Inhaled Insulin: Too Soon To Be Forgotten?

Abstract

Inhalation is a potentially viable route of administration for numerous agents. In diabetes mellitus, the need for frequent injections to achieve ideal glycemic control remains a significant limitation for initiating and complying with insulin therapy in a large number of patients. To overcome this barrier, inhaled insulin was developed. The inhalation form of regular human insulin has been tested and administered in a large number of trials. Respiratory capacity was evaluated in patients with normal lung parenchyma in whom inhaled insulin was administered without complications. However, issues like cost, bulky device, fear for lung safety, and the small number of studies in subjects with underlying respiratory disease prevented widespread use of this new mode of delivery. In the present review, we will suggest a number of methods that could be applied in this form of administration to maximize drug absorption and fully exploit the advantages of this route of administration.

Introduction

Diabetes is a global public health concern. In the United States, it currently affects approximately 20.8 million people.⁽¹⁾ Despite all experiments of alternative modes of delivery, until now insulin is still administered subcutaneously, limiting patient compliance, especially when multiple injections are required. Aerolized medications have been used for centuries to treat respiratory diseases.⁽²⁾ This led to the development of inhaled insulin. So far, however, clinical trials with this new insulin have failed to establish it for widespread use. Novel devices can deliver insulin particles into the alveoli. An aerosol of solubilized fast acting insulin can be mechanically or electronically released.^(2,3) Pulmonary toxicity due to inhaled insulin has not been reported, based on a large number of studies, of which one included pulmonary function data up to 8 years of follow-up.^(4–20) The efficiency of insulin delivery by inhalation may be compromised by: (1) losses within the device and the environment, (2) deposition in the throat and bronchial tubes, and (3) incomplete absorption from the alveoli.⁽²¹⁾ The peak of activity of inhaled regular insulin occurs at 60 min, which is similar to that of subcutaneous quick-acting insulin analogs. Several pharmaceutical companies have developed inhaled insulin products.⁽²⁾ Only one of these (Exubera^®, Pfizer, New York, NY) has been approved by the Food and Drug Administration (FDA), whereas others are currently undergoing clinical trials to prove efficacy and safety. Exubera was also approved by the European Medicines Agency (EMA) in 2006. The present review will outline a number of experimental compounds and methods that could be applied in this form of administration to maximize drug absorption. We will focus on adult subjects, because of the vast literature published in this population, but a brief allusion is made to children and adolescents as well.

Search Strategy

We performed an electronic article search through PubMed, Google Scholar, Medscape, and Scopus databases, using combinations of the following keywords: inhaled insulin, diabetes mellitus, inalation, aerosol, and treatment. All types of articles (randomized controlled trials, clinical observational cohort studies, review articles) were included. Selected references from identified articles were searched for further consideration. We selected the manuscripts that best described the following characteristics in their report FEV₁ (forced expiratory volume 1 sec), FVC (forced vital capacity), DLCO (diffusing lung capacity of carbon monoxide), FPG (fasting plasma glucose), HbA_1C (glycated hemoglobin), weight change.

Normal Lung Anatomy

At the beginning of the trachea, normal airways comprise thick-walled bronchial tubes, which have low permeability to insulin. Moving along the tubes toward the periphery of the bronchial tree, thickness progressively diminishes until the thin-walled alveoli, which are permeable. The former divide up to 23 times before branching into the latter. Until now, it has not been known if insulin permeability may actually be high in the distal small airways before one gets to the alveoli.⁽²²⁾ Inhaled route of drug delivery has many theoretical advantages. Human lungs have a large (>100 m²), thin (0.1–0.2 μm), highly vascular epithelial surface area for lung absorption. They can immunologically tolerate administered polypeptides, and the distal airways lack significant mucociliary transport, allowing time for absorption.

Drug formulation is crucial in producing effective inhalable medications. The latter must not only be pharmacologically active, but they also have to be efficiently delivered to their main site of action in the lungs. Following lung delivery, their local concentration must remain high until the desired pharmacological effect occurs. Insulin must be deposited in peripheral lung tissue to ensure maximum systemic bioavailability. Thus, formulations that can be retained in the lungs for the desired period of time, thereby avoiding pulmonary clearance mechanisms are absolutely necessary. To meet this need, dry powder formulations have recently been developed. Such formulations are obtained either by micronization via jet milling, precipitation and freeze-drying or by spray-drying, which involves the use of various excipients, such as lipids and polymers, or other carrier systems.^(2,21–35)

Numerous factors that affect the efficacy and bioavailability of aerolized drug formulations.⁽²³⁾ These factors may be summarized as follows:

Aerosol particle size: The inhaled drug formulation should consist of a specific particle size in the range of 1–3 μm to achieve good alveolar deposition.⁽²¹⁾ Inhaled insulin of this size becomes trapped in the alveoli and taken up in vesicles by alveolar epithelial cells, so that it can be carried across and released through them on the opposite side into the narrow interstitial fluid compartment between the epithelial cells. Insulin molecules are then taken up within vesicles by the endothelial cells, transported across the width of these cells, and released into the alveolar capillary bloodstream.⁽²¹⁾ This process of particle migration into, across, and out of a cell is known as transcytosis. Other drug formulations given via inhalation as corticosteroids or anticholigenics do not have to be less than 2–3 μm in size, because they act on the larger braches of the bronchial tubes. By contrast, inhaled insulin has to be absorbed by the vesicles, which exist only in the alveoli, and so the size of inhaled particles has to be between 1 and 3 μm.

