This document discusses various technologies for insulin delivery that aim to improve upon traditional subcutaneous insulin injections. It summarizes 12 different insulin delivery methods: oral insulin, intranasal insulin, inhaled insulin, transdermal insulin, insulin pens, intravenous insulin, rectal insulin, insulin pumps (CSII, implantable, closed-loop, nano pump), implanted insulin producing cells, beta cell/pancreatic transplantation, and stem cell therapy. For each method, it provides a brief overview of the approach and discusses advantages and disadvantages. The goal is to find a painless and simple method of insulin delivery to better control blood glucose levels and reduce long-term health issues.

1. PRESENTED BY – DIPJYOTI BISWAS (M.PHARM) DEPARTMENT
OF PHARMACEUTICS
ROLL NO—18HMPS03
SUBMITTED TO – DR. CHIDAMBARAM SOUNDARAPANDIAN

2. INTRODUCTION:-The total number of diabetic patient in our country is 35 million
among the total number of diabetic patients(100 million) in the world. There are 4 types of
diabetics are present in the world Type 1 , Type 2, Type 3, Type 4. Out of this 5-8% are Type 1
diabetics. All Type 1 diabetics need to be on insulin, while all Type 2 diabetics will ultimately
need insulin at some stage in their lives. The problem diabetics face is injecting insulin many
times a day for the rest of their lives and carrying the drug with its needles, swabs, etc. at all
times if they travel. Poor compliance due to pain and hassle of injections, variable absorption of
subcutaneous insulin and lack of feedback control, hypoglycemia and hyperglycemia due to
unphysiological insulin delivery, poor diabetes control and weight gain are some of the other
problems with the current subcutaneous insulin therapy. The new technologies like - are insulin
inhalers, insulin spray, insulin pill, insulin analogues, insulin complement, islet cell transplant,
implantable insulin pumps and guardian continuous glucose monitoring system.

4. ADVANTAGES:-
 Lower pain and stress.
 It also improves the patient complaints.

5.  Through this technique administration of proteins, peptides and local anaesthetics are easy.
 These vaccines are used in the treatment of influenza. Typhoid, diphtheria, pertussis and
hepatitis A etc.
 Higher antigen dispersion .
 It helps to avoid skin problem associated with using needle.
DISADVANTAGES:-
 Complexity is greater.
 Start up cost is higher.
 It can not be used for iv Root.
 Wetness associated with skin surface with this vaccine.

6.  Through this technique administration of proteins, peptides and local anaesthetics are easy.
 These vaccines are used in the treatment of influenza. Typhoid, diphtheria, pertussis and
hepatitis A etc.
 Higher antigen dispersion .
 It helps to avoid skin problem associated with using needle.
DISADVANTAGES:-
 Complexity is greater.
 Start up cost is higher.
 It can not be used for iv Root.
 Wetness associated with skin surface with this vaccine.

7. It is, therefore, an endeavour of researchers to find a painless and simple way of delivering
insulin, which would control diabetes to target and also prevent the long-term morbidity and
mortality. The following routes of insulin delivery have been tried:
1. Oral insulins (including buccal and enteric insulin).
2. Intranasal insulin.
3. Inhaled insulin.
4. Transdermal insulin.
5. Insulin pens.
6. Intravenous insulin.
7. Rectal insulin.
8. Insulin pumps.
9. Implanted insulin producing cells (gene therapy).

8. 10. Beta cell transplant/pancreatic transplant.
11. Per ocular insulin.
12. Stem cell therapy.

9. 1.ORAL INSULIN:-
Buccal mucosa forms a good surface for rapid absorption of insulin. It is easily accessible,
highly vascularized and has a large surface area 100-200cm2. The convenience being easy to
spray before each meal, painless and the action lasts 2 hours, therefore no fear of
hypoglycaemia. Added to a basal 24 hour insulin it appears to be the ideal way to control
diabetes. The disadvantage is that patient still needs a basal insulin injection .
Oral insulin is commercially available by the name of oralyn in Eucador, where most of the
trails , have taken place. The oral insulin spray had a faster and shorter duration of action than
subcutaneous regular insulin. Type 1 diabetics, comparing subcutaneous preprandial insulin
with split prandial doses of oral spray over 9 days and found near normalization of DM
metabolic control in all cases and better levels of HbA1C in the oral insulin group.

