Nutrition 26 (2010) 33–39 www.nutritionjrnl.com Review article Inhaled insulin—Intrapulmonary, intranasal, and other routes of administration: Mechanisms of action R. I. Henkin, M.D., Ph.D.* Center for Molecular Nutrition and Sensory Disorders, The Taste and Smell Clinic, Washington, D.C., USA Manuscript received April 17, 2009; accepted August 3, 2009.Abstract Background: After discovery of insulin as a hypoglycemic agent in 1921 various routes of admin- istration to control blood glucose were attempted. These included subcutaneous, oral, rectal, sublin- gual, buccal, transdermal, vaginal, intramuscular, intrapulmonary and intranasal delivery systems. While each delivery system controlled hyperglycemia the subcutaneous route was given priority until 2006 when the Federal Drug Administration (FDA) approved the ﬁrst commercially available pulmonary inhaled insulin. Methods: A review of major publications dealing with intrapulmonary administration of insulin was made to understand the physiological basis for its use, its efﬁcacy in controlling hyperglycemia, its side effects and a comparison of its efﬁcacy with other delivery methods. Results: The large surface area of the lung, its good vascularization, capacity for solute exchange and ultra thin membranes of alveolar epithelia are unique features that facilitate pulmonary insulin deliv- ery. Large lung surface area (w75 m2) and thin alveolar epithelium (w0.1–0.5 mm) permit rapid drug absorption. First pass metabolism avoids gastrointestinal tract metabolism. Lung drug delivery depends upon a complex of factors including size, shape, density, charge and pH of delivery entity, velocity of entry, quality of aerosol deposition, character of alveoli, binding characteristics of aerosol on the alveolar surface, quality of alveolar capillary bed and its subsequent vascular tree. Many studies were performed to optimize each of these factors using several delivery systems to enhance pulmonary absorption. Availability was about 80% of subcutaneous administration with peak activity within 40– 60 min of administration. Intranasal insulin delivery faces a smaller surface area (w180 cm2) with quite different absorption characteristics in nasal epithelium and its associated vasculature. Absorption depends upon many factors including composition and character of nasal mucus. Absorption of intra- nasal insulin resulted in a faster absorption time course than with subcutaneous insulin. Interpretation: After many studies the FDA approved Pﬁzer’s product, Exubera, for intrapulmonary insulin delivery. While the system was effective its expense and putative side effects caused the drug company to withdraw the drug from the marketplace. Attempts by other pharmaceutical companies to use intrapulmonary insulin delivery are presently being made as well as some minor attempts to use intranasal delivery systems. Ó 2010 Elsevier Inc. All rights reserved.Keywords: Insulin; Hormones; Glucose metabolism; Inhalation; Lung; Nose; Insulin metabolism; Nasal mucusIntroduction administer this key agent to control blood glucose. Initial attempts delivered the hormone intramuscularly, intrave- Discovery of insulin as a hypoglycemic agent by Banting nously, and eventually subcutaneously. Other routes ofand Best in 1921  and its subsequent puriﬁcation indicated administration of the drug were explored. These includedthat this hormone was of great value to patients with diabetes oral, rectal, sublingual, buccal, transdermal, vaginal, intra-mellitus. The practical question at that time was how to muscular, intrapulmonary, and intranasal delivery systems. The purpose of these latter studies was to determine a non- injectable method to deliver insulin to patients with type 1 * Corresponding author. Tel.: þ202-364-4180; fax: þ202-364-9727. and 2 diabetes that would effectively lower blood sugar, con- E-mail address: email@example.com (R. I. Henkin). trol hemoglobin A1c (in much later studies), and allow0899-9007/10/$ – see front matter Ó 2010 Elsevier Inc. All rights reserved.doi:10.1016/j.nut.2009.08.001
34 R. I. Henkin / Nutrition 26 (2010) 33–39patients a simpler, less invasive, and more direct control of Particle sizetheir underlying disease process. Only recently has interestin alternative administration routes to the commonly used Absorption of particles by the lung has been shown tosubcutaneous and intravenous routes been forcefully revived. have an optimal aerodynamic diameter from 1 to 5 mm. ToHowever, there were no a priori concepts that would direct its target the alveolar region speciﬁcally, aerosol droplet diame-delivery by one or another method. As clinical events ter has been determined to be no more than 3 mm with parti-occurred it became clear that absorption of the insulin mole- cles >6 mm deposited in the oropharynx but <1 mm exhaledcule by any route could be improved. Thus, absorption during normal