Overview Of Pulmonary/Inhalation Route Of Drug Administration

The pulmonary or inhalation route of administration has been traditionally used for drug administration to the respiratory tract, in pathologies like chronic obstructive pulmonary disease or COPD, asthma, cystic fibrosis, etc. Pulmonary drug delivery is the inhalation of drug formulation through the mouth and the further deposition of inhaled pharmacological agent in lower airways. The large surface area of the human lung, along with its rich blood supply, rapid onset of drug action with high bioavailability, and other physiological advantages makes it suitable for drug delivery.

Pulmonary/inhalation of drug

Drug delivery by inhalation is a common route, both for local and for systemic actions. It enters the bloodstream by diffusing across the alveolar membrane. This is the method of administration of volatile drugs.

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To be able to reach the lungs, through the bronchial tree, a drug must be in powder aerosol form and pressurized metered-dose aerosols containing the drug in liquefied inert propellant generated by an appropriate device. Aerosols are relatively stable two-phase systems consisting of condensed and finely divided matter suspended into a continuous gaseous phase. Due to the size restrictions imposed by this route, dispersion must be colloidal, and the dispersed phase may be a liquid (mist), solid (suspension), or a combination of both.

Anatomy Of Pulmonary Route

The lung is composed of more than 40 different cells. The human respiratory system is a complex organ system having two vital regions: the conducting airways and the respiratory region. The airway is further divided into nasal cavity, and associated sinuses, and the nasopharynx, oropharynx, larynx, trachea, bronchi, and bronchioles. The respiratory region consists of respiratory bronchioles, alveolar ducts, and alveolar sacs. The transepithelial transport of drugs along the respiratory epithelium from these two regions is characterized by large quantitative differences. The drug transport in upper airways is limited due to smaller surface area and lower regional blood flow. Furthermore, this region possesses a high filtering capacity and removes up to 90% of delivered drug particles. Further inhaled substances deposit on the mucus layer, which coats the walls of the conducting airways. Mucus is secreted by goblet and submucosal gland cells and forms a gel-like film consisting of mucin as the major component. Ciliated cells are also present in this region; they cause propulsion of mucus upward and out of the lung, thus the lung will be cleared of foreign substances. In contrast, the smaller airway and alveolar space accounts for more than 95% of the lung's surface area and is directly connected to the systemic circulation via the pulmonary circulation. Apart from this, morphology of the major alveolar epithelial cells, the pulmonary blood-gas barrier system, and size of pores and tight junction depth of alveolar and endothelial cells are most likely reasons that govern the transepithelial drug transport.

Mechanism Of Drug Adsorption Of Pulmonary Route

Through pulmonary route, the drug can be administered by two primary modes: first, intranasal administration, which has narrower airway lumen as anatomical limitations. Second oral inhalation administration. By oral inhalative administration, far better results can be expected as it allows the administration of very small particles with a concentration loss of only 20% in comparison with 85% by nasal route. Oral inhalative administration can again be classified as intratracheal instillation and intratracheal inhalation. In the intratracheal instillation which is more commonly used, a small amount of drug solution or dispersion is delivered into the lungs by a special syringe. This provides a fast and quantifiable method of drug delivery to the lungs. The localized drug deposition is achieved with a comparatively small absorptive area. So, the instillation process is much simpler, non-expensive, and has non-uniform drug distribution. Inhalation method uses aerosol technique by which we can get a more uniform distribution with great penetration. However, this method is more costly and difficult to measure the exact dose in the lungs. The deposition of drugs by aerosol administration in the pulmonary airway mainly takes place by three mechanisms:-gravitational sedimentation, inertial impaction, and diffusion. If the drug particle size is comparatively bigger, then, deposition takes place by first two mechanisms where, either sedimentation occurs due to gravitational force or inertial impaction occurs due to hyperventilation. When the particle size is smaller they deposit mainly by diffusion mechanism, which in turn is based on the Brownian motion. Apart from the pulmonary morphological aspects and ventilatory parameters, size of the particles or droplets and the geometry is quite important. The size of a particle or droplet in terms of diameter along with the surface electrical charges, shape of the particulate matter if it is a fiber and hygroscopy also have profound influence on drug deposition through the pulmonary route. The term mass median aerodynamic diameter is used and it depends on size, shape, and density of the particulate system.

Devices

The devices most commonly used for respiratory delivery includes nebulizers, metered-dose inhalers, and dry powder inhalers.

Nebulizers

Nebulizers are available, namely jet nebulizers, ultrasonic nebulizers, and vibrating mesh nebulizers. Jet nebulizers are driven by compressed air. Ultrasonic nebulizers use a piezoelectric transducer in order to create droplets from an open liquid reservoir. Vibrating mesh nebulizers use perforated membranes actuated by an annular piezo element to vibrate in resonant bending mode.

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Meter Dose Inhaler

A metered-dose inhaler (MDI) is a device that delivers a specific amount of medication to the lungs, in the form of a short burst of aerosolized medicine that is usually self-administered by the patient via inhalation. A metered-dose inhaler consists of three major components; the canister which is produced in aluminium or stainless steel by means of deep drawing, where the formulation resides; the metering valve, which allows a metered quantity of the formulation to be dispensed with each actuation; and an actuator (or mouthpiece) which allows the patient to operate the device and directs the aerosol into the patient's lungs. The formulation itself is made up of the drug, a liquefied gas propellant and, in many cases, stabilising excipients. The actuator contains the mating discharge nozzle and generally includes a dust cap to prevent contamination. There are two methods for using an MDI. In many cases, the preferred method is with a device called a valved holding chamber. An MDI can also be used without a chamber.

Dry Powder Inhaler (DPI)

Today there are essentially two types of DPIs, those that drug use filled into discrete individual doses doses, e.g., either a gelatin capsule or a foil–foil blister, and those that use a reservoir of drug that meters out doses when required. Both are now widely available around the globe and are gaining broad acceptance.

Unit‐Dose Devices: Single‐dose powder inhalers are  devices in which a powder containing capsule is placed in a holder. The capsule is opened within the device and the powder is inhaled. The capsule residue must be discarded after use and a new capsule inserted for the next dose.

Multidose Devices: Multidose device uses a circular disk that contains either four or eight powder doses  on a single disk. This typically would be treatment for one to two days. The doses are maintained in separate aluminum blister reservoirs until just before inspiration. This device is a true multidose device, having 60 doses in a foil–foil aluminum strip  that is opened only at the point just prior to patient inspiration.

Single/-multiple dose dry powder inhalers (DPI) available in the market deliver proteins to the lungs. Aqueous suspensions and solutions are nebulized effectively.