The document discusses nasal drug delivery, including its advantages, challenges, and opportunities for nose-to-brain delivery. The key advantages are rapid absorption avoiding first-pass metabolism. Challenges include a limited dose volume, short absorption window due to mucociliary clearance, and irritation concerns. Strategies to address challenges involve optimizing formulations through viscosity, mucoadhesion or permeation enhancers to improve bioavailability. Permeation enhancers may enable delivery of large molecules like peptides to the brain via the nose-to-brain pathway.

1. Nasal Drug Delivery: Opportunities and Challenges

2. 2
AGENDA
• Anatomy of the Nose
• Advantages of Nasal Drug Delivery
• Challenges of Nasal Drug Delivery
• RegulatoryAspects
• Addressing the Challenges
• Nose to Brain Delivery
• Questions?
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3. • Nasal chamber is
– Highly vascular epithelia
– Highly permeable
– Surface area : 130 -160 cm2
– Basal, goblet and columnar cells
– Cilia
•Continual mucociliary clearance
mechanism (15-20 min cycle)
•Potential for nose to brain delivery
via olfactory lobe possible
– Delivery of neuropeptides
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Anatomy of the Nose
3

4. • Non-invasive
• Ease of administration/ self administration
• Convenient
• Direct route to systemic circulation.
• No first pass effect
• GI
• Hepatic
• Rapid absorption vs oral
• No disintegration/ dissolution time lag
• Potential as a convenient rescue therapy (compared to IV) to mitigate an acute event
• Narcan - respiratory failure (drug overdose)
• Valtoco - seizure
• Tosymra - migraine
• Nose to brain direct delivery via olfactory lobe (by passing BBB)
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Advantages of Nasal Drug Delivery

5. • Anatomical and physiological constraints
• Dose volume limited to NMT 100-125 µL
– Solution drips out of nostril
– Dose gets swallowed via nasopharynx into GI
• Time for absorption is limited
– Mucociliary action limits absorption window to approximately 15-20 minutes
• The nose is sensitive and easily irritated limiting formulation (and drug)
options for nasal delivery. May result in
– Sneezing
– Irritation, inflammation, and pain
– Alteration of blood vasculature
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Challenges of Nasal Drug Delivery

6. • Anatomical and physiological constraints (contd)
• Drug/ formulation properties impact permeation/ absorption by affecting
transcellular and paracellular transport
• Potential for lung penetration of small droplets
– (droplets < 10µm may travel through the respiratory tract to lung)
• Seasonal allergies and/ or co-administration of decongestants etc.,
impacting drug absorption
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Challenges of Nasal Drug Delivery

7. • Physicochemical constraints
• Drug load/ drug solubility
– Need to be able to deliver the dose in 1or 2 x 100 µL administrations (or a further
2 doses 15 minutes later e.g., Migranal)
• Drug lipophilicity and size
• Limited excipients that are non-irritating and approved for nasal
administration
• pH limitation to avoid irritation. Nasal cavity is around pH 5.5-6.5
• Drug must be rapidly absorbed. Lipophilic drugs are better but have
poorer solubility in aqueous systems
• Quality characteristics of active and excipients need to be comprehensive
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Challenges of Nasal Drug Delivery

8. • Delivery constraints
• Delivery system (pump) must be
– Reproducible performance
o Pump delivery (SCU), droplet size distribution, plume geometry, spray pattern etc.
o Priming, repriming (various orientations), resting
– Robust
o Shipping (high temperatures, freeze-thaw, mechanical shock, pressure changes)
– Portable/ discreet
– Orientation independent (emergency/ rescue setting)
– Easy to use by carer/ self administration
o Supported by HF studies etc.
– Support an acceptable shelf-life at CRT
– Biocompatible (mucosa etc.)
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Challenges of Nasal Drug Delivery

9. • Classified as combination products (21 CFR Part 4)
• Usually single-entity products
– A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic,
or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a
single entity
– Device and drug are constituent parts-both are regulated
o Drug: CFR 210 and 211
o Device: CFR 820 (QS regulations)
– Streamlined approach permissible (21 CFR 4.4(b))
o Follows GMPs with certain provisions from device QS regulations (21 CFR4.4(b)(1))
o Follows QS regulations with certain provisions from CGMPs (21 CFR4.4(b)(2))
• Guidance for Industry and FDA Staff: Current Good Manufacturing Practice
Requirements for Combination Products
• Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension, and Spray
Drug Products--Chemistry, Manufacturing, and Controls Documentation
CONFIDENTIAL 9
Regulatory Issues

10. • Nasal sensitivity, permeation changes, product quality
• Excipient selection (for quality, solubility and stability)
– Buffers, preservatives, stabilizers
– Limited (select from Inactive Ingredient Database or additional preclinical studies required)
• Seasonal allergies
• Clinical data or limit labeling
• Pump performance
• DSD (inc. % <10µm), SP, PG, PD assessments
• Dose – volume constraints
• Absorption optimization
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Addressing the Challenges

