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Advanced Drug Delivery Reviews (v.58, #9-10)

Editorial Board (pp. ii).

Challenges and innovations in effective pulmonary systemic and macromolecular drug delivery^☆ by Mark Gumbleton Theme editor; Glyn Taylor Theme editor (pp. 993-995).

Clinical perspectives on pulmonary systemic and macromolecular delivery by Gerhard Scheuch; Martin J. Kohlhaeufl; Peter Brand; Ruediger Siekmeier (pp. 996-1008).

The large epithelial surface area, the high organ vascularization, the thin nature of the alveolar epithelium and the immense capacity for solute exchange are factors that led the lung to serve as an ideal administration route for the application of drugs for treatment of systemic disorders. However, the deposition behaviour of aerosol particles in the respiratory tract depends on a number of physical (e.g. properties of the particle), chemical (e.g. properties of the drug) and physiological (e.g. breathing pattern, pulmonary diseases) factors. If these are not considered, it will not be possible to deposit a reproducible and sufficient amount of drug in a predefined lung region by means of aerosol inhalation. The lack of consideration of such issues led to many problems in inhalation drug therapy for many years mainly because physiological background of aerosol inhalation was not fully understood. However, over the last 20 years, there has been considerable progress in aerosol research and in the understanding of the underlying mechanisms of particle inhalation and pulmonary particle deposition. As a consequence, an increasing number of studies have been performed for the lung administration of drugs using a variety of different inhalation techniques. This review describes the physical and in part some of the physiological requirements that need to be considered for the optimization of pulmonary drug delivery to target certain lung regions.

Keywords: Aerosol inhalation; Pulmonary drug delivery; Drug delivery; Particle deposition; Regional pulmonary drug targeting

Particle engineering techniques for inhaled biopharmaceuticals by Sunday A. Shoyele; Simon Cawthorne (pp. 1009-1029).

Formulation of biopharmaceuticals for pulmonary delivery is faced with the challenge of producing particles with the optimal properties for deep lung deposition without altering the native conformation of these molecules. Traditional techniques such as milling are continuously being improved while newer and more advanced techniques such as spray drying, spray freeze drying and supercritical fluid technology are being developed so as to optimize pulmonary delivery of biopharmaceuticals. While some of these techniques are quite promising, some are harsh and impracticable. Method scale up, cost-effectiveness and safety issues are important factors to be considered in the choice of a technique. This paper reviews the presently developed techniques for particle engineering biopharmaceuticals.

Keywords: Biopharmaceuticals; Protein/peptide; Particle engineering; Aerodynamic diameter; Spray drying; Supercritical fluid

In vivo, in vitro and ex vivo models to assess pulmonary absorption and disposition of inhaled therapeutics for systemic delivery by Masahiro Sakagami (pp. 1030-1060).

Despite the interest in systemic delivery of therapeutic molecules including macromolecular proteins and peptides via the lung, the accurate assessment of their pulmonary biopharmaceutics is a challenging experimental task. This article reviews in vivo, in vitro and ex vivo models currently available for studying lung absorption and disposition for inhaled therapeutic molecules. The general methodologies are discussed with recent advances, current challenges and perspectives, especially in the context of their use in systemic pulmonary delivery research. In vivo approaches in small rodents continue to be the mainstay of assessment by virtue of the acquisition of direct pharmacokinetic data, more meaningful when attention is given to reproducible dosing and control of lung-regional distribution through use of more sophisticated lung-dosing methods, such as forced instillation, microspray, nebulization and aerosol puff. A variety of in vitro lung epithelial cell lines models and primary cultured alveolar epithelial (AE) cells when grown to monolayer status offer new opportunity to clarify the more detailed kinetics and mechanisms of transepithelial drug transport. While continuous cell lines, Calu-3 and 16HBE14o-, show potential, primary cultured AE cell models from rat and human origins may be of greater use, by virtue of their universally tight intercellular junctions that discriminate the transport kinetics of different therapeutic entities. Nevertheless, the relevance of using these reconstructed barriers to represent complex disposition of intact lung may still be debatable. Meanwhile, the intermediate ex vivo model of the isolated perfused lung (IPL) appears to resolve deficiencies of these in vivo and in vitro models. While controlling lung-regional distributions, the preparation alongside a novel kinetic modeling analysis enables separate determinations of kinetic descriptors for lung absorption and non-absorptive clearances, i.e., mucociliary clearance, phagocytosis and/or metabolism. This ex vivo model has been shown to be kinetically predictive of in vivo, with respect to macromolecular disposition, despite limitations concerning short viable periods of 2–3 h and likely absence of tracheobronchial circulation. Given the advantages and disadvantages of each model, scientists must make appropriate selection and timely exploitation of the best model at each stage of the research and development program, affording efficient progress toward clinical trials for future inhaled therapeutic entities for systemic delivery.

Keywords: Inhalation; Lung; Preclinical; Deposition; Disposition; Absorption; Mucociliary clearance; Metabolism

Clinical evaluation of inhaled insulin by Lucy D. Mastrandrea; Teresa Quattrin (pp. 1061-1075).