10. Insulin inhaler
Fig:-1
Insulin spray
Fig:-2
Oral insulin capsuleFig:3

11.  ORAL ENTERIC INSULIN:-
ADVANTAGES:-Absorption is very rapid, direct delivery of drug into the liver, it results in
lower systemic insulinemia, it also controls the output of hepatic glucose and it also enhances
compliance.
DISADVANTAGES:- It effects different types of foods, gastrointestinal dysmotility,
tastesmell of the preparation. If activated insulin is taken directly by mouth then it is denatured
in the intestine and degraded by proteolytic enzymes. Only 1% of insulin swallowed is
absorbed. Earlier attempts were made with basic and acidic dyes to inhibit proteolysis,
combined with insulin surfactants in tablet form and were partially successful in reducing
blood glucose. However, they were discontinued because of skin colouring by the dye.

12. Liposomally entrapped insulin also lowers blood glucose but the effect is not predictable or dose
dependent. Insulin incorporated into biodegradable polymeric particles, which are absorbed via
portal circulation and taken up by Kupffer cells in the liver, from where there is slow dissolution
and release of insulin.

13. 2. INTRANASAL INSULIN:-
It is first investigated in the 1920s and 1930s. Nasal mucosa provides about 150cm2 area for
absorption. However, there is low bioavailability (10-20%), nasal irritation (25% of subjects),
and unpredictable responses. There is a potential to damage of nasal-ciliary function in long-
term exposure. Increased absorption has been achieved by bile salts, proteolysis inhibition,
increased monomer formation and Ca++ ion binding which loosen the tight junction between
the cells. Other enhancers are ethers and esters that disrupt membranes, other enhancers are
phospholipids, that increase absorption. Incorporating insulin in gelling microspheres increases
contact time with the nasal mucosa. Gelified preparations were found to be more effective than
liquid aerosolized preparations. Repeated administration of nasal insulin is often required for
bio effectiveness. Nasal insulin is effective in the short-term in controlling postprandial
hyperglycaemia in Type 2 diabetics.

14. Type 1 diabetics need an injectable basal insulin in CSII or as long acting basal insulin along
with nasal administration, and clinical trials have not shown any improvement in control
compared to entirely injection-based regimens .
Intranasal insulin
Fig no:-4

15. 3. INHALED INSULIN:-
Since the 1920s it has recently emerged as a promising needleless method of insulin delivery.The
alveoli which has a huge surface area of >100m2 that is 70 times the surface area of our body and
it also has a rich blood supply, from a large absorptive surface in our body. The peak action and
plasma insulin concentration of inhaled insulin is about 30 minutes, comparable to that after
injection of lispro or aspart and earlier than that after regular short acting insulin. Therefore, it is
best given at mealtimes. Long-acting inhaled insulin formulations have not yet been successful
Bioavailability is low at 10-20% and can be increased by adding absorptive enhancers to the
insulin. The inhalation flow rate, particle size (1-3 um), and position of the insulin bolus in
inhalation determine the absorption.Asthma decreases its absorption, and smoking increases the
bioavailability of inhaled insulin, both conditions being contraindications to inhaled insulin
therapy at present.

16. Clinical trials have been reported both on Type 1 and Type 2 diabetics.(23) In a 12 weeks trial in
73 Type 1 diabetics, in which pre-prandial inhaled insulin and ultra-lente at bedtime were
compared with the usual subcutaneous insulin injections given two to three times a day,
glycemic control was similar with the two regimens. Smokers and patients with respiratory
diseases or impaired lung function were excluded. The inhaled insulin was well tolerated and
had no effect on respiratory function.
Inhalable Insulin Device fig:-5 fig:-6

17. VARIOUS BODY PARTS OF THE INSULIN INHALER
FIG:-6

18. 4. Transdermal insulin:-
The stratum which is corneum of the skin makes it impermeable to insulin. The iontophoresis
with some experimental success helps in the insulin transportation through the skin. Low
frequency ultrasound(sonopheresis) and photomechanical waves applied to the skin are also
able to promote transdermal insulin delivery. UT-strip has been patented which has a dermal
patch containing up to 100 unit of insulin and can be changed once daily ,with an ultrasonic
device that increases pore size and delivers insulin without needles. It is still under development
and not yet approved by the FDA.
Transdermal insulin device
fig:-7

20. 5.INSULIN PENS:-
This is a subcutaneous insulin injection . It is much easier and simple process in the prefilled
pen delivery system. Refrigeration is not needed for this insulin pens and it can be easily carried
by the patient. Insulin pens are generally made of plastic and also have prefilled syringes inside.
The required dose can be dialled and the pen can deliver a exact amount of dialled dose when
the plunger is pressed. There are different typesof compunds like Human insulin or
humulin{rDNA}, Aspart insulin, Lispro, Glargine, Glulisine, Exanetide, pramlintide etc. A new
Human Memoir has digital memory to help keep track of does. There are some disadvantages
are also present like long and short acting preparations cannot be mixed as in a syringe.

