Lecture 21 Flashcards
Parenteral Solid Dosage Forms (Topical; Transdermal) - Yeo
stratum corneum
main barrier to permeation
brick and mortar model (dead cells and lipids)
deal cells are not permeable thus permeation occurs by partitioning through the lipid material between the dead cells
functions as a lipid barrier
state of hydration is directly related to the ease of permeation
living epidermis
viable epidermis
living cells without capillaries
cells get nutrition by diffusion from dermis
source of skin color and tanning
dermis
contains capillaries
drug needs to reach these capillaries to achieve systemic action
contains pain, thermal, and tactile sensors
injury must reach dermis to produce scarring
hair follicles and sweat glands
secondary route of drug absorption that bypasses the stratum corneum
functions of the skin
containment
microbial barrier
chemical barrier
radiation barrier
electrical barrier
thermal barrier and body temperature regulation
containment function
confine underlying tissues and restrain their movement
microbial barrier function
pH of the skin is 5 which inhibits the growth of bacteria
sebum contains bacteriostatic and fungistatic fatty acids (like propanoic, butanoic, hexanoic, and heptanoic acids)
chemical barrier function
permeability resistance of stratum corneum is several orders of magnitude greater than other barrier membranes of the body
radiation barrier function
expsoure to UV stimulates synthesis of melanin, which absorbs UV rays
electrical barrier function
offers high impedance to the flow of an electrical current
need to treat the skin with salt solutions and overcome the impedance to measure body potentials (like with ECG) – use granular salt suspensions, creams, pastes containing electrolytes
thermal barrier and body temperature regulation function
maintains 98.6F by dilating/contracting blood vessels or sweating
topical drug delivery
local effects on barrier function (surface effects and stratum corneum effects)
drug action on the skin’s glands
effects in deep tissue
transdermal drug delivery
systemic
surface effects of topical examples
zinc oxide paste for diaper rash
sun blocks and sunscreens
lip balms for chapped lips
calamine lotion for poison ivy and poison oak
antibiotics
deodorants
medicated sopas
stratum corenum effects of topical examples
emollicency (softening horny tissue)
keratolysis (chemical digestion and removal of horny tissue)
drug action on the skin’s glands examples
antiperspirants
acne
hair removers (depilatories)
antiperspirants example
aluminum chloride
irritate and close the orifice of eccrine glands to impede sweat flow
acne example
soap, alcoholic solutions, antibiotics
retinoids –> reset the process of epidermal proliferation and differentiation to prevent the formation of lesions
types of ointments
hydrocarbon bases (most hydrophobic)
silicone bases
absorption bases
water soluble bases (most hydrophilic)
hydrocarbon based ointments
most hydrophobic
examples – petrolatum and polyethylene dissolved in mineral oil (plastibase)
silicone based ointments
contain polydimethylsiloxane oil
absorption based ointments
ointment containing w/o emulsifiers
example - w/o emulsion containing aqueous solution of a drug
water soluble based ointment
most hydrophilic
example - polyethylene glycol ointment
pastes
ointments into which a high concentration of insoluble particulate solids (starch, calcium carbonate, talc) are added
creams
o/w or w/o emulsion
gels
liquid phase trapped in matrix of a natural or synthetic polymer (like tragacanth, pectin, carrageenan, methylcellulose, carboxymethylcellulose, carbopol)
example - topical scalp gels (not too greasy)
rigid foams
air or other gas emulsified in a liquid phase (like whipped cream)
liquid phase may contain a drug
example – aerosol shaving creams, medicated quick-breaking antiseptic foams
components of transdermal drug delivery
backing membrane
drug reservoir containing drug molecules
rate-controlling microporous membrane
skin contact adhesive
transdermal drug delivery basics
generally impenetrable (principle resistance is stratum corneum)
permeability correlates with drug’s MW and Ko/w
useful for drugs with high skin permeability or low dose requirement
may need frequent dosing if drug has a short systemic half-life/undergoes extensive first pass metabolism
permeability equation
log P is roughly equal to 2.7 + 0.71log Ko/w - 0.0061MW
transdermal patches types
membrane modulated
adhesive dispersion
matrix dispersion
membrane modulated patches
examples – scopolamine (transderm-scop); nitroglycerin (transderm-nitro)
backing membrane, drug reservoir, rate-controlling microporous membrane, adhesive
adhesive dispersion patches
example - nitroglycerin (deponit)
backing membrane, drug reservoir, rate-controlling adhesive
matrix dispersion patches
example - nitroglycerin (nitrodur)
