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NDDS OF INSULIN

PARSHVANATH CHARITABLE TRUST’S

VEER MATA HIRABEN P. SHAH COLLEGE OF


PHARMACY

GHODBUNDER ROAD, KASAR VADAVLI , THANE (W)

SEMINAR REPORT

ON

NOVEL DRUG DELIVERY


SYSTEM ON INSULIN

SUBMITTED BY: SALIL C. KADAM

GUIDE: Prof. AMJAD KHAN

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CERTIFICATE

PARSHWANATH CHARITABLE TRUST’S


VEER MATA HIRABEN P. SHAH
COLLEGE OF PHARMACY.
Kasarvadavali,Ghodbunder Road, Thane (W)

This is to certify that SALIL C. KADAM exam

seat no has submitted the seminar report entitled Novel Drug

Delivery System on Insulin in partial fulfillment of requirement

for semester –VI of Bachelor of Pharmacy during the academic

year 2007-2008.

GUIDE PRINCIPAL EXTERNAL


EXAMINER

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ACKNOWLEDGEMENT

First & foremost, I would like to thank our Honorable Trustee &
Patron Mr. Teckchand . J. Shah

for providing us with all the facilities required for the completion
of this seminar.

I would like to thank our Hon. Principal Dr (Mrs). Sudha Rathod


for her support.

I would even thank my parents for their support and love.

Further, I would like to thank my guide Prof. Amjad Khan for his
constant encouragement, support & valuable guidance without
whom this seminar could not be accomplished.

I am also very thankful to my friend Abhishek Sharma, Ajay


Mohite, Librarian who gave me a helping hand during the course
of the seminar.

Lastly I am thankful to all those people who encouraged me


throughout the seminar.

Yours sincerely,

Salil C. Kadam

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INDEX

PAGE NO
1. Physiology and action of insulin 5

2. Types of diabetes in which insulin used 9

3. Novel drug delivery system of insulin 18

4. Routes of NDDS of insulin 19

5. Gadget for NDDS of insulin 34

6. Industries manufacturing NDDS of insulin 40

7. Disadvantage of insulin 42

8. Summary 43

9. Conclusion 44

10. Role of pharmacist 45

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PHYSIOLOGY OF INSULIN
1) Developed countries are currently witnessing a surge in the incidence of adult-onset
type 2 diabetes, driven by soaring levels of obesity. Insulin, the hormone that normally
coordinates the disposal of glucose after a meal, becomes less effective in obesity,
resulting in the high blood-glucose concentration that is the hallmark of diabetes. Insulin
is known to target the liver directly has identified an additional pathway by which the
hormone, acting on the brain, sends messages via the nervous system to exert a higher
level of control on glucose output from the liver .

2) The liver has a central role in glucose homeostasis because it extracts glucose from the
bloodstream in times of plenty, and synthesizes glucose in times of need. Thus, it buffers
the body from extremes in glucose concentration -- the relative excess after meals, and
the relative shortage between meals, particularly overnight and during periods of fasting.
The liver recognizes these different energy states through changes in the blood insulin
concentration; insulin binds to its receptor in the liver and directly inhibits glucose
production. But this well-established pathway is far from the whole story

3) In recent years, the idea that glucose metabolism throughout the body is coordinated
by the brain has gained growing support It is increasingly evident, for example, that the
liver receives control signals from the hypothalamus, an area of the brain known to detect
and integrate metabolic signals. Now, Pocai et alshow that insulin, in addition to its direct
effects on the liver, also acts on specialized ion channels, called KATP channels, in the
hypothalamus to control glucose production. These channels, which lie in the outer
membranes of hypothalamic neurons, were named for their ability to release potassium
ions from cells in response to a drop in ATP The results link two findings that had
previously been viewed in isolation: that insulin can modulate liver glucose output
through an unknown action in the hypothalamus and that it opens KATP channels in an
unidentified set of neurons in a part of the hypothalamus that monitors blood metabolites
and hormones.

4) KATP channels are generally known for their ability to convert metabolic signals into
changes in electrical activity in excitable cells such as neurons, cardiac muscle cells, and
some endocrine cells -- including the insulin-producing beta-cells of the pancreas. The
channels close in response to ATP and sulphonylureas (a class of drugs used in the
treatment of type 2 diabetes), and are opened by ADP (a metabolic product of ATP) and
by certain lipids and insulin. KATP channels regulate both the resting membrane potential
and cell excitability. Opening the channels – by

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MEDICAL BIOLOGY: ON INSULIN RESISTANCE

1) Type II diabetes affects some 5% of adults in most developed countries, and a far
higher proportion of the population exhibits insulin resistance, a condition that
predisposes individuals to diabetes. The mechanisms leading to insulin resistance are
unclear, although the abnormal accumulation of certain fats in the liver (hepatic steatosis)
is a contributing factor. Stoffel et al demonstrate that the inactivation of a protein called
Foxa2 promotes steatosis and contributes to the development of diabetes in insulin-
resistant animals. The results have implications for the design of new drugs to treat
insulin resistance and diabetes.

2) Energy balance in mammals resembles today's hybrid cars -- we use a variable mix of
glucose and fat as energy substrates, depending on food intake. During waking and
feeding hours, we use glucose as an efficient source of energy, and under fasting
conditions, during sleep for example, we burn primarily fat. Fat stores, called
triglycerides, are converted to circulating fatty acids, and are further broken down in a
process known as fatty-acid oxidation. In the fasting state, the liver also maintains normal
circulating levels of glucose (which is essential for brain function) by synthesizing
glucose anew, in a process known as gluconeogenesis.

3) The capacity of the liver to synthesize glucose and burn fat is governed by a set of
ignition switches, called transcription factors, that operate in the nucleus to turn genes on
and off. These switches respond to changes in circulating hormones --principally insulin
and glucagon -- that allow the liver cell to change gears between feeding and fasting
metabolism. In response to feeding, insulin triggers the activation of a cascade of proteins
inside the cell, each transmitting the feeding signal to the next through a chemical
modification known as phosphorylation. In insulin-resistant states, the orderly
phosphorylation of certain proteins in response to insulin is damaged, preventing insulin
from correctly regulating glucose and fat metabolism As a consequence, insulin-resistant
individuals exhibit hyperglycaemia (high blood glucose), partly because of elevated
gluconeogenesis in the liver.

4) Despite this inability to inhibit glucose production in diabetes, insulin still seems to be
capable of shutting off the switch that normally promotes fat burning (fatty-acid
oxidation) during fasting. This phenomenon, known as mixed insulin resistance, implies
that the insulin signal is transmitted preferentially to the fatty-acid-oxidation switch
rather than the glucose switch, the unfortunate consequence being that insulin-resistant
individuals are not only hyperglycaemic but also accumulate triglycerides in the liver
rather than breaking them down.[2-4]

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Recent Advances in Our Understanding of Insulin Action and Insulin


Resistance

Insulin signaling at the target tissue results in a large array of biological outcomes. These
events are essential for normal growth and development and for normal homeostasis of
glucose, fat, and protein metabolism. Elucidating the intracellular events after activation
of the IR has been the primary focus of a large number of investigators for decades, and
for excellent reasons. Understanding the signaling pathways involved in insulin action
could lead to a better understanding of the pathophysiology of insulin resistance
associated with obesity and type 2 diabetes, and identifying key molecules and processes
could lead to newer and more effective therapeutic agents for treating these common
disorders.

how insulin acts and outlines some recent developments in our understanding of insulin
action and insulin resistance at the cellular level, beginning with a discussion on the
discovery of evolutionarily conserved molecules of the insulin signaling pathways. This
article will also provide a summary of a few in vitro and cellular models of insulin
resistance and a description of some new paradigms in the cellular mechanisms of insulin
action.

