Lecture 22 Flashcards
Parental Solid Dosage Forms (Mucosal; local) - Yeo
mucosal drug delivery
via accessible body cavities covered with mucosa
examples - oral mucosa, nasal, vaginal, intrauterine, rectal, ocular, pulmonary
can be systemic or local with mucoadhesion
advantages of mucosal delivery
avoids the first-pass effect
non-invasive
relative ease and convenience
disadvantages of mucosal delivery
small area of absorption (nasal, oral)
taste (oral)
delivery limited by molecular weight of a drug
local tissue irritation, sensitivity to pathologic conditions
mucus
secreted by goblet cells or specialized glands (example - salivary glands in the oral cavity)
components - mostly water, mucins (glycoproteins), lipids, and inorganic salts
thickness of mucus layer differs from under 1mcm (oral cavity) to 450 mcm (stomach)
diffusion barrier for drugs
also a target for mucoadhesion
mucus functions
coats nearly all entry points to the human body that are not covered by skin
protects underlying epithelial tissues (example - stomach)
keeps the mucosal membrane moist (lubrication)
mucin
glycoportein of 20% protein and 80% carbohydrates (highly glycosylated)
extra large molecules either membrane bound or secreted
provides a gel-like structure of the mucus
carries a negative charge attributed to high content of sialic acid (sugar)
mucin component
sialic acid (–)
galactose
N-acetylglucosamine
Core sugars
protein core
cysteine-rich subdomains forming intra and/or intermolecular disulfide bonds
mucoadhesion
the state in which a material (polymers) and the mucus are held together for extended periods of time by interfacial forces
prolongs residence time of the dosage form on the mucosal surface
purpose of mucoadhesion
controlled release systems (extended/sustained)
enhancement of poorly absorbed drug molecules
immobilization of the dosage form at the desired site of action
mechanism of mucoadhesion
electrostatic interaction (positive charge of polymer vs negative charge of sialic acid in mucin)
hydrogen bonding (-COOH, -OH, -NH2)
covalent bonding (disulfide bond between thiolated polymer and cysteine-rich portion of mucin)
physical interpenetration
mucoadhesive polymers
alginate
carbomer
hyaluronic acid
carboxymethylcellulose sodium (NaCMC)
pectins
polycarbophil
chitosan
polylysine
hydroxypropyl-cellulose
hydroxypropyl-methylcellulose
oral mucosal
systemic or local
could be sublingual (ventral side of the tongue and floor of mouth) or buccal mucosa (on the cheeks)
advantages of oral mucosal
avoid first-pass effect
rapid absorption and onset of drug effect
easy to remove if therapy needs to be discontinued
disadvantages of oral mucosal
small surface area (around 100cm2) so not suitable for low potency drugs
limited by taste
variations of oral mucosa
buccal - thick, NK, dense submucosa
gums - thick, K/NK, no distinct submucosa
floor of mouth - thin, NK, loose submucosa
ventral surface - thin, NK, no very distinct submucosa layer
sublingual specifics
relatively permeable
rapid onset
suitable for frequent dosing and short-term delivery (emergency)
examples - nitroglycerin SL tablet (prompts relief from acute angina attack)
buccal specifics
relatively less permeable than SL
slower absorption and onset of action than SL
less influenced by saliva
suitable for sustained delivery applications
buccal tablets, patches, and semisolids
drug absorption via oral mucosa
epithelium is main barrier
mechanism for drug diffusion is either transcellular(intra) or paracellular(inter) via intercellular lipids
absorbed into the reticulated and jugular veins then drained into systemic circulation to avoid first-pass effect
drugs primarily delivered via oral mucosa
predominantly lipophilic
mostly smaller MW drugs
maybe hydrophilic macromolecular weight drugs such as peptides, oligonucleotides, polysaccharides (likely require absorption enhancers; may not be stable due to salivary enzymes)
buccal tablets
bioadhesive polymer layer (polyacrylic acids, cellulose derivatives)
second layer to allow unidirectional drug delivery for systemic absorption
matrix containing active ingredient and excipients
Oravig
example of buccal tablet used for the local treatment of oropharyngeal candidiasis in adults
active agent - miconazole (antifungal)
fentora
example of buccal/effervescent tablet that rapidly releases fentanyl into the buccal pouch creating a systemic effect
starting treatment is between the upper cheek and gum
maintenance dose is SL under the tongue
Actiq (cephalon)
fentanyl citrate
lozenge on a stick
either transmucosal or gastrointestinal absorption
buccal patches
thinner and more flexible than buccal tablets
less obtrusive, more acceptable to patients
