Quiz 2 Flashcards
Orally disintegrating tablets
dosage form placed on surface of the tongue, disintegrates with minimal saliva
highly soluble diluents and more disintegrates that conventional tablets
contain flavorants and sweeteners
Advantages of ODTs
packaged in moisture resistant blisters
mimic immediate release tablet formulations
good for dysphasia patients or patients at risk with non-compliance
Chewable tablets
pleasant tasting
disintegrate in mouth with chewing
good for patients with difficulty with swallowing whole tabs
good if prepared as an IR tablet/capsule is too large to swallow
mainly API and diluent
do not usually have disintegrants
Nanoparticles
type of drug delivery system
range from 10-100nm
consist of drug entity and polymers/lipids
What allows for better and favorable interactions of nanoparticles with cellular membranes?
large surface area to volume ratio
What are examples of drug entities that may form nanoparticles?
small molecule drug
peptides/proteins
nucleic acid (mRNA)
Liposomes
bilayered lipid assemblies
can be located with high amounts of hydrophilic drugs
most studied colloidal system for drug delivery
Micelles
nanosized assemblies of surfactants (amphiphilic molecules)
used to load and carry hydrophobic drugs
Polymers can be used to make?
drug conjugates
What is a key advantage of micelles and liposomes as applied to drug solubility?
both increase drug solubility
mRNA is highly x and y charged
hydrophilic
negatively
How do nanoparticles enter a cell?
endocytosis
Are nanoparticles rapidly cleared from the kidneys?
no, their size is the problem
renal filtration cut off is 10nm
Where do nanoparticles circulate and accumulate longer?
in tumors
Less than 10nm means what for the kidneys?
rapid filtration
What characteristics make nanoparticles useful for anti cancer drug delivery?
- greater drug loading capacity
- loading of multiple drug molecules, drug-drug combos
- allow to modify/tune drug release rate
- circulate longer, lesser elimination by the kidneys
- can be modified with PEG to decrease non-specific uptake into liver and spleen; increase circulation times
- multivalency/drug targeting
- enhanced permeability and retention effect
- can overcome drug resistance and still delivery drug to cells
PEGylation
masks the surfaces of nanoparticles
decreases non-specific binding of proteins -> decreases uptake by the liver
increases nanoparticle circulation
causes nanoparticles to have a positive surface charge
Serum albumin is known as opsonin. How does PEG change opsonin’s effect on nanoparticles?
it reduces opsonin association with nanoparticles; increases circulation
PEG is what kind of polymer?
nonionic
Multivalency
concept of nanoparticles being modified/decorated with many ligand copies
Multivalent particles increase and promote what?
increase particle uptake into cancer cells
promote effective drug delivery
Can nanoparticles be internalized into cancer cells at higher amounts compared to the free drug?
yes
Enhanced permeability and retention in tumors allows for what?
greater drug delivery and effective cancer killing
Gaps in between endothelium are > 100nm which means nanoparticles can?
escape and accumulate/ extravasate/ permeate through leaky capillaries into tumor region
Tumors do not have functional lymphatic drainage which means nanoparticles are?
retained there longer
What do nanoparticles avoid getting recognized by? Why is it helpful?
efflux pumps
prevents them from getting sent out of the cell
helps overcome drug resistance
t 1/2
circulation half-life time
time taken for original dose/concentration to reduce to 50%
clearance
volume of blood/plasma cleared of the drug per unit time
Nanoparticles show longer t1/2 circulation times in comparison to ?
the free drug
Nanoparticles show a slower rate of clearance in comparison to ?
the free drug
How do PEG chains impact the half life of liposomes?
increase the circulation half life; reduces clearance
modification with targeting ligands increases tumor cell uptake
In stealth liposomes the lipid bilateral contains polymer lipids which could have what attached to them?