Actions on cellular and metabolic level

Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor
(1) Which in turn starts many protein activation cascades
(2).These include: translocation of Glut-4 transporter to the plasma membrane and influx
of glucose.

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(3) Glycogen synthesis


(4) Glycolysis
(5) and Fatty acid synthesis (6).

The actions of insulin on the global human metabolism level include:

(1) Control of cellular intake of certain substances, most prominently glucose in


muscle and adipose tissue (about ⅔ of body cells).
(2) Increase of DNA replication and protein synthesis via control of amino acid
uptake.
(3) Modification of the activity of numerous enzymes (allosteric effect).

The actions of insulin on cells include:

(1) Increased glycogen synthesis – insulin forces storage of glucose in liver (and
muscle) cells in the form of glycogen; lowered levels of insulin cause liver cells to
convert glycogen to glucose and excrete it into the blood. This is the clinical
action of insulin which is directly useful in reducing high blood glucose levels as
in diabetes.
(2) Increased fatty acid synthesis – insulin forces fat cells to take in blood lipids
which are converted to triglycerides; lack of insulin causes the reverse.
(3) Increased esterification of fatty acids – forces adipose tissue to make fats (i.e.,
triglycerides) from fatty acid esters; lack of insulin causes the reverse.
(4) Decreased proteinolysis – forces reduction of protein degradation; lack of insulin
increases protein degradation.
(5) Decreased lipolysis – forces reduction in conversion of fat cell lipid stores into
blood fatty acids; lack of insulin causes the reverse.
(6) Decreased gluconeogenesis – decreases production of glucose from non-sugar
substrates, primarily in the liver (remember, the vast majority of endogenous
insulin arriving at the liver never leaves the liver) ; lack of insulin causes glucose
production from assorted substrates in the liver and elsewhere.
(7) Increased amino acid uptake – forces cells to absorb circulating amino acids; lack
of insulin inhibits absorption.
(8) Increased potassium uptake – forces cells to absorb serum potassium; lack of
insulin inhibits absorption.
(9) Arterial muscle tone – forces arterial wall muscle to relax, increasing blood flow,
especially in micro arteries; lack of insulin reduces flow by allowing these
muscles to contract.

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TYPES OF DIABETIES

It has been suggested that Biguanides should be used in Type 1 (insulin-dependent)


diabetic patients in order to diminish insulin requirements and reduce the chances of
insulin reactions. The efficacy of these compounds in such patients has been
controversial. We have studied the effect of Metformin (850mg) given at 08.00 h in
diminishing insulin needs after a 60g carbohydrate mixed meal taken at 12.00 h, using an
artificial pancreas and a sequential analysis of the results. The morning test dose of
Metformin or placebo was preceded by 48 h treatment with Metformin (850mg twice
daily) or placebo. After the eighth patient a 26% saving of insulin need was demonstrated
in the Metformin-treated group (p<0.01). Metformin is thus effective in reducing post-
prandial insulin needs in Type 1 diabetic patients, although its use in such circumstances
requires consideration of several other issues.

Type 1 Diabetes only takes a few weeks to develop. The initial symptoms include:

(1) increased production of urine


(2) excessive thirst
(3) tiredness
(4) loss of weight
(5) blurred vision
(6) infections such as thrush or irritation of the genitals

If Type 1 diabetes isn't treated at this stage, the body begins to produce chemicals called
Ketones. This is because it tries to use energy sources other than glucose. The Ketones
build up in the bloodstream, leading to a condition called diabetic Ketoacidosis. Diabetic
Ketoacidosis causes additional symptoms, including:

(1) vomiting
(2) stomach pain
(3) rapid breathing
(4) increased pulse rate
(5) sleepiness

Without treatment, diabetic Ketoacidosis can lead to coma and, eventually, death.

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Causes

Type 1 diabetes develops when the cells in the pancreas which make insulin - called the
islets of Langerhans - are destroyed by the body's own immune system. Because of this,
type 1 diabetes is known as an autoimmune disorder.

Without insulin, glucose builds up in the blood stream, and can reach dangerous levels if
left untreated.

Diagnosis

No one knows exactly what causes type 1 diabetes develops. It might be triggered by a
virus or other autoimmune diseases, or it may be due to inheriting certain genes.

Type 1 diabetes is most common in people under the age of 30, although it can develop at
any age.

Treatment

Type 1 Diabetes can be detected with a blood test to measure the level of glucose in the
blood. This might be a fasting glucose test, which is taken after fasting for at least eight
hours, or a random glucose test, which can be carried out at any time. You may have
another type of blood sugar test called a glucose tolerance test. This measures how your
blood sugar changes over time after you swallow a sugary drink. You need to fast
overnight before having this test.

Controlling your blood sugar

At the moment there's no cure for type 1 diabetes. However, it can be controlled by
giving the body insulin. This allows glucose to be absorbed into cells and converted into
energy, stopping it building up in the blood.

Insulin can't be taken orally because it is destroyed by acid in the stomach - instead, you
need to inject it. Insulin injections are usually self-administered two to four times a day,
using either a small hypodermic needle or a pen type syringe with refillable cartridges.

There are different kinds of insulin that work at different rates and act for different
lengths of time. They can be used to try and get the best control of blood sugar levels.

Recently, devices that let you inhale an insulin powder have been designed. Alternatively,
portable insulin pumps, which are attached to your waist, can be programmed to inject
you with insulin. These newer methods are only used if a good level of blood sugar
control isn't reached with other methods.

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How you take insulin varies between individuals, and your GP will advise you on the
most appropriate method for you.

Carefully controlling blood sugar is the key to maintaining good health if you have
diabetes. If you don't, you can develop either low blood glucose levels (Hypoglycaemia),
or high blood sugar levels (Hyperglycaemia).

Low blood glucose

Low blood glucose happens if you don't eat enough - so not enough sugar from food is
absorbed into the blood - or if you take too much insulin - which causes too much
glucose in the blood stream to be absorbed into cells and used up.

It causes faintness, sweating and a pounding heart. If it isn't treated by eating or drinking
something sugary, it can lead to confusion, collapse and even coma. You will probably
experience a "hypo", or near hypo, from time to time, and should consider keeping some
sugary food or glucose tablets at hand to control it. If "hypo" attacks are too frequent, you
may not notice the warning signs.

High blood glucose

Uncontrolled high blood sugar can lead to a number of long-term complications. Over
time, very small blood vessels become damaged. This can cause irreversible damage to
the eyes and kidneys, leading to blindness and kidney failure, if left unchecked. Nerves
can also be damaged, which can affect your ability to feel sensations and pain.

Badly controlled blood sugar can also damage larger blood vessels. It makes the lining of
arteries more likely to fur up and become narrower (atherosclerosis). This makes heart
disease and stroke more likely.

Damage to your circulation can also increase the risk of leg or foot ulcers, which can lead
to gangrene and even amputation.

