This document discusses various methods of insulin delivery including subcutaneous, inhaled, oral, nasal, buccal, intra-peritoneal, and transdermal routes. Subcutaneous delivery via insulin pens and pumps is currently the standard method but is associated with pain and non-compliance. Newer devices like the i-Port aim to reduce injections. Inhaled insulins like Afrezza offer non-invasive delivery but have limitations. Future areas of research include oral/buccal insulin, islet cell and stem cell transplantation, and gene therapy to better regulate insulin levels.

1. Aromal Satheesh
Dep of Clinical Pharmacy
JSS Hospital , Mysore
INSULIN DELIVERY
METHODS

2. Routes of Insulin Administration
• Subcutaneous
• Inhaled Insulin
• Oral Insulin
• Nasal Insulin
• Buccal Insulin
• Intra-peritoneal
• Transdermal

3. SUBCUTANEOUS ROUTE
A) Vials and Syringes
B) Insulin Pens
C) Insulin Pumps

4. ▪ Insulin can be administered subcutaneously via various methods such as vial and
syringe, insulin pen and continuous subcutaneous insulin infusion (CSII)
▪ Though subcutaneous insulin delivery is the standard route of insulin administration, it
is associated with injection pain, needle phobia, lipodystrophy, noncompliance and
peripheral hyperinsulinemia
▪ Each method has its own advantages and disadvantages.

5. A) Vial and Syringes
▪ The development of syringes dates back to 1853 (Fergusson syringe) that paved the way
for the development of the modern syringes.
▪ In 1924, 2 years after the discovery of insulin, Becton, Dickinson and Company (BD)
made a syringe specifically designed for the insulin injection.
▪ To reduce the incidence of needle associated infections, disposable syringes were
developed. BD mass produced the first glass disposable syringes in 1954, called the BD
Hypak
▪ Despite all the advancements in modern syringes, many patients do not feel to inject
insulin 3-4 times a day as a result of needle phobia

6. ▪ Recently, an injection port has been designed know as i-port Advance®.
▪ It is the 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.
▪ This device is helpful for the insulin requiring patients having needle phobia and helps
them to achieve glycemic control effectively

7. i –Port Advance
▪ The i-Port is applied with a virtually
painless insertion, leaving a soft cannula
under the skin and giving you a means
to inject medications, with fewer
punctures, over three days of normal
activity (including showering, swimming
and exercising). It is compatible with
pens and syringes and can be used by
children and adults.
 If you take an average of five shots a day, you can reduce the number of times you poke yourself from 150 to 10
in just 1 month! That’s 93% less pokes.

9. Syringes
▪ Syringes come in different sizes.
▪ Each line on a 100-unit syringe marks 2 units of insulin.
▪ Each line on a 50-unit or 30-unit syringe marks 1 unit of insulin.
▪ Use a syringe large enough to hold the whole dose of insulin.
▪ The standard needle is 1/2-inch long.
▪ Needles also come in 5/16-inch and 3/16-inch lengths.
▪ The 3/16-inch length is often used for children.
▪ The thinner the needle, the higher its gauge

11. METHOD OF ADMINISTRATION

15. ADVANTAGES DISADVANTAGES
 Most widely available o Less accurate
 Dependable, Easy to use o Chances of human error
 Less expensive o Not patient friendly
 Disposable
 Can use most types of insulin
 Lets you mix two different types of insulin into
one injection (with variable doses)

16. B)Insulin Pens
▪ Insulin pen injectors are convenient and discreet way of administering insulin. They have a built-in dial
that allows us to determine the amount of insulin to be injected, a short needle at one end and a
plunger at the other.
▪ Insulin pens are particularly useful if we need to take premixed insulin
▪ The first insulin pen was manufactured by NovoNordisk in 1985. This was followed by refinements by
various pharmaceutical companies over the past 30 years
▪ The 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

17. ▪ Another advancement in the pen device includes:-
▪ (HumaPen® Memoir™) is built-in recording of the time and date of the last 16 injections.
▪ NovoPen Echo® has been designed to give children and parents increased confidence,
combines dosing in half-unit increments with a simple, easy-touse, memory function.
▪ 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
▪ The newer smart pens are designed to guide the individual about the insulin dosage (by
means of in-built calculators), they have memory functions to remember the amount
and time of insulin dosage and automatic transmission of insulin dose to the mobile
logbook through Bluetooth technologies.

