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Dosage II > 18-20: Biologics > Flashcards

18-20: Biologics Flashcards

1
Q

Biologics

A

-derived from living systems
-recombinants, blood factors, mRNA, vax, cell and gene therapies

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2
Q

Common features of biologic drugs

A

-biological origin (animal or cellular)
-high molecular weight
-higher order structure

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3
Q

Early biologics

A

-insulin from pig pancrease in 1920s
-making vax in eggs 1957 (we still do this)
-recombinants in the 1980s: rinsulin from bacterial cells

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4
Q

mAbs

A

-leading rprotein drug
-first mAB, OKT3 for transplant rejection
-high molecular weight
-2 light chains, 2 heavy chains, disulfide bonds
-produced in mammalian cells bc posttranslational glycosylation is important to function

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5
Q

CAR-T

A

-2017
-Kymriah
-living drug
-T cells removed from blood, transfected w antigen receptor that recognizes cancer antigen
-grown in culture
-returned to patient and infused

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6
Q

mRNA vax

A

-contain mRNA in lipid nanoparticles
-mRNA cosed for spike protein
-four lipids that condense mRNA and enable delivery to cytoplasm
-PEG-lipid, cationic lipid, helper lipid, cholesterol

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7
Q

Biologics today

A

-protein factory (CAR-T)
-transfection reagent (mRNA)
-theraputic agent (mAB)
-instructions for transfected cells (DNA vax)
-flu vax in eggs

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8
Q

Dosage forms for biologics

A

-usually parenteral bc cant survive tummy
-exceptions: oral vax, some oral peptides

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9
Q

Common dosage forms for biologics

A

-solution for injection
-pen or autoinjector
-pre-filled syringe
-lyophillized powder for reconstitution

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10
Q

Biologics Part 1 summary

A

-important repidly growing lcass
-mAbs, mRNA, therapies, vax
-nucleotide and peptides will also be discussed
-injection, pens/autoinjectors, syringes, lyophilized solids

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11
Q

Why solution formulation for biologics

A

-easy and cheap
-convenient bc no reconstitution
-can be inspected visually before admin

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12
Q

clinical concerns for biologics in solution

A

-efficacy
-steriliry
-side effects (dose-limiting immune response)
-pain on injection

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13
Q

Formulation concerns for biologics in solution

A

-stability (aggreagation, shelf-life, storage)
-viscosity and ease of injection (affected by API concentration)
-manufacturing (cost and time)

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14
Q

Formulation variable for biologics in solution

A

-solution properties (pH, ionic strength/tonicity, drug conc, volume, excipients
-container
-storage conditions

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15
Q

pH formulation variable

A

-max stability at 3-4
-but not a good pH for injection
-additives can make this worse

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16
Q

Concentration formulation variable

A

-aggregate content inc w inc protein concentration
-high conc in aggreagation risk

17
Q

How do proteins aggregate

A

-chemical reaction
-unfolding esp partial
-colloid interactions

18
Q

Excipeint formulation variable

A

-help stabilize protein
-preferentially excluded from protein surface promote interactions w water and stabilize native structure

19
Q

Clinical effects of formulation EPO and PRCA example

A

-erythroportein used to treat anemia in renal disease
-anti-EPO antibodies reduces drug effect and natural EPO
-PRCA can result
-inc PRCA associate w inc change in container closure
-formation of EPO aggregates has been suggested

20
Q

What if solution formulation doesn’t work

A

-store at fridge temp
-freeze
-freeze0dry for resonstitiution
-re-engineer protein molecule
-abandon drug candidate

21
Q

Prefilled syringes, pens, and autoinjector reminder

A

-not formulations
-medical device
-solution inside is formulation
-together they are combination products

22
Q

Practical considerations of solution formulations of biologics

A

-store at rec temp
-protect from light
-avoid agitation
-examine vial for particulates prior to admin
-be aware of potential adverse immune responses
-DONT SHAKE

23
Q

Covid mRNA vax

A

-suspenions of LNP in solution
-mRNA in LNPs
-not active w/o LNP
-suspension

24
Q

Biologics part 2 summary

A

-solutions for injections are common for biologics
-solution properties desirable for slinical use may not be optimal for stability
-aggregation is a serious instability influenced by formulation, storage, and handling
-be aware of potential for adverse immune response

25
Q

shaking might make aggregation

A

worse

26
Q

Pros of syringes, pens, autoinjectors

A

-convenience
-ease of transport
-discrete
-inc compliance
-reduce risk of dosage error or contamination

27
Q

Disadvantages of pre-filled syringes, pens, autoinjectors

A

-higher cost than vial plus syringe
-cannot mix 2 drugs
-drug waste due to priming
-greater surface to volume ratio, lubricants, can induce aggregation

28
Q

Common features of pre-filled, pens, syringes

A

-drug solution
-needle
-piston/plunger
-housing

29
Q

Special concerns for pre-filled, pens, autoinjections

A

-higher surface-volume ratio
-lower total volume
-lube, oils could cause droplets in solution

30
Q

Proteins are surfactants

A

-can unfold when exposed to surfaces or interfaces

31
Q

Part 3 summary

A

-prefilled, pens, autos used to deliver solution formulations of biologics
-formulation concerns for biologics in solution apply
-higher surface to volume ratio than in vials and the use of lubricants may promote aggregation

32
Q

Advantages of lypophilized powders

A

-reduce rates of degradation
-improve stability and shelf-life
-fridge usually not needed
-can use in pre-filled, pens, and autos (dual chamber)

33
Q

disadvantages of lypophilized powders

A

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

34
Q

What is lypophilization

A

-freeze-drying
-removes water by sublimation
-occur at low temp and low pressure
-gentler than other methods of removing water
-better for fragile drugs
-same process for instant coffee

35
Q

How does lyophilization work

A

-freezing
-vacuum
-sublimation
-dry powder

36
Q

Lypophilization can cause instability

A

-promote aggregation
-disulfide scrambling can be accelarated
-protein structure can be preturbed (inhibited by lyo and cryo protectancts
-aggregated protein can be observed on reconstitution

37
Q

Clinical considerations of lyophilization

A

-use caution when:
-reconstituting
-storing and handling
-when admin (look at it)

38
Q

Lyophilized summary

A

-used for biologics that are unstable in solution
-must be reconstituted prior to injection
-use care when reconstituting solutions

Dosage II (20 decks)

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