Table of Contents  
REVIEW ARTICLE
Year : 2015  |  Volume : 6  |  Issue : 3  |  Page : 126-129  

Inhaled insulin: A “puff” than a “shot” before meals


1 Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India
2 1Department of Pharmacology, Nepalese Army Institute of Health Sciences, Kathmandu, Nepal

Date of Submission23-Jul-2014
Date of Decision08-Mar-2015
Date of Acceptance15-May-2015
Date of Web Publication4-Aug-2015

Correspondence Address:
Anjan Khadka
Department of Pharmacology, Nepalese Army Institute of Health Sciences (NAIHS), Kathmandu
Nepal
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Source of Support: Nil., Conflict of Interest: There are no conflicts of interest.


DOI: 10.4103/0976-500X.162013

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   Abstract 

Diabetes is a metabolic disorder characterized by relative or absolute deficiency of insulin, resulting in hyperglycemia. The main treatment of diabetes relies on subcutaneous insulin administration by injection or continuous infusion to control glucose levels, besides oral hypoglycemic agents for type 2 diabetes. Novel routes of insulin administration are an area of research in the diabetes field as insulin injection therapy is burdensome and painful for many patients. Inhalational insulin is a potential alternative to subcutaneous insulin in the management of diabetes. The large surface area, good vascularization, immense capacity for solute exchange and ultra-thinness of the alveolar epithelium facilitates systemic delivery of insulin via pulmonary administration. Inhaled insulin has been recently approved by Food and Drug Administration (FDA). It is a novel, rapid-acting inhaled insulin with a pharmacokinetic profile that is different from all other insulin products and comparatively safer than the previous failed inhaled insulin (Exubera).

Keywords: Diabetes, insulin, nasal spray inhaled


How to cite this article:
Brashier DB, Khadka A, Anantharamu T, Sharma AK, Gupta A K, Sharma S, Dahiya N K. Inhaled insulin: A “puff” than a “shot” before meals. J Pharmacol Pharmacother 2015;6:126-9

How to cite this URL:
Brashier DB, Khadka A, Anantharamu T, Sharma AK, Gupta A K, Sharma S, Dahiya N K. Inhaled insulin: A “puff” than a “shot” before meals. J Pharmacol Pharmacother [serial online] 2015 [cited 2019 Oct 18];6:126-9. Available from: http://www.jpharmacol.com/text.asp?2015/6/3/126/162013


   Introduction Top


Diabetes is one of the greatest challenges in medical field affecting 347 million people worldwide. It is projected to be the seventh leading cause of death by 2030 and >80% deaths due to diabetes occur in low- and middle-income countries.[1] Diabetes mellitus (DM) is described by WHO as a metabolic disorder of multiple etiology, characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action or both; the effects of which include long-term damage, dysfunction and failure of various organs.[2]

The goals of therapy for diabetes are to alleviate the symptoms related to hyperglycemia and to prevent or reduce the acute and chronic complications of diabetes. Insulin is the mainstay for treatment of virtually all type 1 and many type 2 diabetes patients though there is a long list of glucose-lowering agents like sulphonylureas, biguanides, thiazolidinediones, glucagon-like peptide analogs, dipeptidyl peptidase-IV inhibitors, amylin analogues, alpha glucosidase inhibitors etc.[3]

Insulin is regarded as the first choice in case of type 2 DM, particularly in thin individuals or those with severe weight loss, in individuals with underlying renal or hepatic disease that precludes oral glucose-lowering agents, or in hospitalized or acutely ill individuals. Insulin therapy is ultimately required by almost all individuals with type 2 DM because of the progressive nature of the disorder and the relative insulin deficiency that develops in patients with long-standing diabetes.[4]

Insulin may be administered intravenously, intramuscularly, or subcutaneously. The major drawback of currently available formulations of insulin is that they have to be injected and moreover fail to mimic physiological postprandial insulin delivery into systemic circulation.[5] There have been continuous efforts to find new insulin formulations and new routes of administration so that it mimics physiological secretion of pancreatic beta-cells.[6] Oral insulin is currently being studied in type 1 diabetes prevention with promising results and inhalational insulin has been recently approved by Food and Drug Administration (FDA) on 27 June 2014 for glycemic control in adults with type 1 and type 2 DM.[7][8][9]

Inhalational insulin has been developed by MannKind Corporation and it is a novel rapid-acting inhaled insulin available as “Afrezza” with a drug device in the form of small easy to use inhaler and the inhalational powder as single-use cartridges.[9] The idea of making inhalation as the route of delivering insulin is not entirely new; seven years ago when Exubera (Pfizer Inc’s) received FDA approval it was thought to be a great achievement, but quickly faded out as concerns were raised about its safety regarding its effect on lung function, its heavy price tag and bulky inhaler.[10]

Various strategies are being worked out to reduce the gap between physiological and non-physiological insulin release so as to reduce the complications. Pulmonary route of insulin delivery appears to be a feasible option to enhance this synchronization as lungs with thin epithelium, rich blood supply and a vast absorbing surface help in rapid absorption of insulin delivered to it.[5],[11][12][13][14]


