Exam 2 Flashcards
Suspensions
type of dispersed system containing finely divided solid particles in water
insoluble drug particles suspended in solvent
thermodynamically unstable
particle size greater than 500nm
Dispersed phase
internal phase of suspensions (particles)
Dispersion medium
external phase of the suspension (solvent)
Examples of pharmaceutical suspensions
orally-administered mixtures
externally applied lotions
injectable preparations
Why are suspensions useful?
Drugs with limited solubility in water (25-100 mg/mL)
taste-masking
improved chemical stability than solutions
longer-acting drugs; slower drug absorption from suspensions
Short (regular) insulin is a solution with a high efficacy after x hours?
2
Intermediate (NPH/long acting form) is a suspension with a high efficacy after x hours
4
Duration of NPR
less than 6 hours
Duration of NPH
up to 14 hours
Desirable characteristics of a suspension
adequate dispersion of particles in solvent
minimal aggregation/clumping of particles in suspension
prevent caking (formation of sedimentation that can’t be resuspended)
Formulation of a suspension has to be prepared such that it can be suspended upon?
moderate agitation/shaking
v= {d^2 x (pi-pe) x g} / 18n
stokes equation; relates sedimentation velocity to particle size and density, and solvent viscosity
As solvent viscosity increases, sedimentation velocity…
decreases
What are the 2 key approaches to improve suspension stability
use a viscosifier: MC/HPMC
use a flocculating agents: electrolytes such as aluminum chloride, polymers, surfactants
Flocs
loosely bound particle clusters
stabilized by weak H-H bonds and van der Waals forces
Flocculated suspensions structure and redispersion
structure: scaffold-like, weak bonds
redispersion: easy
Deflocculated suspensions structure and redispersion
structure: closely packed, cake
redispersion: difficult/impossible
Suspending agent
increases viscosity
wetting agent
disperse hydrophobic drug particles
decrease interfacial tension
Antioxidants
prevent oxidation
Buffers maintain
pH
Biologics
derived from biological organisms/biological material
have action specificity
require lower doses compared to traditional small molecule APIs
improved safety profile of protein drugs
How would you describe biologics approval over time?
steady rise
Major PO delivery factors of biologics
- high molecular mass means lower membrane permeability
- relative hydrophilicity/hydrophobicity balance
- ionic charge- function of proteins hydrophilicity and pH environment
5 challenges to delivery of polypeptide drugs
- lower permeability across biological membranes
- lower solubility of hydrophobic proteins
- smaller molecular mass/particle diameter means rapid kidney clearance
- immunogenicity of recombinant proteins
- susceptibility to proteolytic degradation
Advantages of Oral protein and peptide delivery systems
protect drug from enzymatic degradation and decrease systemic clearance
increased cargo solubility
controlled release and minimize undesirable side effects
improve biodistribution, decrease non specific uptake
low immunogenicity
3 characteristics of PEGylated proteins
- increase in size to reduce kidney filtration
- increase in solubility due to PEG hydrophilicity
- decreased accessibility for proteolytic enzymes and antibodies
Pegylated protein advantages
sustained absorption
increased half life
decreased systemic clearance
How does PEGylation affect dosing?
decreases dosing intervals
increases patient compliance
What are challenges for nucleic acid delivery?
hydrophilic molecules limit permeation into hydrophobic membrane
have a high molecular mass
Short interfering RNA (SiRNA)
interferes with the translation of mRNA into a protein
Vectors
carry nucleic acids to their sites of action
What are the extracellular steps in nucleic acid delivery?
circulation
accumulation
penetration
Intracellular steps in nucleic acid delivery
fusion
endocytosis
release
endo/lysome escape
nuclear localization
mRNA delivery
siRNA delivery
DNA delivery
What barriers can carriers overcome?
extracellular and intracellular barriers
Where are DNA drugs delivered?
nucleus
Where are mRNA drugs and SiRNA delivered?
cytoplasm
Gene therapy
clinical application of DNA molecules
replacement of mutated copy of the gene with a healthy/normal DNA copy
What does ADA deficiency cause?
