Exam 3 Mucosal: Oral Mucosal, Nasal, Other Mucosal Flashcards
What is an overview of mucosal drug delivery?
can’t deliver large hydrophilic drugs like transdermal route but it is more permeable than skin (since it does not have a stratum corneum)
What is the basis of mucosal drug delivery?
delivering drug via accessible body cavities covered with mucosa (not by skin)
What are the different body cavities that can be used for mucosal drug delivery?
- oral mucosa (buccal, sublingual, gingival)
- nasal
- vaginal
- intrauterine
- rectal
- ocular
- pulmonary
What types of drugs are good candidates for mucosal delivery?
drugs that go through liver metabolism (aka first pass metabolism)
Mucosal delivery can be what?
- systemic or local → depends on what you want, can be a local target or go to the blood vessels
- typically involves mucoadhesion → adheres to mucus
What are some advantages of mucosal drug delivery?
- avoid the first pass effect
- non-invasive
- relative ease and convenience
What are some disadvantages of mucosal drug delivery?
- small area of absorption (nasal, oral)
- taste (oral)
- delivery limited by molecular weight of a drug
- local tissue irritation, sensitivity to pathologic conditions
How is mucus secreted?
secreted by goblet cells or specialized glands such as the salivary glands in the oral cavity
What are the functions of mucus?
- mucus coats nearly all entry points to the human body that are not covered by skin → forms a mucus layer
- protects underlying epithelial tissues (like the stomach that protects it from acid)
- keeps the mucosal membrane moist → lubrication
What are the components of mucus?
- mostly water → like a hydrogel
- mucins (glycoproteins)
- lipids
- inorganic salts
How does mucus different in different places in the body?
thickness of mucus layer differs from <1 micrometer (in oral cavity) to 450 micrometers (in the stomach)
Mucus is what?
a diffusion barrier for drugs and can be a target for mucoadhesion
What is the typical histology of a mucosal membrane?
capillary → interstitial fluid → mucus cells → mucus layer → stomach lumen
How important is the mucus layer?
we can blink because of the mucus layer!
What are the components of the tear film (from outer to inner)?
oily layer → watery layer → mucus layer
What is so important about goblet cells?
they have specialized vesicles that produce mucins
What are glycoproteins (mucin) composed of?
- proteins (20%)
2. highly glycosylated carbohydrates (80%) → basically sugar coated proteins
What are mucins (glycoproteins)?
- extra large molecules either membrane bound or secreted
- provides gel-like structure of the mucus → provides the main structure of mucus
- carries a negative charge attributed to high content of sialic acid (sugar)
What is unique about the structure of mucin?
contains cysteine rich subdomains that can form intra and/or intermolecular disulfide bonds
What is important to know about sialic acid?
contains a COOH group that can ionize and provide a negative charge
What features of mucin can be exploited to interact with other molecules?
- negative charge can interact with cations
2. hydrogen bonding
What is an important takeaway about mucus at different sites in the body?
mucin concentration and thickness varies depending on the area in the body
What is 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
What are the purposes of mucoadhesion?
- controlled release systems (extended/sustained release)
- enhancement of poorly absorbed drug molecules
- immobilization of the dosage form at the desired site of action
What are the 4 different mechanisms 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 which makes the drug stay
- physical interpenetration → polymer can entangle with mucin to create mucoadhesion
What are some examples of mucoadhesive polymers?
alginate, carbomer, hyaluronic acid, carboxymethylcellulose sodium (NaCMC), pectins, polycarbophil, chitosan, polylysine, hydroxypropyl-cellulose, hydroxypropyl-methylcellulose, poly(ethylene oxide), poly(vinyl alcohol), poly(vinyl pyrrolidone)
How does alginate interact with mucin?
H-bonding and physical interpenetration
How does carbomer interact with mucin?
H-bonds
How does hyaluronic acid interact with mucin?
H-bonds
How can chitosan interact with mucin?
H-bonding, electrostatic interactions (at specific pH), and physical interpenetration
How can polylysine interact with mucin?
electrostatic interactions
How can hydroxypropyl-cellulose interact with mucin?
H-bonds
What is the mechanism behind disulfide bond formation between thiomers and mucins?
- two mucin molecules are already disulfide bonded and thiomer has a SH group → thiomer and mucin are disulfide bonded + other mucin has a SH group
- thiomer with a SH group + mucin with a SH group → thiomer and mucin make a disulfide bond
Oral mucosal delivery can be what?
systemic or local
Where is the sublingual mucosa?
ventral side of the tongue and the floor of the mouth → more inner, more permeable
Where is the buccal mucosa?
on the cheeks → less permeable
What are advantages to using the oral mucosa to deliver a drug?