Monitoring your blood sugar

You can monitor your blood sugar levels with a home test kit. This can be useful for your
doctor when assessing your treatment. It involves taking a pin prick of blood and
analysing it with either colour-coded strips of paper (which give a blood sugar reading
based on the colour they turn) or, more recently, an electronic monitor. Diet and insulin
can be adjusted to keep the level within the normal range.

Hospital clinics, run by Diabetologists (doctors with a special interest in the disease) and
specialist nurses can provide you with initial guidance and support to do this. After you
have learnt how to manage your blood sugar, you can get support from your GP or
specialist nurses at local diabetic clinics.

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A healthy lifestyle

In addition to controlling blood sugar, lifestyle is a key part of ensuring that diabetes has
the minimum impact on your health.

Diet

A healthy diet is essential for people with type 1 diabetes. So called "diabetic foods"
aren't necessary for a healthy diet; you just need to watch what you eat. This is the same
as the normal, balanced diet that's recommended for good health - low in saturated fat,
sugar and salt; high in fibre, vegetables and fruit.

Carbohydrates should be spread throughout the day to prevent high blood sugar levels
after a meal. Carbohydrates include starchy food such as pasta, potatoes, bread and
cereals and sugary foods including fruit, sweets and biscuits.

It's important to keep your weight under control. This will help keep your risk of getting
cardiovascular disease to a minimum. Talk to a state registered dietitian for more
information.

Exercise

Physical activity promotes a healthy circulation and helps you maintain a healthy weight.
Many successful sports people have diabetes: well-controlled diabetes need not prevent
an active life. To stay healthy the government recommends that you do at least half an
hour of moderate activity, at least five days a week.

Alcohol

If you have diabetes, there's no need to give up alcohol. However, women should limit
themselves to two to three units of alcohol a day, and men shouldn't drink more than three
to four units a day. You should also avoid drinking on an empty stomach.

Smoking

Smoking also damages the circulation and, like diabetes, increases the risk of
cardiovascular disease. Smoking is unhealthy for everyone, but it's especially important
for smokers with diabetes to give up because of the damage to does to circulation.

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INSULIN

Insulin is a hormone that is used to treat type 1 diabetes and some people with type 2
and gestational diabetes. People with type 1 diabetes require insulin injections because
the beta cells of their pancreas are no longer manufacturing sufficient amounts of
insulin to control their blood sugar levels. Insulin allows glucose to leave the
bloodstream and enter the cells of the body, where it’s used for energy.

How much insulin you need and when you take it depends on several factors—the type
of insulin your doctor has prescribed, your nutrition and exercise habits, other co-
existing medical conditions and medications you may be taking for them, and how
much insulin (if any) your pancreas is still producing.

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Patient information: Diabetes type 2: Insulin treatment


Type 2 diabetes mellitus occurs when the pancreas (an organ in the abdomen) produces
insufficient amounts of the hormone insulin and/or the body's tissues become resistant to
normal or even high levels of insulin. This causes high blood glucose (sugar) levels,
which can lead to a number of complications if untreated.

People with type 2 diabetes require regular monitoring and ongoing treatment to maintain
normal or near-normal blood glucose levels. Treatment includes lifestyle adjustments,
self-care measures, and medications, which can minimize the risk of diabetes-related and
cardiovascular complications (eg, heart attacks and strokes). Learning to manage diabetes
is a process that continues over a lifetime. The diagnosis of diabetes can be
overwhelming at the beginning; however, most people are able to lead normal lives and
many patients become experts in their own care.

TYPES OF INSULIN — There are several types of insulin. These types are classified
according to how quickly the insulin begins to work and how long it remains active
Injectable insulin

(1) Rapid-acting (eg, insulin lispro [Humalog®], insulin aspart [Novolog®], and
insulin glulisine [Apidra®])
(2) Short-acting (eg, insulin regular)
(3) Intermediate-acting (eg, insulin NPH)
(4) Long-acting (eg, insulin glargine [Lantus®], insulin detemir [Levemir®])

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Type Appearance Onset Peak Duration Can be


mixed with
Short acting Clear 0.5-1 2-4 6-8 All
Regular preparation
(soluble) regular
insulin lente
preparation
Prompt Cloudy 1 3-6 12-16
insulin zinc
suspension
(amorphous)
or semilente
Intermidiate
acting
Insulin zinc Cloudy 1-2 8-10 20-24 Regular,
suspension semilente
or lente
(ultra:
semi:7:3)

Neutral Cloudy 1-2 8-10 20-24 Regular


Protamine
Halogen
(NPH) or
Isophane
Insulin
Long acting
Extended Cloudy 4-6 14-18 24-36 Regular
insulin zinc Semilente
suspensesion
(crystalline)
or ultralente

Protamine Cloudy 4-6 14-20 24-36 Regular


zinc insulin

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Diabetic injection sites

Site of injection — Clinicians usually recommend rotating injection sites to minimize


tissue irritation. When changing sites, it is important to keep in mind that insulin is
absorbed at different rates in different areas of the body.

Insulin is absorbed fastest from the abdominal area, slowest from the leg and buttock, and
at an intermediate rate from the arm. This may vary with the amount of fat present; areas
with more fat under the skin absorb insulin more slowly.

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It is reasonable to use the same general area for injections given at the same time of the
day. Sometimes abdominal injections, which are absorbed more quickly, are preferred
before meals. Injection into the thigh or buttock may be best for the evening dose because
the insulin will be absorbed more slowly during the night.

Technique for injecting insulin

Injection angle — Insulin is usually injected under the skin using a needle and syringe. It
is important to use the correct injection angle since injecting too deeply could deliver
insulin to the muscle, where it is absorbed too quickly. On the other hand, injections that
are too shallow are more painful and not absorbed well.

The best angle for insulin injection depends upon a patient's body type, injection site, and
length of the needle used. A healthcare professional can help determine the right angle of
injection.

Novel Drug Delivery Systems for Insulin


Copyright 2003 Adis Data Information BV

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INTRODUCTION

Diabetes mellitus is a very common disease in the elderly and its complications are
responsible for excess morbidity/mortality, loss of independence and impaired
quality of life. Recent studies, while not performed in the elderly, have outlined the
importance of achieving tight glycaemic control in order to prevent complications.
Eighty years after its discovery, subcutaneous insulin remains a major treatment
for diabetes. It is used as a first-line agent in type 1 diabetes, and in type 2 diabetes
when oral antihyperglycaemic agents combined with diet and exercise fail to
achieve an appropriate metabolic control.

To avoid injections, other routes of insulin administration have been studied,


including oral, dermal and rectal routes but they were not found to be appropriate
for clinical use. Buccal or nasal insulin combined with absorption enhancers
proved to have interesting properties.

Inhaled insulin appears to be suitable for use in patients with diabetes because of
its better bioavailability and a pharmacokinetic profile that mimics the time
kinetics of insulin secretion after a meal. Clinical studies were conducted among
small numbers of patients with type 1 or type 2 diabetes who had been treated with
subcutaneous insulin. Inhaled insulin was given three times daily, just before
meals, and was combined with a bedtime subcutaneous injection of long-acting
insulin. In patients with type 1 or type 2 diabetes the metabolic control achieved
with inhaled insulin was similar to that obtained with a subcutaneous insulin
regimen. Tolerance of inhaled insulin was good and treatment satisfaction was
better than that with the subcutaneous regimen.

