1
Q
Nasal cavity has ____ vascularity
A
Rich
2
Q
What is beneficial about nasal cavity w/ respect to bioavailability?
A
Topical administration provides rapid blood levels comparable to IV route
3
Q
How can be drugs administered topically to the nasal cavity?
A
Drug solution as a fine mist, which adheres to mucosa as a thin film
4
Q
Why shouldn’t large droplets be applied to the nasal cavity?
A
Will coalesce and run off instead of be absorbed
5
Q
What are advantages to nasal drug delivery?
A
- Rich vascularity provides direct route into bloodstream from drugs that easily cross mucous membranes
- Avoids GI exposure and hepatic first pass metabolism
- For some drugs, rate of absorption is comparable to parenteral administration, and often better than SC or IM
- Intranasal administration has easy access, is painless, and convenient
- Nasal mucosa close to brain, and in some situations may provide access to CSF
6
Q
What are some limitations to the intranasal route?
A
- Absorption area limited, so only compounds w/ high potency and small therapeutic dose can be administered
- Damage or irritation to nasal mucosa from colds/allergy will affect residence time and absorption
- Mucociliary clearance is a big factor; drug may be carried away before it can be absorbed
7
Q
Which drug delivery systems are classified as alternative routes?
A
- Buccal
- Sublingual
- Nasal
8
Q
What is nasal drug delivery mainly used for?
A
Local therapeutic treatments, like allergic rhinitis, common cold, and nasal inflammation
9
Q
Nasal drug delivery is being actively researched for possibility of delivering _____ drug
A
Protein and peptide
10
Q
What do decongestant nasal sprays do?
A
Constrict blood vessels in lining of nose and open up nasal passages
11
Q
What can prolonged decongestant use cause?
A
- Damage to mucous membranes
- Increased inflammation
- Called rhinitis medicamentosa (RM) or rebound effect
12
Q
What are some decongestant drugs?
A
- Phenylephrine
- Oxymetazoline
- Ipratropium
- Tetrahydrozoline
- Azelastine
13
Q
How do antihistamines work in the nasal cavity?
A
Compete for receptor sites to block function of histamine, thereby reducing inflammatory effect
14
Q
What are some antihistamine nasal sprays?
A
- Azelastine
- Levocabastine
- Olopatadine
15
Q
What are intranasal corticosteroids used for?
A
Sinusitis, hay fever, allergic rhinitis, and non-allergic rhinitis
16
Q
What do corticosteroids do in the nasal cavity?
A
- Reduce inflammation and histamine production in nasal passages
- Relieve nasal congestion, runny nose, itchy nose, and sneezing
17
Q
What are some intranasal corticosteroids?
A
- Beclomethasone
- Budesonide
- Ciclesonide
- Flunisolide
- Fluticasone
- Mometasone
- Triamcinolone
18
Q
Which vaccine is available as a nasal spray?
A
LAIV (live attenuated influenza vaccine)
19
Q
What must happen for drugs delivered intranasally to have a systemic effect?
A
Must pass through nasal mucosa layer and then the epithelial layer
20
Q
How is passage of drugs across nasal mucosa achieved?
A
- Paracellular passage – between cells through tight junctions; main pathway for polar drugs w/ low MW
- Transcellular passage – passive diffusion through cells; major pathway in absorption of lipophilic drugs
- Facilitated diffusion – diffusion helped by protein channels; no energy expenditure
21
Q
Can drugs be actively transported across nasal mucosa?
A
Yes
22
Q
What is transcytosis?
A
When particles and macromolecules are taken inside a vesicle and passed through the cell
23
Q
____ molecules are absorbed rapidly across the nasal mucosa
A
Lipophilic
24
Q
____ molecules generally have poor absorption across nasal mucosa. How can absorption of these drugs be increased?
A
- Low MW hydrophilic
- Can increase absorption by adding absorption enhancers to the formulation
25
Do anti-migraine drugs require absorption enhancers when given intranasally?
No, they are sufficiently lipophilic to cross nasal mucosa in high enough quantities to meet desired therapeutic effect
26
Which anti-migraine drugs are given intranasally and how?
- Sumatriptan delivered as a powder form
| - Dihydroergotamine (antihistamine for nausea associated w/ migraines) delivered as a spray
27
Which peptide drugs are given intranasally? What are they used for?