Diabetes affects over 18.2 million individuals in the United States alone. Current therapy to treat type 1 diabetes relies on subcutaneous insulin administration either by injection or continuous infusion. In addition, patients with type 2 diabetes who fail lifestyle intervention and oral therapy require subcutaneous insulin. Optimal injection protocols to achieve tight metabolic control often prove burdensome to patients. Thus, development of pulmonary insulin delivery to supplement and/or replace subcutaneous insulin injections may be an effective alternative, allowing patients to achieve intensive diabetes management. This review will discuss the devices in development for the delivery of inhaled insulin. In addition, the efficacy of inhaled insulin in both type 1 and type 2 diabetic populations will be discussed. Finally, the available safety data with respect to the unique pulmonary effects of inhaled insulin will be covered.

Keywords: Type 1 diabetes; Type 2 diabetes; Insulin; Inhalation; Hemoglobin A1c; Lung; Glycemic control; Diabetes; Insulin administration; Drug administration routes

Pulmonary delivery of opioids as pain therapeutics by Stephen J. Farr; Babatunde A. Otulana (pp. 1076-1088).

Pulmonary opioid delivery, on the basis of the fact that small molecular entities can be rapidly and completely absorbed from the peripheral lung, poses a unique opportunity for the treatment of severe (breakthrough) pain, which currently is treated with intravenous therapy. Early clinical studies involving inhaled opioids were focused on treatment of dyspnoea and not pain management, but they showed that inhalation of various opioid compounds is safe, even in severely ill patients. The advent of specialized and efficient pulmonary drug delivery systems has facilitated the evaluation of inhaled opioids, such as morphine and fentanyl, for management of severe pain associated with surgery or malignant disease. This review will summarize recent literature on the pharmacokinetics and pharmacodynamics of inhaled opioids and will discuss safety and efficacy in comparison to injection and other opioid dosage forms available for pain therapy. Finally, regulatory considerations will be discussed towards the approval of this new delivery paradigm for opioid drugs.

Keywords: Pulmonary; Aerosol; Opioids; Pharmacokinetics; Pain management; Efficacy

Inhaled cytokines and cytokine antagonists by John Thipphawong (pp. 1089-1105).

Cytokine and cytokine antagonist have provided novel and effective therapies for many human diseases. A number of approved cytokines including the interferons (α, β and γ), interleukin-2 (IL-2), granulocyte macrophage colony stimulating factor (GM-CSF) as well as novel cytokine antagonists have been administered by the pulmonary route for both local lung disease and as a non-invasive method for systemic delivery. We review the published clinical experience of inhaled cytokines and cytokine antagonists. We discuss the limitations of the existing data and the type of clinical data desired to establish the advantages and safety of inhaled cytokines and cytokine antagonists.

Keywords: Aerosol; Interferon; Interleukin

Pulmonary administration of therapeutic proteins using an immunoglobulin transport pathway by Alan J. Bitonti; Jennifer A. Dumont (pp. 1106-1118).

We have applied a “physiologic�? approach to the pulmonary delivery of therapeutic proteins, utilizing an immunoglobulin (antibody) transport pathway recently shown to be present predominantly in the conducting airways of the human respiratory tract. Therapeutic proteins are fused to the Fc-domain of an IgG1, allowing them to bind with high affinity to the antibody transport receptor, FcRn. Liquid aerosols are administered into the lung using normal breathing maneuvers and efficient delivery of several different Fc-fusion proteins has been achieved with retention of biological activity and an increase in circulating half-life. A new paradigm for the pulmonary delivery of therapeutic proteins and a fundamental advance in the construction of Fc-fusion proteins for this purpose will be described.

Keywords: FcRn; Transepithelial transport; Erythropoietin; Interferon alpha; Interferon beta; Follicle stimulating hormone; Aerosol; Fc-fusion protein; Neonatal Fc receptor; Lung

Inhaled delivery of aerosolized cyclosporine by T.E. Corcoran (pp. 1119-1127).

Aerosolized cyclosporine was the first calcineurin inhibitor to be developed for inhaled administration. Its use as a topical immunosuppressant after lung transplantation is reviewed. Animal studies in transplant and non-transplant models are considered, as is nebulized delivery of the drug, including the results of scintigraphy and pharmacokinetic studies. Open label clinical studies of the drug for the treatment of chronic and acute lung transplant rejection are detailed. Placebo controlled trials for rejection prophylaxis are described and future directions for the drug are considered. Aerosol cyclosporine provides an excellent example of how inhaled aerosol delivery can provide therapeutic concentrations of drug in the lungs while minimizing the side effects associated with high systemic concentrations. In the case of lung transplantation, the drug is delivered directly to the airways, the location of the pathology resulting in most mortality in this population (chronic allograft rejection), maximizing the efficacy of this dose-dependent immunosuppressant.

Keywords: Lung transplantation; Cyclosporine solution for inhalation; Aerosol deposition; Aerosol immunosuppressant; Bronchiolitis obliterans; Lung transplant rejection; Aerosol pharmacokinetics

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Advanced Drug Delivery Reviews (v.58, #9-10)

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Advanced Drug Delivery Reviews (v.58, #9-10)