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Review article
Inhaled insulin—Intrapulmonary, intranasal, and other routesof 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 until2006 when the Federal Drug Administration (FDA) approved the first commercially availablepulmonary inhaled insulin.
Methods:
A review of major publications dealing with intrapulmonary administration of insulin wasmadetounderstandthephysiologicalbasisforitsuse,itsefficacyincontrollinghyperglycemia,itssideeffects 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 andultra thin membranes of alveolar epithelia are unique features that facilitate pulmonary insulin deliv-ery. Large lung surface area (
w
75 m
2
) and thin alveolar epithelium (
w
0.1–0.5
m
m) permit rapid drugabsorption. First pass metabolism avoids gastrointestinal tract metabolism. Lung drug deliverydepends 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 aerosolon the alveolar surface, quality of alveolar capillary bed and its subsequent vascular tree. Many studieswereperformed tooptimize each ofthesefactors usingseveraldelivery systems toenhancepulmonaryabsorption. Availability was about 80% of subcutaneous administration with peak activity within 40– 60 min of administration. Intranasal insulin delivery faces a smaller surface area (
w
180 cm
2
) withquitedifferentabsorptioncharacteristics innasal epitheliumand itsassociated vasculature.Absorptiondepends 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 studiesthe FDA approvedPfizer’s product,Exubera,for intrapulmonaryinsulin delivery. While the system was effective its expense and putative side effects caused the drugcompany to withdraw the drug from the marketplace. Attempts by other pharmaceutical companies touse intrapulmonary insulin delivery are presently being made as well as some minor attempts to useintranasal delivery systems.
Ó
2010 Elsevier Inc. All rights reserved.
Keywords:
Insulin; Hormones; Glucose metabolism; Inhalation; Lung; Nose; Insulin metabolism; Nasal mucus
Introduction
Discovery of insulin as a hypoglycemic agent by Bantingand Best in 1921[1]and its subsequent purification indicatedthat this hormone was of great value to patients with diabetesmellitus. The practical question at that time was how toadminister this key agent to control blood glucose. Initialattempts delivered the hormone intramuscularly, intrave-nously, and eventually subcutaneously. Other routes of administration of the drug were explored. These includedoral, rectal, sublingual, buccal, transdermal, vaginal, intra-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 1and 2 diabetes that would effectively lower blood sugar, con-trol hemoglobin A
1
c (in much later studies), and allow
* Corresponding author. Tel.:
þ
202-364-4180; fax:
þ
202-364-9727.
E-mail address:
Ó
2010 Elsevier Inc. All rights reserved.doi:10.1016/j.nut.2009.08.001Nutrition 26 (2010) 33–39www.nutritionjrnl.com
patients a simpler, less invasive, and more direct control of their underlying disease process. Only recently has interest in alternative administration routes to the commonly usedsubcutaneous andintravenousroutesbeenforcefullyrevived.However,there werenoa priori concepts thatwoulddirectitsdelivery by one or another method. As clinical eventsoccurred it became clear that absorption of the insulin mole-cule by any route could be improved. Thus, absorptionenhancers were used to improve hormone absorption. Inthismanner, protaminezinc was formulatedearly in thetreat-ment process with significant improvement in hormoneaction. Other enhancers were considered later.In January 2006 the United States Food and DrugAdministration approved Exubera (Pfizer Pharmaceuticals,New York, NY) as the first pulmonary inhaled insulin. Inactuality attempts to explore various methods to deliver in-sulin using intrapulmonary delivery had occurred since1925[2]. Approval of Exubera was the result of many yearsof work by many groups of scientists who had to overcomemany obstacles to obtain this event.In the present work some of the physiologic bases for intrapulmonary, intranasal, and other delivery routes are dis-cussed, in addition to advantages and disadvantages of eachapproach and mechanisms of action.
