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Dosage II > Ex 3 L6: Mucosal > Flashcards

Ex 3 L6: Mucosal Flashcards

1
Q

Mucosal drug delivery areas

A

Via accessible body cavities covered with mucosa
-Oral mucosa
-Nasal
-Vaginal
-Intrauterine
-Rectal
-Ocular
-Pulmonary

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2
Q

Mucosal drug delivery

A

Systemic vs local
Mucoadhesion

Advantages
-Avoid the first-pass effect
-Non-invasive
-Relative ease and convenience

Disadvantages
-Small area of absorption (nasal, oral)
-Taste (oral)
-Delivery limited by MW of a drug
-Local tissue irritation, sensitivity to pathologic conditions (nasal cavity is very sensitive)
-Not a lot of room for manipulating PH
-Not a lot of use for surfactants

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3
Q

Mucus

A

Secreted by goblet cells or specialized glands (e.g. salivary glands in the oral cavity)

Functions
-Mucus coats nearly all entry points to the human body that are not covered by skin
-Protects underlying epithelial tissue (e.g. sotmach)
-Keeps the mucosal membrane moist -> Lubrication
Components: mostly water, mucins (glycoproteins), lipids, inorganic salts
Thickness of mucus layers differs from <1 micrometer (oral cavity) to 450 micrometer (stomach)
Diffusion barrier for drugs
Also a target for mucoadhesion

Mucus always humidified and kept in place by the nasal cavity
Helps to keep moist and lubricate
Mostly water
Mucins – blood protein (sugar degraded protein)
Lipids, electrolyte solution
Very thick mucus layer in the stomach
Eyes – very THIN mucosal layer
Barrier for drug diffusion
Keeps the barrier on surface

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4
Q

Mucin

A

Glycoprotein
-Proteins (20%)
-Highly glycosylated (80% carbohydrates)
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)

= lots of sugars
Produced by goblet cells, line the mucosal layer and protect organs from degradation

protein covered with a lot of sugar - has a negative charge because of carboxylic acid (salic acid)

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5
Q

Mucin cont.

A

Cysteine rich subdomains forming intra-and/or intermolecular disulfide bonds
Ending with carboxylic

Gives a lot of feature to the mucus

KNOW THAT IT IS A SUGAR WITH LOTS OF CARBOXYLIC GROUP AND HYDROXYL

Can be easily ionized to give off hydrogen bonding

Cysteine residue ending with thiol group

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6
Q

Mucoadheasion

A

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

Purposes
-Controlled release systems (extended/sustained release)
-Enhancement of poorly absorbed drug molecules
-Immobilization of the dosage form at the desired site of action

-If drug goes away – do not get a lot of exposure to drug

If drug is difficult to absorb – need to secure long enough time for the drug to be attached to the layer

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7
Q

Mechanisms of mucoadhesion

A

Electrostatic interaction
-Positive charge of polymer vs. negative charge of sialic acid in mucin

Hydrogen bonding
-COOH, –OH, -NH2

Covalent bonding
-Disulfide bon between thiolated polymer and cysteine-rich portion of mucin

Physical interpenetration

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8
Q

Polymers

A

Review structures in slides

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9
Q

Oral mucosal

A

Systemic or local
Sublingual mucosa (Ventral side of the tongue and the floor of the mouth)
Buccal mucosa (on the cheekcs)

Advantages
-Avoid first-pass effect
-Rapid absorption and onset of drug effect
-Easy to remove if therapy needs to be discontinued

Disadvantages
-Small surface area (~100cm^2): not suitable for low potency drugs
-Limited by taste

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10
Q

Principal features and regional variations of oral mucosa

A

Buccal
-Thick epithelium
-NK
-Dense

Attached gingiva
-Thick epithelium
-K, PK
-No distinct submucosa

Floor of mouth
-Thin epithelium
-NK
-Loose

Ventral Surface of tongue
-Thin epithelium
-NK
-Not very distinct layer

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11
Q

Oral mucosal - sublingual

A

Relatively permeable
Rapid onset
Suitable for frequent dosing and short-term delivery (emergency)
E.g., Nitroglycerin sublingual tablet (prompt relief from an acute angina attack)

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12
Q

Oral Mucosal - Buccal

A

Relatively less permeable than sublingual
Slower absorption and onset of action than sublingual
Less influenced by saliva
Suitable for sustained delivery applications
Buccal tablets, patches semisolids

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13
Q

Drug absorption via oral mucosa

A

The epithelium is the main barrier to drug absorption
Mechanisms for drug diffusion:
-Transcellular (intracellular)
-Paracellular (intercellular) via intercellular lipids
Absorbed into the reticulated and jugular veins -> drained into systemic circulation (avoids first-pass effect)

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14
Q

Drugs delivered via oral mucosa

A

Predominantly lipophilic
Mostly small molecular weight drugs
Maybe hydrophilic macromolecular weight drugs such as peptides, oligonucleotides, polysaccharides
-Likely require absorption enhancers (e.g. Fatty acids, bile salts, surfactants)
-May not be stable due to salivary enzymes

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15
Q

Buccal tablets

A

Bioadhesive polymer layer (e.g. polyacrylic acids, cellulose derivatives)
(Second layer to allow unidirectional drug delivery for systemic absorption)
Matrix containing active ingredient and excipients
Example: Oraving (Dara BioSciences)
-Active agent: Miconazole (antifungal)
-Buccal tablet for the local treatment of oropharyngeal candidiasis in adults
Example: Fentora (Cephalon inc)
-OraVescent technology
-Effervescent tablet that rapidly release fentanyl into the buccal pouch -> systemic effect

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16
Q

Buccal patches

A

Thinner and more flexible than buccal tablets - Less obtrusive, more acceptable to patients

17
Q

Nasal

A

Advantages
-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
-Possible tissue irritation
-Rapid removal of the drug from the site absorption (mucociliary clearance)
Cold or allergies may alter nasal bioavailability significantly
Limited area of drug absorption
Has caused permanent smell problems (loss of)

18
Q

Nasal Examples

A

Zicam (Gel-Tech LLC, CA)
-Zinc ion for cold symptoms
Miacalcin nasal spray
-Calcitonin (32 amino acids polypeptide)
-Post-menopausal osteoporosis
-Long term delivery

19
Q

Nasal Cavity

A

Olfactory - directly related to the CNS
-Very small area - hard to get drugs there
Respiratory
-systemic drug delivery

20
Q

Nasal cont.

A

respiratory region
-Main site for systemic drug delivery
-Relatively large surface area (~150 cm2)
-Epithelium covered with mucus that provides:
Humidification and warming of inhaled air
Physical and enzymatic protection against foreign compounds (including drugs)
-Mucus sticks to inhaled particles or pathogens and lets them removed by mucociliary clearance

Olfactory Region
-Small surface area (1-5 cm2)
-Provides a direct connection between the central nervous system and the atmosphere
-Contains small glands that produce secretions acting as a solvent odorous substances

21
Q

Nasal Systemic vs Local

A

Systemic
-Via respiratory region
-Fast and extended drug absorption
Analgesics (morphine)
CV drugs (propranolol, carvedilol)
Hormones (Levonorgestrel, progesterone, insulin)
Anti-inflammatory agents (indmethacin, ketorolac)
Anti-viral (acyclovir)

Local
Treatment of topical nasal disorders
-Antihistamines, corticosteroids (rhinosinusitis)
-Nasal decongestants (cold symptoms)

22
Q

Nasal vaccines

A

Vaccines
-Nasal mucosa: first site of contact with inhaled antigens (e.g. 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

Potential route for drug delivery to central nervous system
-Via olfactory region

23
Q

NALT

A

Nose-associated lymphoid tissue (NALT)
-B cells, T cells
Named for region

24
Q

Vaginal

A

Covered with thick mucus

Systemic or local delivery

Drug permeation across the vaginal

Advantages
-rich blood supply
-High permeability to certain drugs
-Avoidance of hepatic first-pass effects

Disadvantages
-Hormone-dependent changes (e.g pH)

25
Q

Vaginal delivery systems

A

Gels and Creams
-Most widely used
-Drawback: leakage, messiness, requires an applicator
-Antimicrobial pessaries or creams
-Estrogen creams
-Spermicidal gels and creams
-E.g. Replens (bioadhesive gel)

Films
-E.g. 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
-Eg contraceptive rings

Gels and creams most widely used

26
Q

Intrauterine

A

Intrauterine device (IUD): small plastic device placed into the uterine cavity for sustained intrauterine drug release for contraception
Progesterone, levonorgestrel
E.g. Mirena IUD
-Local progestogenic effects in the uterine cavity (Thickening of cervical mucus preventing passage of sperm into uterus, inhibition of sperm capacitation or survival, alteration of endometrium)
-Zero-order release up to 5 years (20 mcg/day)

27
Q

Rectal

A

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
Pediatrics, geriatrics

28
Q

Rectal dosage forms

A

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 enemas
-Liquids introduced into the rectum and colon via the anus
Solution

29
Q

Ocular

A

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

30
Q

Challenges in ocular delivery

A

Loss due to dilution in the tear film, fluid spillage, drainage
-Eye drop = 20-50 microliters, but precorneal space accommodates only ~7 micro liters

Short residence time
-rapid turnover of tears and aqueous humor

not much flexibility in formulation adjustments
-pH, osmolarity and solubility

Cannot delivery a lot of drug through eyes because blood-retina barrier is tight and does not let drug in

Age
Age related necro-degeneration
Age-related condition that leads to blindness

Very tiny window for designing the delivery system
Suspension
Cannot manipulate pH, colors, or thickness too much because eyes are sensitive

Not a whole lot of space – eyes can only hold 7 micro liters of drug

31
Q

Ocular dosage forms

A

Eye drops
-Improved eye drops
-Reduce drainage by the use of viscosity-enhancers
-Polyvinyl alcohol, methyl cellulose
-Timoptix-XE gel (GELRITE gellan gum)
-DuraSite (polyacrylic acid formulations)
-Ointments
-Ocusert
-Contact lenses
-Erodable or non-erodable implants

32
Q

Port delivery system

A

Permanent, refillable implant
Surgically inserted through a small incision in the sclera and pars plana
Four components:
-Extrascleral flange
-Self-sealing septum
-Body (drug reservoir)
-Porous metal release control element

Dosage II (25 decks)

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