Lecture 18 Pulmonary Drug Delivery Flashcards
(35 cards)
Describe the importance of pulmonary drug delivery in the context of human lungs and medication absorption.
Pulmonary drug delivery is crucial due to the extensive surface area and thinness of human adult lungs, facilitating direct entry of medications into the bloodstream. With ~300 million alveoli for gaseous exchange, this route offers access to all body parts, including the brain.
What does pulmonary drug delivery refer to, and what are the drivers for growth in the traditional inhalable market?
Pulmonary drug delivery refers to infusing drugs into the body through inhalation. Growth drivers include topical drug deposition for fast respiratory therapeutic effects, rising respiratory disorder incidence, importance of self-administration for chronic conditions, innovations in pharmaceutical formulations, and consumer preference for non-injectable alternatives.
How has technology limited pulmonary drug delivery, and what are some common aerosol delivery devices used in this context?
Technological limitations have hindered the full utilization of pulmonary drug delivery. Common aerosol delivery devices include nebulisers, jet, ultrasonic, pressurised metered dose inhalers (pMDIs) with or without spacer, and dry powder inhalers (DPIs).
Define the potential benefits of efficient systemic ‘inhalables’ in expanding growth beyond respiratory markets.
Efficient systemic ‘inhalables’ have the potential to expand growth in non-respiratory markets by offering an alternative to injectables, enabling the delivery of protein and peptide-based pharmaceuticals, and driving innovations in sophisticated inhaler device designs.
Describe the primary role of human adult lungs and how it relates to the direct route of entry for medications into the bloodstream.
The primary role of human adult lungs is gaseous exchange through approximately 300 million alveoli. This extensive surface area and thinness (0.1–0.2 μm) of the lungs provide a direct route for medications to enter the bloodstream, allowing access to all parts of the body, including the brain.
Describe the challenges faced by the inhalable insulin Exubera, including reasons for its discontinuation and issues with acceptance and cost.
Exubera, the first inhalable insulin, faced challenges such as lack of acceptance by patients and clinicians, high cost (3.5x injectable insulin), and poor sales. It was discontinued in 2007, costing Pfizer $2.8 billion due to factors like government refusal to pay unless patients had needle phobia.
How did the inhalable insulin Afrezza differ from Exubera in terms of approval, partnerships, and market reception?
Afrezza, unlike Exubera, received FDA approval in 2014 and maintained a global licensing deal worth $925 million between Sanofi and MannKind. While Exubera failed, Afrezza managed to stay in the market despite initial challenges with overpricing and reimbursement.
Define the key features and innovations sought in the development of inhalable insulin devices, focusing on aspects like drug delivery, device size, patient convenience, and drug actuation.
Innovations in inhalable insulin devices aim for consistent drug delivery, high lung penetration, multiple dosing, small device size, patient convenience, and optimized drug actuation with minimal user effort. These features enhance usability and effectiveness of the insulin delivery system.
Describe the landscape of inhalable insulin products beyond Exubera, including companies involved, product outcomes, and notable partnerships.
Following Exubera’s failure, other companies like Alkermes, Eli Lilly, MannKind, Aradigm, and Novo Nordisk pursued inhalable insulin. By 2008, most products were discontinued except for MannKind’s Afrezza, which received FDA approval in 2014. Sanofi’s $925 million deal with MannKind aimed to advance Afrezza despite pricing and reimbursement challenges.
Explain the reasons behind the failure of Exubera as an inhalable insulin product, detailing factors like patient acceptance, cost, and market performance.
Exubera failed due to low patient and clinician acceptance, high cost (3.5x injectable insulin), and poor sales (only $4 million quarterly). Governments refused to pay for it unless patients had needle phobia. These issues led to its discontinuation in 2007, costing Pfizer $2.8 billion.
Describe the indications for Afrezza and its use in adults with type 1 or type 2 diabetes mellitus. What are the specific contraindications for Afrezza use?
Afrezza is indicated for adults ≥ 18 years with T1DM or T2DM, used with long-acting insulin in T1DM. Contraindications: children, pregnant/breastfeeding women, patients with diabetic ketoacidosis.
How does Technosphere® insulin work in the body after inhalation? What are the key characteristics of FDKP, the molecule involved in Technosphere® technology?