example - dentipatch (lidocaine) and bema
advantages of nasal
avoidance of hepatic first-pass elimination and destruction in the GI tract
rapid absorption of drug molecules across the nasal membrane
relatively easy and convenient
disadvantages of nasal
possible tissue irritation
rapid removal of the drug from the site of absorption (mucociliary clearance)
pathologic conditions such as cold or allergies that may alter significantly the nasal bioavailability
limited area of drug absorption
nasal examples
zicam (zinc ion for cold symptoms)
miacalcin nasal spray (calcitonin, post-menopausal osteoporosis, long term delivery)
respiratory region of nasal cavity
main site for systemic drug delivery
relatively large surface area (around 150cm2)
epithelium covered with mucus that provides humidification and warming of inhaled air; physical and enzyme protection against foreign compounds (including drugs)
olfactory region of nasal cavity
small surface area (1-5cm2)
provides a direct connection between the CNS and the atmosphere
contains small glands that produce secretions acting as a solvent for odorous substances
systemic nasal
via respiratory region
fast and extended drug absorptions
examples - analgesics (morphine), CV drugs (propranolol, carvedilol), hormones (levonorgestrel, progesterone, insulin), anti-inflammatory agents (indomethacin, ketorolac), and anti-viral (Acyclovir)
local nasal
treatment of topical nasal disorders
examples - antihistamines, corticosteroids (rhinosinusitis) and nasal decongestants (cold symptoms)
nasal vaccines
nasal mucosa is the first site of contact with inhaled antigens (like influenza a/b virus, proteosoma-influenza, and adenovirus-vectore influenza)
lymphoid tissue underneath the nasal epithelium (dendritic cells, T-cells, and B-cells)
vaccination against respiratory infections
advantages of vaginal mucosa
rich blood supply
high permeability to certain drugs
advoidance of hepatic first-pass effect
disadvantage of vaginal mucosal
hormone-dependent changes (like pH)
vaginal delivery systems
gels and creams
films
vaginal rings
vaginal gels and creams
most widely used
drawback – leakage, messiness, requires an applicator
types – antimicrobial pessaries or creams, estrogen creams, spermicidal gels and creams
examples - replens (bioadhesive gel)
vaginal films
example - vaginal contraceptive film
vaginal rings
pliable drug delivery system that can be inserted into the vagina, where it slowly releases hormones to be absorbed into the blood stream
example - contraceptive rings
intrauterine delivery system
IUD containing progesterone and levonorgestrel
example - mirena IUD
IUD
small plastic device placed into the uterine cavity for sustained intrauterine drug release for contraception
mirena IUD
local progestognenic effects in the uterine cavity
thickening of cervical mucus preventing passage of sperm into uterus, inhibition of sperm capacitation or survival, alternation of endometrium
zero-order release up to 5 years (20mcg/day)
rectal drug delivery
drugs ordinarily administered by the oral route can be administered by lower enteral route, through the anal portion into the rectum or lower intestine
local effect - inflammatory bowel disease (IBD)
systemic effect - when oral administration is not feasible
less popular now with improvements in other delivery systems, used mostly in pediatrics or geriatrics
either suppositories or rectal emenas
rectal suppositories
solid dosage forms intended for insertion into the rectum (or vagina) where they melt, soften, or dissolve, and exert local or systemic drug delivery
rectal emenas
liquids introduced into the rectum and colon via the anus
ocular drug delivery
local - great need (blood-retina barrier)
requirements
- need to be clear
- good corneal penetration
- prolonged contact time with the corneal epithelium
- simplicity of use
- non-irritating, comfortable
challenges in ocular delivery
loss due to dilution in the tear film, fluid spillage, drainage (eye drop is around 20-50mcL, but space is only 7mcL)
short residence time (rapid turnover of tears and aqueous humor)
not much flexibility in formulation adjustments (pH, osmolarity, and solubility)
ocular dosage forms
eye drops
ointments
ocusert
contact lenses
erodible or non-erodible implants
improved eye drops
reduce drainage by the use of viscosity-enhancers
examples - polyvinyl alcohol, methyl cellulose, timoptix-XE gel, and durasite
port delivery system
permanent, refillable implant
surgically inserted through a small incision in the sclera and pars plana
components of port delivery system
extrascleral flange
self-sealing septum
body (drug reservoir)
porous metal release control element