Insulin inhalation appears to be an interesting way of insulin delivery for elderly


patients with diabetes. However, no studies have been conducted in elderly
patients with diabetes to assess this route's acceptability, convenience and ease of
use in this particular population. In addition, it is necessary to conduct
pharmacokinetic studies in the elderly because lung aging might reduce the
bioavailability of inhaled insulin.

ROUTES OF NOVEL DRUG DELIVERY OF INSULIN

The Transdermal Insulin Drug Delivery (TDD) System

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The Transdermal Drug Delivery (TDD) System employs a flexible patch design integral
to the new two-part TDD called the Medi-Cap. The Sonic Applicator And Control Device
will power the transducers and produce the alternating ultrasonic waveform signal which
will pass through the skin and deposit the drug stored within the TDD. A series of
experiments have been conducted using laboratory animal and human cadaver skin to
determine the rate of insulin permeation with the U-Strip.

An alternating ultrasonic waveform enlarges the diameter of the skin pores and enables
large molecule drugs to permeate through the skin (stratum corneum) into the dermis.
From there the drug enters the blood stream. Ultrasound forces the drug through either of
two pathways: (1) Hair Follicles or (2) Sweat Pores. Ultrasound is used to "enlarge" the
Skin Pathway and then to drive the drug through the opening. Mechanically the drug
follows the hair follicles to the bloodstream (near IV injection) or the sweat pores to the
fatty tissue (Sub-Q Injection).

The U-Strip Drug Delivery System generates ultrasonic transmissions of variable intensity and frequency,
which are pulsed through a modified transdermal patch, acting to kinetically motivate the drug contained
within the patch.

The transducer patch array generates an ultrasonic signal which serves to dilate the skin
pores and increase the likelihood of absorption of the drug through the skin.

The U- Strip device


can be programmed
to deliver a
prescribed
amount of active

pharmaceutical agents on a programmed drug delivery regimen, customized for each


patient.

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The portability of this drug delivery system is designed to improve the quality of life for
many patients afflicted with chronic diseases requiring the constant delivery of
therapeutic medicines.

Encapsulation Systems Previews the U-Strip(TM) Insulin Patch, the Next


Generation of Transdermal Drug Delivery for the Treatment of Diabetes

"The U-Strip Insulin Patch is an ultrasonic drug delivery system using an alternating
sonic transmission to effect pore dilation and deposit large molecule drugs into the
dermis," says Bruce K. Redding, Jr., President and CEO, Encapsulation Systems, based in
Havertown, Pennsylvania. "Although our primary market is Type 2 diabetics, our insulin
delivery transdermal patch is able to deliver a basal and bolus dose of insulin under a
programmable regimen to both Type 1 and Type 2 diabetics."

"While the U-Strip Insulin Patch is in Phase-2 clinical trials and not yet approved for
human use by the FDA, I believe the U-Strip will provide a major breakthrough in the
transdermal delivery of insulin for Type 2 diabetics," states Dr. Rex Kessler,
endocrinologist and Director of Research at the Kessler Research Institute in Media, PA.
"Compared to insulin injections and continuous subcutaneous delivery systems,
transdermal delivery eliminates the pain associated with these invasive methods. The
ultrasonic applicator unit records the dose delivered and stores the information for 60
days. The U-Strip Insulin Patch enhances patient compliance because of a programmed
insulin drug delivery profile and ease of use."

Construction and Working:-

The U-Strip is a patent pending drug delivery system consisting of 3 components: the
sonic applicator module, the battery strap and the modified transdermal patch.

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Transdermal Patch is specially designed to hold the target drug.

Sonic Applicator Module is a programmable ultrasonic transmitter that


fits directly above the patch. The ultrasonic transmitter can be
programmed to deliver a constant or pulse of ultrasonic energy, through the
transdermal patch. Ultrasound from the Sonic Applicator Module pushes the
drug (insulin) contained within the patch through the skin.

A rechargeable battery system is located within the strap, which holds


the ultrasonic transmitter over the patch.

U-STRIP Advantages over SC form:-

The U-Strip offers a number of advantages to both the patient and to medical
professionals which include:

Non-Invasive - No needles are required with this totally non-invasive


drug delivery system.

Safe and effective - U-Strip controls the patient's medication so


there is less change of over/under dosage.

Direct bloodstream absorption - This on-demand delivery system


bypasses the stomach and the intestine where drug potency can be destroyed.

Individualized drug regimen - Medical professionals can easily


individualize drug regimen tailored for each patient's needs.

Easy to Follow - The automatic drug delivery ensures heightened


compliance for pediatric and elderly patients, because there is nothing to
remember and no schedules to follow. Patients simply "Set it and Forget it"
and ensure their drug regimen is more easily followed.

Additional Pharmaceutical Applications - The U-Strip technology may


open the door to a number of advanced pharmaceutical delivery applications
for other chronic medical conditions.

THE FUTURE - U-STRIP INSULIN SYSTEM

The U-Strip(TM) is a patent pending drug delivery system in Phase-2 clinical trials that is
not yet approved for human use by the FDA. However, the development of a
programmable, portable, ultrasonic instrument will extend the number and types of drugs
that can be given with the transdermal patch.

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ANATOMY AND PHYSIOLOGY OF NASAL ROUTE FOR DRUG


DELIEVERY

The olfactory region

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In human, the olfactory region is located on the roof of the nasal cavities, just below the
cribriform plate of the ethmoid bone, which separates the nasal cavities from the cranial
Cavity. The olfactory tissue is often yellow in colour, in contrast to the surrounding pink
tissue. Humans have relatively simple noses, since the primary function is breathing,
while other mammals have more complex noses better adapted for the function of
olfaction.

A Schematic diagram of olfactory epithelium

Advantages of Nasal Drug Delivery System over others:-

1) Drug degradation that is observed in the gastrointestinal tract is absent.

2) Hepatic first – pass metabolism is absent.

3) Rapid drug absorption and quick onset of action can be achieved.

4) The bioavailability of larger drug molecules can be improved by means of absorption


enhancer or other approach.

5) The nasal bioavailability for smaller drug molecules is good.

6) Drugs that are orally not absorbed can be delivered to the systemic circulation by nasal
drug delivery.

7) Studies so far carried out indicate that the nasal route is an alternate to parenteral route,
especially, for protein and peptide drugs.

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8) Convenient for the patients, especially for those on long term therapy, when compared
with parenteral medication.

Nasal Drug Absorption:


Mechanism of Drug Absorption

Several mechanisms have been proposed but the following two mechanism have been
considered predominantly. The first mechanism involves an aqueous route of transport,
which is also known as the paracellular route. This route is slow and passive. There is an
inverse log-log correlation between intranasal absorption and the molecular weight of
water-soluble compounds. Poor bioavailability was observed for drug with a molecular
weight greater than 1000 Daltons.

The second mechanism involves transport through a lipoidal route is also known as the
transcellular process and is responsible for the transport of lipophilic drugs that show a
rate dependency on their lipophilicity. Drug also cross cell membranes by an active
transport route via carrier-mediated means or transport through the opening of tight
junctions. For examples, chitosan, a natural biopolymer from shellfish, opens tight
junctions between epithelial cells to facilitate drug transport.

Factors affecting nasal drug absorption:-

Many factors affect the systemic bioavailability of nasally administered drugs. The
factors can be attributed to the physiochemical properties of the drugs, the anatomical and
physiological properties of the nasal passage and the type and characteristics of selected
nasal drugs delivery system. These play significant role for most of the drugs in order to
reach therapeutically effective blood levels after nasal administration. The factors
influencing nasal drug absorption are as follows.