Airway geometry and humidity: Progressive branching and narrowing of the airways encourage impaction of particles. The lung has a relative humidity of approximately 99.5%. Drug particles are known to be hygroscopic and grow or shrink in size in high humidity. The increase in particle size above the initial size should affect the amount of drug deposited and particularly, the distribution of the aerosolized drug within the lung.^24,25

Lung clearance mechanisms: Drug particles deposited in the conducting airways are primarily removed through mucociliary clearance. The airway epithelial goblet cells and submucosal glands secrete mucus forming a two-layer mucus blanket over the ciliated epithelium: a low-viscosity sol layer covered by a high-viscosity gel layer. Insoluble particles are trapped in the gel layer and are moved toward the pharynx (and ultimately to the gastrointestinal tract) by the upward movement of mucus generated by the metachronous beating of cilia. In the normal lung, the rate of mucus movement varies with the airway region and is determined by the number of ciliated cells and their beat frequency. For normal mucociliary clearance to occur, airway epithelial cells must be intact, ciliary structure and activity normal, the depth and chemical composition of the sol layer optimal and the rheology of the mucus within the physiological range. Mucociliary clearance is impaired in lung diseases such as immotile cilia syndrome, bronchiectasis, CF and asthma.⁽²⁶⁾ Lipophilic molecules pass easily through the airway epithelium via passive transport. Hydrophilic molecules cross via extracellular pathways, and exocytosis.⁽²⁷⁾ From the submucosal region, particles are absorbed into either the systemic circulation, bronchial circulation, or lymphatic system. Drugs deposited in the alveolar region may be phagocytosed and cleared by alveolar macrophages or absorbed into the pulmonary circulation. Alveolar macrophages are the predominant phagocytic cell for the lung defense against inhaled microorganisms, particles and other toxic agents. There are approximately five to seven alveolar macrophages per alveolus in the lungs of healthy nonsmokers.⁽²⁸⁾ Macrophages phagocytose insoluble particles that are deposited in the alveolar region and are either cleared by the lymphatic system or moved into the ciliated airways along currents in alveolar fluid and then cleared via the mucociliary escalator.⁽²⁹⁾ This process can take weeks to months to complete.⁽³⁰⁾ However, for most proteins degradation in the alveoli is not a major clearance mechanism, with >95% of proteins, 40% for deposited insulin, being absorbed intact from the lung periphery.^(29,31)

Lung disease: Bronchoconstriction, inflammation, and airway narrowing alter lung deposition. Respiratory diseases, such as cystic fibrosis and bronchiectasis, change the architecture of the lung through alterations in bifurcation angles and obstruction of the airways due to mucus accumulation, modifying the deposition and distribution patterns of aerosols. A decrease in the cross-sectional area of the lung caused by obstruction increases air velocities and turbulence in regions where the airflow is normally laminar. Airway obstruction diverts inspired air to unobstructed airways and, thus, very little drug is deposited in obstructed areas, often the areas that need to be reached in order to achieve the optimal therapeutic effect of the drug.⁽²⁶⁾ This parameter has been further investigated and results demonstrated that inhaled insulin is well tolerated, safe, and efficacious in adult diabetes patients during intercurrent respiratory tract infections (iRTIs). During iRTIs, close monitoring of blood glucose concentrations and dose adjustment may be required on an individual basis.⁽³²⁾

Bronchial circulation: The lungs receive the entire cardiac output and represent the most richly perfused organ in the body. However, only the alveolar region is supplied by the pulmonary circulation. Blood flow to the larger airways (trachea, bronchi) is via the systemic circulation and these airways receive approximately 1% of the cardiac output.⁽³³⁾ The endobronchial circulation is recirculated to the peripheral airways and lung parenchyma via the bronchial veins and right atrium. Bronchial blood flow is augmented in diseases, such as bronchiectasis, from 1% to as much as 30% of cardiac output. Theoretically, inhaled drugs that are absorbed into the circulation from the tracheobronchial regions can be redistributed downstream and peripheral to airway obstructions, into otherwise poorly accessible areas of the lung which may aid in the drug's efficacy.^(34,35) Finally, further drug absorption could occur via the lymphatic pathway.^(36,37)