- avoid first pass effect
- rapid absorption and onset of drug effect
- easy to remove if therapy needs to be discontinued
What are some disadvantages to using the oral mucosa to deliver a drug?
- small surface area (about 100 cm^2) → not suitable for low potency drugs
- limited by taste
What are important places to know in the oral cavity?
- buccal mucosa (lip and cheek lining) + gingiva (gums) → thicker and less permeable
- ventral side of tongue + floor of mouth → aka sublingual so thinner and more permeable (especially since it is not keratinized)
What is another difference between buccal and sublingual mucosa?
buccal mucosa typically has a dense submucosa, gums have no distinct submucosa, and sublingual mucosa typically have a loose or not a distinct layer of submucosa
What are some things to know regarding using the sublingual route of administration?
- relatively permeable
- rapid onset
- suitable for frequent dosing and short term delivery (emergency dosing)
What is an example of using the sublingual route of administration?
nitroglycerin sublingual tablet (provides prompt relief from an acute angina attack) → transdermal nitroglycerin patch is not fast acting so if you need a fast acting route, use the sublingual route
What are some things to know regarding using the buccal route of administration?
- relatively less permeable than sublingual
- slower absorption and onset of action than sublingual
- less influenced by saliva
- suitable for sustained delivery applications → slower for absorption
What are some examples of buccal routes of administration?
buccal tablets, patches, semisolids
Using the oral mucosa, what are the layers that the drug has to diffuse through to get into systemic circulation?
mucus → epithelium (mucosal layer) → lamina propria → submucosa (drug has to get through this layer to get to the blood vessels)
What is drug absorption like via the oral mucosa?
- the epithelium is the main barrier to drug absorption
- mechanisms for drug diffusion include: transcellular (intracellular, through the cells) or paracellular via intercellular lipids (intercellular, in between cells)
- absorbed into the reticulated and jugular veins → drained into systemic circulation (avoids first pass effect) → but some may get into the GI tract
What kinds of drugs are delivered via oral mucosa?
- predominantly lipophilic
- mostly small molecular weight drugs
- maybe hydrophilic macromolecular weight drugs such as peptides, oligonucleotides, polysaccharides → but need certain help to do so
How would it be possible for hydrophilic macromolecular weight drugs to be delivered via the oral mucosa?
- likely require absorption enhancers (like fatty acids, bile salts, surfactants)
- may not be stable due to salivary enzymes
What are some things to know about buccal tablets?
- have a bioadhesive polymer layer (containing polyacrylic acids, cellulose derivatives)
- second layer to allow unidirectional drug delivery for systemic absorption → to prevent GI absorption and makes sure drug can only go through the mucosal layer
- contains a matrix containing active ingredient and excipients
What are two examples of buccal tablets?
- Oravig → contains miconazole (antifungal) as the active agent and is used for the local treatment of oropharyngeal candidiasis in adults
- Fentora → effervescent tablet that rapidly releases fentanyl into the buccal pouch → has systemic effects
Where do mucosal layers cover?
they cover parts of the skin that isn’t already covered by the skin
How do you use the Oravig tablet?
- place the flat side of the tablet on your dry fingertip
- gently push the round side of the tablet against your upper gum
- push the tablet up as high as it will go on your gum, the flat side will be facing the inside of your lip
- hold the tablet in place by applying slight pressure with your finger on the outside of your upper lip for 30 seconds to make the tablet stick to your gum
- leave the tablet in place until it dissolves
What happens if you swallow the Oravig tablet with water?
won’t get the intended effects of the drug
What is unique about Fentora?
has both buccal and sublingual administration!
- when starting treatment, it should be placed in the buccal cavity above the rear molar between the upper cheek and gum → switch sides of your mouth for each dose
- once doctor has determined the maintenance dose, can take it sublingually in which you would place a tablet under the tongue and let it dissolve (14-25 minutes) → after 30 minutes, if there is any drug left in the mouth, can drink a glass of water to help swallow the leftover medicine (so some drug can go through the GI tract)
What are important things to know when taking Fentora?
do not crush, split, suck, or chew the tablets or swallow the tablets whole → will get less relief for the breakthrough cancer pain (since it is intended to go through the bloodstream via mucosal layer rather than the GI tract)
What is Actiq (Cephalon)?
- fentanyl citrate
2. lozenge on a stick
How is Actiq taken?
