INTRAUTERINE DRUG DELIVERY

SYSTEMS
Dr. Basavaraj K. Nanjwade

M. Pharm., PhD

KLE University College of Pharmacy

BELGAUM-590010, Karnatka, India.
E-mail: nanjwadebk@gmail.com
Cell No: 00919742431000

KLE College of Pharmacy, Nipani

28th December2012

CONTENTS
Anatomy of uterus.
Development of IUDs.
Types of IUDs.
Copper bearing IUDs.
Hormone releasing IUDs.
References

KLE College of Pharmacy, Nipani

28th December2012

ANATOMY OF UTERUS
The uterus is a pear shaped,

thick-walled, muscular organ

suspended in the anterior wall
of pelvic cavity.
In its normal state, it measures
about 3 inches long and 2
inches wide.
Fallopian tubes enter its upper
portion, one on each side, and
the lower portion of the uterus
projects into the vagina.
The uterine cavity is normally
triangular in shape and
flattened antero- posteriorly.
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The wall of the uterus consists of 3 layers

1.

Endometrium- Inner coat of the uterine wall and is a mucous

membrane. Consists of epithelium lining and connective tissue.
Two types of arteries supply blood to the endometrium- straight
arteries supply the deeper layer; the coiled arteries supply the
superficial layer.

2.

Myometrium- Thick, muscular middle layer made up of bundles

of interlaced, smooth muscle fibers emmbeded in connective
tissue. It is Sub-divided into 3 ill-defined, intertwining muscular
layers containing large blood vessels of uterine walls.

3.

Peritoneum- External surface of the uterus, which is attached to

the both sides of the pelvic cavity by broad ligaments through
which the uterine arteries cross.

KLE College of Pharmacy, Nipani

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Intra Uterine Device (IUD)

It is a small object that is inserted through the cervix and placed in

the uterus to prevent pregnancy.

A small string hangs down from the IUD into the upper part of the

vagina. The IUD is not noticeable during intercourse.

IUDs can show pharmacological efficacy for about 1-10 years.

They work by changing the lining of the uterus and fallopian tubes
affecting the movements of eggs and sperm and so that fertilization
does not occur.

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Location of IUD
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Development of IUDs
Development of IUDs began in the 1920s, with the first

generation of IUDs constructed from silkworm gut and

flexible metal wire. Eg-Grafenberg star and Ota ring.
Fell into disrepute because of the difficulty of insertion,
the need for frequent removal as a result of pain and
bleeding.
Subsequently, plastic IUDs of varying shapes and sizes
were made available.
Various inert, biocompatible, polymeric materials such
as polyethylene, EVAc, and silicone elastomer were
widely used to construct IUDs.
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Development of IUDs
These devices cause more endometrial compression and

myometrial distension, leading to

bleeding,expulsion of IUDs.

uterine cramps,

Researchers developed IUDs in last 30 years with aim - to

add antifertility agents to more tolerated, smaller devices,

such as the T-shaped device, to enhance effectiveness; or
antifibrinolytic agents, such as e-aminocaproic acid and
tranexamic acid to larger IUDs to minimize the bleeding
and pain.

Tatum developed a T shaped device to confirm better to

the contours of uterus. This reduced side effects

significantly.

KLE College of Pharmacy, Nipani

28th December2012

Development of IUDs
Zipper 1968 added contraceptive metals (Cu) and

Doyle and Clewe developed progestin releasing

IUD.

This development initiated a new era of R & D for

long term I. U. contraception, leading to generation of

recent IUDs the medicated IUDs.

Copper

bearing IUDs, such as Cu 7, and

progesterone releasing IUDs, such as Progestasert
(approve by US FDA in 1976), thus evolved.

KLE College of Pharmacy, Nipani

28th December2012

Types of IUDs
A.

Non- medicated IUDs:

These IUDs exert their contraceptive action by

producing a sterile inflammatory response in the
endometrium by its mechanical interaction.

These do not contain any therapeutic agent.

e.g. ring shaped IUDs of s.s., plastic IUDs, lippes loop,

Dalkon shield, Saf-T-Coil.

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Types of IUDs
B.

These
IUDs
are
capable
of
delivering
pharmacologically active antifertility agents.

e.g. copper bearing IUD, progesterone releasing IUD.

There are two types of medicated IUDs:-

1.

Copper bearing IUDs.

Hormone releasing IUDs.

2.
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Medicated IUDs:

KLE College of Pharmacy, Nipani

28th December2012

1. Copper bearing IUDs:

This device uses copper wire

wound to the stem.

The device is made of T shaped

polyethylene plastic.
There are various grades as per

the surface area of the Cu-wire

such as Cu-T-30, Cu-T-200, CuT-380.

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KLE College of Pharmacy, Nipani

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Antifertility Action of Copper

In high concentration copper is cytotoxic. It enhance

the spermatocidal and spermato depressive action of

an IUD.

Cupric ion (Cu++) is a competitive inhibitor of

progesterone and to lesser effect estrogen.

Evoke

sterile
endometrium.

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inflammatory

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response

in

the

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Release of Copper from the device

The release is linear, by chelation, ionization, and

corrosion over the period of 12 years.

Release rate is directly proportional to the surface

area of exposed Cu.

An exposed surface area of 375sq mm releases

37.5mcg/day.
e.g. Cu-T-380A (Population council),
Nova-T (Leiras), Multiload (Multilan)

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Release of Copper from the device

The current version of Cu T IUD is Paragaurd T 380A

(Ortho-Mcneil,USA) has 380sqmm of surface area.

Composed fo polyethylene T with 176mg Cu wire on

stem and 66.5mg on the arms.