21. Insulin pen
fig:-8

22. INSULIN JET INJECTORS :-
It is a type of machine through insulin is delivered in the pores of the skin by high air pressure
without any kind of needles. Advantages are of being needle free and less incidence of fat
atropy at injection sites but it also has some disadvantages like higher cost, issues of insulin,
maintenance and cleaning of the injector, bruising of the skin if the subcutaneous fat is less and
the jets being at times even more painful than the needle prick
Insulin jet injectors fig:-9

23. 6.INTRAVENOUS INSULIN:-
This is the well-established treatment for DKA, in the ICU for other conditions, in surgery in
diabetics and in pregnant patients at the time of delivery. It has the 100% bioavailability in the
infusion into a peripheral vein. If the intravenous insulin infusion is used for longer period
through an indwelling catheter then it is very useful in the management of brittle diabetics,(32)
but several serious complications were noted, including insertion site infection, septicaemia and
catheter blockage with extensive thrombosis. In earlier implantable insulin pump was very
essential in the CNS delivery route, with serious complications. Therefore , intraperitoneal
route has replaced with intravenous route in these pumps.

24. Intravenous insulin, fig-10

25. 7.RECTAL INSULIN:-
This mode of insulin has some bad and poor results in some experiments and also some erratic
absorption, with the short-lived effects.There is a potential of mucosal damage in long-term use
of rectal route. Future options may be gels or emulsions(36) but it has no clinical application
Rectal insulin delivery system,fig-11

26. 8.INSULIN PUMPS:-
There are 4 types of insulin pumps are present like-
a.CSII
b.Implantable insulin pumps.
c.Closed insulin delivery system or CGMS insulin delivery system (it is a artificial
endocrine pancreas)
d. Nano pump with closed insulin delivery system and continuous glucose sensing.

27. A.CSII OR CONTINUOUS SUBCUTANEOUS INSULIN
INFUSION:-
It was first developed in the 1970s as a research tool for investigating the long term effect of
near normoglycemia on the development of microvascular complications. The current CSII
uses a battery driven pump to infuse insulin via a fine canula terminating in a subcutaneously
implanted needle or flexible catheter.
The excellent control of glycaemia on pump therapy has been confirmed by many studie,
improved lipids, ketones, amino acids and quality of life with patient satisfaction accompany
this. Large clinical trials across the world (USA, UK, NORWAY, DENMARK) have shown
marked reduction in long-time mortality associated with diabetes, and any new therapy is
compared to glycemic control by the CSII.

28. INDICATIONS:-
In case of type 1 diabetics because of frequent hypoglycaemia and marked dawn phenomenon
the patients who fails with multiple injection therapy including re-education, dietary advice,
exercise etc.

29. PRE-REQUISITES FOR CSII:-
Patients who are suffering from CSII ,they should be motivated and able to perform the
procedures involved in CSII. They should be well trained for self-monitoring the blood glucose
level. The patient should be under the supervision of a health care team experienced in CSII.
CSII OR CONTINIOUS SUBCUTEOUS INSULIN INFUSION,FIG-
12

30. B.IMPLANTABLE INSULIN PUMPS:-
These type of insulin pumps are totally new . Generally these machines are totally implanted in
the body and release the insulin intraperitoneally and intravenously in our body. An external
electronic communicator which controls the operation and also a side port is present here that
controls the direct access to the delivery. Cannula for clearing occlusions. Some disadvantages
are also present like high cost, the attendant complications of undelivery, catheter blockage, skin
erosion, hematoma, local infection, pump migration, electrical and mechanical pump failures
etc.
The advantages of the pump are intraperitoneal delivery being, it is more physiological and
directed to the portal circulation, the user cannot temper with it. There is a total freedom from
needles or cannula .

31. IMPLANTABLE INSULIN PUMPS,fig-13

32. C.CLOSED-LOOP INSULIN DELIVERY:-
The other name of closed loop insulin delivery system is Feedback controlled insulin delivery ,
here the rate of insulin dosage is altered automatically according to the prevalling blood
glucose concentration. Over the years devices have been made which use intravenous insulin as
per preset algorithms and these were large bedside apparatuses like the biostator and were used
for short-term studies. Currently an implantable insulin pump with closed loop control via an
indwelling glucose sensor placed in a central vein is under trial.

33. D.NANO PUMP:-
Recently it was first developed by the swiss company Debiotech which also reduced the
particular size of the pump. This pump has a closed loop insulin delivery system itself. The
micro glucose chip sensor is present inside it. This sensor is look like a size of penny. The
pump has an alarm program which can alert with slightest under delivery or overdose. There are
some micro needles which are generally used for painless injecting purpose. The insulin is
delivered by the MEMS (micro-electro-mechanical-system) technology. The pump is mounted
on the skin patch and being about an inch in size, is hardly visible outside the patient’s clothes.