tidal breathing .enhancers were used to improve hormone absorption. Inthis manner, protamine zinc was formulated early in the treat- Delivery devicesment process with signiﬁcant improvement in hormoneaction. Other enhancers were considered later. Delivery depends on the character of the delivered drug as In January 2006 the United States Food and Drug liquid or powder. Devices are usually nebulizers that are me-Administration approved Exubera (Pﬁzer Pharmaceuticals, tered-dose inhalers or drug-powder inhalers. The problemNew York, NY) as the ﬁrst pulmonary inhaled insulin. In with liquid nebulizers is that 99% of generated droplets areactuality attempts to explore various methods to deliver in- recycled back into the reservoir to be redelivered during thesulin using intrapulmonary delivery had occurred since next dose . In addition, droplets rendered by nebulizers1925 . Approval of Exubera was the result of many years are heterogeneous, which results in poor drug delivery toof work by many groups of scientists who had to overcome the lower respiratory tract. These devices usually use a hydro-many obstacles to obtain this event. carbon propellant to atomize the drug solution, with a result- In the present work some of the physiologic bases for ing more-uniform spray, but these proteins and peptides areintrapulmonary, intranasal, and other delivery routes are dis- susceptible to denaturation when in contact with a propellantcussed, in addition to advantages and disadvantages of each or with large air–liquid water forces that are constantly gen-approach and mechanisms of action. erated during aerosolization . Dry-powder inhalers are currently the most commonly used devices to deliver pulmonary insulin and treat many pulmo-Intrapulmonary insulin nary conditions. This method improved drug delivery stability and sterility  over liquid aerosols . Although dose-to-dose The lung has been considered a route for systemic deliv- variations occur and delivered material is susceptible to envi-ery of many therapeutic proteins and peptides . This ronmental humidity and moisture and is dependent on inhala-system includes two major anatomical parts. The ﬁrst tion ﬂow rates , this method was chosen because accurateincludes the upper airways, oral cavity, trachea, bronchi, dosing and relatively complete drug delivery were ensured.and all upper airways distal to the bronchioles. The second This choice was based on development of a novel inhalerincludes the lower airways, conducting airways including device, improved powder engineering technology, a functionalrespiratory bronchioles, alveolar ducts, and alveolar sacs. drug carrier, and knowledge of absorption enhancers, whichThe large surface area of the lung, its good vascularization, optimized drug delivery . Mechanically a ﬁxed volume ofimmense capacity for solute exchange, and ultrathin mem- air was used to aerosolize a pre-metered and sealed drugbranes of alveolar epithelia are unique features that facilitate dose into a chamber. The patient inhales the drug into thesystemic delivery of these substances . The lung offers lung using a slow, deep breath, eliminating the complex motora large surface area for drug absorption (w75 m2). The co-ordination required for liquid propellant devices.very thin alveolar epithelium (w0.1–0.5 mm thick) permitsrapid drug absorption. The alveoli can be targeted for effec-tive drug absorption by drug delivery by aerosol with Pulmonary barrier and pulmonary absorptiona mass medium aerodynamic particle diameter <5 mm.First-pass metabolism in this route avoids gastrointestinal These parameters include the amount and character oftract metabolism. Although metabolic enzymes are found respiratory mucus, amount and speed of mucociliary clear-in the lung, their activities and metabolism are different ance, character and thickness of the alveolar lung layer, alve-from those found in the gastrointestinal tract . olar epithelium, basement membrane, pulmonary enzymes, Drug delivery to the lung is deﬁned by a complex of fac- macrophages, and cells that may act as barriers to pulmonarytors including character of moieties to be transported and absorption . Although alveolar and capillary epithelia mayabsorbed, their size, shape, density, charge, pH of delivery be highly permeable to water permeation of many hydro-entity, velocity of entry into the system, quality of deposition philic substances, absorption of moieties of large molecularof aerosol in which the moiety is inhaled, character of alveoli, size and ionic species is limited . Molecular weight cutoffbinding characteristics of the aerosol to the alveolar surface, of tight junctions for absorption by alveolar type I cells isqualities of the alveolar capillary bed, character of the capil- 0.6 mm, although endothelial junctions allow passage oflary bed, and its subsequent vascular tree. larger molecules (4–6 mm) .
