survive shipping and handling
Permeability limited
-characteristic of drug itself
-dissolution fast with sub-saturated fluids
-increasing amount of drug (Cd) increases absorption (dM/dt)
Physiochemical constraints of solubility limited factors
-dissolution fast
-permeability fast
solubility limited observations
-gut saturated by high does
-absorption does NOT increase with increase dose
Physiochemical constraints of dissolution limited factors
-Tdiss greater than residence time in small instestine
-permeability fast
dissolution limited observations
-can be enhanced by particle size reduction
-absorption increases with increased dose
Physiochemical constraints of permeability limited factors
-permeability low regardless of solubility
-dissolution fast
Permeability limited observations
Absorption increases with increased dose
Biopharmaceutics classification system (BCS)
-predicated on known human absorption and dissolution data
-intended to be applies to drugs in clinical use
-does NOT incorporate transporters or metabolism
-NO pharmacogenetic considerations
-several agents can have more than one classification
-4 classes
Class I
-high solubility and permeability
Class II
-low solubility
-high permeability
Class III
-high solubility
-low permeability
Class IV
-low solubility and permeability
Biopharmaceutics Drug Disposition Classification system (BDDCS)
-can predict from earlier stages
-incorporates transporters, enzymes, interplay
-drug disposition characteristics
-better for in vivo bioequivalence based biowaivers
Class 1
-high solubility and metabolism
Class 2
-low solubility
-high metabolism
Class 3
-high solubility
-poor metabolism
Class 4
-low solubility
-poor metabolism
Effect of food absorption
-on gastric emptying time
-absorption of L-dopa inhibited by amino acids produced from breakdown of proteins
-calsium in diet inhibits absorption of tetracycline
Effect of drug metabolism within GI tract on absorption
-enzymes
-within epithelial cells
-microflora
Oral absorption
interplay of physiochem properties of drug, formulation, and physiological barriers
Generic drug
-drug product comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality, performace, and intended use
-therapeutic equivalence
therapeutic equivalence
-pharmaceutical equivalence
-bioequivalence
-same identity, strength, quality, safety, efficacy
Pharmaceutical equivalents have the same
-active ingredient
-dosage form
-route of administration
-strength/concentration
-can differ in shape, excipients, color…
Bioequivalence
-pharmaceutical equivalents whose rate and extnt of absorption are not statistically different when administered to humans at the same molar dose under similar experimental conditions
Bioequivalence measurements
-in vivo measurement of active moieties in biological fluids
-in vivo pharmacodynamic comparison
-in vivo limited clinical comparison
-in vitro comparison
same AUC
-does NOT equal bio/therapeutic equivalents
-Carbamazepine
Carbamazepine (anticonvulsant/analgesic)
-treats seizures
-almost insoluble in water
-76% protein bound in blood
-hepatically metabolized via CYP3A4
-nonlinear kinetics
-28 diff approved preoral presentation and manufacturer combinations
Study of 2885 pateints receiving phenytoin, carbamazepine, or valproic acid
-30% reported an issue with switch to generic product with same AUC
Qualifications for bioequivalence
-90% confidence interval of the ratios of the test to reference log-transformed mean values for AUC and Cmax are within 80-125%
-differences in Cmax and Tmax were due to faster dissolution of genereic products comparative to the RLD
IVIVC??
-all 4 products show linear relationship between %dissolved to %absorbed
-but NO correlation could be found to predict bioavailabilty of all 4
-no correlation possible between dissolution rate and AUC
-THESE PRODUCTS ARE NOT INTERCHANGABLE
Mimicking clinical condition
- consideration of patient related variables
- patient variables not accurately assessed during development and scale up
- Absorption windoes are defined more on physical, chemical properties rather than physiology
- better in vitro and in vivo testing models needed to optimize dosafe dorm design and scale up
Drug performance (PK/PD)
controlled by interplay of excipients (formularion), physiochemical properties, and physiological barriers between GI tract and site of action
Oral formulations
can control absorption rate (Kabs) which has to be optimized with respect to disposition to yield a safe and efficacious response
Dosage form design
-dynamic and unpredictable
-patient habits must be considered
Generic formulations
-not the innovator
-can cause problems with performance