11. • Maximum volume limited to approximately 100 µL
• (multiple dosing is sub-optimal re. patient compliance/ convenience)
• Small molecule solubility strategy improvements
• Polymorph screening
• Salt screening
• Addition of co-solvents
• Suspension options
– Use of nanosizing
• Improvements in bioavailability
• Large molecule solubility strategy improvements
• Improve transmucosal permeation
– Engineering derivatized or cyclic peptides
• Improvements in bioavailability
CONFIDENTIAL 11
Addressing the Challenges: Dose-Volume Constraints

12. • Limited residence time due to continual mucociliary clearance
mechanism (15-20 min cycle)
• Two options
• Increase residence time in nasal passages
• Increase rate of absorption (and thus extent)
– i.e., improve bioavailability
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Addressing the Challenges: Absorption Optimization

13. • Mechanisms of absorption include;
a) Transcellular diffusion,
b) Paracellular transport,
c) Vesicle mediated transport, and
d) Carrier mediated transport.
Addressing the Challenges: Absorption Optimization
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14. • Increase residence time in nasal passages
• Optimize formulation viscosity
– High viscosity formulations will be less susceptible to mucociliary clearance
– Likely residence time will be composition dependent
– Significant impact on spray characteristics: DSD and PG. Fine dispersed spray
→ small droplets
– Increased formulation complexity
• Include a mucoadhesive polymer
– Need to ensure favorable formulation compatibility, biocompatibility,
biodegradation and toxicity
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Addressing the Challenges: Absorption Optimization

15. • Improve rate/ extent of drug permeation by incorporation of a
chemical permeation enhancer
• Advantages
• Improved bioavailability
– Lower drug load required
– Reduces solubility burden
• Less variability
• Potential to deliver large molecules that are typically poorly absorbed
nasally
– Potential for nose to brain delivery for neuropeptides that may not cross BBB
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Addressing the Challenges: Absorption Optimization

16. • Ideal properties
• Non-toxic, non-irritating
– IID for nasal use, GRAS, or food additive
• Commercially available
• Appropriate quality characteristics
• Tasteless, odorless
• Compatible with range of excipients (and drug)
• Soluble and stable in a range of solvent systems
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Addressing the Challenges: Absorption Optimization

17. Example
CONFIDENTIAL 17
s of absorption Enhancers
Class Type Mechanism Uses
Surfactants Bile salts
Fatty acids and derivatives
Phospholipids
Non-ionic surfactants
Bio-surfactants
Animal derived surfactants
Cell membrane perturbations
Tight junction modification
Small and large molecules covering a range of
polarities
Improved paracellular absorption of
macromolecules
Enzyme
inhibitors
Protease inhibitors Protect against enzymatic degradation Enzymatically labile drugs
Cationic
polymers
Chitosan and derivatives
Cationated gelatins
Tight junction modification Water soluble macromolecules
Improved paracellular absorption of
macromolecules
Other Nanoparticles
Liposomes
Dendrimers
Exosomes
CPPs
Surface modifiers
Cyclodextrins
Various Various
Addressing the Challenges: Absorption Optimization

18. Non-ionic surfactant example : Alkylsaccharides
1-O-n-Dodecyl-β-D-maltopyranoside
Addressing the Challenges: Absorption Optimization
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19. Intranasal epinephrine (1mg) v SC/IM epinephrine (0.3 mg)
• 1mg IN dose equivalent to 0.3mg IM injection; Comparable AUC0-t / Cmax
• More Rapid Absorption
 Time to 100pg/mL: IN 9min vs. IM 20 min
 Faster tmax: IN 20 min vs. IM 45 min
Addressing the Challenges: Absorption Optimization
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Source: ARS Pharmaceuticals, Inc.

20. TOSYMRA: Plasma Concentration-Time Profiles of Sumatriptan vs. NASAL IMITREX
Figure shows the plasma concentration-time profiles of a 10 mg intranasal dose of TOSYMRA (sumatriptan formulated with INTRAVAIL) and 20.0 mg intranasal dose of IMITREX
(sumatriptan without INTRAVAIL). The data showed that TOSYMRA had a relative bioavailability of 200%, determined by the area under the curve (AUC) and Tmax was reduced
from 120 minutes to 15 minutes. In addition, in a clinical study, TOSYMRA demonstrated 87% bioavailability to 4 mg subcutaneous injection of sumatriptan.
Addressing the Challenges: Absorption Optimization
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21. Intranasal bioavailability comparable to injection
Large molecules up to 30Kd
Nasal delivery of large molecules
with Intravail achieves high
bioavailability when compared to
IV / sub-Q formulations
Sources: Multiple published studies
Addressing the Challenges: Absorption Optimization
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22. Addressing the Challenges: Absorption Optimization
22
Uncontrolled
35%-40%
Controlled
60% - 65%
Calcitonin (MW 4,432 -32 AA’s)
• Bioavailability 37% @ 1.8% Intravail
• Est. B/A 50% at 0.25% Intravail
Ref: Highly Bioavailable Nasal Calcitonin - Potential for
Expanded Use in Analgesia, ET Maggio, Drug Delivery Technology ET Maggio et al., Drug Delivery Technology 2010;
10(1): 58–63.
PTH (Teriparitide) (MW 4,118)
• Bioavailability 42% at 0.18% Intravail in Ph II studies for nasal
delivery of PTH 1‐34; Est. B/A 60% at 0.3% Intravail
• Nasal spray dosing safe and well tolerated in Ph II trial
Issued PTH Patents: US Pat. Nos. 8,076,290 Dec. 13, 2011; 8,173,594 May 8,2013; 9,114,069 Aug. 25 2015
Ref: The Development of ZT-031: A Novel PTH Analog for the Treatment of Bone Diseases, B MacDonald Modern Drug
Discovery and Development Summit, San Diego, October 16th 2008.
CONFIDENTIAL 2021