Peptides
Doxil
anti cancer drug
dramatically decreases cardiotoxicity of the free drug doxirubicin
What does Daunorubicin treat?
leukemias
What is AmBisome?
amphotericin B- hydrophobic drug localized in lipid bilayers
treats fungal infections
What is paclitaxel?
hydrophobic cancer drug
Micelles can circulate longer and have a slower clearance compared to what?
the free drug
Micelles have improved therapeutic efficacy compared to what?
the free drug
What does GRAS stand for?
Generally recognized as safe
Where do pharmaceutical polymers come from?
natural sources
made synthetically
General uses of polymers
packaging, containers, devices, septa, tubing, contact lenses, stents/inserts, films
liquid dosage forms: flocculating agents, viscosifiers, surfactants, cosolvents
suppository bases
transdermal patches: backing, membranes, adhesives
semisolids/topicals: thickeners/ointment bases
oral: binders, disintegrants, films, controlled drug delivery
What does the degree of polymerization indicate?
how many monomers have combined to form a polymer
What are polymers commonly referred to as?
Large molecules or macromolecules
How does polymerization impact molecular weight?
distribution of polymer chain lengths means no singular molecular weight
average molecular weight is what is usually presented on commercially available polymers
As molecular weight of polymers increases what happens to the melting temperature?
it increases
Oligomers are made of how many monomers?
30-100
Room temperature in celsius
25
Body temperature in celsius
37
Macromolecules have difficulty organizing themselves into ?
lattices
How do polymer molecules organize themselves?
periodically organized (crystalline)
randomly (amorphous)
What are spherulites?
folded polymer chains separated by entangled connecting links with no discernible order
semi-crystalline
What affects how a polymer could be used in pharmacy?
the degree of crystallinity or absence of it
What dissolves faster: amorphous API or crystalline API?
amorphous because there are fewer interactions to break
What is more likely to recrystallize rapidly: amorphous or crystalline?
amorphous
If API molecules are dissolved in amorphous regions of a water soluble polymer what can be prevented?
recrystallization
Molecules cannot be absorbed by the body until?
they have been dissolved in the GI fluid
How can properties of a homopolymer be modified?
chemically reacting polymers together or physically mixing/blending polymers together
co-polymerization
chemical reaction involving in more than one type of monomer
results in different types of copolymers based on individual monomers
What are some types of copolymers?
random - used as binders/viscosifiers
alternate - used for DR or XR
block - used for surfactants
graft - used for specialized XR, not common
Viscosifiers/ Thickening Agents
polymeric excipients, usually cellulosic, used in liquid and semisolid dosage forms
polymers dissolved/dispersed in vehicle of formulation and have long chains
Viscosity
resistance to flow of a system under an applied stress
Water molecule H bonded to polymer functional groups makes the solution more x to flow?
difficult
D = (RT)/ (6pi x viscosity x N)
Stokes-Einstein equation
compares how diffusivity and viscosity affects the movement of molecules
As viscosity of the medium increases, diffusivity x. The amount of time it takes a molecule to diffuse with the concentration gradient by random motion will also y.
decreases
increases
t= (x^2)/ (2D)
Brown’s equation
relates distance and diffusivity to time
The more viscous a liquid, the greater ?
the applied force required to make it flow at a particular rate
Why would we use a viscosifier be used in topical preparations?
desirable texture and consistency
slow separation of components
shear-thinning base = easy application and retention against gravity following application
Why would a viscosifier be used in oral liquid preparations?
acceptable palatability
improve flavor
may help coat throat and soothe inflammation
shear-thinning vehicle allows easier pouring following shaking and slower settling of particles/solutes on storage
Why would we use a viscosifier be used in ophthalmic and intranasal products?
prolonged residence time following administration; allows more time for drug absorption
Why would we use a viscosifier be used in parenteral formulations?