Intrapulmonary insulin
The lung has been considered a route for systemic deliv-ery of many therapeutic proteins and peptides[3]. Thissystem includes two major anatomical parts. The first includes the upper airways, oral cavity, trachea, bronchi,and all upper airways distal to the bronchioles. The secondincludes the lower airways, conducting airways includingrespiratory bronchioles, alveolar ducts, and alveolar sacs.The large surface area of the lung, its good vascularization,immense capacity for solute exchange, and ultrathin mem-branes of alveolar epithelia are unique features that facilitatesystemic delivery of these substances[3]. The lung offersa large surface area for drug absorption (
w
75 m
2
). Thevery thin alveolar epithelium (
w
0.1–0.5
m
m thick) permitsrapid drug absorption. The alveoli can be targeted for effec-tive drug absorption by drug delivery by aerosol witha mass medium aerodynamic particle diameter
<
5
m
m.First-pass metabolism in this route avoids gastrointestinaltract metabolism. Although metabolic enzymes are foundin the lung, their activities and metabolism are different from those found in the gastrointestinal tract [3].Drug delivery to the lung is defined by a complex of fac-tors including character of moieties to be transported andabsorbed, their size, shape, density, charge, pH of deliveryentity, velocity of entry into the system, quality of depositionofaerosolinwhichthemoiety isinhaled,characterofalveoli,binding characteristics of the aerosol to the alveolar surface,qualities of the alveolar capillary bed, character of the capil-lary bed, and its subsequent vascular tree.
Particle size
Absorption of particles by the lung has been shown tohave an optimal aerodynamic diameter from 1 to 5
m
m. Totarget the alveolar region specifically, aerosol droplet diame-ter has been determined to be no more than 3
m
m with parti-cles
>
6
m
m deposited in the oropharynx but
<
1
m
Delivery devices
Delivery depends on the character of the delivered drug asliquid or powder. Devices are usually nebulizers that are me-tered-dose inhalers or drug-powder inhalers. The problemwith liquid nebulizers is that 99% of generated droplets arerecycled back into the reservoir to be redelivered during thenext dose[3]. In addition, droplets rendered by nebulizersare heterogeneous, which results in poor drug delivery tothelowerrespiratorytract.Thesedevicesusuallyuseahydro-carbon propellant to atomize the drug solution, with a result-ing more-uniform spray, but these proteins and peptides aresusceptible to denaturation when in contact with a propellant or with large air–liquid water forces that are constantly gen-erated during aerosolization[3].Dry-powderinhalersarecurrentlythemostcommonlyuseddevices to deliver pulmonary insulin and treat many pulmo-naryconditions.Thismethodimproveddrugdeliverystabilityandsterility[4]overliquidaerosols[5].Althoughdose-to-dose
variations occur and delivered material is susceptible to envi-ronmental humidity and moisture and is dependent on inhala-tion flow rates[3], this method was chosen because accuratedosing and relatively complete drug delivery were ensured.This choice was based on development of a novel inhaler device,improvedpowderengineeringtechnology,afunctionaldrug carrier, and knowledge of absorption enhancers, whichoptimized drug delivery[5]. Mechanically a fixed volume of air was used to aerosolize a pre-metered and sealed drugdose into a chamber. The patient inhales the drug into thelungusingaslow,deepbreath,eliminatingthecomplexmotor co-ordination required for liquid propellant devices.
Pulmonary barrier and pulmonary absorption
These parameters include the amount and character of respiratory mucus, amount and speed of mucociliary clear-ance, character and thickness of the alveolar lung layer, alve-olar epithelium, basement membrane, pulmonary enzymes,macrophages, and cells that may act as barriers to pulmonaryabsorption[3]. Although alveolar and capillary epithelia maybe highly permeable to water permeation of many hydro-philic substances, absorption of moieties of large molecular size and ionic species is limited[3]. Molecular weight cutoff of tight junctions for absorption by alveolar type I cells is0.6 mm, although endothelial junctions allow passage of larger molecules (4–6 mm)[3].
R. I. Henkin / Nutrition 26 (2010) 33–39
34
After reaching the alveoli many proteins are degraded byproteases or are removed by alveolar macrophages that se-crete short-lived peroxidases, inflammatory and immuno-modulatory mediators [including granulocyte colonystimulating factor (GCSF), interleukins, leukotrienes, andproteases], and other host-defense molecules. These mole-cules degrade inhaled peptides and proteins.Pulmonary mucus is the direct surface layer with whichinsulin comes into contact. Pulmonary mucus varies from1 to 10
m
m in thickness. In the mucus is surfactant (0.1– 0.2
m
m thick) that lines the alveoli and forms a barrier toabsorption[3].Much work has been done to develop insulin absorptionenhancers or promoters that increase dry-powder insulin ab-sorption. These include multiple and different types of com-pounds relating to various aspects of enhancing pulmonaryabsorption[6,7]. Addition of these substances improveddrug delivery reproducibility and decreased variability[3,8–10].