20. Insulin Pen ( Novolog Flexpen)

21. PATIENT COUNSELLING
▪ Method of administration

22. Method of Administration
▪ Prepare the skin.
▪ Prime the pen.
▪ Check the pen for air bubbles ( Safety Check)
▪ Dial the required dose of insulin
▪ Inject at a 90-degree angle.
▪ Expose the site of injection
▪ Safely dispose the injected needle in a solid lid container

23. ADVANTAGES DISADVANTAGES
 More Accurate o Cannot mix different types of insulin together
 Less human error o Expensive than syringes
 Doses are easily dialed o Modest hand strength is required to push
button on pen or doser
 Can use most type of insulin o Takes more time to push the pen “button” than
a syringe.
 Reusable

24. C) Insulin Pumps
▪ Insulin pumps are small devices of size of a pager that can be attached to our belt or placed in our
pocket.
▪ They are made up of an insulin reservoir connected to a tube, ending in a cannula or catheter,
which is inserted under the skin of our abdomen.
▪ They can be set to deliver insulin at a slow, continuous rate throughout the day, or to release larger
quantities at meal times or when blood sugar is high.
▪ The main advantage of a pump is that it closely mimics the slow but continual release of insulin by
the pancreas
▪ At present due to its prohibitive cost its usage is very limited. All patients who qualify for insulin
pump therapy should be referred to a centre where expertise for a pump is available.
▪ Pump therapy requires a lot of motivation and time from both - the patient and the clinician

26. Indications
▪ All Type -1 diabetics who are poorly controlled with basal-bolus therapy.
▪ Pregnancy
▪ Frequent hypoglycemia or hypoglycaemic unawareness
▪ Persistently elevated fasting glucose (Dawn phenomenon)
▪ Multiple chronic complications with labile glucose requiring fine tuning of glycemic control
▪ Management of labile diabetes after renal or hepatic transplant
▪ In situations where insulin requirement is very high a trial of pump therapy can be given.

27. Types of Insulin Pumbs
▪ Continuous Subcutaneous Insulin Infusion (CSII)
▪ Implantable insulin pumps
▪ Closed insulin delivery system with CGMS insulin delivery (artificial endocrine pancreas)
▪ Nano pump with closed insulin delivery system and continuous glucose sensing.

28. ADVANTAGES DISADVANTAGES
Designed to allow a more flexible lifestyle Breakdowns in equipments can occur
Eliminates Injection Cost and maintenance is usually more expensive.
Better matches insulin to food, exercise and lifestyle. Insulin delivery can be stopped by a leak in tubing; a
crimp in the catheter
Allows insulin to be given discreetly More advanced diabetes education and skills are
required to properly use
Delivers insulin in tiny amounts as much as 1/10 to
1/20 unit – important for people receiving small doses
of insulin.
Requires a lot of work in daily care (diet, dose
adjustments, checking blood glucose).
Often results in better blood glucose control. Always attached to the pumb

29. INHALED INSULINS
- Exubera
- Afrezza
- Aerodose, Promax

30. Exubera ( by Pfizer)
▪ Approved by US FDA in 2006 and it was later withdrawn in 2007
▪ It was available as 1mg,3mg dry powder form that to be taken with inhaler
▪ It was found to have pharmacokinetic and pharmacodynamic (PK/PD) properties
similar to insulin aspart with a faster onset of action (10-15 min.
▪ In clinical trials in patients with uncontrolled T1DM and T2DM, Exubera® was found to
reduce postprandial blood glucose and A1c significantly.
▪ However, Exubera® was contraindicated in smokers as it increased the risk of
hypoglycemia due to greater absorption compared to nonsmokers.
▪ patients were required to undergo pulmonary function tests before treatment
initiation, after 6 months and annually thereafter.

