1 pulmonary drug delivery dr mohammad issa. 2 pulmonary drug delivery anatomy and physiology of the...

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Pulmonary Drug Delivery

Dr Mohammad Issa

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Pulmonary Drug Delivery

Anatomy and Physiology of the Respiratory System

Advantages of Pulmonary Delivery Lung epithelium at different sites within

the lungs Pulmonary absorptive surfaces Systemic delivery of:

Small hydrophobic drugs Small hydrophilic drugs Macromolecules drugs

Pulmonary Drug Delivery Devices

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The human respiratory system is divided into upper and lower respiratory tracts

The upper respiratory system consists of the nose, nasal cavities, nasopharynx, and oropharynx

The lower respiratory tract consists of the larynx, trachea, bronchi, and alveoli, which are composed of respiratory tissues

The left and right lungs are unequal in size. The right lung is composed of three lobes: the superior, middle, and inferior lobes. The smaller left lung has two lobes

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The nasopharynx is a passageway from the nose to the oral pharynx

The larynx controls the airflow to the lungs and aids in phonation

The larynx leads into the cartilaginous and fibromuscular tube, the trachea, which bifurcates into the right and left bronchi

The bronchi, in turn, divide into bronchioles and finally into alveoli

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The respiratory tree can be differentiated into the conducting zone and the respiratory zone.

The conducting zone consists of the bronchi, which are lined by ciliated cells secreting mucus and terminal bronchioles.

The respiratory zone is composed of respiratory bronchioles, alveolar ducts, atria, and alveoli

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The epithelium in the conducting zone gets thinner as it changes from pseudostratified columnar to columnar epithelium and finally to cuboidal epithelium in the terminal bronchioles

The upper part of the conducting zone (from the trachea to the bronchi) consists of ciliated and goblet cells (which secrete mucus)

These cells are absent in the bronchioles. Alveoli are covered predominantly with a monolayer of squamous epithelial cells (type I cells) overlying a thin basal lamina

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Cuboidal type II cells present at the junctions of alveoli secrete a fluid containing a surfactant (dipalmitoylphosphatidylcholine), apoproteins, and calcium ions

The lungs are covered extensively by a vast network of blood vessels, and almost all the blood in circulation flows through the lungs. Deoxygenated blood is supplied to the lungs by the pulmonary artery

The pulmonary veins are similar to the arteries in branching, and their tissue structure is similar to that of systemic circulation. The total blood volume of the lungs is about 450 mL, which is about 10 percent of total body blood volume

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Comparison of the lung epithelium at different sites within the lungs

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Types of epithelium

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Advantages of Pulmonary Delivery of Drugs To Treat Respiratory Disease

Deliver high drug concentrations directly to the disease site

Minimizes risk of systemic side effects

Rapid clinical response

Bypass the barriers to therapeutic efficacy, such as poor gastrointestinal absorption and first-pass metabolism in the liver

Achieve a similar or superior therapeutic effect at a fraction of the systemic dose, (for example, oral salbutamol 2–4 mg is therapeutically equivalent to 100–200 μg by metered dose inhaler)

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Advantages of Pulmonary Delivery of Drugs To Treat Systemic Disease

A non-invasive, needle-free delivery system

Suitable for a wide range of substances from small molecules to very large proteins

Enormous absorptive surface area (140 m2) and a highly permeable membrane (0.2–0.7 μm thickness) in the alveolar region

Large molecules with very low absorption rates can be absorbed in significant quantities; the slow mucociliary clearance in the lung periphery results in prolonged residency in the lung

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Advantages of Pulmonary Delivery of Drugs To Treat Systemic Disease

A less harsh, low enzymatic environment

Avoids first-pass metabolism

Reproducible absorption kinetics

Pulmonary delivery is independent of dietary complications, extracellular enzymes, and inter-patient metabolic differences that affect gastrointestinal absorption

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Pulmonary absorptive surfaces

The airways (the trachea, bronchi and bronchioles) are composed of a gradually thinning columnar epithelium populated by many mucus and ciliated cells that collectively form the mucociliary escalator

The airways bifurcate roughly 16–17 times before the alveoli are reached

Inhaled insoluble particles that deposit in the airways are efficiently swept up and out of the lungs in moving patches of mucus, and for those deposited in the deepest airways this can be over a time period of about 24 hour

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The monolayer that makes up the alveolar epithelium is completely different. The tall columnar mucus and cilia cells are replaced primarily (>95% of surface) by the very broad and extremely thin (<0.1 µm in places) type 1 cells

Distributed in the corners of the alveolar sacs are also the progenitor cells for the type 1 cells and the producers of lung surfactant, the type 2 cells

The air-side surface of each of the 500 million alveoli in human lungs is routinely 'patrolled' by 12–14 alveolar macrophages, which engulf and try to digest any insoluble particles that deposit in the alveoli

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An excess of 90% of alveolar macrophages are located at or near alveolar septal junctional zones

Insoluble, non-digestible particles that deposit in the alveoli can reside in the lungs for years, usually sequestered within macrophages

Molecules such as insulin are formulated either as liquids or in highly water-soluble aerosol particles that dissolve rapidly in the lungs and thereby largely avoid macrophage degradation

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Protein therapeutics that are taken up by macrophages can be rapidly destroyed in the lysosomal 'guts' of the phagocytic cells

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The effect of particle size on the deposition of aerosol particles in the human respiratory tract following a slow inhalation and a 5-second breath hold

Mouth and throatAlveolar region

Airways

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Systemic delivery of small hydrophobic molecules