R. I. Henkin / Nutrition 26 (2010) 33–39 35 After reaching the alveoli many proteins are degraded by insulin is absorbed, studies have suggested that the degreeproteases or are removed by alveolar macrophages that se- of inhaler absorption is reproducible.crete short-lived peroxidases, inﬂammatory and immuno- Many clinical trials of various dry-powder preparationsmodulatory mediators [including granulocyte colony have indicated that inhaled insulin had a faster onset of actionstimulating factor (GCSF), interleukins, leukotrienes, and than subcutaneous systems [25,26] and a clear dose–responseproteases], and other host-defense molecules. These mole- has been measured [18,19]. Availability of intrapulmonarycules degrade inhaled peptides and proteins. insulin has been shown to be about 80% of that of subcutane- Pulmonary mucus is the direct surface layer with which ous administration . Efﬁciency of insulin delivery dependsinsulin comes into contact. Pulmonary mucus varies from on many factors including losses related to delivery device,1 to 10 mm in thickness. In the mucus is surfactant (0.1– environment of delivery, deposition of insulin in the mouth,0.2 mm thick) that lines the alveoli and forms a barrier to throat, and bronchi with intrapulmonary administration, andabsorption . incomplete absorption from alveoli when introduced into the Much work has been done to develop insulin absorption lung. Through the lung maximum delivery efﬁcacy is esti-enhancers or promoters that increase dry-powder insulin ab- mated to be about 30%, with peak activity occurring withinsorption. These include multiple and different types of com- 40–60 min . The technique was proved reproduciblepounds relating to various aspects of enhancing pulmonary and safe, with intra-subject variability not differing fromabsorption [6,7]. Addition of these substances improved that observed with subcutaneous administration .drug delivery reproducibility and decreased variability Efﬁcacy of intrapulmonary insulin administration com-[3,8–10]. pared with that of subcutaneous insulin has been evaluated by many investigators in many studies in normal and diabeticHuman studies subjects [2,27,28]. Results have demonstrated that inhaled insulin provides equivalent glucose control to that of subcu- In 1925 Gansslen  reported the ﬁrst study of efﬁcacy ¨ taneous insulin as measured by hemoglobin A1C . Someof insulin administration by the pulmonary route; results investigators have indicated that inhaled insulin improvesindicated that inhalation of crude animal pancreas extract glycemic control over that of subcutaneous insulin. Thesereduced blood glucose by 26% within 2.5 h. Many subse- results have indicated that the inhaled system is not onlyquent studies up to the present have provided direct evidence efﬁcacious but also well tolerated, well liked, and results inof absorption of insulin after pulmonary inhalation [12–18]. reproducible results as acceptable or even more acceptableInitial estimates have suggested that about 10–13% of than subcutaneous administration [29,30]. Indeed, treatmentaerosolized insulin product was delivered into the lung satisfaction was greater among patients receiving inhaled(e.g., with a delivery efﬁcacy of about 30%) . Studies compared with subcutaneous insulin . A potential advan-have indicated that postprandial glucose levels could be tage of aerosol insulin is that it is more rapidly absorbedmaintained below diabetic levels by intrapulmonary insulin (serum peak a 5–60 min) and cleared than subcutaneous insu-administration [12–19]. Some investigators have maintained lin (peak at 60–150 min), which provides a more relevant andthat inhaled insulin provides a more physiologic prandial in- convenient mealtime glucose control . Because of thistake replacement than ‘‘regular’’ (i.e., subcutaneous) insulin rapid absorption the onset of action of inhaled insulin is fasterin patients with diabetes . It is not simply a question of than that of subcutaneous injection . Compared with sub-insulin absorption through the lung but under what condi- cutaneous injection the relative efﬁciency of delivery bytions this process can be maximized and controlled . As aerosol has been estimated to be retained from 360–noted, particle size and ventilation parameters including tidal 380 min dependent on dosage administered . Somevolume, inspiratory ﬂow rates, and lung functionality are sig- investigators have considered duration of action of intrapul-niﬁcant factors in determining particle deposition into the monary and subcutaneous administrations to be similarlung with subsequent insulin absorption into the blood by , whereas others have considered action duration ofthe alveolar capillary system . Studies have suggested inhaled insulin to be longer . As noted earlier, insulinthat moieties such as insulin are absorbed into the blood by binding antibody was increased in patients who used thetranscytosis, a process occurring at the alveolar capillary inhaled compared with the subcutaneous method of adminis-membrane by transposition of tiny membrane ‘‘bubbles’’ or tration . With respect to the primary mechanism of actiontranscytotic vessels that are dependent on particle size, mo- of inhaled insulin, as noted earlier, it appears to be absorbedlecular weight, solubility, charge, lipophilicity, pH, and by transcytosis across the