- the dosage unit is administered by rotating and dissolving it against the oral mucosal tissue
- self administer drugs to the oral cavity for either transmucosal or gastrointestinal absorption (since it is swallowed with saliva)
What is unique about Actiq?
can roll the lozenge on the stick in the cheek and can swallow saliva → get both GI and mucosal absorption!
When looking at the graph of the mean plasma concentration v time after a single dose of Fentora and Actiq, what is the difference between the two curves?
patients were given the same dose of Actiq and Fentora (400 mg) but the max concentration and Tmax is different for both curves (Fentora had higher concentrations) → this means they have a different bioavailability so can’t substitute Fentora for Actiq (same reasoning how can’t substitute transdermal patch for the oral pill since they both have different bioavailabilities)
What are buccal patches?
thinner and more flexible than buccal tablets → less obtrusive and more acceptable to patients
What is an example of a buccal patch?
Dentipatch that gives a local delivery of lidocaine → contains a mucoadhesive layer and a backing layer
What is the one downside with buccal patches?
have certain design limitations since the patch can’t be too thick or else patients will feel it
What are the advantages of using the nasal mucosa for drug delivery?
- avoidance of hepatic first pass elimination and destruction in the GI tract → drug goes directly to blood vessels via the mucus membrane
- rapid absorption of drug molecules across the nasal membrane → since it is highly vascularized
- relatively easy and convenient
What are some disadvantages to using the nasal mucosa to deliver drugs?
- possible tissue irritation
- rapid removal of the drug from the site of absorption (mucociliary clearance) → drug gets removed before its absorbed
- pathologic conditions such as cold or allergies that may alter significantly the nasal bioavailability
- limited area of drug absorption (surface area of about 150 cm^2) → need drug with high potency since a low potency drug will need high amounts of the drug
What are some examples of drugs being delivered nasally?
- Zicam → sinc ion for cold symptoms
- Miacalcin nasal spray → calcitonin (a small 32 amino acid polypeptide) used to treat post-menopausal osteoporosis and is for long term delivery
What are two important areas of the nasal cavity?
- respiratory region → majority of the region (150 cm^2)
2. olfactory region
What is important to note about the olfactory region?
smell is a lipophilic molecule that can be extracted as a lipid → it can come in and be transported to the CNS
What are some things to note about the respiratory region?
- main site for systemic drug delivery
- relatively large surface area (about 150 cm^2)
- epithelium covered with mucus that provides: humidification and warming of inhaled air (keeps moisture) AND physical and enzymatic protection against foreign compounds (including drugs) → mucus sticks to inhaled particles or pathogens and lets them be removed by mucociliary clearance
- pretty well vascularized → can be absorbed to systemic circulation
What are some things to note about the olfactory region?
- small surface area (1-5 cm^2)
- provides a direct connection between the central nervous system and the atmosphere
- contains small glands that produce secretions acting as a solvent for odorous substances
The nasal route of administration can be what?
systemic and local
How can nasal drug delivery be systemic?
- via respiratory region → has a larger surface area and well vascularized
- fast and extended drug absorption
What are some examples of drugs that are delivered nasally and have systemic effect?
- analgesics (morphine)
- cardiovascular drugs (propranolol, carvedilol)
- hormones (levonorgestrel, progesterone, insulin)
- anti-inflammatory agents (indomethacin, ketorolac)
- anti-virals (acyclovir)
How can nasal drug delivery be local?
treatment of topical nasal disorders
What are some examples of nasally delivered drugs that have local effect?
- antihistamines, corticosteroids (for rhinosinusitits)
2. nasal decongestants (for cold symptoms) → example is Zicam
What are some things to note about vaccines being a nasal route of administration?
- nasal mucosa: first site of contact with inhaled antigens (like influenza A and B virus, proteosoma-influenza, adenovirus-vectored influenza)
- lymphoid tissue underneath the nasal epithelium: dendritic cells, T-cells, and B cells
- vaccination against respiratory infections
How can the nasal mucosa be a potential route for drug delivery to the CNS?
via the olfactory region
The nasal cavity is wired to what?
to fight off pathogens since the epithelium contains special cells such as dendritic cells, T cells, and B cells
How does drug delivery across the vaginal mucosa work?
drug permeation across the vaginal epithelial membrane
What are some advantages of delivering a drug via the vaginal mucosa?
- rich blood supply
- high permeability to certain drugs
- avoidance of hepatic first pass effects
What is a disadvantage of delivering a drug via the vaginal mucosa?
hormone dependent changes (like pH) → just like the nasal mucosa where there can be different drug levels
What are some examples of vaginal delivery systems?
- gels & creams
- films
- vaginal rings
What are things to note about vaginal gels and creams?
