Technology in insulin delivery systems future directions

1. Technology in insulin delivery
systems & future directions
Dr. Shinjan Patra

2. Why Greater BP reduction in SAI
compared to PAI
• Some patients with SAI may have partial ACTH deficiency,
with higher circulating endogenous cortisol levels than
patients with PAI
• These patients may, therefore, be over-replaced on similar
doses of HC replacement to patients with PAI
• Study included a smaller number of patients with PAI and
therefore was potentially underpowered to appreciate a
significant difference
• PAI have concurrent mineralocorticoid deficiency, making
them vulnerable to fluctuations in salt and water balance
and therefore blood pressure homeostasis

3. Contents
• Various ways of delivering Insulin
• Vials & Syringes
• Insulin pens
• CSII
• Closed loop insulin delivery: Artificial Pancreas
• Inhaled Insulin
• Oral Insulin
• Other Novel ways of delivering Insulin

4. Introduction
• The prevalence of diabetes is increasing
throughout the world
• The International Diabetes Federation estimated
366 million people had diabetes in 2011 and is
expected rise to 552 million by 2030
The Global Burden. International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Brussels, Belgium: InternationalDiabetes Federation; 2013.
Available from: http://www.idf.org/diabetesatlas/5e/theglobal- burden. [Last accessed on 2013 Sep

5. Insulin & its beginnings
• Discovery of insulin one of the greatest medical discoveries of the
last century
• All patients with T1DM and many patients with long standing T2DM
require insulin therapy to achieve good glycemic control
• The early insulins were derived from bovine and porcine pancreas
and were associated with immunological reactions, lipodystrophy
and unpredictable insulin absorption from subcutaneous tissue
• Hence, initial research focused on the purification of insulin
• There has been marked progression in the development of insulins
such as rapid and long acting insulin analogs in the last five decades

6. To simulate endogenous insulin
secretion
• Emphasis evolved to achieving tight glycemic
control with minimal hypoglycemia by
focusing on delivering insulin that mimics
endogenous insulin secretion by the pancreas

7. Routes of insulin administration
• Peptide hormone, therefore, destroyed by gastric
acid if taken orally
• Intra-dermal absorption of insulin not reliable,
and can’t mimic physiological insulin secretion
• Intra-dermal, intramuscular and intravenous
therapy not suitable for self-administration daily
• Subcutaneous route of administration widely
preferred method

8. Newer Insulin techniques
• The newer methods of insulin delivery aim to
deliver insulin with minimal invasiveness in an
accurate and precise manner

10. Vials & Syringes

11. Vial & Syringe
• In 1924, 2 years after the discovery of insulin, Becton, Dickinson
and Company (BD) made a syringe specifically designed for the
insulin injection
• Initial syringes were made of metals and/or glass, reusable and
required boiling after each use to sterilize
• Despite all these advances, many patients do not feel to inject
insulin 3-4 times a day as a result of needle phobia
• Insulin syringes with three different needle lengths 6, 8 and 12.7
mm are available
• Also, three gauge sizes, 31, 30 and 29 are available
The history of injecting and the development of the syringe. Exchange supply tools for harm reduction. Available from: http://
www.exchangesupplies.org/article_history_of_injecting_and_ development_of_the_syringe.php

12. i-port advance
• First device to combine an injection port and an
inserter in one complete set that eliminates the need
for multiple injections without having to puncture the
skin for each dose
• Virtually painless insertion, leaving a soft cannula
under the skin and giving a means to inject
• Normal activity - including showering, swimming and
exercising can be done
• Compatible with pens and syringes

14. Insulin pens

15. History & Advancement
• First insulin pen manufactured by Novo Nordisk in 1985
• Newer insulin pens are reusable, more accurate and
equipped with safety features such as audible clicks with
each dose to improve accuracy and reduce the chances of
human errors
• Another advancement in the pen device (HumaPen®
Memoir™) is built-in recording of the time and date of the
last 16 injections
• Recently, NovoPen Echo® has been designed to give
children and parents increased confidence, combines
dosing in half-unit increments with a simple, easy-to use,
memory function

18. Advantages with pen
• More accurate, convenient, less painful and
patient friendly but associated with higher
cost in comparison with vial and syringe
• Recently developed pen needles are shorter
and thinner (31-32 G× 4-5 mm)
• Less painful and requires less thumb force and
time to inject insulin resulting in improved
patient satisfaction

19. Pen needles
• Available in 4, 5, 6 and 8 mm sizes and are of 32,
31 and 30 gauge
• Shorter needles alleviate the risk of intramuscular
injections while avoiding intra-dermal delivery as
well
• Long enough to pass through the skin into the fat
layer but are short enough not to reach the
muscle tissue.

