exam 3 lecture 7 Flashcards
biologics
meds derived from living organisms
recombinant proteins, peptides, blood factors, vaccines, oliognulceotides, cell-based therapy
biotech drugs or biopharmaceuticals
importance of biologics
top 200 drug sales 2018 –> 73 were biologics
top 100 drug sales in 2003 –> 5 were biologics
monoclonal antibodies (mAb)
two light chains (L)
two heavy chains (H)
linked by SS bonds
antigen binding occurs through variable domain(V) at (CDR)
antibody drug conjugates
trojan horse
linker on ADC attaches to cytotoxic agent
combine target specificity of mAb with efficacy of small molecule drugs
can use mAb fragments rather than whole mAb
cytokines
IL, INF
neulasta, epogen, avonex, rebif, humatrope
insulins
a-chain and b-chain linked by ss bonds
alpha helical structure –> readily associates to form dimers, hexamers
insulin analogs
lispro insulin: fast acting insulin analog, lys and pro on c-terminus are reversed
aspar insulin: fast acting insulin analog, pro on c-terminus of b-chain mutated to asp
glargin insulin: long acting, asn on a21 mutated to gly
peptides
short proteins less than 50 AAs
some secondary structure, no higher order structure
some chemical modifications
peptide vs peptide analog
peptidomimetic (telaprevir)
peptide like structure
vaccines
types: inactivated, attenuated, toxoid, conjugate, subunit
differ widely in size and structure
can be much larger than other biologics
cell therapies –> new biologics
car-t cell therapies
- remove immune cells from patient’s blood,
- genetically program to fight cancer cells,
- multiplied + infused into patient,
- newly programmed car-t cells kill cancer cells
oligonucleotides –> new biologics
used to treat spinal musclar atrophy
dosage forms for biologics
dosing is usually parenteral: except oral vaccines
peptides and proteins cannot be given orally
common dosage forms:
- solution for injection, pen/autoinjector, pre-filled syringe, lyphilized powder
solution formulation
simple and least expensive
convienent for patients and hospital bc they don’t need reconstitution
can be inspected prior to administration
clinical concerns for solutions
efficacy, sterility, side effects (dose-limiting immune response)
pain from injection
formulation concerns solutions
all clinical concerns
stability: aggregation, chem stability, shelf-life, storage conditions
manufacturing: cost, manufacturing time
formulation variables solutions
solution properties: ph, ionic strength, drug conc., volume, excipients.
container: materials
Storage conditions: refrigerator vs room, frozen
formulation variables: pH
rate of sCT degradation depends on pH
pH of maximum stability is 3-4 –> not a pH for injection
additive makes stability worse
formulation variables: concentration
beta lactoglobulin is a milk protein
higher concentration of it results in increased and greater aggregation
SC delivery required small volumes –> mAb concentrations risk aggregation
formulation variables: excipients
stabilize proteins
promote interactions with water and stabilize native protein structure
excipients that bind to proteins can lead to denaturation
exception: protein binding to ligands can stabilize native structure
Eythropoetin
erythropoetin (EPO, Epoetin) is used to treat anemia in renal disease
anti-EPO antibodies
reduces drug effect and that of any naturally occur EPO
Pure red cell aplasia (PRCA)
results in sudden onset anemia, death
increasesd PRCA has been associated with change in container closure (stopper)
what if solution formulation does not work
store at fridge temperature
freeze
freeze-dry or spray-dry to create dried powder for reconstitution
re-engineer protein molecule
abandon drug candidate
practical considerations
store at reccommended temp
protect from light
avoid agitation
examine vial for particulates prior to admin
be aware of adverse immune response
prefilled syringes, autoinjectors, pens
prefilled syringes, pens, autoinjectors are not formulations
pen is a medical device
solution inside pen is formulation
together “combination product”
advantages prefilled, pens, auto
ease of use
ease of transport
discrete
increased pt compliance
reduced risk of dosage error and product contamination
disadvantages prefilled, pens, autos
higher cost than vials + syringes
cannot mix two drugs
drug waste bc of priming
greater surface-volume ratio, presence of lub, induce aggregation of protein drugs
prefilled syringe components
syringe barrel
leur lock
finger grip
plunger
gasket
top cap
insulin pen components
cap
outer needle
inner needle
needle
protective seal
rubber seal
insulin reservoir
dose window
dosage knob
injection button
common features pen, prefilled, autos
solution dosage forms within a device for admin
common features: drug solution, needle, piston/plunger, housing
special concerns prefilled, pens, autos
when compared to vials:
higher surface-to-volume ratio
lower total volume
syringe lubes + oils
aggregation in syringe
proteins are surfactants that can unfold when exposed to surfaces or interfaces
on wall of syringe there is lubricant, which can cause proteins to unfold and dimerize then aggregate
advantages lyphilized powders
reduced rates of chem + physical degradation
improved drug stability + longer shelf-life
refrigerated storage not usually needed
can use lyophilized formulations in prefilled, pens, autos
disadvantages lyophilized powders
must be reconstituted prior inj
less convenient than solutions
more expensive and time consuming
lyophilized powders
freeze drying
removes water by sublimation
occurs @ low temp + low pressure
gentler than other methods of moving water
same for foods
lyophilization can cause instability
freeze-concentration can promote aggregation
disulfide bond scrambling can be accelerated by freezing and drying
protein structure can be perturbed by lyophilization
- excipients to inhibit this: lyoprotectants + cryoprotectants
aggregated and/or degraded protein can be observed on reconstitution
clinical considerations
biologics are usually marketed in lyophilized form because they are unstable in solution
use caution: reconsitution, storing + handling, when administering ; visually inspect for particulates