Human studies
In 1925 Ga¨nsslen[11]reported the first study of efficacyof insulin administration by the pulmonary route; resultsindicated that inhalation of crude animal pancreas extract reduced blood glucose by 26% within 2.5 h. Many subse-quent studies up to the present have provided direct evidenceof absorption of insulin after pulmonary inhalation[12–18].Initial estimates have suggested that about 10–13% of aerosolized insulin product was delivered into the lung(e.g., with a delivery efficacy of about 30%)[19]. Studieshave indicated that postprandial glucose levels could bemaintained below diabetic levels by intrapulmonary insulinadministration[12–19]. Some investigators have maintainedthat inhaled insulin provides a more physiologic prandial in-take replacement than ‘‘regular’’ (i.e., subcutaneous) insulinin patients with diabetes[20]. It is not simply a question of insulin absorption through the lung but under what condi-tions this process can be maximized and controlled[9]. Asnoted, particle size and ventilation parameters including tidalvolume, inspiratory flow rates, and lung functionality are sig-nificant factors in determining particle deposition into thelung with subsequent insulin absorption into the blood bythe alveolar capillary system[21]. Studies have suggestedthat moieties such as insulin are absorbed into the blood bytranscytosis, a process occurring at the alveolar capillarymembrane by transposition of tiny membrane ‘‘bubbles’’ or transcytotic vessels that are dependent on particle size, mo-lecular weight, solubility, charge, lipophilicity, pH, andmembrane permeability[22,23]. This system has been mod-eled to evaluate the contribution of each of these and other factors separately and as a complex system[21]. As withsubcutaneous insulin administration, over time, antibodiesto insulin develop and inhaled insulin has been reported toproduce a larger antibody response than has subcutaneousinsulin[24]. Despite the fact that only a fraction of inhaledinsulin is absorbed, studies have suggested that the degreeof inhaler absorption is reproducible.Many clinical trials of various dry-powder preparationshave indicated that inhaledinsulinhad a faster onset of actionthansubcutaneoussystems[25,26]andacleardose–responsehas been measured[18,19]. Availability of intrapulmonaryinsulin has been shown to be about 80% of that of subcutane-ous administration[8]. Efficiency ofinsulindeliverydependson many factors including losses related to delivery device,environment of delivery, deposition of insulin in the mouth,throat, and bronchi with intrapulmonary administration, andincomplete absorption from alveoli when introduced into thelung. Through the lung maximum delivery efficacy is esti-mated to be about 30%, with peak activity occurring within40–60 min[19]. The technique was proved reproducibleand safe, with intra-subject variability not differing fromthat observed with subcutaneous administration[17].Efficacy of intrapulmonary insulin administration com-pared with that of subcutaneous insulin has been evaluatedby many investigators in many studies in normal and diabeticsubjects[2,27,28]. Results have demonstrated that inhaledinsulin provides equivalent glucose control to that of subcu-taneous insulin as measured by hemoglobin A
1C
[17]. Someinvestigators have indicated that inhaled insulin improvesglycemic control over that of subcutaneous insulin. Theseresults have indicated that the inhaled system is not onlyefficacious but also well tolerated, well liked, and results inreproducible results as acceptable or even more acceptablethan subcutaneous administration[29,30]. Indeed, treatment satisfaction was greater among patients receiving inhaledcompared with subcutaneous insulin[29]. A potential advan-tage of aerosol insulin is that it is more rapidly absorbed(serumpeaka5–60 min)andclearedthansubcutaneousinsu-lin(peakat60–150 min),whichprovidesamorerelevantandconvenient mealtime glucose control[17]. Because of thisrapidabsorption theonset ofactionofinhaledinsulin isfaster than that of subcutaneous injection[27]. Compared with sub-cutaneous injection the relative efficiency of delivery byaerosol has been estimated to be retained from 360– 380 min dependent on dosage administered[29]. Someinvestigators have considered duration of action of intrapul-monary and subcutaneous administrations to be similar [27], whereas others have considered action duration of inhaled insulin to be longer [27]. As noted earlier, insulinbinding antibody was increased in patients who used theinhaled compared with the subcutaneous method of adminis-tration[24]. With respect to the primary mechanism of actionof inhaled insulin, as noted earlier, it appears to be absorbedby transcytosis across the alveolar–capillary membrane[22,23,27].However, the first drug approved to deliver intrapulmo-naryinsulinhaditsdetractors[31].Itsusefulnesswasinitiallyinhibited by its cost, which was significantly greater than that for subcutaneous administration. It was withdrawn from themarket in 2008. Its death knell occurred with reports of sev-eralcasesoflungcancerattributedtoitsuse[32,33],although
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