alveolar–capillary membranemembrane permeability [22,23]. This system has been mod- [22,23,27].eled to evaluate the contribution of each of these and other However, the ﬁrst drug approved to deliver intrapulmo-factors separately and as a complex system . As with nary insulin had its detractors . Its usefulness was initiallysubcutaneous insulin administration, over time, antibodies inhibited by its cost, which was signiﬁcantly greater than thatto insulin develop and inhaled insulin has been reported to for subcutaneous administration. It was withdrawn from theproduce a larger antibody response than has subcutaneous market in 2008. Its death knell occurred with reports of sev-insulin . Despite the fact that only a fraction of inhaled eral cases of lung cancer attributed to its use [32,33], although
36 R. I. Henkin / Nutrition 26 (2010) 33–39the drug company marketing the drug denied this was the blood–brain barrier and can pass directly into the brain.cause of the withdrawal . The former method of absorption was measured indirectly by comparing levels of endogenous insulin in blood, nasalIntranasal insulin mucus, and saliva under varying conditions [36–38]. Results of these studies have illustrated that the metabolism of insu- Many of the same absorption issues related to intrapulmo- lin, insulin receptor, IGF-I, or IGF-R3 differ signiﬁcantly innary insulin administration relate to intranasal inhalation of blood plasma, nasal mucus, and saliva, suggesting that mech-insulin. Although this mode of administration has not been anisms that control insulin secretion and utilization differ instudied as extensively as has intrapulmonary inhalation, it these three ﬂuids. The latter method of absorption, usinghas been used for the past 25 y. Although the surface area these same data, suggests that one aspect of these differencesfor intrapulmonary insulin inhalation is quite large could relate to neural control of insulin metabolism through(w75 m2), the surface area for intranasal insulin inhalation endogenous nasal absorption of insulin. This hypothesis sug-is much smaller (w180 cm2) . However, characteristics gests that intranasal administration of insulin may offerof the upper airways may make intranasal insulin administra- a unique and useful method of insulin administration thattion a more suitable surface for drug administration . may provide an important and novel method that could tap Insulin itself is secreted into nasal mucus by serous glands into important and heretofore unanticipated methods of con-that line the nasal mucus membrane . This secretion trol of insulin administration. This could not only controlchanges physiologically with obesity, decreased food intake, blood glucose directly but also control insulin effects onand in patients with type 2 diabetes . Insulin receptors are central nervous system (CNS) metabolism and secretion ofalso secreted into the nasal mucus  and are similarly substances by which insulin feedback mechanisms could beresponsive to obesity, decreased food intake, and in type 2 enhanced.diabetes . Similarly, insulin-like growth factor (IGF)-I Control of insulin metabolism by insulin replacementand IGF receptor 3 (IGF-R3) are secreted into nasal mucus through inhalation and CNS processing is an important issueand have been previously reported to be present in this that has not been fully addressed. Kern et al.  reportedﬂuid . that intranasal insulin reduced amplitudes of auditory-evoked Delivery of intranasal insulin, as with intrapulmonary potentials and increased latency of some waveforms that theydelivery, is dependent on many anatomic and physiologic interpreted as demonstrating direct insulin entry into the brainfactors that enhance and inhibit absorption. These include and directly inﬂuencing CNS function. Sigurdsson et al. nasal mucus concentration, character of the nasal mucus using I125-insulin demonstrated the transport of intranasally, speed of mucociliary clearance, character and thickness administered insulin directly into the brain and systemicof the mucociliary membrane, nasal mucus enzymes, macro- absorption. They concluded that insulin gains entry into thephages, and other cells that may act as barriers to intranasal CNS from the olfactory region of the upper nose by a non-absorption and—groups of moieties not present in pulmo- speciﬁc pathway . Other studies suggesting direct CNSnary secretions—xenobiotics, bacteria, fungi, and other effects of intranasal insulin administration relate to intranasalactive microbial and antimicrobial agents present in the insulin improving human memory [42,43], acting on adipos-nose that are not present in the lower airways or in lung. In- ity signals , and improving several aspects of cognitivedeed, the nose, compared with the lung, is a ‘‘dirty’’ area in function . Intranasal administration of IGF-I has alsowhich interactions among microbial, antimicrobial, and been shown to bypass the blood–brain barrier and have a di-xenobiotic agents are present at all times; this type of interac- rect CNS effect protecting against focal cerebral ischemiction, although present to some extent in portions of the upper damage , reducing infarct volume after middle cerebralairways, is not present in lung alveoli, which are usually artery occlusion , and improving neurologic functionsterile. after this procedure . Intranasal