Knipp 2 Flashcards
coatings
control diffusion rates by modulating release properties
solid coatings
protect agent from air/humidy
mask taste
provide special drug release
aesthetics
prevent inadvertant contact w/ drug
aqueous coatings
film-forming polymers
plasticizers for flexibility and eslastic
colorant and opafier
vehicle
disinigrants
control regions of release based on physiological properties
lubricants
can slow dissolution based on properties
internal excipients
used to modify the release rate as well: swellable matrices, non-swelling matrices, inert plastics
enteric coating
add to dosage form to prevent early release of API.
1. prevent acid sensitive API from gastric fluids
2. prevent gastric distress from the API
3. target API delivery to site in intestine
4. to provide delayed/sustained release
5. deliver API in higher local conc in intestine for better absorption
sustained release
pharm dosage form to slow release therapeutic agent such that appearance in systemic circulation is delayed/prolonged. AKA onset pharmalogic action is delayed but therapeutic effect has sustained duration
controlled release
goes beyond sustained release and reproducibility/predictability
examples of traditional controlled release formulations
coated beads, granules, microspheres: coating on the beads controls release by programmed erosion
multitablet system: small tabs placed in gelatin
microencapsulated: solids, liquids, gases encapped in walled material allowing microparticles across surface
drug embed in slow eroding or hydrophilic matrix: drug is homogenously dispersed in eroding matrix and release is controlled by eosion rate
steady state
rate going into the body must be equal to diposition (rate distributed/metabolized/excreted throughout the body)
characteristics of drugs best for oral controlled release
either slow/fast rate of absorption/secretion
uniformly absorbed from GI tract
administered in relative small doses
have good safety/therapeutic window
chronic therapies better suited than acute
physiological factors affecting absorption
absorbing surface area
residence time at absorption site
pH changes in lumen (unionized will get absorbed)
permeability
dietary fluctuations/effects
complexation/protein binding
biliary uptake and clearance
epithelia
predominantly used for external surfaces although endothelial cells are epitheliod
simple squamous
simple columnar
translational
stratified squamous
composition of bio membranes
most of surface area
all living cells are enclosed with 1+ membranes
membrane isolates cellular components from environment
cell membrane is semi-permeable membrane, permits rapid passage of chemicals while slowing others
cellular lipid composition is polarized, so outter is different from inner
cholesterol effects on membrane?
no. it provides fluidity at lower levels. when exceeds a certain level in membrane, it causes a phase of transition and forms liquid crystalline state. called hardening atherosclerosis when occurs in vasculature
intestinal transport mechanisms
passive(non saturable): paracellular (between cells), transcellular (through cells)
carrier-mediated(saturable): active (energy), facilitated diffusion (no energy)
general interpretation of caco-2 vs pampa
passive difussion
has linear relationship between active transport and efflux
drug transporters
membrane-bound proteins involved in clearance
role is to move important molecules across membranes
crucial determinant of tissue and cellular distribution of drugs
variation can be determinant of drug response
primarily been identified in adults
SLC (solute carrier)
43 subfamilies
300 members identified
generally influx or secretory efflux transporters
ABCs
7 subfamilies
50 members
generally efflux-multidrug resistant transporters
PgP, MRPs
Absorption
many routes of permeation:
influx transport mediated
passive transcellular influx + efflux
passive paracellular
metabolism
efflux of the metabolite
conventional terminology
influx: transporters transfer into cells
efflux: transporters pump substrate out of cell back into compartment
absorptive: transporters transfers substrate into systemic blood
secretory: transporters transfer their substrates from blood into bile, urine, GI lumen
passive paracellular permeation
hydrophilicity
molecular size + shape
pKa of ionizable groups
linear increase in permeability w/ increasing conc
adjuvants can open tight junctions
facilitative/active trans permeation
affinity, Vmax
concentration dependent saturation
expression level
function(drug-drug & drug-nutrition interactions, competitive inhibition)
exicpeints like surfactant can limit effects of efflux by PgP or BCRP
GI tract epithelia
oral cavity-buccal
esophagus is comprised of strat squamous
stomach is mainly columnar epithelial w/ mucus goblet cells
small and large intestines have columnar epithelial cells
rectum is best place for absorption w/ simple columnar and strat sqamous epithelia
stomach
digest food and control flow into intestine
fast pH is <3
fed pH is 5-7
gastric emptying half-time is ~30 mins
fasted emptying has 4 phases
fed has no cycles
