Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Dosage - Exam 3 > Lectures 19/20 > Flashcards

Lectures 19/20 Flashcards

Peptides, Proteins, and Biopharmaceuticals - Topp

1
Q

biologic drugs

A

medicinal agents derived from living systems, in contrast to more conventional “small molecules” drugs produced by chemical syntehsis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

types of biologic drugs

A

recombinant proteins
plasma immunoglobulins (IVIG)
some peptides
vaccines
DNA
RNA, mRNA
cell and gene therapies
cell-based therapies
AAV vectors
gene editing (CRISPR)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

peptides and oligonucleotides (tides)

A

have properties intermediate between small and large molecules
also included in biologics

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

common features of biologics

A

biological origin. (animal or cellular/molecular biology)
high molecular weight
higher order structure

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

early biologics – 1920s

A

making insulin in the 1920s through extraction of porcine insulin from pig pancreas at Eli Lilly
high sequence homology among human, porcine, bovine insulin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

early biologics – 1957

A

making flu vaccine in eggs
eli lilly workers in greenfield, IN
candidate vaccine viruses (CVVs) are grown in chicken eggs –> CVVs are injected into fertilized chicken eggs and incubated for several days –> fluid containing virus is harvested from the eggs –> vaccine viruses are inactivated (killed) –> virus antigen is purified

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

recombinant proteins in the 1980s

A

created the central dogma of biology (DNA to RNA to Protein)
first recombinant form of human insulin created by Eli Lilly in October 1982
bacterial cell as protein factory
development of methods to grow cells in culture, isolate, and purify the protein produce

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

recombinant proteins (mAbs)

A

leading recombinant protein drugs
first mAb, OKT3, approved in 1986 to prevent transplant rejection
high molecular weight
produced in mammalian cells because posttranslational glycosylation is important to their structure and function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

CAR-T

A

approved in august 2017
chimeric antigen receptor (CAR) T-cel therapy
examples – Kymriah, CTL019, Tisagenlecleucel, Novartisc
contrast – allogeneic cell therapy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Kymriah

A

first living drug
autologous T-cell therapy
T-cells are removed from a patients blood –> transfected with an antigen receptor that recognizes a cancer antigen –> grown in culture –> return to the patient and infused

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

mRNA vaccines

A

new revolution, circa 2020
contains mRNA in lipid nanoparticles
example – Covid-19
mRNA codes for the spike protein of the virus
rapid introduction has started the revolution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

LNP

A

contains four types of lipids that condense mRNA and enable delivery to the cytoplasm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

characters of biologics

A

DNA
mRNA
cells
proteins
viral vector
animal source

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

biologics timeline

A

early biology – isolated from animal tissues
recombinant proteins – expressed in transfected cell lines; act as protein factories

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

role of cells in biologics

A

protein factory
therapeutic agent (ex. CAR-T)
therapeutic target

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

role of viral vectors in biologics

A

transfection reagent
therapeutic agent
therapeutic target (ex. COVID-19)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

role of animal tissue in biologics

A

flu vaccines (chicken)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

role of proteins in biologics

A

therapeutic agent
therapeutic target (receptor)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

role of DNA in biologics

A

instructions for transfected cells
therapeutic agent (ex. DNA vaccines)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

why is biologic dosing usually parenteral?

A

due to biologics being degrading extensively in the GI tract
exception - oral vaccines, some orally administered peptides
examples - solution for injection, pen or autoinjector, pre-filled syringe, lyophilized powder for reconstitution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

why are solution formulations popular?

A

simplest and least expensive to manufacture
convenient for patients and hospital personnel since they do not require reconstitution
can be inspected visually prior to adminsitration

22
Q

clinic concerns for biologics

A

efficacy
sterility
side effects (dose limiting immune response)
pain on injection (volume administered, pH, tonicity ionic strength)

23
Q

formulation concerns

A

all clinical concerns and
stability
solution viscosity and ease of injection (can be affected by API concentration)
manufacturability (cost, manufacturing time)

24
Q

factors of stability

A

aggregation
chemical stability (deamidation, oxidation)
shelf-life
storage conditions

25
Q

formulation variables

A

solution properties (pH, ionic strength tonicity, drug concentration, volume and exicipients)
container, closure (materials)
storage conditions (fridge vs room vs frozen)

26
Q

pH variable

A

formulation variables
salmon calcitonin (sCT) peptide is used to treat osteoprosis with the rate of degradation depending on pH
pH of maximum stability is 3-4; not a good pH for injection
additives make the stability worse

