Lecture 17 Nasal Drug Delivery

Question 1

Describe the anatomy of the respiratory region involved in nasal drug delivery. What are the characteristics of the three scroll-shaped bony elements in the nasal cavity? How do they contribute to the nasal cavity’s surface area and air flow?

Answer 1

The anatomy of the respiratory region for nasal drug delivery includes three thin scroll-shaped bony elements known as nasal conchae or turbinates. These structures create air passages in the nasal cavity, increasing its surface area significantly compared to its volume, facilitating efficient airflow.

Question 2

What are the different morphological features present in the respiratory region relevant to nasal drug delivery? Explain the roles of ciliated cells, non-ciliated cells, goblet cells, gel mucus layer, sol layer, basal cells, and basement membrane in the nasal cavity.

Answer 2

The respiratory region involved in nasal drug delivery contains various features like ciliated cells, non-ciliated cells, goblet cells, gel mucus layer, sol layer, basal cells, and basement membrane. These components work together to maintain the nasal cavity’s function, including mucus secretion, cell protection, and structural support.

Question 3

Describe the basic functions of the nose and nasal secretions.

Answer 3

The nose functions in heating, humidification, olfaction, resonance, and defense through filtration, mucociliary clearance, and antimicrobial actions. Nasal secretions, mainly mucus, protect the mucosa, aid in heat transfer, regulate cilia beat, and facilitate ion transport.

Question 4

How does mucociliary clearance work in the nasal passages?

Answer 4

Mucociliary clearance involves a mucus blanket with two layers - a low viscosity sol layer and a highly viscous gel layer. Particles adhere to the mucus, get transported by cilia towards the nasopharynx, and are eventually discharged into the gastrointestinal tract to prevent respiratory infections.

Question 5

Define the composition and production of nasal secretions.

Answer 5

Nasal secretions primarily consist of mucus produced by submucosal glands and goblet cells. Mucus covers the mucosa, providing physical and enzymatic protection, facilitating heat transfer, regulating cilia beat, and aiding in ion transport. Approximately 1.5-2 liters of mucus are produced daily.

Question 6

What are the key components of the mucus blanket in mucociliary clearance?

Answer 6

The mucus blanket in mucociliary clearance consists of two layers - a lower sol layer with low viscosity that bathes the cilia, and an upper gel layer with high viscosity. Particles adhere to the mucus lining, are transported by cilia towards the nasopharynx, and are expelled into the gastrointestinal tract.

Question 7

Describe the importance of maintaining proper mucociliary clearance in the respiratory system.

Answer 7

Maintaining effective mucociliary clearance is crucial to prevent lower respiratory tract infections. Any impairment in the mucus or cilia function can hinder the clearance of particles, such as dust, bacteria, and viruses, leading to potential respiratory issues.

Question 8

Describe the rationale for intranasal drug delivery and its advantages over intravenous injection.

Answer 8

Intranasal drug delivery is favored due to the thin, porous nasal epithelium with high permeability, large surface area, direct systemic circulation transport, potential nose-to-brain delivery, lower enzymatic activity than the gastrointestinal tract, self-medication feasibility, enhanced patient compliance, and reduced risk of over-dosage.

Question 9

What are the limitations of intranasal drug delivery despite its advantages?

Answer 9

Limitations include the limited volume of the nasal cavity, restricted absorption of large hydrophilic molecules, presence of an enzymatic barrier, mucociliary clearance with a half-life of approximately 21 minutes, irregular deposition, and potential mucosa sensitivity.

Question 10

How can an optimal nasal drug delivery system be defined in terms of drug candidate characteristics?

Answer 10

An optimal system requires a drug candidate with suitable aqueous solubility and absorption properties, minimal nasal irritability (lack of toxic metabolites or noxious odors), rapid onset of action, low dosage (<25 mg), stability, and compatibility with the drug delivery device.

Question 11

Explain the potential for nose-to-brain delivery in intranasal drug administration.

Answer 11

Nose-to-brain delivery is feasible due to nerves penetrating the upper olfactory region of the nasal cavity, allowing drugs to bypass the blood-brain barrier and directly target the brain. This route offers a promising approach for treating neurological disorders.

Question 12

What are the key advantages of using intranasal drug delivery as an alternative to other routes of administration?

Answer 12

Intranasal delivery offers advantages such as rapid onset of action, direct systemic circulation transport, potential nose-to-brain delivery, lower enzymatic activity compared to the gastrointestinal tract, self-medication feasibility, enhanced patient compliance, and reduced risk of over-dosage.

Question 13

Describe the products that use the intranasal route for systemic delivery. Include examples of hormones, analgesics, and vaccines administered through this route.