Breathing frequency (F), tidal volume (TV), and duration of inhalation: These factors affect the depth of absorption and quantity of the drug formulation that is inhaled in every breath. There are methods to alter TV and F, in order to improve the technique of the drug administration, and these will be herein further explained.^(38–40)

Inhaled Insulin Devices

A large number of devices has been developed and studied in a variety of clinical protocols over the past 20 years. The ideal device should not only be capable of delivering inhaled insulin through the bronchial tree, but also be convenient for patients, portable, and user-friendly. Existing systems differ in the formulation of inhaled insulin (liquid vs. dry-powder formulations) and the delivery device with respect to size, mechanism of insulin release, and regulation of insulin administration (mechanical vs. electronic). The bioavailability of inhaled insulin differs among the various inhaled insulin products (range 10–46%).^(41,42) Table 1 summarizes the features of inhaled insulin delivery systems that have been mainly studied.

Table 1.

Inhaled Insulin Systems

Inhalation status system	Insulin formulation	Insulin equivalents ^a	Inhaler device	Method of inhalation	Device Size ^b	Device benefits	Current
Exubera^®	Dry powder blisters	1 mg = 3U 3mg = 8U	Mechanical	User dependent	20 × 4 cm	Collapsible	FDA-approved off-market
AERx iDMS^®	Liquid insulin, blisters	I AERx unit = IU	Electronic	Guided system	8 × 4 cm	Download capability	No further development
AIR^®	Dry powder, capsules	6 mg = 2 U 9 mg = 6 U	Mechanical	Breath actuated	7 × 2 cm	Small device Size	No further development
Technosphere^®	Dry powder microspheres, catridges	6 TU = 1.56 U 12 TU = 3.12 U 24TU = 6.24 U	Mechanical	User dependent	10 × 5 cm	Placebo formulation	Phase 3 trials FDA—new application
Afrezza^™	Dry powder (TI)^c	Unit dose catridges	Mechanical	Breath actuated	5 × 2 cm	Small device Size	Phase 1 trials FDA—under review

Compared to regular insulin; ^bapproximate size; ^cTechnosphere insulin.

TU, technosphere units.

Pharmacology, Pharmacokinetics, and Glucodynamic Data of Inhaled Insulin

In order to be a viable alternative to injectable insulin, an inhaled insulin system must demonstrate dose–response and dose–reproducibility that are comparable to those achieved by standard subcutaneous delivery. This evaluation can usually be made with measurement of serum insulin levels following drug administration, in order to determine onset and duration of the hypoglycemic effect. The ideal system would closely mimic β-cell insulin secretion with rapid onset of action followed by sustained activity over a period of 2–3 h to control rising glucose concentrations while limiting delayed hypoglycemic effects.

Studies to assess serum concentrations of insulin following inhalation have been performed in healthy volunteers as well individuals with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The majority of these compared different inhaled insulin delivery systems to regular insulin administration subcutaneously (peak effect 30–60 min) and inhaled insulin (peak effect 12–55 min). In addition, although the total insulin exposure for inhaled insulin was comparable to that of subcutaneous insulin, the exposure time was shorter with inhaled insulin, suggesting that the risk of delayed hypoglycemia may be less with the inhaled formulation.^(42,43)

However, it should be mentioned that a number of factors interfere with absorption of inhaled insulin. First, smoking increases its bioavaibility, accentuating hypoglycemia, as evidenced by a small number of studies.^(43–48) However, it should be noted that smokers were excluded from all development programs, so further experience is needed. Second, body mass index (BMI) plays a crucial role, because diabetic patients embarking on insulin will need to adjust their doses to their body weight. Based on the literature, injected insulin absorption is significantly influenced by a number factors including BMI. Interestingly, inhaled insulin may be more reliable than subcutaneous insulin in obese diabetic subjects.^(49,50) Third, underlying comorbidities, such as chronic obstructive pulmonary disease (COPD) and asthma may also affect the bioavaibility of inhaled insulin, reducing its absorption when on exacerbation. Specifically, studies that were conducted in patients with mild to moderate asthma showed that the drug can safely be used by this group of patients, only if the disease is controlled; otherwise, glycemic control cannot be achieved.^{(44,45,51,52)} The same holds true for patients with underlying COPD. In stage I–II COPD (GOLD 2010 guidelines ERS/ATS), it was observed that such patients short-term exposure to AIR inhaled insulin was well tolerated, showing similar time–exposure and time–action profiles, but with reduced insulin absorption and metabolic effect compared with healthy subjects. This reduced insulin absorption could be due to failure of the drug to reach the distal alveoli. Moreover, the AIR studies concluded that inhaled insulin is not a proper treatment for COPD stage III–IV. Further clinical evaluation is warranted in patients with diabetes and COPD.⁽⁴³⁾ However, both these patient groups (especially those with asthma) seem to benefit from pretreatment with bronchodilators.^{(43–48,51,52)} Finally, studies in healthy volunteers with intercurrent upper respiratory infection have shown no decrease in absorption of inhaled insulin.^(32,53)