27
Q

concentration formulation variables

A

example beta lactoglobulin
milk protein, structurally similar to mAbs
aggregate content increases with increasing protein concentration
since SQ delivery requires small volumes, mAb concentrations are being pushed to 100mg/mL, increasing aggregation risk

28
Q

higher concentration = ? aggregation

A

greater aggregation thus greater turbidity

29
Q

protein aggregation mechanisms

A

chemical reaction
colloidal interactions
unfolding (highest energy)

30
Q

partial unfolding at air/liquid interface

A

is worse with agitation
especially prominent at three-phase boundary (container, air, solution formulation)

31
Q

stabilized protein structure

A

excipients that are preferentially excluded from the protein surface
promote interactions with water and stabilize native protein structure
exception – protein binding to ligands can stabilize native structure

32
Q

de-stabilized protein structure

A

cosolvent surrounds protein in preferential binding
can lead to denaturation

33
Q

erythropoetin

A

EPO, Epoetin
used to treat anemia in renal disease
formulation of anti-EPO antibodies reduces drug effect and that of any naturally occurring EPO that remains

34
Q

pure red cell aplasia (PRCA)

A

can result in sudden onset anemia, death
in europe, increased incidence of PRCA has been associated with a change in container closure (stopper)

35
Q

what if the solution formulation doesn’t work?

A

store at refrigerated temperature
freeze
free-dry (lyophilize) or spray-dry to create a dried powder for reconstitution
re-engineer the protein molecule
abandon drug candidate

36
Q

practical considerations for solution formulations of biologics

A

store at recommend temp
protect from light if recommended
avoid agitation (dont shake my baby!!!)
examine vial for particulates prior to adminstration
be aware of the potential for adverse immune responses

37
Q

covid mRNA vaccine

A

suspensions of lipid nanoparticles (LNP) in solution which the mRNA being inside of it
mRNA is not active without LMP

38
Q

what is prefilled syringes, pens, and autoinjectors?

A

medical devices
not formulations
the solution inside it is a formulation so together it is called a combination product

39
Q

advantages of pre-filled syringes, pens, and autoinjectors

A

ease of use, convenience
easier to transport than vial and syringe
discrete
increased patient compliance
reduced risk of dosage error
reduced risk of product contamination

40
Q

disadvantages of pre-filled syringes, pens, and autoinjectors

A

higher cost than vial plus syringe
cannot mix two drugs
drug waste due to priming
greater surface to volume ration, presence of lubricants, can induce aggregation of protein drugs

41
Q

pre-filled syringe components

A

syringe barrel
luer lock
finger grip
plunger
gasket
top cap

42
Q

location of leur lock

A

in between the top cap and the syringe barrel

43
Q

components of insulin pens

A

pen cap
outer needle cap
inner needle cap
needle
protective seal
rubber seal
insulin reservoir
dose window
dosage knob
injection button

44
Q

common features of pre-filled syringes, autoinjectors, and pens

A

drug solution
needle
piston/plunger
housing

45
Q

special concerns for pre-filled syringes, autoinjectors, and pens

A

higher surface to volume ratio
lower total volume
syringe lubricants/oils

46
Q

addition of syringe lubricants or oils

A

change interaction of proteins with solid surface (hydrophobic lubricant lines container)
droplets in solution (provide additional hydrophobic surface area)

47
Q

advantages of lyophilized powders

A

reduced rates of chemical and physical degradation
improved drug stability and longer shelf-life
refrigerated storage is not usually needed
can use lyophilized formulations in pre-filled syringes, pens, and autoinjectors in dual chamber

48
Q

disadvantages of lyophilized powders

A

must be reconstituted prior to injection, less convenient than solutions
more expensive and time-consuming to manufacture

49
Q

lyophilization

A

also known as freeze-drying
removes water by sublimation
occurs at low temperature and low pressure
gentler than other methods of removing water (like boiling) so better for fragile drugs
same process is used for some foods (like instant coffee)

50
Q

lyophilization and instability

A

instability is caused by lyophilization as “freeze-concentration” can promote aggregation
disulfide bond scrambling can be accelerated by freezing and drying
protein structure can be perturbed by lyophilization
aggregated and/or degraded protein can be observed on reconstitution

51
Q

role of lyoprotectants and cryoprotectants

A

stop lyophilization from perturbating the protein structure

52
Q

clinical considerations of lyophilization

A

use caution when
- reconstituting
- storing and handling the reconstituted solution
- administering (visually inspect for particulates)

Dosage - Exam 3 (9 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions