TD: Nasal drug delivery Flashcards
What is drug delivery to the nasal cavity and what can it be used for?
Why is it useful?
Drugs delivered into the nasal cavity for….
- Localised effect
- Systemic effect
- Vaccine delivery
Why? - Usually when oral route is unavailable, localised effect, convenient and accessible route, rapid onset of action, avoid hepatic/GI metabolism, treat chronic disorders, low cost.ose – brain delivery (BBB?)
Give examples of conditions the nasal route can be used for and drugs that can target these:
- Local
- Systemic
- Vaccine
What preperations are available?
OTC or POM Liquid (solution, emulsion, suspension), gel, ointment, cream, powder
Local Delivery
- Allergic rhinitis, nasal congestion, nasal infection
- Antihistamines (Azelastaine hydrochloride), Sympathomimetic (Ephedrine hydrochloride), antibacterials (Mupirocin)
- Ointment, cream, drops, spray
Systemic Delivery
- Diabetes, pain, smoking cessation, osteoporosis, prostate cancer, migraine.
- Hormones (Desmopressin acetate), opioids (Fentanyl citrate), Alkaloid (Nicotine), Polypeptide hormone (Salmon calcitonin), Gonadorelin analogue (Buserelin), 5-HT1 agonist (Sumatriptan).
- Spray
Vaccines
- Influenza (live – attenuated) – FlumistTM
- Pre – filled syringe
What are the different regions of the nasal cavity?
Describe the nasal cavity anatomy
- Two cavities (each 15ml) - divided by nasal septum
- Large surface area 160cm 2
- 120 – 140 mm from nostrils to nasopharynx
- Contains a broad range of enzymes
- Turbinate region (80 – 90% surface area) – superior, middle, inferior
- Continuously secretes mucus (turbinate region)
What gives the turbinate regions its large SA?
What happenens to particles in the turbinate region?
- Inferior / middle / superior folds - give large SA
- Turbulent air flow – hits walls, deposits particles
- Hot air breathed in and carriers particles to turbinate region. Mucus here sweeps particles to nasaopharynx where particles swallowed or coughed up
The following refers to the turbinate region. Fill in the gaps:
- •It has convoluted projections -
- •Rich supply of
- •Main site of
- It has convoluted projections - columnar epithelium
- Rich supply of blood vessels
- Main site of drug absorption
What are turbinate cells called?
What cells make up these?
What are these cells characterisitics and functions?
•Columnar Epithelial cells – goblet/ciliated and non – ciliated / basel cells.
Goblet cells – continuously secrete mucus
- •Covers epithelium: 1 – 10 µm thick
- •Above periciliary layer (cilia and microvilli ~ 7 µm)
- •97% water/3% solids (mucin, proteins, salts, lipids)
- •pH – 5.5 – 6.5
- •Barrier to drugs (large molecules)
Ciliated cells – cilia beat and move mucus (Mucociliary Clearance)
Describe the 2 mechanisms of absorption of particles?
Transcellular Diffusion
- lipophilic molecules (mainly passive diffusion)
- Through lipid rich membranes of epithelial cells
- Endocytosis / active transport: large hydrophobic molecules
Paracellular Diffusion
- Small hydrophilic molecules (0.39 - 0.84 nm)
- Through aqueous intercellular spaces between cells – smaller area – slower
- Rate proportional to molecular size
What are factors affceting absorption?
Mucociliary clearance
- Drugs deposited on mucociliary ‘conveyor belt’ – cleared from nasal cavity – LIMITED CONTACT TIME!
- Solutions - readily absorbed (lipophilic, low molecular weight) / Suspensions – drug particles must dissolve
- Reported to be 12 – 15 minutes
Mucus Layer
- Nasal mucosa protected by muscus = BARRIER TO DRUG DELIVERY
- Diffusion is a function of molecule size
Enzymic activity
- Broad range of enzymes – phase I/II metabolism (less than GI tract)
- Amount of drug, physiochemical properties, rate of clearance, rate of absorption
Epithelial barrier
e.g. efflux transporters actively transport drug back into nasal cavity
What are ways to improve drug absorption?
- Increase Nasal Resistance time - Mucoadhesion
- Muchoadhesive polymers
- e.g. Cellulose, starch, chitosan
- Increase Drug Solubility
- change molecular form: Prodrugs, salts, co – solvents, cyclodextins, surfactants
- Enzyme Inhibitors
- Prevent hydrolysis, enhances permeability
- Permeation enhancer
- alter epithelium – improve stability
What is mucoadhesion and what is bioadhesion
Bioadhesion
Mechanism by which two biological materials are held together by interfacial forces
Nasal epithelial surface
Mucoadhesion
Attachment of a drug carrier system to the mucus layer of a mucosal epithelium to maintain intimate contact for extended periods
Required to over come mucociliary clearance
What can be used for mucoadhesion and how do these work?
- Mucoadhesive polymers - under go physical or chemical bonding
- Work by: Hydration / carriers / permeability
- Hydration - Polymer comes into contact with mucus with promotes hydration and extention of polymer chains which hold carrier system in place
- Carrier - Carries and protects drug (less enzyme degr)
- Permeability - As polymer hydrations the cells dehydrate and this opens tight junctions
- Powders, liquids, gels - Temp / pH
What are the stages of mucoadhesion?
1.Contact stage
Intimate contact between mucoadhesive and mucosa
- Consolidation Stage
Interpenetration: Mucoadhesive penetrates crevices of epithelium – physical bonding between the glycoprotein (responsible for adhesive and cohesive properties of mucus) and polymer chains
Formation of chemical secondary bonds: Van der Waals, hydrogen, hydrophobic interactions (anionic/non – ionic), electrostatic interactions (if cationic – mucus anionic)
What are other factors affecting absorption
Physiochemical Factors Affecting Absorption
• Solubility, concentration, pH, Log P, excipients, pKa, lipophilicity/hydrophobilicity, molecular size
Patient Factors
• Compliance, disease, nasal vascularity, environmental factors
Delivery Device
• Volume, spray, droplet size, site
What factors do you need to consider when developing a nasal prodcut?
ØLiquid (solution, gel or suspension), ointment / cream or powdered solid
Ø Physiochemical drug properties: Solubility, concentration, pH, Log P, excipients, pKa, lipophilicity/hydrophobilicity, molecular size
Ø Stability – temp/light, crystal growth, resuspension, homogeneity, uniformity
Ø Particle size distribution (10 – 50µm)
Ø Excipients – as few as possible
What are examples of excipients you might want to add and their function