- Hormone treatments
- Desmopressin (for diabetes insipidus)
- Oxytocin (increase duration and strength of contractions during labour)
- Calcitonin-salon (treat hypercalcemia)
28
Do peptide drugs require absorption enhancers when given intranasally?
No b/c highly potent so only require a bioavailability around 2-3% to show therapeutic efficacy
29
What are some other miscellaneous drugs given intranasally and for what conditions?
- Midazolam (acute episodes of seizures in children)
- Naloxone (opioid overdoses)
- Ketorolac (NSAID for pain relief)
- Ketamine (investigated for breakthrough pain management)
30
What are the types of packaging of intranasal medications?
- Meter-dose
- Plastic spray bottles
- Dropper (very uncommon now)
31
What function of the nose impacts nasal drug delivery and absorption?
- Nose or URT modifies inspired air by filtration, humidification and warming
- To do this, nose must control rate of air flow, remove noxious agents, and introduce large quantities of fluid into air stream
32
What are the functional zones in the nasal cavity?
1) Vestibular -- surface covered by epithelium w/ long hairs to filter out all airborne particles
2) Respiratory -- surface normally covered by dense layer of mucous; mucous constantly moving toward posterior apertures of nasal cavity by system of motile cilia
3) Olfactory -- above middle turbinate; generally free of inspiratory air flow
33
What covers a normal mucosa?
Mucous secreted from various nasal glands
34
Nasal mucous is renewed about every ____
10 minutes
35
How much mucous is produced daily? What does it contain?
- About 1.5-2 L produced daily
| - Contains 90-95% water, 1-2% salts, and 2-3% mucin
36
What is the normal surface area of nasal mucosa in an adult?
150-200 cm^2
37
What is the most important defense mechanism of the respiratory tract?
- Nasal mucociliary clearance, which carries airway secretions backward to nasopharynx and stomach through swallowing
- In the anterior nares, mucociliary clearance moves forward to provide clearance by nose blowing or wiping
38
What is the average rate and transit time of nasal clearance?
- Average rate = 6-8 mm/min
| - Transit time = 12-15 minutes
39
What effect does nasal mucociliary clearance have on drug delivery? How can this be changed?
- Could lead to drug loss if the product isn't formulated correctly
- Can add an excipient to enhance residence time on mucosa
40
What is the normal pH of adult nasal secretions? When does this change?
- 5.5-6.5
- Can lean on alkaline side during allergic rhinitis, acute sinusitis, and acute rhinitis
- Can be altered by heat or cold (cold air produces drift towards alkalinity and heat yields drift toward acidity)
- pH also varies w/ sleep, rest, food ingestion, emotion, and infection
41
What can happen if nasally administered medications contact olfactory mucosa?
- Molecular transport can occur directly across the tissue and into CSF
- Mucosa can transport directly into the brain, skipping the BBB potentially achieving CSF levels higher and faster than IV administration
- This is called the nose-brain pathway; good for sedatives, anti-seizure drugs, and opiates
42
What must be considered when using the nasal route for drug administration?
That some CNS absorption may occur
43
Which viral diseases can enter the body through the nasopharynx?
Measles, common cold, and chicken pox
44
What should be done for nasal doses?
Should be divided in half w/ each nostril receiving half the dose to double the absorptive surface area
45
A ______ gives a very good nasal mucosa distribution
Atomized pump delivery system
46
What is the ideal particle size for the nasal mucosa?
- 10-20 um are deposited on nasal mucosa
| - Less than 2 um pass through and deposit into lungs
47
What happens if drugs are introduced into the nasal mucosa as soluble particles?
They readily dissolve into nasal lining secretions and then are absorbed into blood
48
_____ of the drug are the most important parameters in dosage form design
Physicochemical properties
49
What is the ideal molecular weight for paracellular absorption?
Under 300
50
What is the maximum volume that can disperse onto nasal mucosa? What happens if more than this is administered?
0.5 mL; excess will run off mucosa into the throat or out of nostril and be lost
51
What is the ideal volume for one nostril?
0.25-0.3 mL
52
What will cause reduced effect of nasal drugs?
Px w/ bloody noses or high mucous production in nasal cavity
53
When are absorption enhancers used for nasal drugs?