20. Needle length
• There is no medical reason to recommend
needles longer than 4–6 mm to either children or
adults
• Extremely lean patients should be using a skin
fold to inject even with a 4-mm and 5-mm needle
• Shorter needle length (4-6 mm) considered safe
and efficacious in children
Forum for Injection Technique (FIT), India: The Indian Recommendations 2.0, for Best Practice in Insulin Injection Technique 2015

21. Continuous Subcutaneous Insulin
Infusion (CSII)

22. History & Background
• Physiologic delivery of insulin has been a long-standing goal
• High glycemic variability associated with MSI
• The first portable insulin pump invented by Kadish in 1963;
however, it was limited by its size and technical issues
• The first commercial insulin pump introduced in 1979 in the
USA
• Current generation of insulin pumps are more patient
friendly as a result of smaller size and smart features such
as built-in-dose calculators and alarms
Kadish AH. A servomechanism for blood sugar control. Biomed Sci Instrum 1963;1:171

25. Function & Evidences
• Consist of an insulin reservoir and a delivery
catheter that infuses insulin continuously into the
subcutaneous tissue
• CSII use in people with T1DM is associated with
0.4–0.5% lower HbA1c than from MSI
• In T2DM, mean HbA1c declined by 1.1% in the
CSII group and by 0.4% in the MDI group (p <
0.0001)

26. Mechanism
• Generally placed in the anterior subcutaneous
tissue of chest/abdomen
• Primary driving force for delivery is the
pressure difference generated by pressurizing
a drug reservoir with a pump
by osmotic action (osmotic pumps)
by direct mechanical actuation

27. Bolus calculators & insulin on board
• The insulin : carbohydrate ratio (the number of grams of
carbohydrate covered by 1 unit of insulin) and correction/sensitivity
factor (a measure of the glucose-lowering effect of 1 unit of insulin)
is programmed into the pump software
• When calculating an insulin dose, the pump software will consider
the amount of active insulin on-board resulting from earlier boluses
(commonly referred to as IOB) and subtract this IOB from the
recommended dose
• In practice, the major consideration in setting the insulin duration
of action in the bolus calculator software is usually a best guess
based on a clinical assessment of the hypoglycemia risk of the
individual and imperative for achieving tight glycemic control

28. Basic advantages
• Accurate dosing of insulin boluses in fractions of a unit
allows the patient to correct hyperglycemia more precisely
without overshooting and causing hypoglycemia
• Diurnal variations in basal insulin requirements caused by
the dawn phenomenon and steroid therapy have been
reported to be more readily managed using the multiple
basal rates provided by the pump than by long-acting
injected insulins
• Special benefit for the person with diabetes post-renal
transplant, pre-conception, pregnancy

29. Characteristics of Ideal pump
• Deliver drug within prescribed rates for extended periods (2-5 yrs)
• Accuracy & precision
• Reliability
• Chemical, physical & biological stability
• Compatibility with drugs
• Non-antigenic & non-carcinogenic
• Must have overdose protection
• Convenient to use
• Able to monitor the performance of the pump
• Must be sterilizable
• Have wide delivery rate for basal & bolus deliveries to meet patient
variability
• Long reservoir & battery life and easy Programmability

30. Types of Pump
• Peristaltic pump
• Fluorocarbon propellant-driven pump
• Osmotic pump
• Controlled-release micro-pump

31. Peristaltic pump
• Performed using local anesthesia & on outpatient
basis
• Use of wide variety of drugs
• Precise delivery
• Less risk of infection since it is fully implanted
• Presence of alarm system makes the pump more
safe

32. Fluorocarbon propellant-driven pump
• Construction:
 Hollow titanium disk, moveable pistons
 2 chambers—inner-->drug; outer-->flurocarbon liquid
 Self-sealing silicon rubber & Teflon, bacterial filters,
catheter
• Working:
 Vaporization of flurocarbon leads to drug release
through catheter
 Adjust flow rate by increasing viscosity

33. Osmotic pump
• Moveable piston
maintain pressure in
reservoir
• Presence of Semi-
permeable membrane

34. Controlled release micro pump
• Diffusion across a rate-controlling membrane
for basal delivery
• Augmented by rapidly oscillating piston acting
on a compressible disk of foam
• Achieved without valves

35. Limitations
• Higher cost compared with MDI
• Increased risk for subcutaneous infections
• Inconvenience of being attached to a device

39. Sensor augmented pump therapy
• It has become feasible to combine two
technologies (pump and CGM)
• CGM readings used to adjust insulin delivery
through insulin pump
• The use of SAP reduces A1c by 0.7-0.8%
compared to baseline or MDI therapy in patients
with T1DM
• SAP requires patient involvement for using CGM
glucose readings to adjust
• SAP susceptible to human errors

