Full Answer
What size aerosol is needed for pulmonary drug delivery?
In the case of pulmonary drug delivery for systemic absorption, aerosols with a small particle size would be required to ensure peripheral penetration of the drug [37]. Particles <3 µm have an approximately 80% chance of reaching the lower airways with 50–60% being deposited in the alveoli [23, 38].
What determines the particle size of aerosolized drugs?
The type of inhalation devices and drug formulation are determinants of the drug aerosol's particle size. In Part II, the inhalational delivery devices’ and drug formulations’ effect on the therapeutic effectiveness of aerosolized drug therapy will be reviewed.
What is the minimum particle size required to deliver a drug?
For example, if a pharmaceutical company is formulating liquid medication with suspended drugs and the goal is to deliver aerosol droplets with a mean particle size of 3.0 µm, the component drug suspended inside the liquid droplets must have a particle size smaller than 3.0 µm.
Why is aerosol particle size important?
Aerosol particle size characteristics can play an important role in avoiding the physiological barriers of the lung, as well as targeting the drug to the appropriate lung region. The type of inhalation devices and drug formulation are determinants of the drug aerosol's particle size.
What is the optimal particle size for nebulized medications desired to reach the lower airways and the alveolar region of the parenchyma?
Particle size plays an important role in this. For an aerosol particle to be considered within a respirable range or having the potential to reach the periphery of the lungs and airways, the particle must be between 1–5 microns in size. Particles that are 1–2 μm are optimal for deposition in the alveolar area.
What is the optimal particle size range for good deposition in the upper and lower airways?
Particles 1 μm in size are ideal for this purpose because of their very low deposition on their way to the targeted region and their large deposition in the small peripheral lung structures during breath-holding.
What is the therapeutic range of aerosol particle size?
Most aerosolized particles for therapeutic purposes are in the range of 2–5 μm and diffusion is the predominant mechanism for lung deposition. The optimal technique for aerosolization is important to achieve distal airway and alveolar deposition.
What is the device used to deliver an aerosolized medication into the lungs?
Nebulizers. A variety of nebulizers are available to generate aerosols for inhaled drug delivery. There has recently been increased interest in the use of nebulizers due to the high cost of HFA formulations. A liquid solution or suspension is added to the nebulizer for each treatment.
How particle size affects deposition in the airway and drug distribution?
The larger the particle size, the greater the velocity of incoming air, the greater the bend angle of bifurcations and the smaller the airway radius, the greater the probability of deposition by impaction [39].
Where are drug particles with a diameter between 2 to 5 microns most likely to deposit?
Small particles (<2 μm) deposit mainly in the alveolar region, whereas particles in the size range 2–5 μm deposit preferentially in the central and small airways.
What is the optimal particle size for aerosol delivery of a bio agent?
Consequently, particle sizes of 1–5 µm are best for reaching the lung periphery, whereas 5–10 µm particles deposit mostly in the conducting airways, and 10–100 µm particles deposit mostly in the nose.
What is the optimum particle size to aid deposition into the lungs?
Particles 1 μm in size are ideal for this purpose because of their very low deposition on their way to the targeted region and their large deposition in the small peripheral lung structures during breath-holding. For the treatment of airway diseases drugs should be directed to the second region.
Which device is used to increase the efficiency of drug delivery via aerosols?
Nebulizers are devices that transform solutions or suspensions of medications into aerosols that are optimal for deposition in the lower airway.
What is the particle size range for pulmonary diagnostic and therapeutic applications?
Optimal particle size for most inhaled respiratory medications to achieve deposition in the periphery of the lung falls into the particle size range of 1–5 μm. As particle size increases above 5 μm, aerosol deposition shifts from the periphery of the lung to the conducting airways.
What are the 3 most common devices methods used to deliver inhaled drugs?
Devices used to deliver therapeutic agents as aerosols are based on one of the three platforms: nebulizers, pressurized metered-dose inhaler (pMDI), and dry powder inhalers (DPIs).
How do you administer aerosol therapy?
Ask patient to hold inhaler between thumb at the base and index and middle fingers at the top. Ask patient to tilt head back slightly and inhale deeply and slowly through mouth, while simultaneously depressing inhaler canister. Ask patient to hold breath for about 10 seconds without exhaling medication.