slower diffusion of the drug away from the injection site
prolonged therapies
Semi synthetic cellulose derivates
based on cellulose- a structural polymer of fibrous stalks and branches in plants
modify cellulose-> functional groups easily hydrated by water
viscosifer
methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose
Natural polymer
gums
derived from high molecular weight polysaccharides from seaweeds, plants, or bacteria
hydrophilic, good for gel forming and viscosifiers
acacia, tragacanth, xanthan gum, carrageenan, sodium latinate
Synthetic Polymers
viscosifiers made from precisely designed chemical reactions
controlled growth and chemical cross linking from these is good for hydrogels
carbomer, poloxamer
Pharmaceutical gels form when lyophilic colloidal particles interact with?
liquid vehicles to form a 3D continuous network
Gelling agents
excipients that activate to form a gel on contact with fluid or are in manufactured gels
Type 1 gels
chemical gels
covalently cross-linked at junctions between homopolymer chains
highly hydrophilic but not soluble in water
sometimes termed hydrogels
mechanically rigid
Type 2 gels
physical gels
physically interact at junction zones via non covalent interactions
hydrophilic homopolymer
disperse with mixing; form gels at rest- demonstrate shear-thinning rheology
Gel Preparation
- other dry components are pre-mixed with the powdered gelling agent
- mixture is pre-wetted using propylene glycol, glycerol, or ethanol
- mixture is slowly and deliberately added to a vortexed medium to avoid clumping
- gelatin is triggered using prescribed stimulus (pH and temperature)
Examples of gelling agents
carbomers
carboxymethylcellulose
sodium carboymethylcellulose
sodium alvin ate
propylene glycol alginate
tragacanth
poloxamers
gelatin
methylcellulose
colloidal silicon dioxide
Macroscopic hydrogels
sizing between mm and cm
typically implanted surgically/ used for transdermal delivery
microgels
hydrogel particles typically sized less than 5um
delivered through oral or pulmonary routes
nanogels
hydrogel particles typically sized 10-100nm
delivered parenterals
What kind of bonds are drugs to mesh structures?
covalent
(rmesh/rdrug) > 1
drug freely diffuses through the mesh
XR takes 1-24 hours
(rmesh/rdrug) = 1
drug slowly diffuses through mesh
XR takes days
(rmesh/rdrug) < 1
drug is immobilized, mesh must degrade or swell for drug to be released
XR takes months
Thermoreversible Polymers
undergo a reversible sol-gel transformation, forming gels at high temperatures and solutions at low temperatures
Why would hydrogels be good for injections?
Injected as a liquid, forms a solid, controlled release over time
Passive diffusion
spontaneous movement of molecules through a membrane that does not actively participate in the process
driven by a concentration gradient
Donor side of the membrane
where delivery occurs
typically GI lumen
Receptor side of the membrane
typically blood
Transcellular diffusion
passive diffusion
how most small molecule API are absorbed by the body
through the cell
Paracellular diffusion
passive diffusion through leaky junctions
Transcytosis/Receptive mediated
active process
receptors bind to ligand and cytoplasm around engulfs it
transports through the cell, then exocytosi
Mass transport processes are important to
drug absorption, elimination, and delivery
osmosis
filtration and dialysis
What do mass transport models help show?
how groups of molecules move spontaneously
Diffusion
process where molecules move spontaneously from one location to another by a concentration gradient
[high] -> [low]
Diffusion proceeds until the solution becomes ?
homogenous
no areas of [high] or [low]
flux
diffusion rate per unit area [mass/(area x time)]
proportional to diffusivity
represented by the letter J
Diffusivity
diffusion coefficient [area/time]
reflects amount of solute diffusing across an area in a fixed amount of time under the influence of a concentration gradient
(dW/dt) = -DA(dC/dX)
Fick’s FIrst Law of Diffusion
J = dW/ (Adt) = -D(dC/dt)
flux
is proportional to diffusivity
(dC/dt) = D ((a^2)x C) / (ax^2)
Fick’s 2nd law of diffusion
how concentration with time also change with respect to position
J = (D(C1-C2)) / h
given time and constant donor and receptor compartment concentrations, gradients reach a constant value
falls under Fick’s second law of diffusion
What is the steady-state?
constant slope of the diffusion layer
What are sink conditions?