Clearly, further studies are needed to ascertain whether inhaled insulin should be administered in patients with upper and lower respiratory tract disease. In a series of other inhaled drug novel therapies, an exclusion criterion was the presence of pulmonary lesions preventing peripheral distribution of the drug and/or pulmonary lesions larger than 5 cm mass median diameter (MMD).^(54–56) Clearly, if a large lung parenchyma surface area is accessible, distribution of the aerosol is feasible, but there would be a limitation for patients with poor performance status. Similar criteria need to be defined for inhaled insulin application. Ultimately, however, the therapeutic decision rests with the clinician.

Pulmonary Function and Underlying Conditions

Naturally, the potential effect of inhaled insulin on lung parenchyma is an area of great concern. Accordingly, several studies have sought to investigate this issue. It should be noted that all subjects evaluated in such reports had no concomitant respiratory disease, for example, COPD or asthma. We identified 12 studies in type 1 diabetes and 8 studies in type 2 diabetes. In total, 2650 subjects with type 1 diabetes were evaluated for up to 3 years and 2046 subjects with type 2 diabetes for up to 3 years (Table 2). All patients were assessed with pulmonary function tests (spirometry, DLCO, 6-min walking test). During the first 3 weeks, a 1–2% nonprogressive, reversible decrease in FEV₁ was observed, primarily caused by the low molecular weight excipients. No patient had a further decrease, and values returned to normal after 1 month. The most common adverse effect was cough (almost 20% of patients), which gradually regressed with continuous use of inhaled medication.^(4–20)

Table 2.

Major Findings in Included Studies

Author	Year	DM	Patients	FVC	FEV₁	DLCO	Product	Weight	HbA_1c	QOL	Follow-up
Dailey et al.	2007	1/2	Review	—	−57.3 mL/y	−56.0 mL/y	Exubera	—	−6.78	√	4 y
Barnett et al.	2007	1/2	922	—	0.00	0.222	Exubera	+3.6	−1.8%	—	2 y
Skyler et al.	2008	1	290	—	−0.169	−1.468	Exubera	−1.24	+0.338	—	2 y
Rosenstock et al.	2008	2	635	—	−0.121	−0.069	Exubera	1.7	−0.33	—	2 y
Cefalu et al.	2008	1/2	1290	—	−0.053	−0.738	Exubera	—	−7.91/8.64%	—	2 y
Liu et al.	2008	1/2	44	—	−0.067	−0.699	Exubera	26.4/30.2	7.8/8.2	—	3 m
Woltz et al.	2008	1	39	—	—	—	AIR	—	—	—	4.5 m
White et al.	2008	1	121	—	—	—	Exubera	—	−0.23	—	3 m
Comulada et al.	2009	1	500	−0.017	−0.014	−1.047	AIR	−0.28	+0.17	—	6 m
Gross et al.	2009	2	208	p = 0.041	p = 0.031	—	AIR	—	−0.117	—	2 y
GARG et al.	2009	1	385	—	−0.165	−1.730	AIR	−1.09	+0.44	—	2 y
Rosenstock et al.	2009	2	316	—	−0.045	−0.277	Exubera	—	0.05	—	3 y
Forst et al.	2009	1/2	12	—	—	—	Exubera	—	—	√	360 min
Ang et al.	2009	1	232	p = 0.773	p = 0.444	p = 0.028	AIR	−0.39	−0.063	—	1 y
Moses et al.	2009	1	205	—	—	−2.03%	AERxiDMS	−2.5	0.18%	—	1 y

FVC, forced vital capacity; FEV₁, forced expiratory volume in 1 sec; DLCO, diffusing lung capacity of carbon monoxide; — = not measured/no data in manuscript (values presented are based on the data that are provided from the written manuscripts); QOL, quality of life: — = not evaluated; √ = evaluated; weight: — = not measured/no data in manuscript; HbA_1C, — = not measured/no data in manuscript; y, year; min, minute; m, month.

It is crucial at this point to address concerns about potential damage to the lung parenchyma with the following facts. Hundreds of studies more than 10,000 patients have documented that inhaled insulin is reasonably safe. Conversely, poor compliance with long-term subcutaneous insulin is detrimental to glycemic control. Lung parenchyma is constantly exposed to endogenous insulin in healthy subjects. Moreover, lung exposure to insulin may be particularly high in type 2 diabetic patients with extreme insulin resistance, who need very large doses. In addition, chronic high local insulin concentration is maintained in injection sites. Each injection is a microinjury with localized inflammation. By contrast, inhaled insulin is noninvasive and does not cause injury. After accounting for losses in the device, package, mouth, and throat, the body is exposed to roughly three times more insulin per dose by inhalation than by injection. However, unlike the very high injection site concentrations, the inhaled dose is spread over a huge surface area and dissolved in 30–40 mL of lung lining fluids. Taken together, this data suggests that inhaled insulin exhibits substantial advantages over subcutaneous insulin.

