Pulmonary Administration

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Drugs can be introduced into the pulmonary system as gases or in aerosol forms. An almost instantaneous absorption can be expected due to the extremely large surface area available for absorption. The primary mechanism of absorption is passive diffusion but the lipid solubility tends to play a smaller role than in gastrointestinal absorption. The main limiting step in the utilization of this route has been the need to design dosage forms which accurately deliver the drugs. Most of these drugs are administered as aerosols, and their delivery to a great extent is dependent on the particles size distribution. Particles greater than 10 U are almost completely removed by impaction in the nasal passages. IMPACTION refers to the deposition of particles in the respiratory tract. The precipitation of particles arises from the tendency of a particle moving in a stream of air to continue in its original direction when the air current changes direction at bronchial branch points and at curves in the bronchial tree. Impaction due to diffusion is negligible except for very small particles. Particles below 10 U in diameter are of great significance since these include bacteria, viruses, smoke, industrial fumes, dust laden with fission product, pollens, insecticide dusts and sprays, and inhalant sprays used in the therapy of pulmonary diseases.

In order for a drug to be absorbed from an aerosol its particles must impact, preferably in the alveolar sacs, and dissolve in the available fluids. Larger particles are retained in the upper respiratory tract and smaller particles penetrate deeper into the pulmonary tree. Particles larger than 2 U in diameter probably do not reach the alveolar sacs. Particles sizes approximating l U are most desirable, but there is a greater tendency for these particles to be exhaled without being impacted. Thus many formulations include hygroscopic substances in the formulation to increase the size of particles deeper into the trachea. The tidal volume is also an important consideration. At a given respiratory rate, the air stream velocity is greater at high-tidal volumes and thus particles of all sizes tend to be driven deeper into the pulmonary tree before impaction.

Pulmonary administration has been used mainly for local therapy. For example, aerosols of epinephrine, isoproterenol, and dexamethasone are commonly used for acute asthmatic attacks, and antibiotics are sometimes incorporated for the treatment of complicated bronch-opulmonary infections. In some instances, the systemic absorption of drugs administered for local action may be appreciable. For example, isoproterenol in a 0.5% aerosol is an effective bronchodilator, but a l% aerosol is apt to cause undesirable cardioacceleratory and hypertensive actions after only a few inhalations. The quick responses can, however, be beneficial in the treatment of anaphylactic episodes, as in the use of epinephrine.

Although the pulmonary route is used mainly for local effects, several drugs have been successfully administered in this way for systemic effect, including penicillin, glycosides, diuretics, and tranquilizers. More recently, an inhalation form of insulin has been marketed where the primary mechanism is impaction of very fine particles.

The problem of accurate dosing in pulmonary dosing in pulmonary administration remains a serious obstacle to greater use of this route. The use of metered dose devices is certainly an improvement and some products use the drug as a powder aerosol. The powder particles sizes range primarily between 2 and 6 U. This device, currently used for disodium cromoglycate (cromolyn sodium: Aarane® inhaler) provides a greater and more consistent absorption than can be obtained from other metered dose devices.

The pressurized MDIs the use of environmentally friendly propellants means choice of hydrofluoroalkanes wherein the dosage form can be a suspension of solution form. The problems of formulating suspensions as discussed above apply here as well but particularly with respect to interactions with the formulation components specific to pressurized inhaler systems. Solution dosage forms require selection of propellants wherein the drug can dissolve without crystallizing and may require addition of surfactants and cosolvents. However, there are toxicological issues with the use of surfactants. The solubility of drugs in solvents is determined by filtering the suspension in pressurized can into another can and then evaporating the clear solution (bringing to room temperature) and determining the amount of drug in it. High solubility in propellants can lead to crystal growth as propellants evaporate. Ostwald ripening common to suspensions applies to inhalation suspensions; the changes in the property of suspension can be studied using microscopy and observing changes in the axial ratio of crystal.

Drugs for inhalation therapy in a powder form required particular particle size which is achieved by the process of micronization between 1 to 6 nm to allow deep penetration through the lung alveoli system. There are number of devices which can deliver drugs to the lungs as dry powders, e.g., Turbuhaler™ or Diskhaler™. These dosage forms rely on a larger carrier particle, such as a-lactose monohydrate, to which the drug is attached. The lactose is usually fractionated such that it lies in the size range 63-90 nm. Upon delivery, the drug detaches from the lactose and, because the drug is micronized, it is delivered to the lung, whereas the lactose is eventually swallowed. It should be realized that the polymorphic form of the lactose used could affect the aersosolization properties of the formulation. The P-forms were easily entrained, but held onto the drug particles most strongly when flow properties are studied. The anhydrous a-form shows an opposite behavior and the monohydrate a-form demonstrates intermediate behavior. Interactions with packaging materials can also alter powder characteristics; for example, long contact times with PVC, polyethylene or aluminum should be avoided since the adhesion force between the drug and these surfaces is much higher than between it and the lactose carrier. Thus, detachment and loss of drug in the formulation could occur. Because lactose is widely used as a carrier, its compatibility with the new drugs should be studied in detail specially if there are any amino groups in the structure. The surface property of lactose is also important. With increasing specific surface area and roughness, the effective index of inhalation decreases due the drug being held more tightly in the inhaled airstreams. Therefore, characterization of the carrier particles by, e.g., surface area measurements, SEM and other solid-state techniques are recommended preformulation activities.

The recent approval by the U.S. FDA of Exubera®, an inhalation form of insulin is a classical example where the dosage form is an integral part of drug action. Using the Nektar company's delivery system to create a fine powder mist, insulin in Exubera is absorbed as the mist of fine reaches into deep portions of lung structure without getting impacted. Whereas reduction in particle size is pivotal to pulmonary delivery of drugs, micronization makes powders difficult to flow and these changes should be studied using such techniques as DVS, microcalorimetry and inverse gas chromatography (IGC). The high energy at the surface of micronized powders can often be relieved by exposing it to higher humidity air which can crystallize the amorphous high-energy regions. As a result, the common preformulation stage evaluations include measurements of the micromeritic, RH and electrostatic properties of the powder. Different salt forms show variant flow properties; for example, stearate salts generally are better for aerosol formulation.

Nebulizer formulations are normally solutions but suspensions (particle size of less than 2 nm) are also used. Important preformulation considerations include stability, solubility, viscosity, and surface tension of the solution of suspension.

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