41. Alternate Controller Enabled infusion
pump (ACE pump)
• Can be used with
different components
that make up diabetes
therapy systems
• Other compatible medical
devices, including
automated insulin dosing
systems, continuous
glucose monitors, blood
glucose meters or other
electronic devices

42. Patch pumps
• Low, flat profile that fit snugly against the body
• Generally do not have the ability to deliver
multiple basal rates or preprogrammed boluses
• Primarily intended for use in T2DM, various
configurations of patch pumps may deliver only
basal insulin at a prefixed rate
• Insulin boluses in fixed increments when
manually activated by the user

44. Closed loop insulin Delivery:
Artificial pancreas

45. Closed loop insulin delivery: Artificial
pancreas
• Integrates a continuous glucose monitor and
insulin pump, together with an automated
algorithm to control insulin delivery
• Technical obstacles:
Glucose sensors need to be both accurate and
reliable (e.g. minimal calibration drift, limited
potential mechanisms for sensor failure)
Physiological lag, which can be particularly
problematic during times of rapid rates of change
in blood glucose levels

49. Medtronic Minimed 640G

50. Minimed 780G
• Advanced hybrid closed
loop
• Automated correction
boluses for high blood
sugars, Bluetooth and a
mobile app for remote
monitoring
• More than 80% Time in
Range (TIR)

51. Hybrid Closed-loop system DBLG1
• Kaleido insulin pump
worn on the body
• Dexcom G6 CGM
• Diabeloop’s own
locked-down touch-
screen controller

52. Inhaled insulin
• It has long been appreciated that insulin
delivery by aerosol reduces blood glucose
• Advantages of the pulmonary route include
a vast and well perfused absorptive surface
absence of certain peptidases that are present
in the GI tract that breaks down insulin
the ability to bypass the first pass metabolism

53. History
• The first inhaled product, Exubera® was approved by the US
FDA in year 2006
• Dry power formulation available as 1 mg and 3 mg doses to
be taken with the help of an Inhance™ inhaler device
• Found to have pharmacokinetic and pharmacodynamic
(PK/PD) properties similar to insulin aspart with a faster
onset of action (10-15 min)
• Contraindicated in smokers as it increased the risk of
hypoglycemia due to greater absorption compared to
nonsmokers
Heinemann L. Alternative delivery routes: Inhaled insulin. Diabetes Nutr Metab 2002;15:417-22.

54. Other issues
• Patients required to undergo pulmonary function
tests before treatment initiation, after 6 months
and annually thereafter
• Transient nonproductive cough and a modest
reduction in lung function initially are the
common side-effects
• The bioavailability approximately 10%
• One 1mg and one 3 mg blisters are equivalent to
approximately 3 IU and approximately 8 IU
subcutaneously administered insulin

55. Afreeza
• Based on Technosphere® dry powdered
formulation
• The onset of action of Afrezza inhaled insulin
is 15 min and duration is 2-3 h

56. Newer inhalational therapy
• The AERx insulin Diabetes Management
System, Aerodose, ProMaxx (protein matrix
microsphere) and advance inhalational
research are newer inhalational devices being
investigated in clinical trials

58. Characteristics
• In healthy males receiving inhaled insulin, rates of glucose
infusion were higher in the first hour after dosing than in
those receiving regular insulin by injection correlating with
the more rapid rise in serum insulin levels
• Total glucose consumption was comparable for
bioequivalent doses of inhaled vs regular insulin
• In individuals with T1DM, the glucose infusion rate profile
showed an early peak rate with inhaled insulin vs regular
insulin with a similar glucose consumption

59. Cough & Inhaled Insulin
• Cough has been reported in 22% to 30% of patients with diabetes on both
Exubera & Afreeza
• The cough tended to occur within seconds to minutes after inhalation and
was generally rated as mild
• The cough was rarely productive and rarely occurred at night
• Cough prevalence was greatest in the first month of use, then decreased
by 20% to 40% over the next 3 months, and remained constant thereafter
• In clinical studies only 4% of patients discontinued because of cough
Raskin P, Heller S, Honka M, et al. Pulmonary function over 2 years in diabetic patients treated with prandial inhaled Technosphere insulin or
usual antidiabetes treatment: a randomized trial. Diabetes Obes Metab 2012;14:163–173

60. Oral Insulin
• Challenges in making oral insulin include:
 Inactivation by proteolytic enzymes in the GI tract
 Low permeability through the intestinal membrane due to
larger size
 Hydrophobicity of insulin resulting in poor bioavailability
• Several pharmaceutical companies are engaged in
developing carriers to protect insulin from GI degradation
and facilitate intestinal transport of insulin to deliver insulin
to the circulation with sufficient bioavailability
Soares S, Costa A, Sarmento B. Novel non-invasive methodsof insulin delivery. Expert Opin Drug Deliv 2012;9:1539-58
Flood T. Advances in insulin delivery systemsand devices: Beyond the vial and syringe. Insulin 2006;1:99-108

