Drug delivery via RS Flashcards
what is a lung?
The lung is the organ of external respiration, in which oxygen and carbon dioxide are exchanged between blood and inhaled air
The lung offers a large surface area for drug absorption, of approximately
Applications and advantages of pulmonary drug delivery
Treatment or prophylaxis of airways diseases (bronchial asthma, chronic obstructive pulmonary disease and cystic fibrosis);
Pulmonary administration results in a rapid onset of activity (e.g. for delivering bronchodilating drugs for the treatment of asthma);
Smaller doses can be administered locally compared to delivery by the oral or parenteral routes;
This route is also useful where a drug is poorly absorbed orally (e.g. sodium chromoglicate) or where it is rapidly metabolised orally (e.g. isoprenaline);
The lung may also be used as a route for delivering drugs having systemic activity
what is inhalation aerosols
To deliver a drug into the airways, it must be presented as an aerosol (except for medical gases);
In pharmacy, an aerosol is defined as a two-phase system of solid particles or liquid droplets dispersed in air or other gaseous phase. Aerosols should have small size to ensure their stability
Mechanisms responsible for particulate deposition in the lung
Impaction
Gravitational sedimentation
Diffusion
what is gravitational sedimentation
Gravitational sedimentation of an inhaled particle is dependent on its size and density, in addition to its residence time in the airways. Sedimentation is an important deposition mechanism for 0.5 – 3 m particles, in the small airways and alveoli, for particles that have escaped deposition by impaction.
what is inertial impactation?
This is the dominant deposition mechanism for particles > 1 m in the upper tracheobronchial regions. A particle with a large momentum may be unable to follow the changing direction of the inpired air as it passes the bifurcations and as a result will collide with the airway walls.
what is brownanian diffusion?
This is of little significance for particles > 1 m
Particles below this size are displaced by a random bombardment of gas molecules, which results in particle collision with the airway walls.
The probability of particle deposition by diffusion increases as the particle size decreases.
Deposition of particles in various regions of the respiratory tract
Particles larger than 10 m will impact in the upper airways and are rapidly removed by coughing, swallowing and mucociliary processes;
Smaller 0.5 – 5 m particles may escape impaction in the upper airways and will deposit by impaction and sedimentation in the lower respiratory regions
Physiological factors affecting particle deposition in the airways
Lung morphology
To travel down the airways, the drug particles must pass through a successive series of branching tubes of constantly decreasing size.
Oral versus Nasal breathing
During normal nose breathing the majority of inhaled environmental particles are deposited in the nose and pharynx. For pulmonary drug delivery, the aerosols are inhaled via the mouth.
Inspiratory flow rate
Increasing inspiratory flow rate will enhance deposition by impaction in the larger airways.
Breath holding
Breath holding after inhalation enhances the deposition of particles by sedimentation and diffusion
Optimal aerosol deposition occurs with slow, deep inhalations to total lung capacity, followed by breath-holding prior to exhalation.
Pharmaceutical factors affecting aerosol deposition
Aerosol velocity Size and size distribution Shape Density Physical stability
The fate of particles in the airways
Mucus barrier
If the drug is given as an aerosolised powder then it first needs to dissolve in the mucus layer. Dissolution may be a rate determining step, especially for poorly soluble drugs.
Once in solution, the drug will diffuse through the mucus layer and enter the aqueous environment of the epithelial lining liquid.
The rate of diffusion through the mucus will depend on the thickness of the mucus layer; mucus viscosity; molecular size of drug; and interactions between the drug and mucus.
Mucociliary clearance
In the healthy lung, the mucus layer does not exist as a stagnant layer but is constantly being propelled along the airways by the rhythmic beating of cilia on epithelial cells;
Particles deposited in the ciliated conducting airways are cleared by mucociliary clearance within 24 hours and are ultimately swallowed.
Advantages of pulmonary drug delivery for locally-acting drugs
The dose needed to produce a pharmacological effect can be reduced compared to oral dosing;
Low concentrations in the systemic circulation are associated with reduced systemic side-effects;
Rapid onset of action;
Avoidance of gastrointestinal upset;
Avoidance of intestinal and hepatic first-pass metabolism
Advantages of pulmonary drug delivery for systemically acting drugs
Large surface area for drug absorption;
The permeability of the lung membranes towards many compounds is higher than that of small intestine and other mucosal routes;
Highly vascular surface promotes rapid absorption and onset of action
Less hostile environment than the oral route to most drugs, including proteins and peptides.
Disadvantages for delivery of systemically-acting drugs
Complex delivery devices are required to target drugs to the airways and these devices may be inefficient;
Aerosol devices can be difficult to use (more than 50 % adult patients have difficulty)
Various factors affect the reproducibility of drug delivery
Drug absorption may be limited because of mucus
Mucociliary clearance reduces the retention time of drugs within the lungs
Current technologies for drug delivery
Pressurised metered-dose inhalers (pMDI)
Dry powder inhalers (DPI)
Nebulisers