Technosphere® insulin particles dissolve in the lung, rapidly absorbed into circulation. FDKP is a white solid, highly soluble in water at neutral pH, with exposed carboxylic acid groups.
Define the Technosphere® technology used in Afrezza. How are Technosphere® particles structured, and what is their purpose in drug delivery?
Technosphere® is a drug delivery platform allowing pulmonary administration. Particles are like 3-D spheres made of FDKP microcrystals, providing high internal porosity for drug delivery.
Describe the preparation process of Technosphere®/Insulin (AfrezzaTM). How does the charge difference and surface area promote insulin adsorption in this formulation?
Insulin is precipitated onto preformed surfaces to form Technosphere®/Insulin powder. Charge difference and high surface area promote insulin adsorption due to slightly +vely charged insulin and slightly -vely charged FDKP.
Explain the onset of action, peak time, and duration of activity of Afrezza. How does it compare to traditional insulins in terms of speed and duration of action?
Afrezza has an onset of 12-15 minutes, peak at 60 minutes, and duration of 2.5-3 hours. It is ultra-rapid-acting, faster than traditional insulins, providing quick mealtime insulin coverage.
How does molecular modeling predict the morphology of FDKP in Technosphere® technology? What is the significance of the crystalline plates associating into microspheres in drug delivery?
Molecular modeling predicts a plate-like morphology of FDKP with exposed carboxylic acids. Crystalline plates form microspheres, providing a large surface area and high internal porosity for effective drug delivery.
Describe the pharmacokinetics of Afrezza and how it differs from Exubera.
Afrezza’s insulin is already in monomeric form, leading to a quicker peak insulin level compared to Exubera’s hexameric form. Afrezza mimics natural insulin response better, reducing hypoglycemia risk. Afrezza has a shorter duration of action (2-3 hrs) compared to Exubera (unknown).
How does the delivery method of Afrezza contribute to its potential success compared to Exubera?
Afrezza uses a breath-activated inhaler, making it more convenient and discrete than Exubera, which required a manual ‘activation while breathing’ process. Afrezza’s single-use cartridges are simpler to use than Exubera’s multi-step administration.
Define the role of Technosphere particles in the pharmacokinetics of Afrezza.
Technosphere particles stabilize monomeric insulin, allowing for rapid absorption in the lungs. These particles dissolve quickly at the lung surface, dispersing insulin evenly in the deep lung. The particles ensure optimal delivery to the deep lung for efficient absorption.
What are the key differences in cost between Afrezza and Exubera, and how might this impact their acceptability?
Exubera had an annual cost of ~$2750, while Afrezza costs around $1150 per year. The lower cost of Afrezza compared to Exubera may contribute to its ongoing acceptability among patients due to reduced financial burden.
Describe the device characteristics of the MedTone inhaler used for Afrezza delivery.
The MedTone inhaler is a passive, high-resistance, low-flow, dry powder delivery device. It is designed for single-use cartridges (2.5-10 mg) and does not require manual activation or coordination. The inhaler discharges powder into the oral cavity when the patient inhales through the device mouthpiece.
How does the particle size distribution of Afrezza contribute to its effectiveness in delivery to the deep lung?
Afrezza’s particles have a uniform size distribution (>90% in the respirable range of >0.5 and <5.8 mm), with an average size of 2.5 mm. This size range is optimal for delivery to the deep lung, ensuring efficient absorption of insulin monomers. The particles dissolve rapidly at the lung surface for quick absorption.
Describe the concept of Powderhale technology in relation to minimizing variability in exposed powder surfaces and achieving improved delivery uniformity.
Powderhale technology aims to minimize variability in exposed powder surfaces by providing a well-engineered coating of a single agent like magnesium stearate. The additive ‘Force control agent’ masks underlying surface properties of new compound drugs, ensuring stable uniform surface with known properties. This approach enhances dispersion efficiency and delivery uniformity over multiple doses.
How does Aspirair deliver high ultra-fine doses while minimizing deposition in the oropharynx?
Aspirair delivers high ultra-fine doses (<3 mm) while minimizing deposition in the oropharynx by using mechanically pressurized air as an energy source for powder de-aggregation through a miniature cyclone dispersion system. The blister is pierced, and the charge of air compressed by the patient triggers the release, flowing into a vortex nozzle for dispersion.