31. Advantages
▪ Noninvasive
▪ ↑Patient compliance
▪ Rapid onset of action (10-15 min)
▪ Better PPBG control
Disadvantages
• Bulky delivery device
• Patient need to undergo frequent PFT
• Expensive

32. Afrezza
▪ Prescription Afrezza® is a man-made rapid-acting mealtime inhaled insulin breathed in
through your lungs and is used to control high blood sugar in adult patients with diabetes.
▪ FDA-approved AFREZZA is the only inhaled insulin working to help control blood sugar
during mealtime.
▪ When using the AFREZZA inhaler at the beginning of a meal, insulin enters the
bloodstream through your lungs.
▪ AFREZZA is rapid acting mealtime insulin that starts to work in approximately 12 minutes,
peaks at about 35 to 45 minutes and is done working in 90 to 180 minutes (for the 4 unit
and 12 unit respectively). For the 48 unit dose, it starts working in about 12 minutes,
peaks at about 55 minutes and is done working in approximately 4.5 hours.

33. CONTRAINDICATIONS
AFREZZA is contraindicated in patients:
▪ During episodes of hypoglycemia.
▪ With chronic lung disease (such as asthma or chronic obstructive pulmonary disease
[(COPD)] because of the risk of acute bronchospasm.
▪ With hypersensitivity to regular human insulin or any of the AFREZZA excipients.
SIDE EFFECTS
• Hypoglycemia (sweating, confusion, headache, blurred vision, slurred speech etc)
• Decreased Lung function
• Severe allergic reactions
• Hypokalemia

34. Limitations
▪ AFREZZA is not a substitute for long-acting insulin. AFREZZA must be used in combination
with long-acting insulin in patients with type 1 diabetes mellitus.
▪ AFREZZA is not recommended for the treatment of diabetic ketoacidosis.
▪ The use of AFREZZA is not recommended in patients who smoke or who have recently
stopped smoking (less than 6 months).
▪ It is not known if AFREZZA is safe and effective in children under 18 years of age.

35. FUTURE TRENDS

36. ▪ AERODOSE
▪ TECHNOSPHERE
▪ AERx
Advanced inhalational
research devices
currently under Phase
3 : result awaited
Challenges
• Technical issues
• Cost
• Long Term Safety

37. ORAL & BUCCAL INSULIN

38. ORAL INSULIN
▪ Oral route of insulin administration may be the most patientfriendly way of taking insulin and it
could more closely mimic physiological insulin delivery
▪ Natural and synthetic nanoparticles have been used as a carrier or vehicle for insulin such as
chitosan, liposomes, polymeric nanovesicles, polylactides etc inorder to overcome the main
challenge of oral insulin : poor bioavailability
▪ Combination of Self-Nano Emulsifying Drug Delivery System (SNEDD’s) and Thiolated Chitosan is
promising and innovative approach to improve bioavailability

39. BUCCAL INSULIN
▪ Initially, Generex Biotechnology developed Oral-lyn™ which is a liquid formulation of
short acting insulin that is administered using Generex’s metered dosage aerosol
applicator (RapidMist™) .
▪ Phase 1 and 2 trials showed progressive report, currently its under phase 3 studies
▪ Another molecule being developed by Shreya Life Sciences Pvt. Ltd., India is oral
Recosulin® and the results of the phase 2 and phase 3 trials are awaited
▪ Another formulation “insulin loaded orally dissolved films” is undergoing PK/PD
investigation

40. NASAL INSULIN

41. ▪ Currently, two technologies are under investigation: 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 2 and 3 clinical trials are awaited.
▪ Intranasal delivery has several advantages over oral (bypass GI peptidases), subcutaneous
(noninvasive and painless) and inhalation route (no issue with lung function) which makes
this route attractive for the delivery of insulin.
▪ Intranasal delivery has shortcomings such as limited permeability of a large molecule
through the nasal mucosa and rapid mucociliary clearance resulting in variable
absorption.