A) Physiochemical properties of drug.

• Molecular size.
• Lipophilic-hydrophilic balance.
• Enzymatic degradation in nasal cavity.

B) Nasal Effect

• Membrane permeability.
• Environmental pH
• Mucociliary clearance
• Cold, rhinitis.

C) Delivery Effect

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• Formulation (Concentration, pH, osmolarity)


• Delivery effects
• Drugs distribution and deposition.
• Formulation effect on mucociliary clearance.
• Toxic effect on ciliary function and epithelial membranes.

Formulation Development Research In Nasal Drug Delivery:-

Most of the over the counter nasal preparation are formulated as solution, to treat the
nasal symptoms of allergic rhinitis and common cold. A simple drug solution is adequate
for this purpose as it produces better dispersion over greater surface area. The nasal
residence time of such formulation is short (3-20 min) and exhibit high inter individual
variability. This route provides fast peak levels in circulation15.

Large number of drugs has been evaluated for systemic bioavailability after transnasal
administration in experimental animal models. Transnasal administration of drugs in
diverse dosage forms such as sprays, powders, and microspheres has been attempted for
improved residence and bioavailability. The nasal delivery is receiving attention for
management of postoperative pain; mucosal administration requires only a 1.1-1.5 time
higher dose of fentanyl than i.v. dose. The nasal delivery of vaccines is a very attractive
route of administration in terms of efficacy.

Physiochemical Properties of Drugs:

Chemical form:

The form of a drug can be important in determining absorption. For example, conversion
of the drug into a ester form can alter its absorption. It was observed that in –situ nasal
absorption of carboxylic acid esters of L-Tyrosine a significantly greater than that of L-
Tyrosine.

Polymorphism:

Polymorphism is known to affect the dissolution rate solubility of drug and thus their
absorption through biological membranes. It is therefore advisable to study the
polymorphic stability and purity of drugs for nasal powders and/or suspensions.

Molecular Wt.:-

A linear inverse correlation has been reported between the absorption of drugs and
molecular up to 300 Daltons. Absorptions decreases significantly if the molecular weight
is greater than 1000 Daltons except with the use of absorption enhancers.

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Particle Size:

It has been reported that particle sizes greater than 10 μm are deposited in the nasal
cavity. Particles that are 2 to 10 μm can be retained in the lungs, and particles of less than
1 μm are exhaled.

Solubility and Dissolution Rate:

Drug solubility and dissolution rates are important factors in determining nasal
absorption from powders and suspensions. The particles deposited in the nasal cavity
need to be dissolved prior to absorption. If drugs remain as particles or is cleared away,
no absorption occurs.

Delivery Systems:

The selection of delivery system depends upon the drug being used, proposed indication,
patient population and last but not least, marketing preferences. Some of these delivery
systems and their importants features are summarized below:

Nasal Drops:

Nasal drops are one of the most simple and convenient systems developed for nasal
delivery. The main disadvantage of this system is the lack of the dose precision and
therefore nasal drops may not be suitable for prescription products. It has been reported
that nasal drops deposit human serum albumin in the nostrils more efficiently than nasal
sprays.

Nasal sprays:

Both solution and suspension formulations can be formulated into nasal sprays. Due to
the availability of metered dose pumps and actuators, a nasal spray can deliver an exact
dose from 25 to 200 μm.The particles size and morphology (for suspensions)of the drug
and viscosity of the formulation determine the choice of pump and actuator assembly.

Nasal Gels:

Nasal gels are high-viscosity thickened solutions or suspensions. Until the recent
development of precise dosing device, there was not much interest in this system. The
advantages of a nasal gel includes the reduction of post-nasal drip due to high viscosity,
reduction of taste impact due to reduced swallowing, reduction of of anterior leakage of
the formulation, reduction of irritation by using soothing/emollient excipients and target
to mucosa for better absorption.

Nasal Powder :-

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This dosage form may be developed if solution and suspension dosage forms
cannot be developed e.g., due to lack of drug stability. The advantages to the nasal
powder dosage form are the absence of preservative and superior stability of the
formulation. However, the suitability of the powder formulation is dependent on the
solubility, particles size, aerodynamic properties and nasal irritancy of the active
drug and /or excipients. Local application of drug is another advantage of this
system.

NASAL ROUTE FOR INSULIN DRUG DELIEVERY

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Inhalable Insulin in Phase 3 Trials

The MannKind inhaled insulin delivery system consists of a proprietary dry powder
Technosphere formulation of insulin that is inhaled into the deep lung using a proprietary
inhaler which utilizes single-use, disposable plastic cartridges containing Technosphere
Insulin powder.
Novel drug delivery techniques like inhalable insulin and inhalable vaccine make it easier
for patients or caregivers -- not just doctors -- to administer medications. The powder
format travels better and typically requires less stringent refrigeration. In some cases,
medicines previously delivered by a doctor's office injection could be delivered over the
counter.

Such an easy, painless, needle-free injection might seem the stuff of purest science
fiction, but the technology to administer drugs without use of the standard hypodermic
syringe has been under development for at least 60 years. Could it be that the old-
fashioned needle and syringe, first perfected more than 150 years ago, is on its way out at
last?

The path to the needle's eventual extinction has not been an easy one. Infiltrating drugs
past the body's defenses requires great ingenuity, not only in the creation of new devices
and the exploitation of previously unused biological uptake pathways, but also in the

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tailoring of the molecules being delivered. Oftentimes, the perfect marriage of drug and
device requires some finicky, clever match-making. The recent development of Exubera,
the first inhalable insulin, and of its novel delivery device -- a collaboration by Pfizer,
Nektar Therapeutics and The Tech Group -- is illustrative of the challenges faced by
researchers in this area .

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Glucometer and Insulin Pump

INSULIN PUMP

Having diabetes is certainly not fun, and probably is pretty inconvenient. You’ve got to
remember to bring all your supplies, be it a glucometer, insulin, and anything else you
need to keep healthy everywhere you go. That can’t be fun.

The folks over at Cambridge Consultants realize that and want to make it a bit less
inconvenient. Recently they announced a device that integrates close-proximity wireless
with an insulin pump and a glucometer.

The device utilizes the close-proximity wireless standard, NFC, to wirelessly link the
insulin pump and glucometer. Your glucometer will record your blood sugar level then
recommend a dose of insulin. If you accept the dose, all you need to do is swipe the
glucometer against the insulin pump, which can be hidden under your clothes, and it will
issue the dosage.

Insulin Pump

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Bang & Olufsen C-Cap, Smells Like Insulin

For instance, when it's time for a diabetic to take their insulin, the C-Cap's light will
glow green. If they are late, the color will turn to yellow and the pen may chime as
a reminder. Then, after the patient takes their meds, the pen will turn red until the
next dose. It's not the most advanced system on the planet, but if it keeps you from
dying, more power to it. We think an autolock (that could be overridden) would be a
nice feature to prevent overdosing. The C-Caps go on sale overseas soon, but there's
no word on whether or not they'll be available for recreational use.

iPod or pager insulin pump

This is the MiniMed pump, an unobstrusive gadget that isn't an iPod nor a pager. It's an
insulin pump. Small and lighweight the MiniMed Paradigm 522/722 comes in clear, blue,
smoke and purple. You can even choose a skin to personalize your unit. The devices hold
a maximum capacity of 176 - 300 units which meets the needs of most people who take
up to 50 units a day.