Answer 13

Products using the intranasal route for systemic delivery include hypothalamic hormones like buserelin and nafarelin, other hormones like desmopressin, antimigraine medications like sumatriptan, opioid analgesics like fentanyl, and vaccines like Fluenz (FluMist). These products are administered as nasal sprays or suspensions for various medical indications.

Question 14

How is Fluenz (FluMist) administered and what are its key characteristics?

Answer 14

Fluenz (FluMist) is administered as a divided dose in both nostrils. It is a live, attenuated influenza vaccine containing strains of influenza A and B. The vaccine may contain residues of egg protein and gentamicin. It is a colorless to pale yellow suspension with small white particles. The dosage is 0.2 ml, with 0.1 ml administered per nostril.

Question 15

Define the indication and dosage of Fluenz (FluMist) for prophylaxis of influenza in individuals.

Answer 15

Fluenz (FluMist) is indicated for the prophylaxis of influenza in individuals aged 24 months to less than 18 years, excluding contraindications. The dosage is 0.2 ml, administered as 0.1 ml per nostril using a single-use glass applicator with various components.

Question 16

Describe the components of the single-use glass applicator used for administering Fluenz (FluMist) intranasally.

Answer 16

The single-use glass applicator for Fluenz (FluMist) includes a nozzle, nozzle tip-protector cap, plunger rod, plunger-stopper, and a dose-divider clip. These components are essential for the accurate and safe administration of the vaccine in both nostrils.

Question 17

Do patients need to actively inhale or sniff during the administration of Fluenz (FluMist)?

Answer 17

No, patients do not need to actively inhale or sniff during the administration of Fluenz (FluMist). They can breathe normally while the vaccine is being administered, making the process more comfortable and convenient for the individual receiving the intranasal vaccine.

Question 18

Describe the role of the mucus layer in drug absorption and how it impacts the passage of different types of particles.

Answer 18

The mucus layer plays a crucial role in drug absorption by serving as a barrier. Low molecular weight, non-polar particles can easily pass through, while larger or charged particles face difficulty. Factors like structural and environmental changes, temperature, pH, and the presence of mucin influence the movement of particles.

Question 19

How do different mechanisms like Paracellular Pathway, Transcellular Pathway, Transcytosis, and Receptor-mediated pathways contribute to drug absorption through the nasal mucosa?

Answer 19

Various mechanisms such as Paracellular Pathway, Transcellular Pathway, Transcytosis, and Receptor-mediated pathways play a role in drug absorption through the nasal mucosa. The pathway chosen depends on the molecular weight and lipophilicity of the drug substance.

Question 20

Define the impact of physiological factors like mucociliary clearance (MCC) on drug absorption through the nasal mucosa.

Answer 20

Physiological factors like mucociliary clearance (MCC) influence drug absorption through the nasal mucosa. MCC affects the diffusion path, leading to a rapid rise in peak plasma concentrations but also limits the available time for absorption due to rapid clearance from the mucosa.

Question 21

Describe how stability, enzymatic degradation, nasal blood flow, and pathological conditions can affect drug absorption through the nasal mucosa.

Answer 21

Factors like stability, enzymatic degradation by enzymes like cytochrome P450, carboxylesterases, and glutathione S-transferases, nasal blood flow influenced by vasodilators/vasoconstrictors, and pathological conditions such as infection or nasal obstruction can impact drug absorption through the nasal mucosa.

Question 22

Explain the significance of molecular weight and lipophilicity of drug substances in determining the absorption pathway through the nasal mucosa.

Answer 22

The molecular weight and lipophilicity of drug substances are crucial in determining the absorption pathway through the nasal mucosa. These factors dictate whether the drug will follow pathways like Paracellular, Transcellular, Transcytosis, or Receptor-mediated for absorption.

Question 23

Describe the physicochemical factors that influence nasal drug absorption.

Answer 23

Physicochemical factors affecting nasal drug absorption include molecular size (above 1000 Da decreases absorption), pH (ideal range 4.5-6.5 for mucosa health and drug availability), lipophilicity, osmolarity, viscosity, density, and concentration/dose/volume.

Question 24

How does pH impact nasal drug absorption and why is a specific range preferred?

Answer 24

pH affects nasal drug absorption by influencing mucosa irritation, MCC & lysozyme activity, and drug ionization for absorption. A pH range of 4.5-6.5 is preferred to maintain mucosa health and enhance drug availability.

Question 25

Define the role of osmolarity in nasal drug absorption and its impact on drug delivery.

Answer 25

Osmolarity affects nasal drug absorption by influencing tonicity, where hypertonic solutions can inhibit cilia beat and shrink epithelial cells. This can impact drug delivery efficiency and effectiveness.