insulin delivery of IGF- The optimal particle size for intranasal insulin administra- I into the brain and spinal cord was considered to travel alongtion is not well characterized. However, it may be assumed olfactory and trigeminal pathways . Transport into thethat similar-size or somewhat larger particles than those pre- brain, as with systemic absorption through the nose, wassented to pulmonary alveoli would be absorbed. Intranasal dependent on molecular characteristics including size,delivery devices may be similar with respect to intrapulmo- charge, solubility, lipophilicity, and other molecular charac-nary drug presentation, with dry powder preferable to ﬂuid teristics. Nasal delivery avoids the major action of liver me-aerosol sprays. tabolism, as occurs with the subcutaneous route, although What makes intranasal insulin administration more attrac- cytochrome P-450 activity in the olfactory region of the nasaltive than intrapulmonary administration is that absorption airway is higher than in liver due to a higher content ofinto the nose not only bypasses gastrointestinal inhibition nicotinamide adenosine dinucleotide phosphate/cytochromeof insulin absorption but also offers two important physio- P-450 reductase. There are also peptidases and proteases inlogic processes for insulin absorption: 1) absorption by the nasal mucus that limit direct insulin delivery.the large available complex plexus of small blood vessels That intranasal insulin acts similarly to subcutaneous insu-in the nose and 2) absorption that is not limited by the lin administration in the control of blood glucose is well
R. I. Henkin / Nutrition 26 (2010) 33–39 37known . There have been many clinical studies of this in each route of administration, but nasal absorption wasroute of insulin administration demonstrating long-term suc- induced the greatest, with the rank order effect changedcessful control of plasma glucose [49–57]. such that nasal > rectal > sublingual, with nasal and rectal As with intrapulmonary delivery composition, the intrana- being about half as efﬁcacious as intramuscular insulinsal delivery system has been reported to play a signiﬁcant role . In the absence of an absorption promoter substantialin insulin absorption. Intranasal absorption has been amounts of buccal insulin were not absorbed, but withimproved by using absorption enhancers such as aminobor- absorption enhancers (sodium taurocholate, sodium laurelonic acid derivatives, amastatin, and enzyme inhibitors sulfate, sodium methoxy salicylate, sodium dextran sulfate,. Surfactants, such as bile salts, have been reported to ethylenediaminetetra-acetic acid, and Brij-35) buccal insulinincrease absorption by inhibiting the action of proteolytic en- was absorbed and induced hypoglycemia, although pharma-zymes present in nasal mucus . The variety of the compo- cologic availability was dependent on the concentration ofsition of the intranasal delivery systems was reported to play the absorption promoter [66,68]. Bioavailability from buccala signiﬁcant role in insulin absorption. Use of surfactants administration was about 12%, whereas it was about 4% from[50,52], geliﬁed insulin , bioadhesive microspheres oral administration ., phospholipids , chitosan nanoparticles , andother enhancers ampliﬁed absorption of intranasally deliv- Summaryered insulin. Administration of insulin as a dry powder wasconsidered more effective than as a liquid aerosol. However, Insulin absorption can be obtained by many routes ofliquid nose drops containing insulin and alkyl glycerides  administration dependent on the characteristics of the insulinhave also been proved effective. molecule, its absorption enhancement promoters, formula- Intranasal insulin absorption resulted in a faster time tion of the delivery system, nature of the system into whichcourse of absorption than subcutaneous administered insulin insulin is to be delivered, ease and convenience of adminis-. Its bioavailability was 8.3% compared with an intrave- tration, and cost. These factors suggest that, although intra-nous bolus  and a dose-dependent suppression of C-pep- pulmonary insulin administration is not currently available,tide and stimulation of glucagon secretion occurred after this intranasal insulin administration may be a more effectiveroute of administration . non-invasive method of administration . Future studies In general there has been little toxicity associated with will establish whether or not this suggestion will be veriﬁedintranasal insulin delivery ; it has been well tolerated in the marketplace.without any long-term side effects . However, reportsof increased cough, nasal irritation, inﬂammation, or pruritusfrom intranasal insulin delivery have been made , and Referencesimmediate but not long-term hypertension has been reported  Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancre-with intranasal use . Insulin resistance has also occurred atic extracts in the treatment of diabetes mellitus. Can Med Assoc Jafter intranasal insulin administration as it has after all other 1922;12:141–6.methods of insulin administration. This resistance has been  Patton JS, Bukar J, Nagarajan S. Inhaled insulin. Adv Drug Deliv Revsuggested to be a compensatory mechanism related to low 1999;35:235–47.cerebrospinal ﬂuid insulin .  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