Furthermore, inhaled insulin does not appear to have any effect on lung lining composition, as assessed by visual inspection, bronchoalveolar lavage fluid total cell count, and leukocyte differential count (lymphocytes, neutrophils, eosinophils, or macrophages). Similarly, no effect on protein composition of lung lining fluid was noticed on examination of bronchoalveolar lavage total protein, albumin, and fibrinogen. There is no evidence that 12-week treatment with inhaled insulin may induce clinically meaningful cellular changes within the lung suggestive of inflammation or other pathology.⁽²⁰⁾ Hence, the reversible treatment effects on pulmonary function tests cannot be ascribed to inflammation.⁽²⁰⁾

Underlying medical conditions play a pivotal role in the absorption of the inhaled formulation apart from the solution itself. First, studies in asthmatic patients with different disease control have demonstrated that larger amounts of the inhaled formulation were required to achieve levels of glycemic control similar to those of patients with normal respiratory function. Only albuterol improved the pharmacokinetic profile of inhaled insulin, increasing C_max and the area under the curve (AUC) 0–360 min from 25 to 30% in patients with mild asthma and from 45 to 50% in those with moderate asthma. Second, there were no significant changes in FEV₁, FVC, and FEV₁/FVC at 30, 60, and 360 min after inhalation, as compared to baseline values (30 min before dose), and this held even true for larger doses (135 IU). Similarly, no episodes of bronchial hyperreactivity have been observed.^{(44,45,51,52)} Inhaled insulin has a safe pharmacological profile for this group of patients.

Smokers represent a further group of patients to consider. In case a smoker chooses inhaled insulin, he or she should first receive smoking cessation counceling and/or treatment. Indeed, pharmacokinetic and pharmacodynamic profiles of insulin have been shown to nornalize after smoking cessation.^(44–48)

Of note, a major turning point in the development of this treatment was the report issued by Pfizer on increased incidence of lung cancer among former smokers who were treated with Exubera^®.⁽⁴⁵⁾ However, these subjects still need to be further evaluated, in order to establish whether it was different components of the drug regimen or smoking history itself that could be held accountable for the observed association. The frequency of lung cancer among former smokers in the Exubera^® trials was higher than in the comparator group. However, this difference was not significant and, indeed, the frequency in both groups was less than expected based on predicted incidence in diabetic patients who were former smokers. The potential association with cancer is a matter of ongoing debate and needs to be confirmed or refuted.

Finally, iRTIs need to be considered. Accoriding to the evaluation of a large number of subjects, no alterations in pharmacokinetic and pharmacodynamic profile of inhaled insulin occur.^(32,53) Recent literature is also confirmatory: iRTIs have been assessed in more than 2500 patients.^(32,43) Inhaled insulin was well tolerated, safe,. and efficacious in this group of patients, but a close monitoring and dose adjustment was needed in a small number of subjects.

Inhaled Insulin in Children and Adolescents

In one study, inhaled insulin demonstrated no inferiority, compared to subcutaneous administration. The usual side effects where observed: cough was the major adverse effect and pulmonary function tests demonstrated a decline in FEV₁ and DLCO. Pulmonary function tests were stable after 4 months and reverted to normal after withdrawal of inhaled insulin. Glycemic control was well established, there was no weight gain, and no antibodies to insulin were observed.⁽⁵⁷⁾ Another study focused on the satisfaction and quality of life in an adolescent population. This study implied that inhaled insulin would be preferred in these patients because it demonstrated a high satisfaction quality index based on questionnaires given to the patients.^(5,7)

Treatment Modalities Hitherto Applied for Inhaled Insulin

Numerous novel modalities of administering inhaled insulin have been employed. Insulin inhalation Pfizer/Nektar Therapeutics: HMR 4006 is an inhaled PEG-insulin that uses the polyethylene glycol (PEG) technology to successfully deliver insulin across the lungs and to promote its prolonged serum concentration. PEG is a neutral, water-soluble, nontoxic polymer comprising any number of repeating units of ethylene oxide. PEG-ylation is designed to increase the size of the active molecule and, ultimately, improve drug performance by optimizing pharmacokinetics, increasing bioavailability, and decreasing both immunogenicity and dosing frequency. The patent covers a method for delivering of 0.5–15 mg of aerosol dry powder insulin per dosing session in 1–4 individual dosages into the deep lung for systemic absorption.⁽⁵⁸⁾

