Peptide delivery via the pulmonary route: a valid approach for local and systemic delivery
Introduction
Molecular biological research has contributed significantly to the identification of new therapeutic targets. This has resulted in an explosive growth in the number of peptide and protein drugs derived from both recombinant technology and conventional peptide drug design. Low membrane permeability, inadequate stability, potential safety issues and relatively short half-lives of many of these protein and peptide therapeutics limits their potential since they can only be administered by injection. Development of suitable non-injectable routes of administration (e.g. low cost, reproducible and safe) could significantly enhance patient compliance thereby increasing the benefit to be derived from these novel therapeutics. This has led to investigation of a variety of routes 1, 2, 3, 4, 5and a multitude of approaches to `package' peptides and proteins to circumvent potential delivery issues (e.g. stability, membrane permeability, clearance). However, an inability to achieve adequate delivery of many of these peptides and proteins via conventional routes (e.g. oral, nasal, transdermal) even in the presence of agents designed to `enhance' membrane permeability 6, 7together with the observations that many peptides and proteins are relatively well absorbed when delivered by the lung has provided the impetus for further evaluation of the airway as a route for systemic delivery 5, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27. Successful development of approaches for delivery of protein and peptide therapeutics via the airways requires an understanding of: (1) the barriers to absorption presented by the respiratory tract (e.g. geometry, morphology of the cells comprising the air-blood interface, mucociliary and enzymatic clearance mechanisms), (2) methodological approaches for evaluating lung delivery and absorption and potential limitations of these models, (3) advances in formulation development designed to address the inherent instability of these molecules, and (4) progress in device design which will enhance reproducibility and efficiency of delivery to the lung thereby optimizing absorption and reducing variability.
The respiratory tract has several unique features which make it an attractive site for peptide and protein drug delivery including: (1) a large surface area which can be exposed to drug almost simultaneously as opposed to the intestine which has a similar total surface area but does not allow for simultaneous exposure, (2) a high blood flow which does not directly expose absorbed drug to the clearance mechanisms present in the liver, and (3) relatively less metabolic activity. The upper respiratory tract including the trachea and large bronchi have a relatively limited surface area for absorption compared to the alveolar region which provides more that 95% of the surface area of the lung [28]. These results suggest that systemic absorption of peptides and proteins occurs in the alveolar region of the lung but the site of action for agents with local effects may be in either the alveolar region or in the larger airways.
The following review will summarize information relating to our current understanding of the barriers involved in the efficient delivery of peptides and proteins to the lung, mechanisms involved in transport of peptides and proteins across the respiratory tract epithelium, examples of molecules which have been or are being developed for local or systemic delivery via the lung and a brief overview of future directions.
Section snippets
Barriers to efficient delivery and absorption from the respiratory tract
There are a number of barriers to the efficient delivery of drugs to the respiratory tract including geometry of the airways, morphology of the airway epithelial cells and clearance mechanisms which are present in the respiratory tract (Fig. 1). Successful development of therapeutics for administration by the respiratory route requires an understanding of these barriers to allow rational design of the aerosol formulation and device to achieve optimal delivery.
Aerosol can be delivered to the
Localized delivery of DNase
Cystic fibrosis is a genetic disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) 46, 47, 48. CFTR is present in the apical membrane of airway epithelial cells (and other organs) and has been shown to be the channel through which chloride is secreted into the lung lumen 49, 50, 51. This process contributes to the control of the volume and composition of the fluid layer immediately adjacent to the airway epithelium. Defective secretion of chloride
Localized gene therapy
Identification and cloning of the gene which encodes CFTR was the first step in developing a gene therapy approach for pulmonary complications associated with cystic fibrosis 59, 60, 61. Accordingly, studies are ongoing to identify the airway epithelial cells which normally express CFTR and appropriate vector systems to target these cells and determine safety of gene transfer and expression 62, 63, 64, 65. Initially it was argued that gene delivery might only be required in the upper airways
Systemic delivery of peptides and proteins
During the past few years there has been an exponential rise in the number of reports describing absorption of peptides and proteins following administration to the lung (for review see Wall[16]). Results from these studies have clearly demonstrated the feasibility of systemic peptide and protein delivery via this route. At present, development of leuprolide is in stage III clinical trials and will probably be the first peptide developed for systemic delivery following administration via the
Summary
From the preceding discussion, it is apparent that opportunities for systemic delivery as well as efficient local delivery of peptides, proteins and genes exists. As our understanding of the barriers involved in efficient delivery/absorption of molecules increases, the number of development candidates will increase. A major hurdle for continued progress with pulmonary delivery will be the successful development of a stable formulation/device combination which provides efficient delivery to the
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2012, European Journal of Pharmaceutical SciencesCitation Excerpt :However, due to the low absorption rate and instability in gastrointestinal tract, the administration of these active agents was mainly limited to parenteral routes. Among many non-invasive administration routes the lungs have shown to be the most promising alternative to injection to deliver biopharmaceuticals such as peptide and protein drugs to obtain systemic absorption (Codrons et al., 2003; Gonda, 2000; Smith, 1997). Currently, three types of aerosol formulations and devices are available: nebulizers (jet or ultrasonic), (pressurized) metered dose inhalers (pMDIs) and dry powder inhalers (DPIs).