SCID
What drives the need for safer alternative gene delivery?
limited packaging capacity of viral vectors and their immunogenicity
What are the 3 main extracellular barriers/challenges to nanoparticle delivery of nucleic acids?
renal filtration
non-specific uptake by the liver/spleen
nuclease degradation
What are the 3 main intracellular barriers/challenges to nanoparticle delivery of nucleic acids?
cellular entry
endosomal escape
nuclear uptake
10-100 nm are useful as?
drug carriers
Endosome
acidic compartments
Polymers and lipids used for nanoparticle formation for nucleic acid delivery are ?
cationic chemical groups
amino groups are the most common
What do amino groups in carriers bind to?
phosphate groups in nucleic acids
What can go into a lipid nanoparticle?
DNA
siRNA
mRNA
Proteins
small molecules
What does CAR stand for?
Chimeric Antigen Receptor
CAR T-Cell Therapies
involve engineering the patient’s own immune cells to treat their cancer
The CAR gene can be delivered to the patient’s T-cell using what?
a viral/non viral NP carrier
What will CAR-T bind to ?
the patient’s cancer cell antigen
CAR has improved over time for the?
Expansion of CAR-Ts after infusion
persistence of injected CAR-T
What does the the extracellular domain of CAR do?
recognition/binding of a specific antigen by a T cell
What does the intracellular domain of CAR do?
stimulate T-cell proliferation, cytolysis, and cytokine secretion to eliminate the target cell
CD19
antigen present on cancer cells
anti CD-19 CAR
binds to CD-19 on cancer cells
Are CAR-T therapies patient specific?
yes
Biological challenges of CAR-T therapies
on target toxicity; CAR-T struggles to tell the difference between normal and cancerous B cells
off target toxicity; cytokine release syndrome
Manufacturing Challenges of CAR-T cell therapies
high cost
heterogeneity of personalized products
What does Kymriah treat?
pediatric leukemia
What does Yescarta treat?
adult B cell lymphoma
How is ER different from IR dosage forms?
- maintains steady [drug] compared to immediate release dosage forms
- avoids fluctuations in plasma
Eneteric polymers are usually polyacids with a pKa around?
5
Which dosage forms are always coated with enteric polymers?
DR
Purposes of DR dosage forms?
- protect the acid-sensitive API from degrading in the stomach
- protect stomach mucosa against the irritating effects of the drug
- local delivery effects in the small intestine
Characteristics of ER systems
- prolong duration of drug release
- avoids fluctuations of [drug] and increases patient compliance
controlled release membrane
mechanism where release of API is extended/ controlled over prolonged periods
Diffusion mechanism
tablet core surrounded by ethyl/methyl cellulose asymmetric/porous membrane
water soluble portion of the membrane dissolves away leaving pores through which water and drug diffuse
Dissolution based er drugs
dissolution of the polymetric matrix in addition to dissolution of the API molecules
PLGA
poly(lacticacid)- co-glycolic acid
Key factors that control the rate of drug release
- molecular mass of the PLGA polymer
- [API/drug] that’s loaded in the PLGA polymer matrix
Osmotic release oral system
- GI fluid enters through semipermeable membrane, hydrates the push layer containing an osmogen
- Osmogen creates the osmotic pressure
- osmotic pressure is the driving force for zero-order drug release
Factors affecting rate of drug degradation
temperature
pH
light intensity
excipients
solvents
reaction rate
speed or velocity of the reaction
expressed in terms of changes in reactant/product concentration over time
rate law
a quantitative relationship between the reaction rate and the concentration of reactants and other species present
reaction order
describes the concentration dependence of a reaction rate on the concentration of reactants
In a zero order reaction, rate is independent of?
concentration
First order
rate = k [A]
Second order
rate = k[A]^2 OR k [A][B]
Third Order
rate = k[A]^2[B] or k[A][B][C]
What type of dosage forms are useful to formulate high drug concentrations or drugs with limited water solubility?
suspensions
As a drug solubilizes in solution, more drug is released so that concentration stays?
constant
half-life
time it takes for a drug to decompose to half of its original concentration
You should pick the R^2 value closest to which number?
1
A0
starting/ initial [drug]
K
rate constant
shelf life
time a drug product is expected to remain within its approved specification
t90
used to widely indicate shelf life