- Small hydrophilic drugs
- Peptides, proteins, nucleic acids
- Polysaccharides
54
Which molecules are more affected by mucociliary clearance?
Polar molecules which are more slowly absorbed across nasal mucosa
55
What are mucoadhesive agents?
Hydrocolloids that can form weak covalent, ionic, and H bonds w/ mucous and slow mucociliary clearance
56
What do mucoadhesive agents do?
Increase viscosity to increase residence time that drug is in contact w/ nasal mucosa
57
What are some examples of mucoadhesive agents?
- Carbopol
- Chitosan
- Sodium carboxymethylcelluose
- Polyacrylic caids
- Hydroxypropyl methylcellulose
- Hydroxypropyl cellulose
58
What does nasal mucous contain? How does this react for mucoadhesive agents?
- Anionic and contains more sulfate groups
- Polymers are able to interact electronically or H-bond (anionic polymers like carbopol and HMPC can form H-bonds; cationic polymers like chitosan can interact ionically)
59
Why is poloxamer 407 a bad mucoadhesive agent? How can it be improved?
- Forms a gel at body temp in the nose
- Non-ionic
- Can be improved by addition of a polymer
60
What are some properties involved in selecting a polymer for bioadhesion?
- Molecular weight
- Concentration
- Hydrophobicity
- Ionic charge
- Degree of cross-linking
61
How can some polymers affect ciliary beat frequency?
- Ciliary beating requires calcium ions
| - Acrylic acids complex calcium, slowing down beat frequency and mucociliary clearance
62
What can happen w/ chronic use of mucoadhesive agents?
- Reduce effectiveness of mucociliary clearance as a defensive process
- Could allow inhaled microorganisms the opportunity to grow and cause local and respiratory infections
63
What are absorption promoters?
Agents that increase permeation of drugs across the mucosa by disrupting nasal epithelium (usually surfactants)
64
Which molecules are used as absorption promoters? What is a disadvantage to these?
- Laureth-9, bile acids, and bile acid derivatives; chitosan is also an absorption promoter through regulating tight junctions in cell membrane
- Irritate the nasal mucosa, so must weigh risk vs. benefit
65
What are some drugs that show enhanced absorption when administered w/ an absorption promoter?
- Budesonide
- Caffeine
- Ketorolac
- Metoprolol
- Midazolam
- Nicotine
- Tobramycin, gentamicin, vancomycin
66
What happens when a drug is given nasally as a powder?
Tends to slow mucociliary clearance and absorb water at tight junctions between cells
67
Formulations of drugs w/ chitosan showed better absorption as ____ than ____, but may cause ______
- Better absorption as powders than solutions
| - May cause irritation w/ prolonged use
68
How should a drug be formulated to encourage prolonged residence time?
Isotonic and have pH around 7.4
69
Drugs should be in _____ state for maximum absorption
Unionized (so should be below 5.5 or above 6.5)
70
What is the pH of nasal secretions?
5.5-6.5
71
What must be considered since nasal drugs may be delivered to the lungs?
- Must consider microbial quality of the product
| - Multi-dose products should contain a preservative
72
What droplet size is optimal for deposition on nasal mucosa?
5-7 um
73
What should be considered when choosing a nasal device?
- Droplet size
- Spray pattern
- Nature of formulation
74
What are nano- and micro-particulate systems?
Matrix systems where drug is dispersed in polymeric material
75
How is drug loaded into a nano- or micro-particulate system?
Through incorporation w/ the system or adsorption on particulate system
76
How is drug released from particles in a nano- or micro-particulate system?
- Release from particle surface
- Diffusion of drug from swollen polymer matrix
- Drug release through erosion of polymers
77
What is important about nano- and micro-particulate systems?
Have mucoadhesive properties to aid in retention and action in nasal mucosa
78
What are some properties of chitosan?
- Cationic polymer w/ strong mucoadhesive properties
| - Also enhances penetration through its ability to transiently open tight junctions in nasal mucosa
79
How is mucoadhesion achieved w/ chitosan?
Ionic interaction of positively charged amine groups of D-glucosamine units of chitosan w/ negatively charged sialic acid groups of mucin or other negatively charged groups of mucosal membrane
80
What determines the systemic bioavailability of intranasal corticosteroids?
- Sum of nasal and intestinal absorption
| - Clearance by first-pass hepatic metabolism