What is the optimum particle size to aid deposition into the lungs?
Particles 1 μm in size are ideal for this purpose because of their very low deposition on their way to the targeted region and their large deposition in the small peripheral lung structures during breath-holding. For the treatment of airway diseases drugs should be directed to the second region.
What size of inhaled particles can be deposited in the bronchial areas?
0.5–2 μmParticles between 2 and 10 μm are normally deposited in the tracheobronchial region. Particles of size 0.5–2 μm are deposited in the alveoli and small conducting airways due to gravitational sedimentation.
What size particles can enter the lungs?
A respirable particle (one that can reach the lungs) is a particle around 10 microns or less. Larger particles may still be inhaled, but the body has built in defense mechanisms to keep them from reaching the deep portions of the lung.
What size particle can penetrate to the alveoli of lungs when inhaled?
Smaller particles with an aerodynamic diameter of about 0.003 to 5 µm are deposited in the tracheobronchial and alveolar regions.
How does aerosol size affect the effectiveness of a drug?
Since particle size affects the lung deposition of an aerosol, it also can influence the clinical effectiveness of a drug. Johnson and colleagues showed that the bronchodilation response to cumulative doses of ipratropium bromide delivered either as a 3.3-µm or 7.7-µm aerosol was identical, whereas the response to salbutamol was significantly greater with the finer (3.3 µm) aerosol, suggesting targeting drug aerosol to the location of their receptors in the lung does influence its effectiveness (Figure 1) [9]. Rees et al. [10] reported the varying clinical effect of 250 µg of aerosolized terbutaline from a metered dose inhaler (MDI) given as three different particle sizes: <5 µm, 5–10 µm and 10–15 µm. In asthmatics, the greatest increase in forced expiratory volume in 1 s (FEV1), specific airway conductance (sGaw) and flow at 50% of vital capacity (V50) was found with the smallest particle size (<5 µm), suggesting that the smaller particle aerosol was considerably more effective than larger particle size aerosols in producing bronchodilation since it has the best penetration and retention in the lungs in the presence of airway narrowing. Using three monodisperse salbutamol aerosols [mass median aerodynamic diameter (MMAD) of 1.5 µm, 2.8 µm, 5 µm], Zanen and colleagues [11] demonstrated in patients with mild to moderate asthma that the 2.8 µm particle size aerosol produced a superior bronchodilation compared with the other two aerosols. In patients with severe airflow obstruction (FEV1<40%), Zanen et al. [12] demonstrated that the optimal particle size for β2agonist or anticholinergic aerosols is approximately 3 µm. They examined the effect on lung function of equal doses of three different sizes of monodisperse aerosols, 1.5 µm, 2.8 µm and 5 µm, of salbutamol and ipratropium bromide. Their findings suggest that small particles penetrate more deeply into the lung and thereby, more effectively dilate the small airways than larger particles, which are filtered out in the upper airways. The 1.5-µm aerosol induced significantly less bronchodilation than the 2.8-µm aerosol, suggesting this fine aerosol may be deposited too peripherally to be effective since smooth muscle is not present in the alveolar region.
What is the effect of aerosol size on therapeutic efficacy?
(a) Percent improvement in forced expiratory volume in 1 s (FEV1) following inhalation of two different size aerosols of salbutamol, 3.3 µm and 7.7 µm. The dose–response curves show that, for the β-agonist, salbutamol, the small particle aerosol (3.3 µm) produced a greater bronchodilator response at all doses compared with the larger particle size aerosol. (b) Percent improvement in FEV1following inhalation of two different size aerosols of ipratropium bromide, 3.3 µm and 7.7 µm. For the muscarinic antagonist, ipratropium bromide, there were no significant differences in the dose–response curves between the two aerosols. (From Johnson MA et al. Chest1989; 96: 1–10 [9].)
How does aerosol therapy affect the lung?