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An Italian study found that diabetics using insulin pumps such as these had 70% less
therapy-related dissatisfaction that those patients that used multiple injection therapies.
The MiniMed pump, and other like it, are finally giving diabetics the privacy, a little bit
of style and choice that they deserve

List of Manufacturers of INSULIN PUMPS

Abbott Laboratories

Amylin Pharmaceuticals Inc

Bristol-Myers Squibb

Bayer Group

Eli Lilly and Company

F. Hoffman-La Roche Ltd

GlaxoSmithKline plc

Keryx Biopharmaceuticals

LifeScan Inc

Medtronic Inc.

Merck & Co.Inc

Novartis Pharmaceuticals

Novo Nordisk A/S

Pfizer

Sanofi-Aventis

Takeda Pharmaceutical Company Ltd

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Disadvantages:

(i) Delayed action


(ii) Irritant drugs can not be given
(iii) Some drugs are destroyed by gastro- intestinal enzymes ex. insulin, penicillin etc.
(iv) Absorption may be uncertain
(v) Cannot be administered to an unconscious patient
(vi) Cannot be given to patients having gastrointestinal upset such as diarrhea and
vomiting

Parenteral (Injection):

Routes of internal drug administration other than oral are called parenteral but it
generally refers to administration by injection

Disadvantages:
There is pain and chance of local sepsis and sometimes a risk of serious reactions and
even death especially from intravenous administration and moreover it is costly.
Technical skill & aseptic measures are necessary.

Intravenous Injection (I.V.):

Disadvantages:
(i) High skill & experience are necessary.
(ii) More chance of venous thrombosis, air embolism and death.
(iii) High aseptic measures are necessary

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Newer Drug Delivery System in Insulin

Oral Delivery

Insulin molecule is too large to be absorbed from gastrointestinal tract and is broken
down before it is absorbed. The possibility of delivering insulin orally is attractive, but is
often limited by poor bioavailability. The poor bioavailability of orally administered
insulin is attributed to its degradation or inactivation by presystemic metabolism due to
highly acidic gastric fluid, gastrointestinal pancreatic enzymes and intestinal proteolytic
enzymes .Furthermore, poor permeability of insulin across intestinal barrier adds a
detrimental impact on its oral absorption, thus making insulin inaccessible by this route.
It has been reported that only a very small fraction of an oral insulin dose becomes
available for absorption through the gastrointestinal membrane .A desire to deliver insulin
orally has prompted many scientists to explore the various possibilities of improving oral
bioavailability of insulin by in vitro and in vivo studies in animal models. In the last
several decades, various strategies have been employed to overcome the formidable
barriers of enzymatic digestion and poor absorption to improve permeability and to
facilitates absorption by concurrent administration with protease inhibitors and
entrapping insulin within Microparticles ,Liposomes ,Ethosomes ,and Nanoparticles etc.
Trotta et al., reported that solid lipid microparticles also appear to have interesting
possibilities as delivery systems for oral administration of insulin .The feasibility of using
liposomes as potential oral delivery systems for the systemic delivery of insulin has also
been studied. Moufti et al., were able to produce a 50% reduction in blood glucose levels
in normal rats by an insulin-containing Liposome. Dobre et al., also illustrated a lowering
of blood glucose levels in normal rats following the oral administration of insulin
entrapped in phosphatidylcholine/cholesterol liposomes. Preliminary studies with
plasmids and insulin revealed that the ethosomal carrier might be used for enhanced
delivery of these agents .Positive developments in coating soft gelatin capsules
containing insulin with enhancers and/or enzyme inhibitors like sodium salicylate and
sodium cholate have also been reported. The insulin nanoparticles might represent a
promising formulation for oral delivery of insulin when prepared by a water-in-oil-in-
water emulsification and evaporation method using blends of biodegradable poly-epsilon-
caprolactone and of Eudragis RS .A novel oral dosage formulation of insulin consisting
of a surfactant, a vegetable oil, and a pH-responsive polymer has been developed. The
insulin release from the resultant dry emulsion responded to the change in external
environment simulated by gastrointestinal conditions, suggesting that the new enteric-
coated dry emulsion formulation is potentially applicable for the oral delivery of peptide
and protein drugs .It is evident from these studies that the inclusion of
enhancers/promoters and/or enzyme inhibitors and other advancements do expedite the
diffusion of insulin molecule across the epithelial membrane, but achieving the higher
oral bioavailability still remains an unmet need.

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Pulmonary Administration

Pulmonary route is a non-invasive route for systemic delivery of proteins/peptides based


therapeutic agents because lungs provide a vast (50–140 m2, 500 million alveoli) and
well-perfused surface for absorption .This delivery of insulin may result in improved
patient compliance, may facilitate intensified therapies and avoid the delay of initiating
insulin administration because of patient’s reluctance .The inhalation of insulin was
conceptualized by the mid-1920s, but the first successful testing of inhaled insulin
occurred in the mid-1990s .Inhaled insulin appears to be suitable because of its better
bioavailability than oral insulin and a pharmacokinetic profile that mimics the time
kinetics of insulin secretion after a meal .Another advantage with lung as a site of drug
delivery is that it lacks peptidases that are present in the gastrointestinal tract and hepatic
"first pass metabolism" is also avoided. Moreover, very thin alveolar-capillary barrier
facilitates a rapid uptake of peptides in the bloodstream resulting in and a rapid onset of
action after inhalation .The use of enzyme inhibitors (proteases and peptidases) in
improving drug therapeutic activity through the lungs has also been reported .In addition,
some studies have concluded that a combined approach using absorption enhancers
(sodium glycocholate) with enzyme inhibitors (bacitracin and bestatin) can effectively
deliver insulin and salmon calcitonin via the lungs .Chitosan/tripolyphosphate
nanoparticles have been developed that promote peptide absorption across mucosal
surfaces .Recent clinical studies suggest a possible role for inhaled insulin in fulfilling
meal-related insulin requirements in persons with Type 1 and Type 2 diabetes .A new
drug delivery system, technosphere was developed to facilitate the absorption of
technosphere/insulin via pulmonary administration .Among various difficulties of the
pulmonary insulin delivery, the use of an effective promoter, which is capable of
increasing the bioavailability of insulin, is a crucial issue. The cost of such insulin
administration might also be a problem. Moreover, aerosol delivery requires six times as
much insulin for the same effective dose as subcutaneous injection, which may create a
cost barrier to widespread use. Also, the long-term safety of delivering large amounts of
insulin to the alveoli is not known. The careful studies concerning the safety of this kind
of administration, particularly potential long-term pulmonary toxicity, are mandatory
.Until recently, inhalation therapy focused primarily on the treatment of asthma and
chronic obstructive pulmonary disease, and the pressurized metered-dose inhaler was the
delivery device of choice. However, the role of aerosol therapy is clearly expanding
beyond that initial focus. This expansion has been driven by the Montreal protocol and
the need to eliminate chlorofluorocarbons from traditional metered-dose inhalers, by the
need for delivery devices and formulations that can efficiently and reproducibly target the
systemic circulation for the delivery of proteins and peptides .