time at which C1-C2 is a constant and no longer changing
Partitioning
movement of molecules from one phase into another across an interface
concentrations at equilibrium are determined by the affinity of the molecules in each phase
A diffusant will have a different affinity for the membrane than for ?
donor and receptor compartments
Permeability
coefficient having units of cm/s or distance/time
constant for a molecule partitioning into a material/environment, reflective of its affinity for that environment
P = (DK)/ h
permeability, how fast something moves
In delivery from transdermal systems to API partitions from membrane into skin. How is the API removed from the delivery site?
blood
Transdermal delivery systems overload the reservoir of API, why?
To keep C1 constant; constant delivery
Sink conditions assume donor and receptor compartments will?
reach an equilibrium where C1> C2 and the difference between them remains constant
Diffusion at a steady-state is what kind of process?
a constant rate process
Does diffusion at a steady-state immediately establish a concentration gradient?
no
W = PAC1 X t
equation for constant rate diffusion
Lag effect: W= PAC1 (t-tL)
slow initial release; takes time to speed up to steady state
occurs when membrane is unsaturated at t=0
diffusion experiments
physiological experiments
Burst Effect: W = PAC1 (t + tB)
rapid initial release; takes time to slow down to a steady state
occurs when membrane is pre saturated at t=0
devices
drug products
tL = (h^2)/ 3D
lag time equation
tB= (h^2)/3D
burst time equation
A molecule diffusing through a series of consecutive layer will be rate limited by?
the least permeable layer
In a multi-layer series diffusion the overall diffusion rate will be described by?
an apparent permeability
Observed flux for diffusion through a series of consecutive layers is determined by?
the apparent permeability
What is the general process of the Higuchi molecule?
- API partitions into and then diffuses through lipid layer
- API partitions into hydrous layer and then diffuses through it
- API transits away from region by blood- maintains sink conditions
What does the Higuchi model consider rate limiting for pathways?
layer where diffusion encounters the greatest resistance
To eliminate patient-to-patient physiologic variability, many drug products are designed to have what?
a rate-limiting boundary
Resistance
reciprocal of permeability
has units of s/cm or time/distance
how much difficulty a molecule has diffusing through a layer
The greater the resistance in a layer, the slower the?
diffusion
Greater resistance in a layer means permeability is?
low
If Ri is significantly larger than other layers (greater than 10), diffusion through the layer is rate determining and ?
Rtot is about the same as Rapp
Which layer in the Franz Diffusion cell is subject to stirring? Which is not?
Bulk of solution is
Static diffusion layer is not
Rtot = (2hw)/Dw + (hm)/(DmKm)
resistance at physiological conditions
If Rm> Rx what kind of diffusion is it?
membrane limited
The layer a molecule diffuses through the fastest in parallel pathways is?
rate determining
What does partition coefficient K describe?
relative affinity of a molecule for water an lipid phases
magnitude is proportional to its permeability
assumes unionized molecules only
K>1
lipophilic molecule
K<1
hydrophilic molecule
logP>0
lipophilic molecule
logP<0
hydrophilic molecule
Ionization makes molecules more?
polar
pH-partition hypothesis
biological membranes are largely lipophilic, drug permeability will be higher in regions regions where the unionized form is predominant
When pH<pKA for an acidic api?
the unionized form will be greater than the ionized form
Molecules with a lower affinity causes molecules to diffuse
slower
Increasing ionization reduces the affinity that API have for?
lipid membranes
Distribution coefficient
K’
assumes only unionized molecules
when logD=logP the pH favors ?
the unionized form of the molecule
ionization is insignificant
What is significant for alphaionized?
greater than 0.50
As alphaionized becomes significant, what happens to K’, P, and the absorption rate?
they all decrease
When ionization is significant, K’>K, permeability of a mixture of ionized and unionized species will be xxx compared to completely unionized species?
smaller
Mass transport from a solution containing a mixture of ionized and unionized species will be xxx compared to completely ionized species
slower
