Elsevier

Drug Discovery Today

Volume 20, Issue 3, March 2015, Pages 380-389
Drug Discovery Today

Review
Post screen
Recent advances in controlled pulmonary drug delivery

https://doi.org/10.1016/j.drudis.2014.09.020Get rights and content

Highlights

  • Controlled pulmonary drug delivery is a promising system.

  • Novel strategies are developed to avoid the formidable airway clearance mechanisms.

  • Large porous particles can lead to higher aerosolization efficiency.

  • Swellable microparticles can release drug in a controlled manner at the lung surface.

  • The porous nanoparticle–aggregate particles (PNAPs) can sustain drug release.

Characterized by large surface area, high vascularization and thin blood–alveolar barrier, drug delivery by the pulmonary route has benefits over other administration routes. However, to date most of the marketed inhalable products are short-acting formulations that require the patient to inhale several times every day, thus reducing patient compliance. Controlled pulmonary drug delivery is a promising system but the formidable airway clearance mechanisms need to be avoided. This review mainly introduces the barriers impeding the development of controlled pulmonary drug delivery and strategies used to overcome them. We believe that large porous particles, swellable microparticles and porous nanoparticle–aggregate-based particles are the most promising carriers to control drug release in the lung.

Introduction

With the acceleration of industrialization, especially in developing countries, environmental contamination has received increasing attention because many individuals suffer from respiratory diseases. According to WHO, there were 235–330 million asthmatics around the world in 2011 and about 250 000 die annually. Also, chronic obstructive pulmonary disease, which is presently the fourth leading cause of death [1], affected 329 million people globally in 2010. Moreover, 8.6 million people got sick and 1.3 million died due to tuberculosis in 2012. Meanwhile, pneumonia, being the foremost cause of pediatric death, kills about 1.1 million children under five each year.

From the epidemiological analysis of several main respiratory diseases above, we can observe the prevalence and seriousness of the problem. For alleviation and treatment of these diseases, oral, parenteral and pulmonary delivery methods are the most frequently used administration routes for patients and medical practitioners. Characterized by large surface area, high vascularization and thin blood–alveolar barrier, drug delivery by the pulmonary route has many outstanding features compared with oral or parenteral routes, including local targeting, circumvention of first-pass hepatic metabolism and rapid onset of action. Moreover, high therapeutic ratio, increased selectivity, lower administered dose and reduced side-effects are also advantages 2, 3. In addition, for locally applied drugs, the systemic side-effects could be reduced because of minimized systemic exposure by targeting to the desired site (particularly for drugs with a narrow therapeutic window).

In addition to the application for respiratory medicine, the pulmonary route can also act as a portal for systemic delivery of therapeutic agents, especially for those with poor oral bioavailability. Among all the attempts for a systemic effect via the pulmonary route, inhalable insulin is the most common. Despite the temporary survival of Exubera® in the market for various reasons after years of endeavor, the enthusiasm of those seeking academic and commercial triumph in the use of inhalation systems for treating non-pulmonary diseases has not faded [4]. The recent approval of MannKind Corp's inhaled insulin, Afrezza®, by the FDA might be the best example of this, and could further facilitate the development of pulmonary drug delivery systems.

However, currently available inhalation products on the market are mainly rapid release formulations, although numerous efforts have been made to develop controlled release delivery systems. An obvious shortcoming concerning the present products is that drug concentration peaks initially and then declines promptly, which can cause unpleasant adverse effects at the onset and inadequate therapy subsequently for drugs with actions relating to their tissue and blood concentrations. By contrast, drug release rate modulation provides plentiful advantages over traditional preparations, such as reduced frequency of drug administration, improved patient compliance and releasing the drug at the targeted region. What is more, controlled release formulations enable the drug to be retained in the physiological state for longer time periods with improved therapeutic efficacy.

Unfortunately, the formidable airway clearance mechanisms, including mucociliary clearance, macrophage clearance, systemic absorption and metabolic degradation, are the main challenges for developing controlled release formulations. Nevertheless, using current knowledge of lung–particle interactions, some novel strategies are developed to avoid these mechanisms. With innovative drug carriers, pulmonary controlled release is no longer impossible. Thus, this article will focus on particle deposition and clearance mechanisms in the airways, promising polymers as the carrier for controlled pulmonary drug delivery system design, preparation of different delivery systems and corresponding mechanisms for avoiding clearance in the lung. Perspectives in this field are also discussed.

Section snippets

Particle deposition and clearance mechanisms in the airways

Once inhaled orally, there are three universally accepted deposition mechanisms for particles accessing the lung: inertial impaction, gravitational sedimentation and Brownian diffusion. Impaction and sedimentation have predominant roles in the deposition of microparticle and nanoparticle agglomerates. For instance, microparticles with diameters larger than 5 μm are prone to deposit in the oropharynx owing to their large size, which results in great gravitation and inertia (Fig. 1a). The behavior

Polymers for controlled pulmonary drug delivery

So far, a large amount of polymeric material has been studied as carriers for pulmonary drug delivery, including natural polymers [albumin, carrageenan, chitosan (CS), gelatin, hyaluronic acid (HA)], synthetic polymers [poly(lactic acid), oligo(lactic acid), poly(vinyl alcohol), acrylic acid derivatives] and copolymers [poly(lactic-co-glycolide acid) (PLGA)] [7]. While screening for appropriate polymers, biocompatibility and biodegradability are the predominant properties to consider [2]. Among

Conventional microparticles

Considering that particles with larger diameters (usually >5 μm) are prone to deposit in the oropharynx (Fig. 1a), whereas smaller particles (usually <0.5 μm) are easily exhaled, the microparticles should be in the size range of 1–5 μm to achieve efficacious pulmonary deposition (Fig. 1b). Microparticles fabricated with biodegradable materials are the conventional carriers to sustain drug release in the lung. By loading active pharmaceutical ingredients (APIs) in the microparticles, direct contact

Concluding remarks

Until now, no inhaling formulations with a controlled release feature have reached the clinical stage, although no efforts have been spared to extend the action time of pulmonary medicine experimentally. To accomplish controlled pulmonary delivery, innovative carriers are developed to overcome the formidable airway clearance mechanisms, including mucociliary clearance, macrophage clearance, systemic absorption, cough clearance and so on; the advantages and disadvantages of different delivery

Acknowledgments

This project is financially supported by Liaoning Institution’s excellent talent support plan (No. LR2013047), China and the Liaoning Province Science and Technology Construction Project of the Drug Innovation Incubator Platform, China.

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