   Issue with Pulmonary Delivery of Insulin Top


The idea of pulmonary delivery of insulin has passed various hurdles. All the below-mentioned factors favor inhaled insulin (Afrezza) than the earlier version Exubera.[5],[13],[14]

  • The preparation of freeze-dried powder insulin in a stable form of micro particles (Bis-3, 6 (4-fumarylaminobutyl)-2, 5-diketopiperazine or FDKP) as excipient which translates into microcrystalline plates under slightly acidic conditions onto which insulin can be adsorbed. FDKP is an inert excipient and is absorbed but not metabolized and will be excreted via urine
  • These particles have an average diameter of 2.5 μm, with >90% being in range of 0.5-5.8 μm (suitable for inhalation as will be delivered into alveoli without hindrance)
  • The high solubility of these particles at pH >6 matches with the prevailing physiological pH in lungs that helps in easy dissolution and absorption into systemic circulation.



   Pharmacokinetics Top


It is ultra-rapid-acting insulin which mimics a linear dose-related pharmacokinetic profile in patients of type 1 and 2 DM.[13] Maximum plasma drug concentration reached between 10 and 15 min (Tmax) which is very early compared to regular insulin or other rapidly acting insulin analogues (20-45 min). This is important as it mimics first-phase insulin release after food seen in non-diabetic individuals. Duration of action is around 2-3 hrs.[13][14][15] 60% of the inhaled drugs gets deposited in the lungs.[14] Inhaled insulin is designed to be used within 20 min of beginning a meal [Figure 1].
Figure 1: Insulin inhaler[20]

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   Device System Top


Breath-powder inhaler is used which can be re-used after changing the cartridge for 15 days. The procedure has been made very simple to enhance the compliance in which the cartridge of powdered insulin is placed, then close the device and with a single breath the powder will be inhaled; later open the device, remove the cartridge out and then discard.[16]

This device offers various advantages:[13],[16],[17]

  • The device is small and easy to carry along
  • No need of synchronizing with the inhalation as this device is designed in such a way that it senses and gets activated with inhalation on its own
  • Effectively protects the powdered insulin from getting affected by moisture
  • Re-usable


Inhalational insulin system uses “flow balance concept.” The powder placed in the cartridge has to be broken up and dispersed (de-agglomerated) before delivery into lungs. The air which flows through the device initiates this process and lifts all the powder in the cartridge to reach the exit port; but there is a by-pass channel carrying air which also reaches the exit port and intersects the air coming from mouthpiece and completes the process of de-agglomeration.[13],[14],[17],[18][19][20]

Inhalational insulin is available in two strengths [Figure 1] and [Figure 2] in foil packages. One foil package consists of two blister cards and there are five strips per blister card. Each strip contains three cartridges. It is administered using a single inhalation per cartridge. Cartridge should be stored at 2-8°C (36-46°F).[13],[15],[18][19][20] [Figure 2] [Figure 3] [Figure 4].
Figure 2: 4 Units inhalational insulin[20]

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Figure 3: 8 Units inhalational insulin[20]

Click here to view
Figure 4: Mealtime inhaled insulin (Afrezza) dose conversion table[20]

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   Clinical Efficacy Top


A study showed that the after injecting 60 U of TI (Technosphere insulin = Afrezza) in patients of type 2 DM, the maximal suppression of postprandial endogenous glucose production occurred within 45 min compared to 10 U of SC rapidly acting insulin analogs.[16],[17],[19],[20]

Efficacy and safety data from a clinical trial where in both type 1 (3017 patients) and type 2 (1991 patients) were studied which showed a reduction of HbA1c levels reduction by 0.4% in both groups at the end of 24 weeks. In another 24 week study involving 500 patients of type 1 DM, glycemic control was equal among Afrezza and injected rapidly acting insulin group, but the Afrezza group had less incidence of hypoglycemia probably due to rapid and short duration of action.[20],[21]

A 52-week randomized, open-label, parallel –group study evaluating the safety and efficacy of long-acting insulin + prandial TI (Technosphere Insulin) versus a twice daily injection of premixed insulin in patients of type 2 DM showed similar and non-inferior results.[16],[17],[20]

It is not a substitute for long-acting insulin. It must be used in combination with long-acting insulin in patients with type 1 diabetes, and it is not recommended for the treatment of diabetic ketoacidosis (DKA) as trials suggest an increased incidence of DKA in patients on Afrezza. It is better not to be used in smokers as there is a possible risk of reduction in lung function.[17],[20]


   Adverse Effects Top


The most common adverse reactions include hypoglycemia, cough, throat pain and irritation. There is some evidence reduction in FEV1 of lung function, but overall long-term effects and the need for withdrawal has not yet been established as it is for its predecessor Exubera [Figure 5]. Serious risk includes bronchospasm in patients with asthma, COPD and smokers.[17],[20][21][22]
Figure 5: Insulin (Exubera) inhaler

Click here to view



   Precautions and Contraindications Top


Precaution should be taken in patients of asthma and COPD and in fluid retention and heart failure. It is contraindicated in hypoglycemia, hypersensitivity to regular human insulin, chronic lung disease such as asthma or COPD, active lung cancer and hypokalemia.[17],[20][21][22]

Pregnancy: Category C.