Transdermal Delivery

The delivery of large peptides through the skin poses a significant challenge, and various
strategies are under active investigation for enhancing the transdermal permeation
.Transdermal iontophoresis is a physical enhancement strategy primarily for charged
molecules and offers a number of advantages for the delivery of peptides and proteins.
The singular advantage of iontophoresis lies in the precise control of dose by

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manipulating the current protocol. A low-level electrical current is used to enhance the
delivery of drug ions into the skin and surrounding tissues. The permeation of insulin was
found to increase as a function of current strength and duration of current application.
Skin barrier integrity and electrochemical stability of insulin was dependent on the charge
applied during iontophoresis .Iontophoretically delivered bovine insulin has been
observed to produce a concentration-dependent reduction in plasma glucose levels in
depilated diabetic rats .When carriers are employed to administer macromolecules
epicutaneously, the drugs must be associated with specifically designed vehicles in the
form of highly deformable aggregates and applied on skin non-occlusively .Using
optimized carriers, transfersomes, ensures reproducible and efficient transcutaneous
carrier and drug transport. Transfersomes transport the insulin with at least 50% of the
bioefficiency of a subcutaneous injection. The application of insulin-laden transfersomes
over a skin area 40 cm2 would provide the daily basal insulin needs of a typical patient
with type 1 diabetes .Insulin loaded transferosomes can deliver the drug through the non-
compromised skin barrier with a reproducible drug effect that resembles closely to that of
an ultra lente insulin injected under the skin. Transfersome mediated drug delivery
through the skin is little affected by the molecular size of the carrier associated active
ingredient. Skin penetration experiments done with transferosomes in vivo revealed that
the preferred path of the vesicle transport through the barrier always involves the regions
of lowest skin penetration resistance .The data also confirm the essential role of hydration
gradient across the skin that provides the necessary energy for the skin penetration by
transferosomes ,To further improve patient compliance, carrier-mediated transdermal
insulin and inhaled insulin ,offer an attractive combination for truly non-invasive diabetes
therapy. Transdermal insulin, which acts for at least 24 h after a single application ,could
become a replacement for basal insulin injections whereas inhaled insulin, with its fast
onset and relatively short duration of action ,could eliminate the need for preprandial
insulin injections. An ultrasound-mediated transdermal drug delivery offers a promising
potential for noninvasive drug administration.

The feasibility of low-cost, lightweight cymbal array for enhanced transdermal insulin
delivery using ultrasound has also been studied by Lee et al., .The skin poration with
acoustic ,electrical, photomechanical or thermal ,means can yield excellent delivery
results, but generally suffers from the problem of temporary barrier destruction and
potentiality of dermal immunization .

Intranasal Route

Nasal drug administration has been used as an alternative route for the systemic
availability of drugs, which were earlier, restricted to intravenous administration. Became
popular due to large surface area of nasal cavity, its porous endothelial membrane, large
blood flow, avoidance of hepatic first-pass metabolism and ready accessibility .The nasal
administration is quite an easy method for patients and most successful among all the
mucosal routes of drug delivery. McMartin et al., suggested that the nasal route is suitable
for the delivery of drugs with molecular weight less than 1000 Da without the aid of an
absorption enhancer and at least 6000 Da with the aid of absorption enhancer. Insulin
administered nasally is delivered rapidly that makes it useful for prandial administration

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.Significant bioavailability can be attained depending on the factors like dose, timing, and
frequency of insulin administration .Permeability enhancers may also be incorporated in
nasal formulations of insulin to augment the low bioavailability .Sucrose cocoate (SL-
40), ester containing a mixture of sucrose esters of coconut fatty acids in aqueous ethanol
solution, has also been emerged as an effective enhancer of nasal peptide drug absorption
.Several approaches have been discussed for increasing the residence time of drug
formulations in the nasal cavity, resulting in improved nasal drug absorption. The nasal
mucosa presents an ideal site for bioadhesive drug delivery systems. Bioavailability and
residence time of the drugs that are administered via the nasal route can be increased by
bioadhesive drug delivery systems. Drug delivery systems, such as microspheres,
liposomes and gels have been demonstrated to have good bioadhesive characteristics and
swell easily when in contact with the nasal mucosa .Since, nasal route is very sensitive to
irritation, therefore, the excipients and other material used to fabricate the system should
not have serious irritant or adverse effects .

Ocular Route

The eye presents unique opportunities and challenges when it comes to the delivery of
pharmaceuticals, and is most accessible to the application of topical medications. Insulin,
because of its high molecular weight, is one of the most challenging drugs to deliver
reproducibly via the ocular route .Eye drop formulations yielded only low bioavailability.
Viscous aqueous solutions, oil solutions, and emulsions can be drained from the eye by
the lachrymal system. Yamamoto et al., conducted an extensive study on eye drop
delivery in rabbits and suggested that an ocular insert would be another feasible approach
to prolong and thus enhance the delivery of insulin via the ophthalmic route. Simamora et
al., introduced an ocular insert for the delivery of insulin using Gelform® as a drug
carrier to deliver sodium insulin with the aid of Brij-78 as an absorption enhancer
.Conjunctival cul-de-sac has been targeted as potential route for insulin delivery. Factors
like local irritation, loss in drainage, blinking limits bioavailability of the drug through
this route. To overcome this limitation, novel polymeric systems are being investigated.
Permeation enhancers such as BL-9, Brij-78 and alkylpolysaccharides have been found to
be safe and stimulate systemic absorption of insulin .

Rectal Route

Insulin administered via rectum successfully avoids the hepatic first pass metabolism, is
independent of intestinal motility, gastric emptying time, and presence of diet and
encounters less degrading enzymes. Insulin is probably the most investigated polypeptide
with regard to rectal administration. Yamasaki et al., examined the effectiveness of
insulin administration by rectal suppository in normal and non-insulin dependent
nonobese diabetic subjects.100-IU insulin suppository 15 minutes after meals, three times
daily significantly reduced postprandial hyperglycemia and urine glucose .A thermo-
reversible insulin liquid suppository was developed, which was able to undergo a phase
transition to bioadhesive gels at body temperature and enhance the bioavailability of
insulin. It was concluded to have a potential to be developed as a more convenient, safe
and effective rectal delivery system of insulin .Ritschel et al., delivered insulin using

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rectal gels made of emulsion system prepared from pH 8 buffer solution containing
insulin, an oleaginous phase, a surfactant (bile salt) and viscosity enhancer .Water-in-oil-
in-water multiple emulsions incorporating 2% Docosahexaenoic acid or eicosapentaenoic
acid administered directly into the colonic and rectal loops dose dependently decreased
serum glucose levels. Insulin-loaded W/O/W multiple emulsions composed of medium-
chain triglycerides have been shown to decrease the blood glucose level after oral
administration to diabetic rats .

Vaginal/Uterine Route

Insulin delivery through vaginal mucosa also prevents presystemic degradation. Attempts
have been made with lysophosphatidylcholine-containing insulin as an aqueous solution
and as lyophilized powder with bioadhesive starch microspheres .Insulin has also been
administered through intrauterine delivery in rats and found to be absorbed in
biologically active form in the uterus of rats .

Buccal Route

Buccal or delivery into the mouth involves a device that delivers a spray of insulin, which
is absorbed in the lining at the back of the mouth and throat. It avoids problems from
putting large amounts of insulin in the lungs. Drugs are absorbed through thin mucosa
into the reticulated veins and enter into the systemic circulation directly, thus bypassing
the hepatic metabolism. Nagai and Machida have improved systemic bioavailability of
insulin by buccal delivery using sodium glycocholate as absorption promoter into a
mucosal adhesive delivery system .Xu et al., from the rabbit and rat experimental results
showed that insulin buccal spray, a formulation with soybean lecithin and propanediol
combined as absorption enhancer, is an effective buccal delivery system, which is
promising for clinical trial and the future clinical application .