backing membrane, drug + adhesive = matrix
common active ingredients of patches
clonidine
ethinyl oestradiol, norelgestromin
fetanyl
lidocaine
lidocaine, epinephrine
nicotine
nitroglycerin
17b-oestradiol
oestradiol, norethindrone
oxybutynin
scopolamine
testosterone
transdermal nitroglycerin (membrane-modulated)
half-life - 3 min
slightly soluble in water, soluble in common organic solvents
indication - prevention of angina pectoris (chest pain) due to coronary artery disease; not for immediate relief of acute attacks
transdermal rivastigmine (adhesive dispersion)
exelon patch (novartis)
approved by the FDA in 2007
indication - memory problems (dementia) associated with alzheimer’s disease or parkinson’s disease
if total daily dose is under 6mg then dose 4.6mg/24h patch
if total daily dose is 6-12mg then dose 9.5mg/24h
rivastigmine transdermal
sparingly soluble in water, very soluble in ethanol, acetonitrile, n-octanol, ethyl acetate
logP - 2.3
water solubility - 2.04mg/mL
acrylic copolymer is poly(butylmethacrylate, methylmethacrylate)
transdermal contraceptive (matrix dispersion)
examples - ortho evra (d/c in 2014) and xulane
150mcg/day of norelgestromin and 35mcg/day EE
components are backing layer (polymer layer for structural support), middle layer (adhesive, matrix, and active ingredients), and third layer (release liner)
once a week for three weeks
apply to upper outer arm, abdomen, buttock, or back
drug diffusion through skin
protein-rich cells (bricks) separated by thin layer intracellular lipids (mortar)
three different ways:
1. across the cellular-intracellular regions in series
2. across the lipid intracellular spaces
3. across thin lipid layers sandwhiched between flattened protein cells
factors affecting permeability
hydration
solubility of a drug in stratum corneum
excipients (solvents, surfactants)
pH
hydration affecting permeability
the more hydrated, the greater drug permeability
water associated with polar head groups of lipid bilayer loosens the lipid packing and make the bilayer more fluid
pH affecting permeability
affects drug ionization status
penetration enhancement types
iontophoresis
electroporation
ultrasound
prodrugs
(chemical) penetration enhancers
iontophoresis penetration enhancement
uses low voltage electrical current to drive charged drugs through the skin
electroporation penetration enhancement
uses high voltage (short) to create transient pores in the skin
early stage, but very good
ultrasound penetration enhancement
uses low frequency ultrasonic energy to disrupt the stratum corneum
prodrugs penetration enhancement
make more lipophilic
chemical penetration enhancers
alcohol, dimethyl sulfoxide (DMSO), surfactants, acetone, ethyl acetate
ionic surfactants enhacing
disorder the lipid layer of stratum corneum to swell and/or leach out some of the structural components, thus reducing the diffusional resistance
ascorbate, dithiothreitol enhancing
reducing agents
disrupt disulfide bonds of proteins in keratinized cells
azone enhancing
nonpolar, oily liquid
fluidize intracellular lipid lamella region of stratum corneum
dimethyl sulfoxide (DMSO)
dipolar solvent
enter aqueous region of stratum corneum, interact with the lipid polar heads to expand hydrophilic region between the polar heads
dissolving microneedles
type of polymeric MN that can degrade or dissolve post-insertion into the skin, leading to the delivery of the encapsulated drug at site of application
separable microneedles
rapidly dissolvable backing layers
with weaker connections between the backing layers and the MN tips
based on a hydrogel backing layer
hydrogel forming microneedles
have cross-linked hydrogel structure that can collect interstitial fluid upon skin application –> in-situ hydrogel
hollow microneedles
each needle incorporates a hollow cavity within and a bore on the needle tips, to which small volume of drug solutions can be injected
common application sites
chest (upper)
back (upper and lower)
upper arm (on the part facing out)
flanks (side of the body, abdomen levels) except for exelon
common frequencies of patches
daily (nicotine, rivastigmine)
twice daily (diclofenac)
twice weekly
weekly (buprenorphine, clonidine, estradiol)
every 72h (fentanyl)
common errors in patch admin
preparation
removal
application
monitoring
storage and disposal
preparation errors
removal of the patch from the packaging
removal of the protective foil
alternation of the patch
monitoring errors
influence of heat
patch displacement
some patients do not realize
- patch must be applied directly to the skin (not taped on top of each other)
- must remove the protective liner
- need to use one patch at time
- where to place (rec - rotate the area of application to avoid skin irritation)
- when to change
- transparent parents
- tts: transdermal therapeutic system
- pediatric patch issue: some patches cannot be cute