23. Addressing the Challenges: Absorption Optimization
23
Uncontrolled
35%-40%
Controlled
60% - 65%
Source: Maggio, E. T. (2007). "Non-
Invasive Peptide Delivery,
Reformulation, and the Pharma Finance
Environment”, Drug Delivery Report,
Autumn/Winter 2007: 2-6.
*Byetta is a registered trademark of
Amylin Pharmaceuticals
Intranasal
CONFIDENTIAL 2021
Intranasal Byetta®* Intravail vs. Subq Injectable
Pharmacodynamics profiles in diabetic ob/ob mouse model

24. The human nose-to-brain anatomy. The nasal cavity contains three major regions based
on epithelial type. The first most anterior vestibule (dark yellow), is comprised of squamous
epithelial cells and does not play a significant role in drug absorption/uptake.
Just posterior to the anterior vestibule is the respiratory epithelium (yellow). Drugs (green
arrows) absorbed across the respiratory epithelium can be deposited into the lamina propria
where they gain access to an extensive pathway to the brain along the branches of the
trigeminal nerve. Drugs can travel intraneuronally or in a perineural and perivascular
distribution to enter the brain via the trigeminal ganglion (red) and brainstem (red).
Finally, posteriorly and dorsally lies the olfactory epithelium (bright yellow), which houses
the olfactory neurons (blue), and is situated at the posterior and dorsal aspect of the nasal
cavity. These neurons send cilia into the nasal cavity lumen. Drugs can be absorbed into
the olfactory receptors or traverse the olfactory epithelium to gain access to the olfactory
bulb by transcellular or perineuronal/perivascular routes within the lamina propria. From
the olfactory bulb (blue), drugs (green arrows) gain access to the brain (pink).
Nose to Brain Delivery
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25. Potential for
• Rapid onset
• Attractive in the rescue setting
• Acute repetitive seizures, (diazepam)
• Overdose/ respiratory failure (naloxone)
• Anaphylaxis (epinephrine)
• Preferable to IV/ IM
• Delivery of neurotherapeutics
• Bypass the BBB. Especially difficult for drugs that are
• High molecular weight
• Ionized
• Hydrophilic
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Nose to Brain Delivery

26. Pathways
• Olfactory nerve
• Trigeminal nerve
• Rostral migratory stream
 Connection between OB and brain (subventricular zone)
• Vascular pathway
• Relative importance of each route is still being established
• Dependent on drug and formulation factors
Transport mechanisms
• Intracellular
• Extracellular
CONFIDENTIAL 26
Nose to Brain Delivery

27. Pathways
• Olfactory nerve
• Trigeminal nerve
• Rostral migratory stream
 Connection between OB and brain (subventricular zone)
• Vascular pathway
• Relative importance of each route is still being established
• Dependent on drug and formulation factors
Transport mechanisms
• Intracellular
• Extracellular
CONFIDENTIAL 27
Nose to Brain Delivery

28. Nose to Brain Delivery
Formulation
• pH
• Osmolality
• Viscosity
• Physical form
• Excipients
Considerations for efficient drug delivery:
Physiochemical
• Molecular weight
• Molecular size
• Partition coefficient
• Dissociation constant
• Lipophilicity
• Solubility/ Dissolution
• Salt form
• Polymorphic form
• Morphology
Physiological
• Nasal blood flow
• Site of drug disposition
• Mucociliary clearance
• Transport and efflux systems (e.g., Pgp)
• Physical state of mucosa
• Pathological conditions
• Environmental conditions

29. Nose to Brain Absorption Enhancement Agents
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30. Baraket et al, Journal of Pharmacy and Pharmacology, 2006, 58: 63–72
Nose to Brain Delivery
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31. • Nasal delivery provides significant advantages over other routes
• Formulation strategies have significant physicochemical, anatomical, and
physiological limitations
• Permeation enhancement strategies add additional complexity but offer the
opportunity for improved bioavailability and non-invasive delivery of macromolecules
• At this time limited permeation enhancers have been approved
• Regulatory aspects more complicated
• Opportunities to develop unique treatments via the NtB pathway that can provide
significant improvements over the current standard of care
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Conclusions