Diabetes,Insulin structure, Approaches to deliver insulin; Oral insulin delivery

1. Novel Approaches To
Deliver Insulin
Presented by:
Sidharth
M.Pharm. 1st sem
{Pharmaceutics}
Guided by:
Dr. Munish Ahuja
Professor
Institute Of Pharmaceutical Sciences
GURU JAMBHESHWAR
UNIVERSITY OF SCIENCE &
TECHNOLOGY;HISAR

2. INTRODUCTION
 Insulin is a hormone that lowers the level of glucose in
the blood. It's made by the beta cells of the pancreas and
released into the blood when the glucose level goes up, such
as after eating. Insulin helps glucose enter the body's cells,
where it can be used for energy or stored for future use.
 Type 1 diabetes is also called insulin-dependent diabetes. It
used to be called juvenile-onset diabetes, because it often
begins in childhood.
 Type 1 diabetes is an autoimmune condition. It's caused by
the body attacking its own pancreas with antibodies. In
people with type 1 diabetes, the damaged pancreas doesn't
make insulin.
 In type 2 diabetes, the pancreas usually makes some insulin.
But either the amount made isn't enough for the body's
needs, or the body's cells resist it.
 The current estimate of the number of diabetic patients in the
world is 171.2 million & predicted to be 366.2 million by the
year 2030.

3. Insulin Therapy:-
 Insulin was isolated in 1921 with its first
clinical use in 1922. It was extracted by
Banting & Best.
 Insulin is a two chain polypeptide
having 51 amino acids. The A-chain
has 21 while B-chain has 30 amino
acids joined together by Disulfide
brides.
 Insulin has an isoelectric point of
5.3,charge -2 to -6 in pH range 7-11.
 The conventional form of insulin
delivery is through subcutaneous
injections and more than 60,000
injections are taken by an average
hyperglycemic patient.
 Insulin is measured in IU.One unit of
insulin is defined as the amount of
insulin that will lower the blood glucose
of a healthy 2kg rabbit that has fasted
for 24 hours to 2.5 mmol/l within 5

4. Types of insulin preparations and insulinanalogues:-

6. 1) Insulin syringes:-
 Prefilled disposible syringes contain specific types or
mixtures of regular and modified insulins.
2) Insulin Pumps:-
 Portable infusion devices connected to a subcutaneously
placed cannula— provide ‘continuous subcutaneous insulin
infusion’ (CSII).
 The first CSII pump was introduced in market in 1974.
 The insulin pumps has three parts i.e. a reservoir filled with
insulin, pump operated on battery and computer chip that
allows the patient in controlling insulin delivery. The insulin
reservoir is connected to a subcutaneous catheter, which is
changed every 2 or 3 days.

7. 3) Insulin Pen Device:-
 The first insulin pen (NOVOPEN®) was introduced by
Nova Nor Disk in 1987.
 Two types of insulin pens: Prefilled insulin pen device &
Reusable insulin pen device.
 In using insulin pens, the patient must attach a
needle,prime the pen, set the dose by a dial and
depresses the plunger to administer the selected dose.
 The needles for pens are available in varying lenghts
(from 8mm to 12.7mm) and varying gauges (from 29 to
31 guages).

8. 4) Insulin Jet Injectors:-
 Jet injectors (introduced in
1980) are designed to deliver
a fine stream of insulin
transcutaneously at high
speed & high pressure to
penetrate the skin without a
needle.
 The available jet injectors
allow a dose range of 2 to 50
units of insulin.
 Insulin jet injectors decrease
the chance of subcutaneous
infection.
 It is mainly used in patients
with Needle Phobia.

9. Disadvantages of Insulin
Injections:-
Control is complex.
Multiple injections in same day.
Side effects to chronic S.C.
administration are Lipoatrophy or
Lipohyperatropy.
Local Pain.
Occasional Hypoglycemia.

12. 1)Ocular Delivery:-
• The rate of absoption was seen fast in the ocular route
than the injection.
• Delivered by the use of
nanoparticles,liposomes,ocular inserts & gels.
• Advantages: less side effects & avoidance of hepatic
first pass metabolism.
• Limitations: low bioavalibility and irritation & loss
of drug molecules via. blinking,tearing.
• Enhancers:
saponin,dodecylmaltoside,tetradecylmaltoside,fusidic
acid and glycolate.
• Fusidic Acid and Glycolate were proven to increase
ocular insulin absorption in rabbits,especially when
administered at higher pH levels.
• Until date,no human trial has been reported with this
route and an animal study failed to achieve significant
plasma insulin concentration.
• GELFOAM® an absorbable gelatin sponge ocular
devices have been developed as insulin carriers for
systemic administration of insulin. Price:Rs. 14,665

13. 2)Inhaled Delivery:-
• Inhaled drugs are absorbed into the alveolar capillary
network, which has advantage of having large surface
area(100 Sq. In.) and thin diffusion barrier.
• Advantages:Vast and well perfused absorptive surface,
absence of certain peptidases that are present in GIT,Faster
onset of action.
• Absorption Enhancers: Cyclodextrin(CD) derivatives like
tetradecyl-β-maltoside (TDM),dimethyl-β-cyclodextrin
(DMβCD) & hydroxypropyl-β-cyclodextrin (HPβCD).
• Examples of Preparations:
a)Exubera-first USFDA approved human insulin in powder
form, developed by Pfizer pharma & Sanofi Aventis.
b)Afrezza- by Mankind & Sanofi.
c)AERx- by Novo Nordisk, a world leader in insulin
manufacture and diabetes care.

