WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Arjun et al. World Journal of Pharmacy and Pharmaceutical Sciences

SJIF Impact Factor 7.632

Volume 8, Issue 12, 471-476 Review Article ISSN 2278 – 4357

A REVIEW ON TECHNOSPHERE INHALED INSULIN (AFREZZA)

Mareena Cyriac1, Neethu Anna Stephen2 and Akhila S. Arjun*

*Department of Pharmacy Practice, Bapuji Pharmacy College Davangere, Karnataka India.

1,2
Pharm D, Department of Pharmacy Practice, Bapuji Pharmacy College Davangere,
Karnataka India.

Article Received on ABSTRACT

07 Oct. 2019, Considerable progress in treatment of diabetes has been made in the
Revised on 28 Oct. 2019,
Accepted on 18 Nov. 2019 nearly 100 years following the discovery of insulin, and advances in
DOI: 10.20959/wjpps201912-15153 insulin therapy have improved convenience, quality of life, overall
glycemic control (A1C), and risk of hypoglycemia. Despite this,
*Corresponding Author glycemic control remains suboptimal in many people with diabetes.
Akhila. S. Arjun Although postprandial glucose control has been improved with the
Department Of Pharmacy development of subcutaneously injected rapid-acting insulin analogs,
Practice, Bapuji Pharmacy
the delayed onset of metabolic action and prolonged period of effect
College Davangere,
induce the risk of postprandial hyperglycemia and late
Karnataka India.
postprandial hypoglycemia. The real and perceived risk of
hypoglycemia and the need for multiple daily injections are widely recognized as key barriers
to effective insulin therapy. Therefore, there is a clear unmet need for a treatment option
which can help mitigate these barriers. Alternative methods of insulin administration have
been under investigation for several years, and pulmonary delivery has shown the most
promise to date. Inhaled Technosphere® Insulin (TI; Afrezza®; MannKind Corporation) was
approved in 2014 for use as prandial insulin in people with diabetes. It is new, quicker acting
inhalable insulin with a different and safer pharmacokinetic profile in comparison to
previously failed inhaled form of insulin.

INTRODUCTION
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. Diabetes mellitus (DM) is
described by WHO as a metabolic disorder of multiple etiology, characterized by chronic

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Arjun et al. World Journal of Pharmacy and Pharmaceutical Sciences

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.[1]

The therapeutic goal in subjects with diabetes on insulin treatment is to maintain a tight
glycemic control preferentially through an insulin regimen that closely mimics physiological
insulin secretion. The Diabetes Control and Complications Trial firmly established the value
of tight glycemic control in preventing or delaying the development of long-term diabetes-
related complications.[2]

Intensive glycemic control often necessitates basal-bolus insulin treatment. However,

hypoglycemia, weightgain, and the burden of multiple injections often lead to poor adherence
(1). Hypoglycemia is considered the main limiting factor for optimizing glycemic control (2).
Mild hypoglycemia may be inconvenient or frightening (3), whereas severe hypoglycemia
can be life threatening (4). Lack of compliance with insulin therapy is a frequent problem in
patients with type 1 diabetes due to pain and embarrassment associated with insulin injections
(5). Concerns about weight gain also contribute to reduced adherence.

Inhaled prandial insulin with rapid kinetics may address some of these concerns and could
provide important therapeutic options for individualized diabetes management.[3]

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. 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.[4]

History
The discovery of insulin in 1922 marked a major breakthrough in medicine and therapy in
patients with diabetes. Long before the discovery of insulin, it was hypothesized that the
pancreas secreted a substance that controlled carbohydrate metabolism. The first injection of