34. NANO PUMP INSULIN DELIVERY SYSTEM
Fig:-14

35. 9. IMPLANTED INSULIN PRODUCING CELLS (GENE
THERAPY):-
Transfection of the pancreas by retrograde ductal injection of a plasmid containing the human
insulin coding sequence Gut Gene Therapy under investigation. .The human fibroblasts which
releases insulin at slow or rapid rates , this total system is controlled by the ligands.
In the manufacturing of insulin directly, gene therapy is very essential: in a oral medications
,consisting of viral vectors containing the insulin sequence , is digested and delivers its genes to
the upper intestines. Insulin protein is reproduced from the intestinal cells , these cells will then
behave like a viral infected cell. The virus is used to infect only the cells, these cells are
designed to response/alert in the presence of glucose, such that insulin is produced only in the
presence of high glucose levels.

36. HUMULIN IN GENE
THERAPY TECHNIQUE
FIG:-15

37. 10. BETA-CELL TRANSPLANTATION/ PANCREATIC
TRANSPLANTATION:-
This is the ideal method of insulin delivery where there is biofeedback, basal and prandial
insulin throughout the day and life of the patients . The attendant immunosuppression needed
for the transplant to survive is a major problem. Pancreatico-renal transplant has fewer
complications than the pure pancreatic transplant. Encapsulated beta-cells with protective
nonantigenic covering are being investigated.

38. 11.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.

39. UP COMING INSULIN DRUG DELIVERY SYSTEMS
1. Bioject’s needle free injection technology
2. Iject®
3. Jupiter jet
4. Multi-port orifices
5. Biojector 2000
6. Vitajet 3
7. Mhi-500
8. Cool Click
9. Serojet
10. Biovalves Mini-ject technology
11. Implaject
12. Crossject
WIFI CONTROLLED
INSULIN DETECTORS

40. APPLICATIONS:- 1. Intramuscular, subcutaneous and intradermal administration of vaccines
e.g. smallpox, polio, measles
2. Used to deliver drugs which consists of protein and peptides
3. A micro thin stream of insulin penetration through the skin is done by Medi-jector vision.
4. Powderject (Powderject pharmaceuticals) technology did a study by delivering insulin to
hairless guinea pig, delivery of macromolecules across this skin and intradermal DNA
immunization against influenza a virus in mice.
5. Jet injectors technologies deliver proteins such as B-interferon and also small organic
conventional therapeutic agents like lidocaine (lignocaine) are used for local anesthesia
6. Intradermal administration of hormones e.g. growth hormone
7. Subcutaneous administration of insulin.

41. CONCLUSION:-
The future needle free injection systems looks bright. Needle free technology offers the very
obvious benefits of reducing patient concern about the use of needle. No needle disposal issues.
The price of needle free devices are expected to erode in the coming years, which in turn are
expected to increase sales volume, spurring revenues for the manufacturers. Not only it can
benefit the pharmaceutical industry in increasing sales, it has a added potential to increase
compliance with dosage regimens and improved outcomes. Many of the needle free technology
are in growth stage. Companies are working on producing devices that are harmless, easier to
use and can deliver more type of medicines.

42. REFRENCES:-
1.Gopalan J, Divya G, Chakravorty D. Needleless Vaccine Delivery Using Micro- shock
waves. Clinical Vaccine Immunology CVI, journal of American Society for microbiology.
2011; 18(4): 539–45.
2. Cernea S, Kidron M, Wholgelernter J, et al. Dose-response relationship of oral insulin spray
in healthy subjects. Diabetes Care 2005; 28:1353-57.
3. Guevara-Aguirre J, Guevara-Aguirre M, Saavedra J, Bernstein G, Rosenbloom AL. Diabetes
Technology and Therapeutics 2007;7(4):394-98.
4. Murlin JR, Gibbs CBF, Romansky MJ, et al. Effectiveness of per-oral insulin in human
diabetics. J Clin Invest 1940;19:709-22.
5. Spangler RS. Insulin administration via liposomes. Diabetes Care 1990;13:911-22.
6. Damge C, Michel C, Aprahamian M, Couvreur P. New approach for oral administration of
insulin with poly-alkylcyanoacrylate nanocapsules as drug carriers. Diabetes 1988;37:246-51.
7. Touitou E, Rubenstein A. Targeted enteral delivery of insulin to rats. Int J Pharm
1986;30:95-99.