The therapeutic effect of aerosolized therapies is dependent upon the dose deposited and its distribution within the lung. The influence of the latter on the effectiveness of inhaled therapies is less clear. Ruffin and colleagues [4] demonstrated that a small dose of histamine aerosol deposited predominantly in the large conducting (central) airways was as effective in increasing airway obstruction as an 11-fold greater dose of histamine aerosol deposited diffusely, suggesting that the receptors for histamine reside mainly in the large airways and that surface concentration of a drug affects response.
Why is the lung important?
Like all major points of contact with the external environment, the lung has evolved to prevent the invasion of unwanted airborne particles from entering the body. Airway geometry, humidity and clearance mechanisms contribute to this filtration process. The challenge in developing therapeutic aerosols is to produce an aerosol that eludes the lung's various lines of defence.
What are the advantages of pulmonary drug delivery?
Pulmonary drug delivery offers several advantages as a route of administration for the treatment of systemic diseases compared with intravenous, oral, buccal, transdermal, vaginal, nasal or ocular administration. The advantages of pulmonary administration are listed in Table 1[20–23]. Until recently, aerosol drug delivery has been limited to topical therapy for the lung and nose. The major contributing factor to this restriction was the inefficiencies of available inhalation devices that deposit only 10–15% of the emitted dose in the lungs. While appropriate lung doses of steroids and bronchodilators can be achieved with these devices, for systemic therapies large amounts of the drug are necessary to achieve therapeutic drug levels, systemically. Recent advances in aerosol and formulation technologies have led to the development of delivery systems that are more efficient and that produce small particle aerosols allowing higher drug doses to be deposited in the alveolar region of the lungs where they are available for systemic absorption.
Where do antibiotics deposition occur?
Successful therapy would theoretically require the antibiotic to be evenly distributed throughout the lungs. However, those confined to the alveolar region would probably benefit from a greater peripheral deposition. Pneumocystis cariniipneumonia, the most common life-threatening infection among patients infected with HIV, is found predominately within the alveolar spaces with relapses occurring in the apical region of the lung after treatment with inhaled pentamidine given as a 1-µm MMAD aerosol [13]. The mechanism suggested for this atypical relapse is the poorer apical deposition of the aerosol. Regional changes in intrapleural pressure result in the lower lung regions receiving relatively more of the inspired volume than the upper lung when sitting in an upright position or standing. This influence on deposition has been shown to occur in an experimental lung model analysing sites of aerosol deposition in a normal lung. The experiment showed a 2 : 1 ratio in overall deposition for a 4 µm aerodynamic diameter aerosol between the lower and upper lobes when in the upright position [14]. Baskin and colleagues [13] demonstrated that this gradient could be reduced by administering aerosolized pentamidine to patients in the supine position. Thus, receiving aerosolized pentamidine in the supine position may reduce the risk of relapse in the apical lobes of the lung by increasing the amount of antibiotic deposited in the upper lung regions. This theory remains to be proven in a clinical trial.
Why is the lung important for drug delivery?
As the end organ for the treatment of local diseases or as the route of administration for systemic therapies, the lung is a very attractive target for drug delivery. It provides direct access to disease in the treatment of respiratory diseases, while providing an enormous surface area and a relatively low enzymatic, controlled environment for systemic absorption of medications. As a major port of entry, the lung has evolved to prevent the invasion of unwanted airborne particles from entering into the body. Airway geometry, humidity, mucociliary clearance and alveolar macrophages play a vital role in maintaining the sterility of the lung and consequently are barriers to the therapeutic effectiveness of inhaled medications. In addition, a drug's efficacy may be affected by where in the respiratory tract it is deposited, its delivered dose and the disease it may be trying to treat.
Why is inhalation therapy important?
For locally acting drugs, the onset of action is immediate. Systemically active inhaled drugs reach the blood stream quickly, within seconds. Rapid onset of action is especially important for rescue medications (such as asthma products), as well as pain medication and time-sensitive therapies such as insulin. Patients cannot always afford to wait the 15 minutes or longer it often takes for a tablet to make its way through the gastrointestinal tract.
What is a sonic disruptor?
Sonic disruptors, or sonicators, break up particles in liquid media with powerful ultrasonic waves, ranging from about 15 to 50 kHz. Ultrasonic waves in these frequencies are inaudible to the human ear, but they are capable of exerting pressures of more than 500 atmospheres and generating temperatures of up to 5,000°C. A probe or horn containing a piezoelectric generator amplifies the waves into an intense beam that creates the cutting or shearing effect on particles. This effect is called cavitation.