- most widely used
- drawback: leakage, messiness, requires an applicator
- antimicrobial pessaries or creams
- estrogen creams
- spermicidal gels and creams
- example: Replens (bioadhesive gel)
What is an example of a vaginal film?
vaginal contraceptive film
What are vaginal rings?
- pliable drug delivery system that can be inserted into the vagina, where it slowly releases hormones to be absorbed into the bloodstream (reservoir type delivery system)
- example: contraceptive ring
What do drug levels look like with vaginal rings?
fairly constant drug delivery for the 3 weeks → no peaks and troughs
What is an intrauterine device (IUD)?
small plastic device placed into the uterine cavity for sustained intrauterine drug release for contraception (has a drug reservoir with a rate controlling membrane) → can deliver progesterone and levonorgestrel
What are some things to know about the Mirena IUD?
- local progestogenic effects in the uterine cavity (thickening of cervical mucus preventing passage of sperm into the uterus, inhibition of sperm capacitation or survival, alternation of endometrium)
- zero order release up to 5 years → constant release rate
What are some things to know about rectal route of administration?
- 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: inflammatory bowel disease (IBD)
- systemic: when oral administration is not feasible
- less popular now with improvements in other delivery systems
- used in pediatrics and geriatrics → populations that have it more difficult to take drugs orally
What are 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
What is an advantage of rectal suppositories?
drug absorption is not too rapid → can control drug levels
What are rectal enemas?
liquids introduced into the rectum and colon via the anus → injected through anus and can get all the way to large intestine → good drug absorption
What does blood concentration of a drug look like for enemas and rectal suppositories?
enema: peak up and then decreases over time
suppository: peaks up and remains fairly steady → stable concentration for a long period but not a very high concentration
What does blood concentration of a drug look like for enemas and rectal suppositories?
enema: peak up and then decreases over time
suppository: peaks up and remains fairly steady → stable concentration for a long period but not a very high concentration
What does blood concentration of a drug look like for enemas and rectal suppositories?
enema: peak up and then decreases over time
suppository: peaks up and remains fairly steady → stable concentration for a long period but not a very high concentration
Why is ocular route of administration local only?
can’t have systemic drug delivery for eye diseases since there is a blood retina barrier → have to use local delivery
What are some requirements for ocular drug delivery?
- need to be clear → so won’t impair vision
- good corneal penetration → example are eye drops
- prolonged contact time with the corneal epithelium
- simplicity of use
- non-irritating, comfortable → eyes are sensitive organs
- also need the right pH so it won’t irritate the eye
What are some challenges in ocular delivery?
- loss due to dilation in the tear film, fluid spillage, drainage → eye drop are about 20-50 microliters but precorneal space accommodates only 7 microliters so the majority gets drained out
- short residence time → rapid turnovers of tears and aqueous humor
- not much flexibility in formulation adjustments → pH, osmolarity, and solubility
What are some examaples of ocular dosage forms?
- eye drops
- ointments
- Ocusert → reservoir type that goes underneath the eye
- contact lenses
- erodable or non-erodable implants → gets stuck in the eyeball and stays there (is grain sized and constantly releases drug → helps with compliance)
What are improved eye drops?
reduce drainage by the use of viscosity enhancers → examples include polyvinyl alcohol, methyl cellulose, Timoptix-XE gel, and DuraSite (polyacrylic acid formulations)
What are some things to note about cell intraocular implants?
- ciliary neurotrophic factor (CNTF) → protects neural cells including photoreceptor cells, retards retinal degeneration
- blood retina barrier: restricts drug access from the blood to the neural retina tissue
- ocular implant: loaded with human retinal pigment epithelium cells transfected with CNTF gene to produce CNTF in situ
- Neurotech NT-501: macular telangiectasia, glaucoma
- Phase II trial ongoing
basically an implant that delivers cells that produce the drug into the eye
What is the device design of cell intraocular implants?
size of a rice grain that contains the cells and there is a membrane that encloses the cells → cells need oxygen and nutrients so it can pass through the membrane to the cells so the cells can make CNTF
What is the purpose of the membrane for cell intraocular implants?
the cells cannot get out and the immune cells cannot get in
What is the port delivery system?
- permanent, refillable implant
- surgically inserted through a small incision in the sclera and pars plana
- has 4 components: extrascleral flange (makes it stuck in the eye and secures the device to the eye), self-sealing septum (faces the outside and if the drug runs out, more drug can be injected into the septum), body (drug reservoir), and the porous metal release control element (drug gets released there and controls the drug release)