   Indications Top


Type 1 and 2 DM: It should be used with regimens that include long acting insulin.[9],[20]


   Conclusion Top


Inhaled insulin has favorable properties compared to currently available drugs and also its predecessor Exubera. It has reproducible insulin delivery, a rapid and a short duration of action compared to regular insulin and rapidly acting analogs of insulin, closely mimicking physiological insulin. The history does not back it and it has to take on the giants in market whenever it comes who are currently ruling and are the regular choice of masses. It has been approved by the FDA but its commercial potential is far from clear.



 
   References Top

1.
Chan JC, Malik V, Jia W, Kadowaki T, Yajnik CS, Yoon KH, et al. Diabetes in Asia: Epidemiology, risk factors, and pathophysiology. JAMA 2009;301:2129-40.  Back to cited text no. 1
    
2.
Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet 2005;365:1333-46.  Back to cited text no. 2
    
3.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al.; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: A consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.  Back to cited text no. 3
    
4.
Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: A multicentre randomised parallel-group trial. Lancet 2008;371:1753-60.  Back to cited text no. 4
    
5.
Tyagi P. Insulin delivery systems: Present trends and the future direction. Indian J Pharmacol 2002;34:379-89.  Back to cited text no. 5
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6.
Gualandi-Signorini AM, Giorgi G. Insulin formulations - A review. Eur Rev Med Pharmacol Sci 2001;5:73-83.  Back to cited text no. 6
    
7.
Joshi SR, Parikh RM, Das AK. Insulin-history, biochemistry, physiology and pharmacology. J Assoc Physicians India 2007;55(Suppl):19-25.  Back to cited text no. 7
    
8.
Nguyen QT, Thomas KT, Lyons KB, Nguyen LD, Plodkowski RA. Current therapies and emerging drugs in the pipeline for type 2 diabetes. Am Health Drug Benefits 2011;4:303-11.  Back to cited text no. 8
    
9.
FDA Approval for Afrezza. Available from: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction = Search. Drug Details. [Last accessed on 2014 Jul 13].  Back to cited text no. 9
    
10.
Gowtham T, Rafi Khan P, Gopi Chand K, Nagasaraswathi M. Facts on inhaled Insulin. Journal of Applied Pharmaceutical Science 2011;1:18-23.  Back to cited text no. 10
    
11.
Balducci AG, Cagnani S, Sonvico F, Rossi A, Barata P, Colombo G, et al. Pure insulin highly respirable powders for inhalation. Eur J Pharm Sci 2014;51:110-7.  Back to cited text no. 11
    
12.
Adams GG, Harding SE. Drug delivery systems for the treatment of diabetes mellitus: State of the art. Curr Pharm Des 2013;19:7244-63.  Back to cited text no. 12
    
13.
Hickey AJ. Back to the future: Inhaled drug products. J Pharm Sci 2013;102:1165-72.  Back to cited text no. 13
    
14.
Kamei N, Nielsen EJ, Khafagy el-S, Takeda-Morishita M. Noninvasive insulin delivery: The great potential of cell-penetrating peptides. Ther Deliv 2013;4:315-26.  Back to cited text no. 14
    
15.
Heinemann L. New ways of insulin delivery. Int J Clin Pract Suppl 2012;35-9.  Back to cited text no. 15
    
16.
Cassidy JP, Amin N, Marino M, Gotfried M, Meyer T, Sommerer K, et al. Insulin lung deposition and clearance following Technosphere® insulin inhalation powder administration. Pharm Res 2011;28:2157-64.  Back to cited text no. 16
    
17.
Neumiller JJ, Campbell RK, Wood LD. A review of inhaled technosphere insulin. Ann Pharmacother 2010;44:1231-9.  Back to cited text no. 17
    
18.
Hohenegger M. Novel and current treatment concepts using pulmonary drug delivery. Curr Pharm Des 2010;16:2484-92.  Back to cited text no. 18
    
19.
Mastrandrea LD. Inhaled insulin: Overview of a novel route of insulin administration. Vasc Health Risk Manag 2010;6:47-58.  Back to cited text no. 19
    
20.
Afrezza (Insulin Human [rDNA Origin]) Inhalation Powder. MannKind Corporation 2014. Available from: http://www.fda.gov/downloads/..../ucm390865.pdf. [Last accessed on 2014 Jul 16].  Back to cited text no. 20
    
21.
Boss AH, Petrucci R, Lorber D. Coverage of prandial insulin requirements by means of an ultra-rapid-acting inhaled insulin. J Diabetes Sci Technol 2012;6:773-9.  Back to cited text no. 21
    
22.
Kling J. Dreamboat sinks prospects for fast approval of inhaled insulin. Nat Biotechnol 2011;29:175-6.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


This article has been cited by
1 Erratum: Inhaled insulin: A "puff" than a "shot" before meals
Journal of Pharmacology and Pharmacotherapeutics. 2015; 6(4): 241
[Pubmed] | [DOI]



 

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    Abstract
   Introduction
   Pharmacokinetics
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    Issue with Pulmo...
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