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Dosage II > Advanced Formulations 1 > Flashcards

Advanced Formulations 1 Flashcards

1
Q

Peptide drug vs protein drugs

A

-amino acids make peptides (>50aa) make proteins 2’

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2
Q

Basic structure of amino acid

A

-NH2 AMINO group
-COOH ACID group
-link w peptide bonds C-N

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3
Q

Semaglutide Ozempic

A

-synthetic
-31 aa
-weight loss

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4
Q

Peptide drug synthesis

A
  1. porous bead of NH2 functional groups
  2. coupling w aa w PG
  3. Deprotection (remove PG)
  4. Coupling w aa w PG
  5. Deprotection
  6. Cleavage (remove bead) or more cylcles
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5
Q

Problems w peptide drug synthesis

A

-coupling yields need to be very high for long synthesis
-yields for consecutive reactions need to be multiplied

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6
Q

Linear yield math

A

-if 80% for 5 aa
-0.8^5 = 0.328 = 32.8% overall

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7
Q

convergent synthesis yield math

A

-yield of just one of them but steps are going on at the same time

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8
Q

Yield of linear peptide 31 aa with 90% yield each step

A

-(0.9)^31 = 0.038 = 3.8%
-very low

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9
Q

protein size

A

greater than 40 aa

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10
Q

Can biologics be compounded?

A

-NO
-too fragile
-denaturation, aggregation

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11
Q

Protein drugs

A

-BIG >1000aa
-too hard to synthesize in lab
-v complex v fragile

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12
Q

How are protein drugs produced?

A

-100-1000L
-pilot plant
-probes for pH, dissolved O2, temp, pressure, biomass, carbon source

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13
Q

Basics of cloning/expression

A

-gene encoding protein drugs
-replication origin
-ampicillin resistance
-plasmid

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14
Q

Protein drug biosynthesis

A

-cloning?
-ribosomal synthesis
-post-trans mods

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15
Q

Bacteria expression systems

A

-no glycosylation
-endotoxins

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16
Q

Chinese hamster ovary

A

-expensive, susceptible to contamination w human pathogens/oncogenes
-best for antibody protection

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17
Q

Post translational modifications

A

-glycosylation adding extra sugars to the drug
-small differences can cause immune response
-careful process analytical tech to prove similarity of batched

18
Q

Gold standard to analyze protein drugs biosimilarity

A

-HPLC + mass spectrometry
-endoglycosidase cuts of glycosylation

19
Q

disulfide bonds can be unstable

A

lead to degradation

20
Q

Conditions that can lead to protein degradation

A

-temp
-agitation
-pH
-deamidation
-oxidation
-photostability

21
Q

Agitation leads to

A

-inc contact w surfaces
=aggregation
-do NOT shake

22
Q

Freezing leads to

A

-ice crystals
=more concentrated mAb solution
=aggregation

23
Q

Aggregation onset

A

-can happen hours after shaking

24
Q

Biologics stabilization

A

-excipients
-interact w surface of protein
-excluded: repell from protein raise energy
-bound: lower energy

25
Q

Unfolded proteins

A

-higher Gibbs free enrgy
-large surface area
-more unstable

26
Q

preferentially excluded excipients

A

-repelled from protein surface
-raise energy
-destabilizer

27
Q

preferentially bound excipients

A

-bind to protein surface
-lower energy
-stabilize

28
Q

Salt concentration effect on protein stability

A

-effect can be dif for dif proteins
-unpreditable
-NEVER compound biologics

29
Q

Nature can store proteins

A

-very long time inside of sugar glass
-Trehalose
-old wise shrimp

30
Q

Sugar glass

A

-Trehalose, water, protein
-slow degradation bc high viscosity
-frozen out motions = stability
-biomimicry for storage of biologics

31
Q

Blincyto

A

-reconstitute bc has trehalose for stability

32
Q

Derivatization

A

-hydrophobic tail binds albumin
=inc half life
-levemir and ozempic (7day half life)

33
Q

Considerations

A

-potency: nasal and pulmonary routes only for high potent drugs bc limited capacity
-variability: high
-safety
-cost

34
Q

Oral semaglutide

A

-qd
-fasting required
-low bioavailability 1%
-does not open tight junctions

35
Q

key challenge w RNA

A

-stability
-extra OH than DNA so less stable
-cleaved RNA can be toxic

36
Q

siRNA

A

-30na
-can be synthesized chemically
-structure mods to inc half life

37
Q

Longer RNAs synthesized by

A

-transciption enzymes
-outside of cell
-more controllable
-isolate enzymes

38
Q

Modification of nucleotides

A

-replace w Me
-reduce immune reaction to mRNA
-inc protein production

39
Q

siRNA length

A

-much shorter
-not transcribed to protein

40
Q

Common RNA mods to ribose part

A

-me
-F
-OCCOC
-eliminate the nucleophilic 2-OH
=inc stability

41
Q

Targeting ligands attached to the 3’ or 5’ ends of RNA can

A

-extend half-life of siRNAs
-acetyl group helps target the liver

42
Q

siRNA product

A

-Leqvio
-injection every 3 to 6 MONTHS
-lowers cholesterol levels
-siRNA is very modified

Dosage II (20 decks)

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