61. • Certain oral insulin preparations such as
Capsulin, ORMD-0801, IN-105, oral hepatic
directed vesicles and Eligen completed phase
1 and phase 2 trials with promising results
• Recently, multifunctional polymers and Self
Nano Emulsifying Drug Delivery System
(SNEDDS) has been tried for oral insulin
Heinemann L. New ways of insulin delivery. Int J Clin Pract Suppl 2010;166:29-40

62. Other Novel methods of Delivering
Insulin

63. Colonic insulin delivery
• Under extensive investigation as a possible
strategy to improve the oral bioavailability of
peptide and protein drugs
• Oral delivery systems intended for colonic release
of insulin devised according to microflora, pH and
time-dependent strategies well described
• Bioavailability and pharmacological availability
data generally still far from being reliable
Maroni A, Zema L, Del Curto MD, Foppoli A, Gazzaniga A. Oral colon delivery of insulin with the aid of functional
adjuvants. Adv Drug Deliv Rev 2012;64:540-56

64. Nasal Insulin
• Shortcomings such as limited permeability of a large
molecule through the nasal mucosa and rapid muco-ciliary
clearance resulting in variable absorption
• Nasulin™ (CPEX pharmaceuticals) and nasal insulin by
Nastech Pharmaceutical Company Inc
• Both insulin preparations have bioavailability of about 15-
25% with the onset of action ~10-20 min
• Results from the phase 3 clinical trials awaited
Illum L. Nasal drug delivery — Recent developments and future prospects. J Control Release 2012;161:254-63.
Stote R, Marbury T, Shi L, Miller M, Strange P. Comparison pharmacokinetics of two concentrations (0.7% and 1.0%) of
Nasulin, an ultra-rapid-acting intranasal insulin formulation. J Diabetes Sci Technol 2010;4:603-9

65. • The substances such as bile salt, surfactant
and fatty acid derivatives are being
investigated to enhance mucosal permeability
of insulin but they increase the risks for local
irritation, nasal secretion, sneezing or burning
sensation

66. Other effects
• Treatment with intranasal insulin improved
memory, preserved caregiver-rated functional
ability and preserved general cognition without
any significant hypoglycemic event
• Improvements in cognitive functions were
correlated with changes in the Aβ42 level and in
the tau protein-to-Aβ42 ratio in cerebrospinal
fluid
Benedict C, Frey WH 2nd, Schiöth HB, Schultes B, Born J, Hallschmid M. Intranasal insulin as a therapeutic option in the treatment of cognitive
impairments. Exp Gerontol 2011;46: 112-5

67. Buccal insulin
• Buccal delivery of insulin has similar benefits as oral
insulin with the advantage of bypassing GI degradation
• Furthermore, the relatively large surface area results in
better bioavailability
• Oral-lyn™ which is a liquid formulation of short acting
insulin that is administered using Generex’s metered
dosage aerosol applicator & Shreya Life Sciences Pvt.
Ltd oral Recosulin® has been used as buccal insulin
Heinemann L, Jacques Y.Oral insulin and buccal insulin: A critical reappraisal. J Diabetes Sci Technol 2009;3:568-84
World’s First Oral Insulin Spray Launched in India. Asia Pacific Biotech News 2008;12:60

68. Transdermal
• Penetration of insulin is halted by the stratum
corneum, the outer most layer of the skin
• Ways of administering: Iontophoresis,
Sonophoresis, Microdermal ablation, as
Transfersulin, Insupatch, Recombinant human
hyaluronidase
Bariya SH, Gohel MC, Mehta TA, Sharma OP. Microneedles: An emerging transdermal drug delivery system. J Pharm Pharmacol 2012;64:11-
29

69. Intra peritoneal
• Direct delivery of insulin in the portal vein mimics
the high portal insulin concentration
• Implanted beneath the subcutaneous tissue in
the lower abdomen
• From this subcutaneous pocket, the peritoneum
is opened, and the tip of the catheter is carefully
inserted and directed towards the liver
Renard E. Insulin delivery route for the artificial pancreas: Subcutaneous, intraperitoneal, or intravenous? Pros and
cons. J Diabetes Sci Technol 2008;2:735-8

70. Take Home Messages
• S/C way of delivering Insulin is still the most rational &
scientific method among all other modes of delivery
• Modern times are the era of ‘Modern Insulin pen’
which patients needs to be educated adequately
• CSII : One of the most attractive choice for T1DM
patients specially who can afford
• Oral Insulin can be the path-breaking discovery in
future times

71. Thank you………………….