Pulmonary drug delivery - Philadelphia University dr… · Pulmonary drug delivery 15/01/2019 Dr. Yazan Al Thaher 1. Introduction Therapeutic agents for the treatment or prophylaxis

Pulmonary drug delivery

15/01/2019 Dr. Yazan Al Thaher 1

IntroductionTherapeutic agents for the treatment or prophylaxis of airways diseases, such as bronchial asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis are usually delivered directly to the respiratory tract. Advantages:

1. Rapid onset of activity (e.g. bronchodilators in asthma)

2. Smaller doses delivered locally avoiding systemic side effects.

3. Delivery of poorly absorbed drugs (e.g. sodium cromoglycate)

4. Delivery of rapidly metabolized drugs if given orally, e.g. isoprenaline

5. The avoidance of first-pass metabolism in the liver. although the

lung itself has some metabolic capability


Introduction

The lung may also be used as a route for delivering drugs having systemic activity, because of :

➢its large surface area,

➢the abundance of capillaries and the thinness of the air–blood barrier.

This has been exploited in the treatment of migraine with ergotamine, and the potential for delivering biopharmaceuticals, such as insulin, vaccines and growth hormone via the airways is now well established.


Lung anatomy

• Oxygen and carbon dioxide are exchanged

between blood and inhaled air.

• The respiratory tract can be considered as comprising of:

1. conducting (central) regions (trachea, bronchi, bronchioles, terminal and respiratory bronchioles) and

2. respiratory (peripheral) regions (respiratory bronchioles and alveolar regions.(Fig. 37.1)


Lung anatomy

• These contain approximately 2–6 × 108 alveoli, producing a surface area of 100–140 m2 in an adult male.


Inhalation aerosols and the importance of size distribution

• To deliver a drug into the airways, it must be presented as an aerosol (with the exception of 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, having sufficiently small size to display considerable stability as a suspension.

• The deposition of a drug/ aerosol in the airways is dependent on four factors:

1. the physicochemical properties of the drug,

2. the formulation.

3. the delivery/liberating device,

4. the patient (breathing patterns and clinical status).


Inhalation aerosols and the importance of size distribution

• The most important physical property of an aerosol for inhalation is its size.

• The particle size of an aerosol is usually standardized by calculation of its aerodynamic diameter, da, which is the physical diameter of a unit density sphere which settles through air with a velocity equal to the particle in question.

• Large porous particles, with large physical diameters of the order of 20 µm are efficiently delivered to and deposited in the lungs.


Particle deposition in the airways

• The efficacy of a therapeutic aerosol is dependent on its ability to penetrate the respiratory tract and be deposited.

• To penetrate to the peripheral (respiratory) regions, aerosols require a size less than about 5 or 6 µm, with less than 2 µm being preferable for alveolar deposition.

• Larger particles or droplets are deposited in the upper respiratory tract and are rapidly removed from the lung by the mucociliaryclearance process.

• Steroid aerosols of sufficiently large size may deposit in the mouth and throat, with the potential to cause adverse effects, including oral candidiasis.



• There are three main mechanisms responsible for particulate deposition in the lung:

1. gravitational sedimentation,

2. impaction

3. diffusion.



➢Impaction:• The air stream changes direction in the throat, or where a bifurcation

occurs in the respiratory tract. • Particles within the air stream, having sufficiently high momentum, will

impact on the airways’ walls rather than following the changing air stream. • This deposition mechanism is particularly important for large particles

having a diameter greater than 5 µm, and particularly greater than 10 µm, and is common in the upper airways, being the principal mechanism for deposition in the nose, mouth, pharynx and larynx and the large conducting airways.

• With the continuous branching of the conducting airways, the velocity of the air stream decreases and impaction becomes a less important mechanism for deposition.



➢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 particles in the size range 0.5–3 µm, in the small airways and alveoli, for particles that have escaped deposition by impaction.



➢Brownian diffusion:

Collision and bombardment of small particles by molecules in the respiratory tract produce Brownian motion. The resultant movement of particles from high to low concentrations causes them to move from the aerosol cloud to the airways’ walls. Diffusion is inversely proportional to particle size. It is the predominant mechanism for particles smaller than 0.5 µm.


Effect of particle size on deposition mechanism

• Different deposition mechanisms are important for different sized particles:➢ Those greater than 5 µm will deposit predominantly by inertial impaction

in the upper airways. ➢Particles sized between 1 and 5 µm deposit predominantly by gravitational

sedimentation in the lower airways, especially during slow, deep breathing and particles less than 1 µm deposit by Brownian diffusion in the stagnant air of the lower airways.

➢Particles of approximately 0.5 µm are inefficiently deposited, being too large for effective deposition by Brownian diffusion and too small for effective impaction or sedimentation, and they are often quickly exhaled. This size of minimum deposition should thus be considered during formulation, the equilibrium diameter in the airways may be significantly larger than the original particle size in the formulation.


Formulating and delivering therapeutic inhalation aerosols• There are currently three main types of aerosol generating device for

use in inhaled drug therapy:

1. Pressurized metered-dose inhalers,

2. Dry powder inhalers

3. Nebulizers.


Pressurized metered-dose inhalers

• Pressurized metered-dose (pMDIs )are the most commonly used inhalation drug delivery devices.

• In pMDIs, drug is either dissolved or suspended in liquid propellant(s) together with other excipients, including surfactants, and presented in a pressurized canister fitted with a metering valve (Fig. 37.2).


Dry powder inhalers

• In dry powder inhaler (DPI) systems, drug is inhaled as a cloud of fine particles. The drug is either preloaded in an inhalation device or fillled into hard gelatin capsules or foil blister discs which are loaded into a device prior to use.

• DPIs have several advantages over pMDIs: • DPI formulations are propellant-free and usually do not contain any

excipient, other than a carrier, which is usually lactose. • They are breath-actuated, avoiding the problems of inhalation/actuation

coordination encountered with pMDIs. • DPIs can also deliver larger drug doses than pMDIs, which are limited by

the volume of the metering valve and the maximum suspension concentration that can be employed without causing valve clogging.



Nebulizers

• Nebulizers deliver relatively large volumes of drug solutions and suspensions and are frequently used for drugs that cannot be conveniently formulated into pMDIs or DPIs, or where the therapeutic dose is too large for delivery with these alternative systems.



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Pulmonary drug delivery - Philadelphia University dr… · Pulmonary drug delivery 15/01/2019 Dr. Yazan Al Thaher 1. Introduction Therapeutic agents for the treatment or prophylaxis