Insulin micro- and nanoparticle precipitation prior to spray drying was carried out using the solvent change method. The deposition pattern of the originator powder delivered with the Exubera device showed significantly lower fine particle fractions and higher residues in comparison to the Aerolizer device. In summary, precipitated insulin particles combined with the delivery from a standard capsule-based inhaler were found to be at least as effective in vitro as the marketed Exubera product. The Aerolizer device was used representing a simple capsule-based dry powder inhaler. It could be shown that the insulin yield of the precipitation process highly depends on the pH employed and the amount of nonsolvent used. Moreover, particle size after spray drying decreases with increasing amount of nonsolvent. Aerodynamic assessment of insulin powders showed that the precipitated insulin particles behave in a superior way in comparison to powder spray dried from solution with respect to particles smaller than 2 microns.⁽⁵⁹⁾

Technosphere drug carrier mechanism is a formulation of regular human insulin designed for efficient transport across the respiratory epithelium into the circulation. The drug carrier mechanism achieves a fast systemic insulin uptake (maximum time approximately 15–20 min), a fast onset of action (maximum activity approximately 25–30 min) and a short duration of action (approximately 2 h). Bioavailability, relative to subcutaneous injection, was established to be between 30 and 50%, with a linear dose–response relationship and low variability. This method provides a new treatment regiment for type 2 diabetes.⁽⁶⁰⁾

Insulin-loaded PLGA/cyclodextrin large porous particles, allow a controlled release of insulin to the lungs. Researchers have attempted to develop large porous particles (LPP) of poly (lactide-co-glycolide) (PLGA) containing insulin with optimal aerodynamic properties. In vivo data showed that PLGA/HPbetaCD/insulin LPP is able to reach alveoli, release insulin, which is absorbed in its bioactive form.⁽⁶¹⁾

PROMAXX technology allows formation of uniform protein microspheres. Safe and efficacious administration of recombinant human insulin inhalation powder (RHIIP) to the deep lung with an off-the-shelf dry power inhaler (DPI) has been achieved. RHIIP showed a fast onset of action and BA/BP comparable to that reported for other inhaled insulin formulations using specifically designed inhalers.⁽⁶²⁾

Solid lipid nanoparticles as insulin inhalation carriers for enhanced pulmonary delivery is a novel DPI system of insulin-loaded solid lipid nanoparticles (Ins-SLNs). Evidence has so far indicated that SLNs have potential application as an efficient and nontoxic lipophilic colloidal drug carrier for enhanced pulmonary delivery of insulin.⁽⁶³⁾

Preparation and physical–chemical characterization of supercritically dried insulin-loaded microparticles for pulmonary delivery would be a further option. Thus, N-Trimethyl chitosan (TMC), a polymeric mucoadhesive absorption enhancer and dextran, a nonpermeation enhancer, have been used as insulin carriers. Unfortunately, mean particle size was 6–10 microns (laser diffraction analysis) and their volume median aerodynamic diameter approximately 4 microns (time-of-flight analysis) too large to reach the alveoli. Nevertheless, SCF drying is a promising, protein-friendly technique for the preparation of inhalable insulin-loaded particles.⁽⁶⁴⁾

Finally, AFREZZA is product of quick-acting inhaled insulin with a fast peak of plasma concentration in just 12–14 min, using the technosphere technology. This product is currently under review by the U.S. Food and Drug Administration (FDA). Technosphere insulin appears to overcome some of the barriers that contributed to the withdrawal of Exubera from the market. Studies with this agent have shown it to be a unique insulin formulation in that it is very rapid acting, has a relatively short duration of action, and is efficacious in improving glycemic control without contributing to increased weight gain and/or hypoglycemia, compared to other prandial insulins.⁽⁶⁵⁾

Insulin Preparations and Methods for Future Application

Current drug delivery devices for pulmonary absorption in the bronchial tubes include (1) nebulizers, (2) metered dose inhalers (MDIs), (3) dry powder inhalers (DPIs). Data from previous studies with other experimental drug formulations indicate that aerosolized regimens via jet nebulizers are feasible and can be distributed to the peripheral alveoli.^(54–56) In addition, experimental works have evaluated a number of novel aerosol systems to overcome defense mechanisms of the respiratory system and prolong the deposition of aerosolized medication.^(66–69)

Until recently, only two kinds of nebulizers were routinely employed in clinical practice. Pneumatic or jet nebulizers use the energy provided by compressed gas flow to disperse a liquid into a fine mist, whereas ultrasonic nebulizers use electricity to vibrate a piezoelectric crystal at high frequency. Standing waves are generated when these high-frequency vibrations are focused onto the surface of a solution. Liquid droplets separate from the crest of these waves to form an aerosol. Recent technological advancements have led to the development of devices that overcome many of the disadvantages of conventional nebulizers (Table 3).^(70,71)

Table 3.