15. 3)Buccal Delivery:-
• The drug is delivered through an aerosol
spray into the oral cavity.
• The molecules absorbed via. The buccal
route enter the internal jugular vein and
reaches the systemic circulation bypassing
hepatic first pass metabolism.
• Absorption enhancers-surfactants, bile
salts, chelators, SLS, HPMC, Carbopol 934
Polysorbate 80, Sorbitol.
• Lysalbinic acid, a product of the alkaline
hydrolysis of egg albumin can increase
insulin’s permeability from the cheek
mucosa.
• Examples of Formulation-
A)Oral-lyn™-developed by Generex
Biotechnology Corporation(Toronto,
Canada).

16. 4)Transdermal Delivery:-
• A transdermal patch is a medicated adhesive patch
that is placed on the skin to deliver a specific dose of
medication through the skin and into the
bloodstream.
• Microneedles (MNs) have been widely studied
for transdermal delivery of insulin as minimally
invasive and painless in human subjects.
• Examples of Preparations-
A)Pectin insulin containing dermal patches-
prepared by dissolving pectin/insulin in deionised
water & solidified with CaCl2.
B)U-Strip™-contain upto 100 units of insulin.
C)Transferosomal gels
D)Insulin emulgel

17. 5)Nasal Delivery:-
• Nasal cavity has large surface
area (150 Sq. cm.)
• Epithelial surface is covered
with numerous
microvilli,hence absorption is
greater and also avoiding loss
of insulin from first pass
hepatic metabolism.
• Examples of
Preparations-
A)Nasulin™ by CPEX
Pharmaceuticals & by
Nastech Pharmaceuticals.

18. 6)Rectal Delivery-
• There are Porto-systemic anatomoses in rectal
vessels. These vessels connect the portal system to
systemic system, hence allowing absorbed drugs to
directly enter the systemic circulation.
• The technique to improve rectal absorption is by
creating an adhesive interaction b/w. the delivery
system & rectal mucosa,increasing drug residence
time at the absorption sites.
• Suppositories containing 100 U insulin & 200 mg
Sodium Salicylate as an absorption enhancer were
tested in humans.Hypoglycemic effects were
achieved in 15 mins. & lasted upto 90 mins. Post
administration.
• Also available Rectal Gels (Pluronic F-127 gel).

19. 7)Oral Insulin Delivery:-
• Joslin tried for first oral insulin in 1922-1923.
• Challenges to development of oral insulin are
Proteolytic enzymes in the GI
tract,Hydrophobicity & low permeability
through the intestinal membrane that results in
poor bioavailability.
• When it is given orally, insulin is directly
channeled from the intestine to the liver and a
high level of insulin is reached in the portal
blood.

20. Barriers to oral delivery:-
Physical Barrier-
• In Epithelial layer, cells are tightly bound to another
by tight junction.
• Epithelial layer have a layer of Mucopolysaccharide
i.e. Glycocalyx which act as a barrier.
Enzymatic Barrier-
• Pepsin in stomach,trypsin, chymotrypsin &
carboxypeptidases from pancreas in small intestine.
• A specific cytosolic enzyme called insulin degrading
enzymes also exists.

21.  Preparation and characterization of insulin
nanoparticles using
chitosan and Arabic gum with ionic gelation
method-
 Material Required-
 Chitosan (95% deacetylated with viscosity of 1% wt/vol. Solution)
 Crystalline recombinant human insulin
 Arabic gum
 Preparation of insulin nanoparticles-
1) The insulin nanoparticles were prepared by ionic gelation
between positively charged chitosan and negatively charged
Arabic gum.
2) Initially, known amounts of chitosan were dissolved in 1.0%
acetic acid aqueous solution to obtain concentrations of 1 mg/mL
and 5 mg/mL under stirring at room temperature.
3) Subsequently, different amounts of insulin according to the
factorial design were added to chitosan solution under magnetic
stirring at room temperature.

22. 4) Consequently, Arabic gum was dissolved in
water to obtain a known concentration under
magnetic stirring at room temperature.
5) Nanoparticles were prepared by adding Arabic
gum solution dropwise to chitosan solution
containing insulin under gentle magnetic
stirring at room temperature.
6) The nanoparticle suspension was centrifuged
for 15 min at 14,000 rpm at 4°C, and the
supernatant was used for measurement of free
insulin by high-performance liquid
chromatography.

23. Characterization of insulin
nanoparticles-
• The sizes of the insulin nanoparticles were measured
with a Malvern zetasizer.
• The particle size distribution is reported as a
polydispersity index (PDI). The range for the PDI is from
0 to 1: Values close to zero indicate a homogeneous
dispersion, and those greater than 0.5 indicate high
heterogeneity.
• The zeta potential of nanoparticles was measured.
Transmission electron microscopy (TEM) was used to
observe the morphology of insulin nanoparticles.
• Release studies- Insulin release from nanoparticles
was performed at three different pH values: 1.2 (0.1 N
HCl), 6.5 (phosphate buffer solution; PBS), and 7.2
(PBS).

26. References:-
1) Mohammad Reza Avadi, Assal Mir Mohammad Sadeghi,
Nasser Mohammadpour, Saideh Abedin, Fatemeh Atyabi,
Rassoul Dinarvand, Morteza Rafiee-Tehrani; Preparation
and characterization of insulin nanoparticles using chitosan
and Arabic gum with ionic gelation method. Available
online at www.sciencedirect.com {Research Paper}
2) KD Tripathi;Essentials of Medical Pharmacology; Ed. 7th;
2013; Jaypee Brothers Medical Publishers (P) Ltd; p.269-270.
3) https://www.slideshare.net/ShashankSoni/novel-
approaches-to-deliver-insulin