Transmucosal Route

High vascularity, easy accessibility and absorptive mucosa make it a potential and
reliable route for insulin delivery. This route is also a noninvasive and bypass presystemic
metabolism. A Transmucosal insulin, Intesulin-A (Coremed) had extremely rapid insulin
peak absorption at 5 min and does not have sustained hyperinsulinemia . Intesulin-B (25
units insulin/ml, Coremed) shows extremely rapid insulin peak absorption at 5 min. in
both diabetic and non-diabetic rats. It lowers glucose linearly over many hours and has
profound hypoglycemic action .New transmucosal insulin,

Rectal delivery system for insulin.

The purpose of this investigation was to first screen for potential effectiveness several
rectal gels as insulin delivery systems and to select one promising dosage form as

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candidate for further evaluation in rabbits and man. Criteria for effectiveness were the
"pharmacologic availability", determined as the ratio between the total area under the
percent glucose reduction versus time curves upon rectal administration and the standard
(I.V. for rabbits and S.C. for man), the maximum reduction in glucose blood
concentration, the time to reach the maximum and the mean residence time of glucose
reduction. The rectal gels consisted of emulsion systems prepared from pH 8 buffer
solution containing insulin, an oleaginous phase, a surface active agent (bile salts, Myrj
or Brij), and a viscosity increasing agent. The finally selected rectal gel was tested in
rabbits both in a parallel and a crossover design in nondiabetic and diabetic animals. The
selected rectal gel in nondiabetic and diabetic rabbits resulted in a pharmacologic
availability of about 25%. By addition of Azone the pharmacologic availability was
further increased, although not significantly (small n). In nondiabetic man the
pharmacologic availability was about 32%, whereas the bioavailability (measured from
plasma insulin) was only about 11%. Drugs undergoing hepatic first-pass metabolism and
for which the liver is the biophase, should show increased pharmacologic availability
with decreased bioavailability (if the latter one is due to first-pass effect).

Eli Lilly offering up undercover insulin pen to US

"There's
already a bevy of devices out there designed to keep track and manage one's diabetes and
glucose levels, but Eli Lilly's innocuous pen-like injector looks to make the process of
taking insulin a bit less invasive. The Huma-Pen Memoir resembles your average ink pen
and shouldn't look too out of place holding it down in your tee's front pocket, but
whenever you need a shot of insulin, it conveniently turns into an injector thanks to the
hidden hypodermic needle encased within. The device also "allows the user to dial the
amount of insulin they need to take," and keeps the dosage, date, and time of the previous
16 shots in order to keep diabetics from overdosing. Users should be able to utilize the
same pen for "around three years," and after a needle is used, another is inserted and
ready to go at the owners request. A few lucky participants have already received their
pen here in the US, and while this nifty invention has been available across Europe for
some time now, it will officially hit American retail shelves next week for around

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SUMMARY

(1) Nowadays diabeties is growing rapidly. So the use of insulin is increasing


all over, due to which the use of novel drug delivery system of insulin is
increasing.

(2) In the given seminar we have seen the physiology of insulin then we have
seen the types of diabeties . we have 2 types of diabeties ie type1& type2.
(3) In type 1 we have seen the symptoms , causes, diet , high glucose level , low
glucose level , diagnoses , treatment.

(4) In type 2 we have seen the action of insulin ie long acting, short acting,
intermediate acting , rapid acting. The site of insulin action, angle of
injection.

(5) Routes of dilevery system on insulin.

1 Ocular routes
2 Transdermal routes
3 Implants
4 Nasal routes
5 Rectal routes
6 Vaginal routes
7 Oral routes
8 Pulmonary routes
9 Buccal routes
10 Transmucal routes

Gadget used in delivery of insulin


1 Insulin pumps
2 Exubera
3 Glucometer
4 Insulin pen
5 Bang & olufen c-cap
6 Ipod \ pager

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CONCLUSION:

WE HAVE STUIDED THE PHYSIOLOGY OF INSULIN .WE HAVE ALSO THE


MEDICAL BIOLOGY ON INSULIN RESISTSNCE, STRUCTUER OF INSULIN
IN THAT WE HAVE SEN ATTACHMENT OF CARBON, HYDROGEN, OXYGEN
AND NIOTROGEN BONDS WE HAVE ALSO SEEN 3D STRUCURE OF
INSULIN DIMER AND INSULIN HEXAMER. WE HAVE ALSO STUDIED THE
ACTION OF INSUIN ON CELLULAR ON METABLIC LEVEL. WE HAVE
DONE TYPE1 & TYPE2 TYPE OF DIABETES. IN TYPE 1 WE HAVE SEEN THE
SYMPTONS, CAUSES, DIAGNOSIS, TREATMENT AND DIET. IN TYPE 2 WE
HAV SEEN TYPES OF INSULIN ACTION i.e RAPID ACTING, SHORT ACTING,
INTERMDITE ACTING, LONG ACTING WITH THEIR APPEARANCE ONSET
OF ACTION PEAK TIME DURATION OF ACTION AND THE DRUGS WHICH
CAN BE COMBINED WITH THEM .IN TYPE 2 WE HAVE SEEN SITE OF
DRUGNACTING AND TECHNIQUE OF INJECTING INSULIN WE HAVE SEEN
DISADVANTAGE OF INSULIN.WE HAVE SEEN VARIOUS DELIVRY SYSTEM
OF INSULIN i.e TRANSDERMAL, VAGINAL, RECTAL, NASAL, OCCULAR.
WE HAVE ALSO STUDIED VARIOUS GADGETS USED IN NDDS OF INSULIN
ie PUMPS, PENS,C-CAP MACHINE etc. THE COMPANIES WHICH PREPARE
NOVEL DRUG DELIVERY SYSTEM ON INSULIN.

41 V.M.H.P.S. COLLEGE OF PHARMACY


NDDS OF INSULIN

ROLE OF PHARMACIST
• A PHARMACIST SHOULD KNOW EVERY THING ABOUT DIABETIES &
INSULIN.
• PHARMACIST SHOULD HAVE KNOWLEDGE ABOUT THE VARIOUS
TECHNIQUE OF ADMINISTRATION OF INSULIN.
• PHARMACIST SHOULD HAVE KNOWLEDGE ABOUT VARIOUS
GADGETS USED IN DELIVERY OF INSULIN & WORKING OF EACH
GADGET.
• PHARMACIST SHOULD KNOW ABOUT THE DOSE OF INSULIN GIVEN
TO PATIENTS AS PER AGE, SEX, BODY WIGHT.
• PHARMACIST SHOULD GIVE COMPLETE KNOWLEDGE OF INSULIN
& ITS DEVICES ADMINISTRATION TECHNIQUE TO THE PATIENT.
• PHARMACIST SHOULD KNOW THAT WICH DRUG SHOULD BE GIVEN
& WHAT IS THE TECHNIQUE OF DELIVERY OF THAT DRUG.
• PHARMACIST SHOULD KNOW THE PROPER COMBINATION OF
DRUG, SO THAT IT GIVES QUICK AND GOOD RESULT TO THE
PATIENT.

42 V.M.H.P.S. COLLEGE OF PHARMACY