Question 26

Describe the importance of particle size in nasal drug administration and its effects on deposition.

Answer 26

Particle size in nasal drug administration is crucial as larger particles (>10 μm) deposit via inertial impaction, while smaller particles (2-10 μm) can reach the lungs and very small particles (<1 μm) are exhaled. This impacts drug deposition and bioavailability.

Question 27

Explain the significance of site and pattern of deposition in nasal drug delivery.

Answer 27

The site and pattern of deposition in nasal drug delivery determine the drug’s target and residence time. Deposition in the turbinates is ideal for systemic delivery, while anterior deposition offers longer residence time despite lower permeability. Posterior deposition has higher permeability but shorter residence time.

Question 28

Describe different formulation options for drug delivery, including drops, sprays, and dry powders. What are the advantages and challenges associated with each option?

Answer 28

Formulation options for drug delivery include drops, sprays, and dry powders. Drops are simple but have dose precision challenges. Sprays can be formulated into solution/suspension forms and offer precise dosing. Dry powders are less common, improve stability, and may not require preservatives.

Question 29

How can solubilisers, stabilisers, and enhancers improve drug absorption? Provide examples of substances that can serve as solubilisers and stabilisers.

Answer 29

Solubilisers, stabilisers, and enhancers can improve drug absorption. Substances like surfactants, cyclodextrins, and lipophilic absorption enhancers can serve as solubilisers and stabilisers. They enhance bioavailability and efficacy of drugs.

Question 30

Define the role of gels, viscosity enhancers, and bioadhesive formulations in drug delivery. Give examples of commonly used substances in each category.

Answer 30

Gels, viscosity enhancers (e.g., 0.25% methylcellulose), and bioadhesive formulations (e.g., Carbopol 934) play a role in drug delivery by improving residence time and bioavailability. They enhance drug absorption and can be tailored for specific applications.

Question 31

Describe different pathways for drug delivery to the brain. Explain how drugs can reach the brain through olfactory bulb pathways, nasal vasculature, paravascular spaces, trigeminal nerve pathways, and oral mucosa.

Answer 31

Drugs can reach the brain through various pathways: olfactory bulb pathways directly into the CSF and brain, nasal vasculature into the systemic circulation, paravascular spaces connecting to brain parenchyma, trigeminal nerve pathways to the brain stem, and oral mucosa/gastroenterally. Each pathway offers unique advantages and challenges.

Question 32

Explain the significance of drug delivery through olfactory bulb pathways. How does this route differ from delivery through nasal vasculature or other pathways?

Answer 32

Drug delivery through olfactory bulb pathways is significant as it allows direct access to the CSF and brain. This route differs from nasal vasculature delivery by bypassing systemic circulation, offering a more direct path to the brain. It provides a unique route for targeted drug delivery to the brain.

Question 33

Describe the process of Nose to Brain Delivery using the Optinose Drug Delivery Devices.

Answer 33

Nose to Brain Delivery involves exhaling into the device, closing off the nasal cavity with the soft palate, triggering the release of particles into airflow through a sealing nozzle, depositing particles at target sites in the olfactory region, and allowing airflow to exit through the other nasal passage.

Question 34

What is the significance of the bi-directional delivery system in Optinose Drug Delivery Devices?

Answer 34

The bi-directional delivery system ensures that there is no lung delivery or loss to the GI tract. It allows for the deposition of particles at target sites within the upper posterior cavity, specifically the olfactory region, while maintaining efficient airflow circulation.

Question 35

How does the future of nasal drug delivery look like based on market projections?

Answer 35

The global nasal drug delivery technology market is expected to grow significantly, reaching USD 81.85 billion by 2026 from USD 44.00 billion in 2016. Systemically-acting drugs are growing at 33% per annum, with advancements in nose-brain delivery for treating CNS disorders, breakthrough pain, migraine, endocrine diseases, and sedation.

Question 36

Discuss the direct route of nose-brain delivery and its implications for treating various conditions.

Answer 36

The direct route of nose-brain delivery bypasses the blood-brain barrier in the olfactory region of the nose. This route enables the treatment of CNS disorders, breakthrough pain, migraine, endocrine diseases, sedation, and other conditions by delivering drugs directly to the brain through the nasal cavity.

Question 37

What are some of the current developments in nasal drug delivery technology?

Answer 37

Current developments include advancements in nose-brain delivery, which offers a direct route to the brain without encountering the blood-brain barrier in the olfactory region of the nose. This innovation opens up new possibilities for treating CNS disorders, breakthrough pain, migraine, endocrine diseases, sedation, and more.