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Arjun et al. World Journal of Pharmacy and Pharmaceutical Sciences

the pancreatic extract to a 14-year-old boy by Banting and Best on January 11, 1922, caused a
sterile abscess, had no effect on ketosis, and resulted in mild blood glucose reduction. Eli
Lilly began producing insulin from animal pancreas but fell short of the demand, and the
potency varied up to 25% per lot.[6] Because the insulin preparation required several
injections daily, investigators worked to find ways to prolong its duration of action. In 1982,
the first insulin utilizing rDNA technology, Humulin® R (rapid) and N (NPH, intermediate-
acting), were marketed. To have an alternative delivery method for insulin, exubera, the first
inhaled insulin, was developed by Sanofi-Aventis and Pfizer and marketed by Pzifer in 2006.
It was taken off the market after two years when it failed to gain acceptance from patients
and providers.[5] In June, 2014, the FDA approved Affreza for both Type I and Type II adult
diabetics, with a label restriction for patients having asthma, active lung cancer or Chronic
Obstructive Pulmonary Disease (COPD).[6]

Inhaled Vs Conventional Insulin

 Inhaled insulin may offer the first practical, noninvasive alternative to insulin injection.[7]
 Literature showed glycemic control as assessed by mean decrease in HbA1c from base
line to end point was comparable between the inhaled and conventional treatment group[8]
 A study showed that patients with type 1 diabetes receiving basal insulin, HbA1c
reduction with TI was non inferior to that of aspart, with less hypoglycaemia and less
weight gain but increased incidence of cough.[3]
 In one study, Technosphere Insulin has a more rapid onset of action than sc Regular
Human Insulin (RHI). About 60% of the glucose-lowering effect of TI occurs during the
first 3 hours after application. In contrast, <30% of the glucose-lowering effect of sc RHI
occurs in this period. Technosphere Insulin demonstrated a lower intrasubject variability
during the 3-hour postprandial period, without reaching statistical significance.[2]

Technosphere Device System

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.[9]

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Arjun et al. World Journal of Pharmacy and Pharmaceutical Sciences

Fig.1: Technosphere insulin (Mannkind Corporation, Valencia, California). (A and B)

The original MedTone Inhaler (Mannkind). (C and D) The Gen 2 device combined with
Technosphere Insulin into the drug-device combination system called AFREZZA.

This Device Offers Various Advantages

• 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.[4]

Both components, insulin and powder (fumaryl diketopiperazine) are almost completely
cleared from the lungs of healthy individuals within 12 hours of inhalation. In contrast to
Exubera (8-9%) only 0.3% of insulin of inhaled insulin remained in lungs after 12 hours.[8]

Clinical Efficacy
A randomized open labelled trial in which patients were randomized to prandial inhaled TI or
usual care (oral antidiabetes drugs alone or with insulin) without TI. It showed that changes

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Arjun et al. World Journal of Pharmacy and Pharmaceutical Sciences

in lung function with TI were small, after the initial decline at the first post-baseline
assessment visit (month 3), annual rates of decline (slope) in FEV1, FVC and DLCO from
months 3–24 were not statistically different between groups, indicating that after the early
decline, PFT changes associated with TI were non-progressive up to 2 years.[10]

Efficacy and safety data from a clinical trial showed that subjects treated with AFREZZA
experienced statistically significantly fewer hypoglycaemic episodes in regard to both
incidence and frequency compared with subjects treated with sc insulin.[11]

A meta-analysis concluded that cough is the most common pulmonary symptom associated
with inhaled insulin and is increased versus the comparison groups with no difference
between type1 DM and type 2 DM.[12]

AFREZZA should be used in combination with long acting insulin, 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.[4]

Precautions and Contraindications

Precaution should be taken in patients of asthma and COPD and in fluid retention and heart
failure while administering AFREZZA. It is contraindicated in hypoglycemia,
hypersensitivity to regular human insulin, chronic lung disease such as asthma or COPD,
active lung cancer and hypokalemia. [4]

Pregnancy: Category C.

CONCLUSION
Inhaled insulin is the first non-invasive alternative to subcutaneous insulin administration,
despite the relatively low bioavailability of most products, pulmonary administration of
insulin provides clinically effective plasma insulin levels and sufficient blood glucose
lowering. Inhaled insulin has favorable properties compared to currently available drugs and
also its predecessor Exubera. Inhaled insulin monotherapy may be as good as or better than
oral agents in achieving glycaemic targets in type 2 diabetic patients who fail on diet or
single-agent oral therapy. The combination of the two is better than either treatment alone. It
has been approved by the FDA but its commercial potential is not clear.

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