Aerosol Devices That Use a Vibrating Mesh or Plate with Multiple Apertures

Aerogen's Aerosol Generator

Aeroneb Portable Nebulizer System

Aeroneb Professional Nebulizer System

Aerodose Inhaler

Omron's Vibrating Mesh

NE-U03

NE-U22

ODEM's TouchSpray Technology

TouchSpray inhaler devices

Pari's device e-Flow

First, Aerogen's aerosol generator consists of a vibrational element and a domed aperture plate. This product has the ability to determine the aerosol particle size and flow rate threw the aperature hole, and these can be modified for specific clinical applications. Devices incorporating the Aerogen aerosol generator can be operated with batteries and are portable. These devices nebulize at a rate ranging from 0.3 to 0.6 mL per minute, generally requiring a shorter time for drug delivery compared with conventional nebulizers. They are relatively quiet because they do not require any compressed gas flow or high-energy vibration for aerosol generation. Moreover, the volume of solution remaining in these devices at the end of treatment (residual volume) is minimal. Indeed, the aerosol generator can aerosolize almost down to the very last drop of the liquid applied to the generator compared with the 0.3 to 1 mL remaining in the device after treatment with conventional jet or ultrasonic nebulizers. Aerogen's aerosol generator efficiently nebulizes suspensions, proteins and peptides.^(72,73)

With these devices, there is negligible risk of denaturing proteins or peptides, or reducing the activity of antibiotics during aerosolization. The Aeroneb^® Portable Nebulizer System is designed for domiciliary use and for patients in accident and emergency department or in hospital. The Aerodose is a hand-held inhaler, which is about the size and shape of a standard pressurized metered-dose inhaler (pMDI). The Aeroneb has a three- to fivefold higher efficiency for delivering drug to the lungs than conventional jet or ultrasonic nebulisers.^(74–76) In view of the higher efficiency of Aerogen's devices to deliver drugs to the lung, similar clinical effects should be obtained with lower nominal doses of drugs with Aerogen's devices compared with conventional nebulizers or pMDIs.

Second, Omron's technology incorporates a piezoelectric crystal that vibrates at a high frequency when electrical current is applied.⁽⁷⁷⁾ The mesh plate used in this system contains numerous (up to 6000) tapered holes (∼3 mm in size). These holes amplify the vibration of the transducer horn throughout the medication and allow efficient generation of a fine-particle mist. The Omron devices are battery operated and alternating current (AC) powered, produce an aerosol with low velocity and require no propellant or compressor. They are portable and can produce an aerosol in almost any orientation. The NEU03 and NE-U22 can nebulise solutions and suspensions almost down to the last drop of liquid, so that the residual volume is negligible. The need for adding a diluent to the drug solution can be eliminated with these new devices.

Third, the TouchSpray technology utilizes a perforate membrane that vibrates at high frequencies against a body of fluid.⁽⁷⁷⁾ TouchSpray inhaler devices can efficiently aerosolize a wide range of fluids and particulate suspensions, including insulin and DNA fragments.⁽⁷⁸⁾ With these devices, the particle size and flow rate of the aerosol can be precisely controlled. These devices are under development in partnership with pharmaceutical companies.

Clinical experience with the use (or misuse) of these newer nebulizers on a routine basis by patients outside the setting of clinical trials is limited. However, most patients can be trained to use them without difficulty. Their cost is also much higher than that of conventional jet nebulizers but may be lower than that of some ultrasonic nebulizers.

New devices are highly effective in delivering aerosol to the lung, and so the drug amount could be significantly reduced. Moreover, their residual volume is negligible, so they have the potential to improve cost effectiveness of administering expensive medications. They nebulize at a faster rate than conventional jet or ultrasonic nebulizers and, accordingly, treatment duration could be shortened. They efficiently nebulize solutions and suspensions and have been successfully used for aerosolizing insulin, other proteins and peptides, and DNA fragments. Furthermore, aerosol characteristics can be modified according to clinical application. Finally, it is possible to precisely control drug delivery to the respiratory tract. Overall, the new devices are likely to find wider clinical application for systemic therapy and gene transfer.

Furthermore, previous studies have demonstrated the effect of adding CO₂ (5–7%) on respiratory rate (RR) and TV. The addition of CO₂ (5–7%) decreased respiratory rate and increased tidal volume by 180%. Thus, subjects were forced to breath slowly and deeply, resulting in a distal absorption of the drug delivered.^(38–40) However, severe dizziness, sleepiness, and confusion occurred when the aerosol was enriched with more than 7% CO₂, suggesting that this is the maximum feasible concentration.^(38–40)

Finally, instead of the usual face mask used with a nebulizer cup, a two-way throttle nozzle (inhalation valve and exhalation valve) should be used. This needs to be breath activated, so as not to release the aerosol to surrounding air (Fig. 1). Furthermore, we suggest that patients with underlying respiratory diseases, such as COPD and asthma, would further benefit from pretreatment with short-acting bronchodilators, even if this modality has shown positive results in a small subgroup of patients. The use of a jet-nebulizer would probably render patients with COPD GOLD stage III–IV (ERS/ATS guidelines) candidates for such treatment. This observation is based both on studies in asthma patients and on research testifying to improved lung ventilation following bronchodilator treatment.^{(21,44,45,51,52)} Another aspect to be investigated is whether PEG-encapsulation succeeds not only in overcoming the lung defense mechanisms, but also in diminishing the development of antibodies to insulin.⁽⁶⁶⁾

FIG. 1.

