Aerosol Technology

The devices that are employed to deliver drugs to the lungs may be divided into three categories: pMDIs, DPIs, and nebulizers.10 Each of these systems delivers aerosols by a different principle, and the chemistry associated with the product varies significantly among them.

16.2.1. Particle Preparation

Before drug particles can be incorporated into aerosol products, they must be prepared in size ranges and with structures suitable for delivery to the lungs. A variety of methods have been developed for the preparation of particles.11,12 The most common method of particle size reduction is one in which bulk drug product, most of which is prepared by conventional crystallization/precipitation followed by drying techniques, is air jet milled at high pressure. Attrition of particles occurs, leading to the micronization of the product. In recent years, methods have been used which combine conversion of the solution to a solid with size reduction or crystal engineering. The first of these methods, spray drying, involves forcing the drug solution through a nozzle at high pressure into a drying airstream from which small particles can be recovered that are suitable for inclusion in aerosol products. These particles occasionally have unique properties that will be discussed later. Supercritical fluid manufacture is a particle construction or crystal engineering method. In its simplest form, this involves dispersing drug in a supercritical fluid (usually carbon dioxide), and by controlling the conditions of temperature, pressure, volume, or the presence of an antisolvent, the drug may be crystallized to form morphologically well-defined particles.

Drugs delivered from pMDIs are initially prepared as suspensions or solutions in a selected propellant.1314 Often other components are added to aid in suspension of particles or drug dispersion into solution. These additives may be cosolvents, such as ethanol, or surfactants, such as oleic acid.

The original pMDIs employed CFC propellants 11, 114, and 12 [e.g., beclo-methasone dipropionate (BDP) products Vanceril and Beclovent.]15 In recent years, these propellants have been replaced with hydrofluoroalkane (HFA) propellants 134a or 227 (e.g., BDP product Qvar) due to concern about atmospheric ozone depletion associated with CFCs.

Containers are filled on a large scale with drug formulation by a variety of techniques, based on high pressure or low temperature to control the state of the pro-pellant during filling.16 Valves are crimped on the opening to the container either before (pressure filling) or after (cold filling) propellant filling occurs.

The principle of aerosol delivery from pMDIs is based on the following sequence of events.14'17 A small volume of a homogeneous dispersion of the drug, in solution or suspension, in a high vapor pressure propellant or a propellant blend from a reservoir, is isolated. The small-volume container (the metering chamber) is opened through an actuator nozzle. The metering chamber filling and opening to the atmosphere are achieved by means of a metering valve. Once opened to the atmosphere, the high vapor pressure contents of the metering valve immediately begin to equilibrate with atmospheric pressure. This has the effect of propelling the contents rapidly through the nozzle, which causes shear and droplet formation. Throughout this process the propellant is evaporating propelling, shearing, and ultimately reducing the size of the droplets produced. The components of an pMDI are shown in Figure 16.1A.

DPIs have been through a number of evolutionary changes over the past 40 years.4 All approved inhalers have been passive, in the sense that they employ the patient's inspiratory flow as the means of dispersion and entrainment of the aerosol into the lungs. The majority of powder products are blends of respirable drug particles and large lactose carrier particles. Early designs employed a unit dose gelatin capsule metering system (Rotahaler, Spinhaler). This has to some extent been superseded by multiple unit dose blister discs (Diskhaler) and rolls (Diskus) or reservoir powder devices (Turbuhaler, Clickhaler). The general principle of powder delivery is shown in Figure 16.1B. A powder bed is exposed to a shearing air supply (usually the inspiratory airflow) that entrains particles. A blend will employ the fluidizing effects of large lactose particles to help disperse the respirable particles associated with their surfaces. The small drug particles will be carried to the lungs of the patient, while the large carrier particles will be deposited in the mouthpiece of the inhaler or the oropharynx of the patient.

A variety of mechanisms for assisting with the dispersion of the powder have been adopted, including impellors (Spiros), compressed air assist (Nektar), vibration (Oriel, Microdose), and impact hammers (3M, DelSys).

16.2.4. Nebulizers

Nebilizers are among the oldest devices used for delivery of therapeutic agents.18 They employ energy from compressed gas or piezoelectric ceramics to generate droplets of water containing drug. The principle of air jet dispersion is shown in Figure 16.1C. Drug solution (or occasionally suspension) is drawn from a reservoir

baffle airflow

solution reservoir compressed air

Figure 16.1. (A) Schematic diagram of a propellant-driven metered dose inhaler. (B) Schematic diagram of a dry powder inhaler. (C) Schematic diagram of a air-jet nebulizer.

through a capillary tube by the Venturi (Bernoulli) effect. In principle, a low-pressure region is created at the exit from the capillary tube when compressed gas is passed at high velocity over the tube, drawing liquid into the air, where droplets are formed. Large droplets are projected onto a baffle, where they are collected, and small ones pass around the baffle and are delivered to the patient's lungs on their inspiratory flow.

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