Is inhalation therapy effective?
Inhalation therapy has proven to be an effective method of administering a number of pharmaceuticals for more than a century. However, achieving the optimal particle size for a treatment with particular pharmaceutical formulations has been a troublesome task. This paper addresses many of the concerns that medical device manufacturers and their pharmaceutical partners have when attempting to achieve the correct particle size for an inhalation device.
How do particles get into the lung?
There are three main ways in which particles become deposited in the lung: inertial impaction, sedimentation, and diffusion. Inertial impaction tends to occur in the upper airways when the velocity and mass of the particles cause them to impact the airway surface. For this reason, inertial impaction can be influenced to some degree by hyperventilation. In contrast, sedimentation occurs in more peripheral airways, is gravitational in character, and tends to be influenced by breath-holding, which allows more time for gravity to have an effect. Diffusion is based on Brownian motion and is relevant to particles < 1 μm in diameter ( 3, 4 ).
What are the three areas of the airway?
To deliver a specific drug to a particular part of the airway as efficiently as possible, we must consider three broad areas: respiratory tract morphology, ventilatory parameters , and aerosol characteristics.
What are the advantages of using inert particles?
The advantages of using inert particles are that they are nontoxic, biologically inert, insoluble, and readily labeled. All of these properties help by reducing the number of variables that need to be accounted for when assessing the results. Examples of inert particles include Teflon, clay, polystyrene, albumin, and iron. Using the drug itself has the advantage of representing the product as it will be used by patients. However, the drug particles need to be labeled, which can be quite difficult; in some cases, the labeling itself can alter the physical properties of the drug particle ( 11 ). It is also possible to study a mixture of drug and inert particles.
What is the mechanism of aerosol deposition for small particles less than 3 m?
diffusion: the mechanism of aerosol deposition for small particles less than 3 µm (Diffusion is also called Brownian motion.)
What is aerosol in medicine?
A “medical aerosol” is any suspension of liq-uid (nebulizer or pMDI) or solid drug particles (pMDI or DPI) in a carrier gas.1 Our respiratory systems evolved to have filtration and elimination systems that must be overcome or bypassed in the process of providing local delivery of medications to the lung. Methods for generating aerosols, formulating drugs, and administering medications effec-tively to the desired site of action constitute the science of aerosol drug delivery. As is the case in any scientific disci-pline, one must first understand the terms and definitions used to describe the principles of aerosol medicine in order to subsequently master its methods.
What is heterodisperse aerosol?
heterodisperse: aerosol particles of different sizes hydrofluoroalkane (HFA): a nontoxic liquefied gas propel- la nt developed to be more environmentally friendly than CFCs and used to administer the drug from a pMDI
How much do PMDIs deliver?
Just like other aerosol generators, drug delivery with the pMDIs is approximately 10–20% of the nominal dose per actuation . The particle size of aerosols produced by the pMDI is in the fine particle fraction range in which the aerodynamic diameter of aerosols is less than 5 µm. Several factors influence the pMDI performance and aerosol drug delivery. Understanding the effects of these factors will improve the efficacy of pMDIs when used for patients with pulmonary diseases. Therefore, both respira-tory therapists and patients must actively control the fol-lowing effects:
How does a respimat work?
The Respimat® utilizes mechanical energy in the form of a ten-sioned spring to generate the soft aerosol plume. The ener-gy from turning the transparent base to the right one-half turn draws a predetermined metered volume of solution from the medication cartridge through a capillary tube into a micro-pump. When the dose release button is depressed, the energy from the spring forces the solution to the mouthpiece, creating a soft aerosol plume that lasts approx-imately 1.5 seconds. Similar to pMDIs, the Respimat® will need to be primed before use and at times when the devicehas had no use. If not used for more than 3 days, actuate the inhaler once. After more than 21 days of no use, it is
What is aerosol output?
aerosol output: mass of medication exiting an aerosol gen- erator
What is nominal dose?
nominal dose: the total drug dose placed in the nebulizer