Two-way throttle nozzle: (A) Inhalation valve, (B) exhalation valve, (C) filter, (D) nebulizer cup. Photo by Paul Zarogoulidis (Pulmonary Department, G. Papanicolaou Hospital, Thessaloniki, Greece).

It is our belief that a fast-acting insulin could be encapsulated (PEG) and aerosolized, as in previous experimental studies.^(66,68) The drawback in long-acting insulin analogs such NPH, Lente, and Ultrlente is that they are composed of large (25–50 μm) crystals that would not penetrate the lungs as aerosols. Furthermore, chemically modified long-acting insulin analogs (glargine and detemir) require acidic formulation pH and localized precipitation at very high concentrations at the injection site. A highly dispersed aerosol of insulin glargine might not be able to provide the sustained release in the lungs that it is achieved in the localized injection site. Moreover, the acidic pH of long-acting analogs raises concern as to whether such formulations could induce local fibrosis.

Interpretation–Implications for Practice

Based on hitherto available data, inhaled insulin currently appears to be safe and effective. This treatment modality has been successfully used by patients with T1DM and T2DM already on insulin therapy, and those with T2DM failing oral agents. Thus far, inhaled insulin does not appear to induce acute or chronic lung inflammation. However, our experience is based on observations limited to maximally 8-year follow-up, so further enquiry is awaited for confirmation.⁽¹⁴⁾ Further works need to include larger patient series. The adverse effects of cough and decrease in FEV₁ and DLCO are not permanent, do not affect the quality of life of the patients, and are reversible.

The cost of inhaled insulin is insignificantly higher than that of subcutaneous insulin, because more drug amount must be inhaled to achieve comparable glycemic control. However, a substantial driving force for the development of inhaled insulin has focused on the concept that availability of alternate insulin delivery systems will increase the likelihood that diabetic patients will adhere to their treatment regimens. Overall, clinical trials have demonstrated that inhaled insulin is superior, or equal to subcutaneous insulin for improving glycemic control.^(5,9,79) In addition, inhaled insulin can serve as a useful therapeutic adjunct in subjects with T2DM suboptimally controlled on oral therapy.

Additional studies should be carried out in patients with COPD, to establish whether this route of administration is applicable or noninferior to the subcutaneous one for these patients. Moreover, smoking cessation should be obligatory for smokers who wish to use inhaled insulin. Another aspect to be further evaluated is drug absorption in the presence of respiratory infection. Indeed, establishing pharmacokinetic and pharmacodynamic profile of inhaled insulin under these conditions is of major practical importance.

In the present review, we have attempted to offer an extensive presentation of novel combinations and ways of administering inhaled insulin. We have also discussed the most important factors affecting the distribution and absorption of an aerolized compound, in this case, inhaled insulin. The potential administration with vibrating nebulizers, with the use of a two-way throttle nozzle (inhalation valve and exhalation valve) and the combination of CO₂ 5–7% could improve aerosol absorption. Pretreatment with a short-acting bronchodilator could also be used to further improve lung ventilation. Additionally, PEGylated insulin should be investigated to produce a sustained release solution, in contrast to the rapid-acting insulin hitherto administered.

All in all, the main reason why many clinicians worldwide support inhaled insulin is that it may lead to better treatment adherence and improved quality of life. It is likely that multiple delivery systems for inhaled insulin will eventually be presented to the FDA for marketing approval. If approved, these products could render inhaled insulin a popular treatment option in the future.

Conclusions

The potential of inhaled insulin has not, in the authors' opinion, been fully explored. Indeed, there are still many compound formulations and ways of administration that need to be investigated. Moreover, there are several patient groups and conditions, in which this route of administration is of questionable value, and this issue needs to be addressed as well. Finally, it should not be underestimated that further enquiry into inhaled insulin may help millions of patients toward better treatment compliance and improved quality of life, avoiding fear of injections. The latter could, although evidence is currently limited, particularly apply to children and adolescents.

Footnotes

Author Disclosure Statement

This work received no funding and was performed independently. N.P. and E.M. have participated in studies sponsored by Novartis, NovoNordisk, and sanofi-aventis.

Authors' Contributions

P.Z. and N.P. conceived and wrote the review; G.K., D.S., K.Z., and E.M. provided useful insights. All authors read and approved the final manuscript.

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