DOSAGE II: Exam 3

Question 1

major dosage forms for biologics

Answer 1

solutions for injection
pens + autoinjectors
pre-filled syringes
lyophilized solids for reconstitution

Question 2

insulin analogs: fast-acting

Answer 2

1. Lispro insulin (Humalog) -> Lys and Pro on C-terminus of B-chain are reversed, blocking dimer formation
2. Insulin aspart (Novolog) -> Pro on C-terminus of B-chain mutated to Asp

Question 3

insulin analogs: long-acting

Answer 3

Insulin glargine -> Asn at A21 mutated Gly and two Arg added to C-terminus of B-chain, promotes microcrystallization

Question 4

Why solution formulations?

Answer 4

1. are simplest and least expensive to manufacture
2. are convenient for patients and hospital personnel since they do not require reconstitution
3. can be inspected visually prior to administration

Question 5

higher concentration [of proteins] leads to…

Answer 5

greater aggregation

Question 6

How do proteins aggregate?

Answer 6

1. Chemical reaction (crosslinking)
2. Colloidal interactions (sticking together)
3. Unfolding

Question 7

excipients that are ____________ ______________ from the protein surface promote interactions with water and stabilizes native protein structure

Answer 7

preferentially excluded

Question 8

advantages of pre-filled syringes, pens, and autoinjectors

Answer 8

1. easier to transport than vial + syringe
2. discrete
3. increased patient compliance
4. reduced risk of dosage error
5. reduced risk of product contamination

Question 9

disadvantages of pre-filled syringes, pens, and autoinjectors

Answer 9

1. higher cost than vial + syringe
2. cannot mix two drugs (i.e. insulin types)
3. drug waste due to priming
4. greater surface-to-volume ratio and presence of lubricants can induce aggregation of protein drugs

Question 10

advantages of lyophilized powders

Answer 10

1. reduced rates of chemical and physical degradation
2. improved drug stability and longer shelf-life
3. refrigerated storage is not usually needed
4. can use lyophilized formulations in pre-filled syringes, pens, and auto-injectors

Question 11

disadvantages of lyophilized powders

Answer 11

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

Question 12

What is lyophilization?

Answer 12

-freeze-drying at low temp and low pressure
-removes water by sublimation (gentler than other methods of removing water)
-used for biologics that are unstable in solution

Question 13

How does lyophilization cause instability?

Answer 13

can lead to aggregation -> freezing and drying can accelerate disulfide bond scrambling

Question 14

Excipients that inhibit protein instability by lyophilization:

Answer 14

1. lyoprotectants
2. cryoprotectants

Question 15

Layers of the skin

Answer 15

(TOP) Stratum corneum
Living epidermis
Dermis
Subcutaneous fatty tissue
(BOTTOM) Hair follicles and sweat glands

Question 16

physiology of the stratum corneum

Answer 16

outermost layer made up of dead cells
-main barrier to permeation
-brick and mortar model (bricks: dead cells, mortar: lipids)
-the dead cells are not permeable
-permeation occurs by going through the lipid (mortar) between the dead cells (bricks)
-the more hydrates, the greater drug permeability

Question 17

physiology of the living epidermis

Answer 17

living cells without capillaries
avascular (cuts won’t bleed)
receives nutrients by diffusion from dermis
source of skin color and tanning

Question 18

physiology of dermis

Answer 18

-contains capillaries (cuts will bleed)
-drugs need to reach these capillaries to achieve systemic action
-pain, thermal, and tactile sensors
-injury must reach dermis to produce scarring

Question 19

microbial barrier of skin (hint: what is pH of skin?)

Answer 19

pH = 5
-this inhibits the growth of bacteria!
-sebum contains bacteriostatic and fungistatic fatty acids

Question 20

chemical barrier of skin

Answer 20

permeability resistance of the stratum corneum is several orders of magnitude greater than other barrier membranes in the body

Question 21

radiation barrier of skin

Answer 21

exposure to UV stimulates synthesis of melanin, which absorbs UV rays

Question 22

topical vs. transdermal drug delivery

Answer 22

topical: local effects on barrier and stratum corneum
transdermal: systemic delivery

Question 23

topical drugs that affect deep tissue

Answer 23

1. topical corticosteroids
2. NSAIDS: diclofenac
3. local anesthetics: benzocaine
4. lighten pigmented skin: hydroquinone
5. skin cancer: 5-fluorouracil

Question 24

types of transdermal patches (3)

Answer 24

1. membrane-modulated (4 layers)
2. adhesive dispersion (3 layers)
3. matrix dispersion (2 layers)

Question 25

examples of membrane-modulated transdermal patch (2)

Answer 25

Transderm-nitro (nitroglycerin)
-prevention of angina due to CAD
Transderm-scop (scopolamine)

Question 26

example of adhesive dispersion transdermal patch

Answer 26

transdermal rivastigmine, or Exelon Patch by Novartis
-dementia associated with Alzheimer’s and Parkinson’s

Question 27

example of matrix dispersion

Answer 27

transdermal contraceptives:
1. Ortho Evra (Janssen)
2. Xulane (Mylan)

Question 28

penetration enhancers: ionic surfactants

Answer 28

disorder the lipid layer of stratum corneum to swell

Question 29

penetration enhancers: reducing agents

Answer 29

Ascorbate and dithiothreitol
-disrupt disulfide of proteins in keratinized cells

Question 30

penetration enhancers: azone

Answer 30

nonpolar, oily liquid - fluidize intracellular lipid region of stratum corneum

Question 31

penetration enhancers: dimethyl sulfoxide (DMSO)

Answer 31

dipolar solvent - enter aqueous region of stratum corneum and expands hydrophilic region between polar heads