42. TRANSDERMAL INSULIN

43. ▪ Trans-dermal insulin delivery eliminates the problems associated with needles and injections
and large surface area of the skin makes it a convenient route for insulin delivery.
▪ However, the penetration of insulin is halted by the stratum corneum, the outer most layer of
the skin. Numerous methods have been explored to overcome the barrier of stratum
corneum.
▪ (a) Iontophoresis, the technique that uses small electric currents
▪ (b) Sonophereis or phonopheresis uses ultrasound waves,
▪ (c) Microdermal ablation by removing the stratum corneum,
▪ (d) Electroporation utilizes high voltage pulses that are applied for a very short time
▪ e) Transfersulin is the insulin encapsulated in transferosome, an elastic, flexible vesicle which
squeeze by itself to deliver drugs through skin pores
▪ (f) Insupatch™, a device developed as an add-on to an insulin pump that applies local heat to the skin
in order to increase the absorption of insulin

44. INTRA-PERITONEAL INSULIN

45. ▪ Direct delivery of insulin in the portal vein mimics the high portal insulin concentration.
This route of insulin delivery has been investigated since the 1970s.
▪ The pump (The MIP 2007C Medtronic/Minimed, Northridge, CA, USA) is implanted
beneath the subcutaneous tissue in the lower abdomen under general anesthesia.
▪ From this subcutaneous pocket, the peritoneum is opened, and the tip of the catheter is
carefully inserted and directed towards the liver.
▪ After implantation, the pump reservoir is refilled in the outpatient clinic transcutaneously
at least every 3 months, depending on the individual insulin requirement.
▪ Clinical trials have shown safety and efficacy of intraperitoneal insulin delivery.
▪ The limitations of this route of insulin administration include it is invasive, may be
associated with subcutaneous infections, cannula blockage, higher cost, portal-vein
thrombosis and peritoneal infection

46. FUTURE TRENDS

47. ▪ Islet cell transplantation
 This is a recently developed surgical procedure - called the Edmonton protocol - whereby islet cells
from a donated human pancreas are injected into the liver of a recipient with type 1 diabetes.
 The transplanted cells begin to secrete insulin, while the recipient needs to take immunosuppressive
medications for life to prevent rejection of the transplanted tissue.
 Clinical trials continue to establish the safety and long- term effectiveness of this procedure as a
means of supplying insulin.
 STEM CELL THERAPY
 Embryonic or bone marrow derived stem cells are a hot topic for research. Voltarelli, et al (2007),
transplanted 15 Type 1 diabetics with autologous stem cells and 14 were able to stop their insulin for
7 to 35 month.50
 The stem cells from the bone marrow are more likely to differentiate into insulin producing cells and
also become glucose responsive. This method holds great promise for the future.

48. ▪ GENE THERAPY
– Scientists have identified a gene called SHIP2 that appears to regulate insulin. Such findings make
SHIP2 a potential gene therapy target for the treatment of type 2 diabetes aimed at improving the
individual insulin regulation.
– A protein that blocks the overgrowth of blood vessels in the eye is being studied as possible gene
therapy for diabetic retinopathy.
– A recent study showed that treatment with the protein, called pigment epithelium-derived factor, or
PEDF, prevented excessive new blood vessel formation in an animal model of retinopathy.
– It may also be used to treat macular degeneration.

49. OTHER NONCONVENTIONAL
ROUTES

50. ▪ Ocular route
– Until date, no human trial has been reported with this route and an animal study failed to
achieve significant plasma insulin concentration.
▪ Rectal route
– Rectal gels and suppositories showed fair results. However, this route is not commercially
viable.
▪ Intra-tracheal
– Administration of insulin was reported in 1924 but is not practical so not taken up for further
development.

51. CONCLUSION

52. ▪ There is a long history of research focusing on identifying a route of administration for
insulin that is minimally or noninvasive, effective, safe, convenient and cost-effective for
patients.
▪ Each route and delivery method has its own potential advantages and disadvantages.
▪ However, if successful, alternative routes of administration could revolutionize the
treatment of diabetes mellitus and help improve patients’ quality of life.
▪ The success of commercial technologies and the emergence of new ones will be
demonstrated only with time.
▪ An oral delivery system of insulin will have tremendous benefits in terms of a decreased
number of injections for diabetic patients and a reduced incidence of side effects.

53. Thank You