stomach anatomy
fundus - contains gas and produces contractions
body - reservoir for ingested food and fluids
antrum - lower part of stomach controls flow into small intestine
stomach phases
1) no activity 40-60 mins
2) mixing contractions 40-60 mins
3) stomach: powerful contractions intestine: peristalsis
4) stomach empty of digestible and indigestible food
intestine
mouth-anus: 24-32 hrs
most absorption occurs in small intestine
small intestine pH 5-6.5
colon drug absorption mainly occurs in ascending region nearest to SI
intestinal surface area
kercking folds
villi
microvilli
all increase SA of SI
columnar epithelium
continuous layer of absorptive cells
Crypt region: 3x more crypt than villi, comprised of undifferentiated cells that proliferate. globlet cells-mucus secreting
Villus region: absorptive enterocytes, a few goblet cells do appear. cells from crypt migrate to villus tip and are extruded at tip lifetime of 2-3 days
colon characteristics
125 cm from caecum to anus
responsible for water and electrolyte absorption to prevent dehydration and leads to formation of solid fecal matter
colon structure
serosa-squamous epithelium covered with adipose tissue
submucosa and mucosa
colonic mucusa: three layers– muscularis mucosae, lamina propria, epithelium
proximinal(ascending) colon is where enteric formulations target by oral admin
distal colon: rectal + suppositories
anal muscles with age
as people age, anal muscles slow down their function
stomach vs. colon
stomach and colon have inverse relationship with drug concentration. as it decreases in the stomach, it increases in the colon
rectum
upper and lower region that transitions to strat squamous.
stratified squamous, non-keratinized allows high drug absorption
lots of high potency drugs that are delivered rectally
gag reflex w/ pills so use suppositories
anal absorption
crystalline: form-low solubility
amporphous: increased solubility
free API: potential confounders are food, protein binding, pH, etc.
GI characteristics
GI volumes do not correspond with dissolution bath volumes
GI transit time variation
gastric residence differs a lot
gastric emptying controls colonic absorption
higher GI residence leads to higher absorption
PT 2 has higher GI so capsule was voided much faster
GI transit fed state
capsule was admin 30 mins before breakfast and 4 hrs before lunch but gastric pH and residence changes still occurred
characteristics of GI fluids
jejunum: pH 7.08
ileum: pH 7.8
colon: pH 8.1
drug solubility changes in GI tract
factors influencing drug solubility:
buffer capacity
bile salts
regional fluids
other drugs
potential issues from endogenous substrates
stomach emptying blood flow
stomach>jejunum 1> jejunum 2 > ileum 1> ileum 2> ileum 3> ileum 4> colon
drug diffuses out, gets released, metabolized
challenges to assumptions of GI
transporters and enzymes vary in GI
a lot of variability in GI fluid
diet and chemical exposure vary
pharmacogenetics and genomics are issues
inter individual variation
drug-nutrient + drug-drug interactions
gut microbiome
SO ONE SIZE FORMULATION DOES NOT FIT ALL
ADMET
Absorption
Disposition: comprised of distribution and elimination
Elimination: describes metabolism and excretion
Toxicity: result of exposure
ADME
Absorption, Distribution, Metabolism, Excretion
Drug is dissolved through intestinal tract
Absorbed through portal vein to liver then blood then tissues
Throughout these processes, theres metabolism of drug and excretion of it
Nature of pharmacokinetic processes
described by concentration time profiles: shape of profiles depend on conc
compartments represent kinetically similar tissue/space
processes can be reversible or irreversible
processes can be linear or nonlinear
fast and slow processes tend to disappear
blood level versus time curve
upward slope is absorption
peak is Cmax + Tmax
after peak is distribution, metabolism, excretion
downward slope is disposition and elimination phase
biopharmaceutics terms
bioavailability - rate and extent of drug absorption
absolute bioavailability - AUC of dosage compared to auc of same dose injected intravenously
relative bioavailability - AUC of dosage form compared to arbitrary reference standard
bioequivalent - does not mean therapeutic effects of two dosage forms are equivalent
concept and use of dose
amount of chemical in which organism is treated
local concentration of the chemical at the biol response state
relationship between dose and receptor concentration is a function of ADME
dosage form design
aborption begins declining as disposition begins to increase
absorption rate Kabs is defined by drug properties of excipients/drug formulation and the physiological barriers between GI and systemic circulation
disease plasma levels
plasma levels peak in therapeutic window
prolonged exposure to subtherapeutic doses or ineffective drugs can lead to development of disease becoming worse
dose relationship to toxic response
toxic repsonse - blood plasma is toxic level/ MTC
safe and efficacious - blood plasma in therapeutic window/TW
non efficacious - blood plasma not reached therapeutic level/ MEC