Small, mildly hydrophobic molecules can show extremely rapid absorption kinetics from the lungs

However, as hydrophobicity increases, molecules can become too insoluble for rapid absorption and can persist in the lungs for hours, days or weeks

Typical drug molecules with log octanol–water partition coefficients greater than 1 can be expected to be absorbed, with absorption half-lives (the time it takes half of the molecules deposited into the lungs to disappear from the tissue) of approximately 1 minute or so; decreasing the log octanol–water partition coefficient to –1 or lower can increase the half-life to around 60 minutes

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Systemic delivery of small hydrophobic molecules

Examples of rapidly absorbed inhaled hydrophobic drugs include nicotine, 9-tetrahydrocannabinol (THC), morphine and fentanyl

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Inhaled morphine (dose = 8.8 mg) compared with intravenous injection (dose = 4 mg) in human volunteers

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Systemic delivery of small hydrophilic molecules

In general, neutral or negatively charged hydrophilic small molecules are absorbed rapidly and with high bioavailabilities from the lungs

This class of molecules has an average absorption half-life of about 60 minutes, in contrast to some of the lipophilic molecules that are absorbed in seconds to minutes

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Systemic delivery of macromolecules

The use of the lungs for the delivery of peptides and proteins, which otherwise must be injected, is one of the most exciting new areas in pulmonary delivery

For reasons that are not completely understood, the lungs provide higher bioavailabilities for macromolecules than any other non-invasive route of delivery

However, unlike the situation with small molecules, for which lung metabolism is minimal, enzymatic hydrolysis of small natural peptides can be very high unless they are chemically engineered (blocked) to inhibit peptidases

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Small natural peptides make poor drugs by any route of delivery because of peptidase sensitivity, whereas blocked peptides show high pulmonary bioavailabilities

As molecular mass increases and peptides become proteins with greater tertiary and quaternary structure, peptidase hydrolysis is inhibited or even eliminated and bioavailabilities of natural proteins can be high

Insulin can be considered to be a large peptide (or small protein), with enough size to avoid much of the metabolism seen with smaller peptides

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The rate of macromolecule absorption is primarily dictated by size — the larger the size the slower the absorption

Molecules such as insulin, growth hormone and many cytokines typically peak in blood following aerosol inhalation in 30–90 minutes, whereas smaller blocked peptides can be absorbed faster

After a 15-year development effort, inhaled human insulin (IHI) applied regularly at meal time has been approved both in the US and the European Union for the treatment of adults with diabetes (Exubera)

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Conjugation of molecules such as interferons, follicle stimulating hormone (FSH) and erythropoietin (EPO) to the constant (Fc) region of antibodies has been shown to prolong the systemic duration

Interestingly, the optimal pulmonary site of absorption of these conjugates seems to be the conducting airways, in contrast to the major site for insulin, which is in the deep lung

The airways are enriched with antibody transcytosis receptor mechanisms. Fc conjugates of proteins have serum half-lives >1 day and are believed to be absorbed with high bioavailabilities (20–50%) from the lungs

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Pulmonary Drug Delivery Devices

Dry Powder Inhalation (DPI) Devices

The Pressurized Metered-Dose Inhalation (pMDI) Device

Nebulizers

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DPIs are used to treat respiratory diseases such as asthma and COPD, systemic disorders such as diabetes, cancer, neurological diseases (including pain), and other pulmonary diseases such as cystic fibrosis and pulmonary infectious diseases

Devices requiring the patient's inspiration effort to aerosolize the powder aliquot are called passive devices because as they do not provide an internal energy source

Active devices provide different kinds of energy for aerosolization: kinetic energy by a loaded spring and compressed air or electric energy by a battery

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Most DPIs contain micronized drug blended with larger carrier particles, which prevents aggregation and promotes flow

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Principle of dry powder inhaler design

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The pressurized metered-dose inhalation (pMDI) device was introduced to deliver asthma medications in a convenient and reliable multi-dose presentation

The key components of the pMDI device are: container, propellants, formulation, metering valve, and actuator

The pMDI container must withstand high pressure generated by the propellant. Stainless steel has been used as a pMDI container material. Aluminum is now preferred because, compared to glass, it is lighter, more compact, less fragile, and light-proof

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Coatings on the internal container surfaces may be useful to prevent adhesion of drug particles and chemical degradation of drug

Propellants in pMDIs are liquefied, compressed gases that are in the gaseous phase at atmospheric pressure but form liquids when compressed

They are required to be nontoxic, nonflammable, compatible with drugs formulated either as suspensions or solutions, and to have appropriate boiling points and densities

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Nebulizers

A nebulizer is a device used to administer medication to patient in the form of a mist inhaled into the lungs

It is commonly used in treating cystic fibrosis, asthma, and other respiratory diseases

There are two basic types of nebulizers: The jet nebulizer functions by the Bernoulli principle by

which compressed gas (air or oxygen) passes through a narrow orifice, creating an area of low pressure at the outlet of the adjacent liquid feed tube. This results in the drug solution being drawn up from the fluid reservoir and shattering into droplets in the gas stream

The ultrasonic nebulizer uses a piezoelectric crystal, vibrating at a high frequency (usually 1–3 MHz), to generate a fountain of liquid in the nebulizer chamber; the higher the frequency, the smaller the droplets produced

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Jet nebulizer

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Ultrasonic nebulizer

1 pulmonary drug delivery dr mohammad issa. 2 pulmonary drug delivery anatomy and physiology of the...

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