DOSAGE II: Exam 3 Flashcards
major dosage forms for biologics
solutions for injection
pens + autoinjectors
pre-filled syringes
lyophilized solids for reconstitution
insulin analogs: fast-acting
- Lispro insulin (Humalog) -> Lys and Pro on C-terminus of B-chain are reversed, blocking dimer formation
- Insulin aspart (Novolog) -> Pro on C-terminus of B-chain mutated to Asp
insulin analogs: long-acting
Insulin glargine -> Asn at A21 mutated Gly and two Arg added to C-terminus of B-chain, promotes microcrystallization
Why solution formulations?
- are simplest and least expensive to manufacture
- are convenient for patients and hospital personnel since they do not require reconstitution
- can be inspected visually prior to administration
higher concentration [of proteins] leads to…
greater aggregation
How do proteins aggregate?
- Chemical reaction (crosslinking)
- Colloidal interactions (sticking together)
- Unfolding
excipients that are ____________ ______________ from the protein surface promote interactions with water and stabilizes native protein structure
preferentially excluded
advantages of pre-filled syringes, pens, and autoinjectors
- easier to transport than vial + syringe
- discrete
- increased patient compliance
- reduced risk of dosage error
- reduced risk of product contamination
disadvantages of pre-filled syringes, pens, and autoinjectors
- higher cost than vial + syringe
- cannot mix two drugs (i.e. insulin types)
- drug waste due to priming
- greater surface-to-volume ratio and presence of lubricants can induce aggregation of protein drugs
advantages of lyophilized powders
- 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 auto-injectors
disadvantages of lyophilized powders
- must be reconstituted prior to injection; less convenient than solutions
- more expensive and time-consuming to manufacture
What is lyophilization?
-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
How does lyophilization cause instability?
can lead to aggregation -> freezing and drying can accelerate disulfide bond scrambling
Excipients that inhibit protein instability by lyophilization:
- lyoprotectants
- cryoprotectants
Layers of the skin
(TOP) Stratum corneum
Living epidermis
Dermis
Subcutaneous fatty tissue
(BOTTOM) Hair follicles and sweat glands
physiology of the stratum corneum
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
physiology of the living epidermis
living cells without capillaries
avascular (cuts won’t bleed)
receives nutrients by diffusion from dermis
source of skin color and tanning
physiology of dermis
-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
microbial barrier of skin (hint: what is pH of skin?)
pH = 5
-this inhibits the growth of bacteria!
-sebum contains bacteriostatic and fungistatic fatty acids
chemical barrier of skin
permeability resistance of the stratum corneum is several orders of magnitude greater than other barrier membranes in the body
radiation barrier of skin
exposure to UV stimulates synthesis of melanin, which absorbs UV rays
topical vs. transdermal drug delivery
topical: local effects on barrier and stratum corneum
transdermal: systemic delivery
topical drugs that affect deep tissue
- topical corticosteroids
- NSAIDS: diclofenac
- local anesthetics: benzocaine
- lighten pigmented skin: hydroquinone
- skin cancer: 5-fluorouracil
types of transdermal patches (3)
- membrane-modulated (4 layers)
- adhesive dispersion (3 layers)
- matrix dispersion (2 layers)
examples of membrane-modulated transdermal patch (2)
Transderm-nitro (nitroglycerin)
-prevention of angina due to CAD
Transderm-scop (scopolamine)
example of adhesive dispersion transdermal patch
transdermal rivastigmine, or Exelon Patch by Novartis
-dementia associated with Alzheimer’s and Parkinson’s
example of matrix dispersion
transdermal contraceptives:
1. Ortho Evra (Janssen)
2. Xulane (Mylan)
penetration enhancers: ionic surfactants
disorder the lipid layer of stratum corneum to swell
penetration enhancers: reducing agents
Ascorbate and dithiothreitol
-disrupt disulfide of proteins in keratinized cells
penetration enhancers: azone
nonpolar, oily liquid - fluidize intracellular lipid region of stratum corneum
penetration enhancers: dimethyl sulfoxide (DMSO)
dipolar solvent - enter aqueous region of stratum corneum and expands hydrophilic region between polar heads
