Drug Delivery Systems Midterm

Describe the LADME process for conventional oral drug delivery

Liberation from drug formation

Absorption into blood

Distribution throughout the body

Metabolism of drug in liver

Elimination of dug via kidneys

Drug has poor bioavaliability; pick a LADME process to intervene to improve delivery of the drug

absorption

many fail due to poor aqueous solubility

Describe a DDS that will improve drug bioavaliabilty, only change the system not the drug or the route or other intervention

molecular dispersion within polymer (PEG) matrix

increases apparent solubility and dissolution rate

Rate controlling membrane systems features

drug reservoir core

surrounded by polymer membrane

controls diffusion rate

zero order release

Matrix based diffusion systems features

drug dispersed throught polymer matrix

diffuses out of the matrix itself

zero order release

preferred circumstances of RCM

narrow therapuetic window → precise control needed

low dose drug and stable within reservoir 

preferred circumstances of MBDS

non absolute constancy of release is ok

robust simple low cost formulation needed

higher drug load

biodegradable polymer for implants

rate controlling membrane disadvantage

risk of membrane rupture or fail

complex and very expensive manufacturing 

membrane based diffusion system disadvantages

less precise control of release rate

possible left over drug in matrix

Flory-Huggins equation

based on

compatability of solvent & polymer

elastic retractive forces

Mc influenced by 3 factors

crosslinker concentration

polymer Mc and concentration before crosslinking

solvent quality (more or less coiled tightly)

experimental conditions of crosslinked hydrogel and how to adjust Mc for particular hydrogel

chemical crosslinking using covalent bonds between monomer and crosslinker

initiate polymerization via thermal,photo,redox initiators

Henderson-Hasselbalch equation

pH = pKa +log(A^- / HA)

which location would you expect better absorption across the epithelium?

for a weak acid stomach is better transcellular absorption

unionized form = more lipophilic and crosses more readily thru passice dissuion 

explain why most oral drugs are primarily absorbed in the small intestines regardless of acid/base characteristics

depends on more than the fraction of unionized

way larger surface area due to villi 

longer residence time 

higher blood flow & efficient uptake systematically

intestinal fluids help solubilize poor soluble drugs 

various transporter methods 

mucus barrier in stomach 

flux equations for pH sensitive hydrogel swelling mechanism

J = -D (dC/dx)

What causes the change in flux (before vs. after swelling) and why it is important

at low pH the hydrogel is collasped and hydrophobic due to hydrogen bonding at COOH groups

at high pH the hydrogel expands due to electrostatic repulsion and the osmotic swelling pressure increases

Diffusion coefficient

magnitude depends on the properties of the solute and the medium through which diffusion occurs

how fast a molecule diffuses in an ideal scenario

effective diffusion coefficient

accounts for drag exerted by ECM and cells as well as porosity, constrictivity and tortuosity of the polymer its travelling thru

how fast a molecule diffuses in actuallity with hindrances and limited water content

3 factors that contribute to effective diffusion coefficient in porous polymer matrix

porosity

constrictivity

tortuosity

how does effective diffusion coefficent change as the hydrogel swells

polymer chains expand( inc porosity)

tortuosity dec (straighter paths)

water uptake inc (medium more similar to bulk solution

flux equation for steady-state diffusion across membrane thickness L with partition coefficient theta

J = -D (dC_m/dx) = (D*theta/L) * (C₀ -C_L)

what happens to flux of membrane thickness doubles

the flux decreases

situation where partition coefficient is much less than 1 and biological significance

solute concentration in membrane is way lower than surrounding area

ex. hydrophilic drug trying to diffuse thru a lipid membrane

bio significance: low permeability, low passive absorption

paracellular trasnport across epithelial barriers

between cells

no molecules bigger than 200 Da

hydrophilic, polar, small, ionized molecules love ts

limited by tight junctions 

strats: nanocarriers or modulators

transcellular transport across endothelial barriers

through membrane

~500 to 700 Da

lipophilic, unionized molecules love ts

simple or facilitated diffusion (passive)

primary or secondary active transport

strats: lipid nanoparticles, liposomes

endocytotic transport across epithelial barriers

uptake and transport via vesicles

macromolecules/nanoparticles like proteins love ts

strat: ligand targeting nanoparticle

zero order release kinetics

rate of drug release is independent of the concentration of drug remaining in the device

Mt = ko * t

ex. surface eroding polymers

first order release kinetics

rate of drug release is proportional to amount of drug remaining within device

Mt = M∞(1-e^-ko*t)

ex. bulk eroding polymeric device (concentration is gradient based)

square root time of release kinetics

release rate decreases proportionally to the square root of time (burst release)

Mt = 2ko √t 

ex. memebrane based (films, patches, ointments)

surface erosion in biodegradable polymers

outer surface of polymer device

water cannot penetrate deep inside

zero order release kinetics controlled by polymer degradation rate

reaction controlled

hydrophobic polymers

why do polyanhydrides exhibit surface erosion while PLGA exhibits bulk erosion

polyanhydrides = highly hydrophobic backbones but anahydride bonds break hella easy

PLGA = highly hydrophilic due to ester bonds so water get into that matrix big fast

osmotic pump dds mechanism of drug release

drug driven out of core through membrane via osmotic pressure

pressure builds as water goes in core

water in = drug out

osmotic pump dds kinetics

zero order kinetics

osmotic pressure remains constant as long as core has drug and water goes in steady

osmotic pump dds conditions and how to increase the release rate

drug in core must be good osmotic agent (more in core = bigger rate)

membrane must let in water but restrict drug exit 

thickness and permeability must be uniform

small, well defined orfice (bigger hole = bigger rate)

water solubility of drug (inc = inc rate)

main causes of device failure in osmotic systems

membrane rupture or defects

orifice blockages

insufficient osmotic pressure (drug solubility issues)

mechanical damage from handling/storage

key considerations in biodegradable polymer selection in DDS

biocompatability of degradation product

degradation mechanisms

degradation kinetics 

how do smart hydrogels work (pH)

ionization induced swelling 

alters porosity and drug diffusion rate

protection of drugs in acidic environment and controlled release in the intestine for oral drug

why do only 0.7% of injected NPs reach target tumors

endotheliakl barrier, tumor penetration

delivery is fighting the RES clearance

animal models aren’t vary similar

tumors have interstitial fluid pressure that opposes inward diffusion

softer NP = more circulation time

why are NPs still promising for tumor therapy despite low numbers

still higher than conventional chemotherapeutics

ligand based targetinf improves intracellular delivery

less side effects than chemo

stimuli responsive 

bulk erosion in biodegradable polymers

fast water penetration

distributed water penetration 

diffusion controlled 

first order or burst release kinetics

swells, cracks, collapses

hydrophilic polymers 

biodegradable polymers degradation mechanisms

hydrolysis 

oxidation

photodegradation

biodegradable polymers biocompatibility

degradation products

limites polymers with fully biocompatibly metabolites

many sources of toxicity (polymer impurities, processing byproducts)

biodegradable polymers degradation kinetics

time dependent release

avoid neg. biological reactions

complex release kinetics and must be measured experimentally

erosion type

fast release biodegradable polymer

low MW

hydrophilic

amorphous

sustained release biodegradable polymer

moderate MW

semi-crystalline

long term biodegradable polymer

highly-crystalline

hydrophobic polymers