Approved by FDA for 10 year use.
The Cu T 380 Ag IUD (Leiras) differs only at Cu has
Ag core that slows the corrosion rate.
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Release of Copper from the device

The Cu-7 (G. D. Searle & Co.) first Cu bearing IUD

approved by USFDA for 3-year use.

Each unit is a propylene plastic device shaped like 7

with 89 mg Cu wire having thickness 0.2-0.4 mm,

surface area 200 sq mm. it releases mean daily dose of
9.87 mcg/day for 40 months.
Advantages : small size, easy insertion, painless removal,

sustained.
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Cu-T-200 and Cu-T-380A:

Difference being Cu located in the transverse arm,

which is in close contact with fundus.

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Multi load Cu IUD

Surface area of 250 sq mm, blunt apex fits in the vault of

uterine cavity.

Low expulsion rates.

Various surface areas such as 250 minimum, 325 medium , 375

large, as per uterine capacity.

Releases Cu for about 5 years at rate of about 2.5 mcg/day.

Tissue compatibility improved by hydrogel coat.

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Multi load Cu IUD

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Side effects
Menstrual problems. About 12% of women have the Copper

T 380-A IUD removed because of increased menstrual

bleeding or cramping.
Perforation. In 1 out of every 1,000 women, the IUD will

get stuck in or puncture (perforate) the uterus. Although

perforation is rare, it almost always occurs during insertion.
Expulsion. About 2% to 10% of IUDs are expelled from the

uterus. This usually happens in the first few months of use.

Expulsion is more likely when the IUD is inserted right after
childbirth or in a nulliparous woman.
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2. Hormone releasing IUDs

Doyle and Clewe first initiated the use of hormone

releasing IUDs.
Scommegna et al in 1970 carried human testing using

conventional IUD having contraceptive steroids.

A T-shaped progesterone releasing IUD having

vertical limb embedded with drug-containing silicone

capsule was evolved.
Coated with polymer for achieving slower release.
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2. Hormone releasing IUDs

Progestasert :

a novel progesterone releasing IUD.

The device has a solid poly EVA side arms and a hollow
core. The microcrystalline progesterone is suspended in the
core in the silicone oil with Barium sulphate.
Dimensions-0.25mm thick, release by diffusion through rate
limiting membrane.
Loaded with 38mg of Progesterone, release rate 65 mcg/day
Approved by USFDA in 1975 for 12 month contraceptive
use.
Pregnancy rate 1.8/100 for parous women and 2.5/100 for
nulliparous women.
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2. Hormone releasing IUDs

Does

not inhibit ovulation but interfere with

implantation in endometrium, thickening of cervical
mucus.
Advantages :

Increased effectiveness, lower menstrual blood flow,

decreased dysmenorrhea.
Disadvantages:

Need to be replaced yearly, intermenstrual bleeding,

ectopic pregnancies.
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Antifertility action of
progesterone releasing IUDs

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1.

They diminish sperm transport through the cervix

to the oviduct by increasing the thickness of the
cervical mucous.

2.

Steroid releasing devices induce progestational

changes that result in endometrial gland atrophy
and inhibit further development of the ova.

KLE College of Pharmacy, Nipani

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Antifertility action of
progesterone releasing IUDs

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3.

Endometrial hypermaturation is unfavorable for

implantation of a blastocyst. This is associated with
decidual formation induced by progesterone.

4.

Effect of estrogen-progesterone system is related to

the presence of a membrane electrical potential that
inhibits the ovum-endometrium contact before the
occurrence of implantations.
KLE College of Pharmacy, Nipani

28th December2012

Biopharmaceutics of intrauterine
progesterone administration
Intrauterine administration was compared with oral

delivery and subcutanous injection. Progesterone

administered I U shows 45 times greater
bioavailability than the other 2 routes.

Apparently the endometrium tissue is extremely

effective for progesterone absorption.

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KLE College of Pharmacy, Nipani

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Clinical effectiveness
Contraceptive efficacy

was related with daily dose of

progesterone release from device.

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Dose
mcg/day
10

%
pregnancy
5.2

25

2.7

65
120

1.1
0.6
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Levonorgesterol releasing IUD

These carry levonorgestrel releasing device [MIRENA].

It is an intrauterine system (LNg-IUS) that has sleeves of

levenorgestrel 52 mg around its stem.
It is composed of a polyethylene stem covered by matrix
Silastin:LNg (2:1) and side arms.
Releasing 20 mcg/day and lasting for at least 5 years.
Initial fast release then at 60 % drug release rate reduces
to 16mcg/day.
Suppresses endometrium and ovulation.
Also, unlike other IUDs, it may reduce the risk of Pelvic
inflammatory disease.
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Mode of action
Prevents fertilization by damaging or killing sperm

and making the mucus thick and sticky, so sperm can't

get through to the uterus.
It also keeps endometrium from growing very thick,

making lining a poor place for a fertilized egg to

implant and grow.
It may relieve irregular menstrual bleeding and

cramping.
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Disadvantages of LNg IUD :

It may cause noncancerous (benign) growths called

ovarian cysts, which usually go away on their own.

It can cause hormonal side effects, such as breast

tenderness, mood swings, headaches, and acne.

When side effects do happen, they usually go away
after the first few months.
And general side effects associated with IUDs.

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References
Y.W.Chein; Novel Drug Delivery Systems, 2nd ed.,

vol.50, pg.no.585-629.
Mathiowitz,

Encyclopedia of
Delivery, Vol-I, pg.no.365-370.

Controlled

Drug

N.K. Jain, Advances in Controlled and Novel Drug

Delivery, 1st ed, pg.no.585-625.

www.wikipedia.com
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E-mail: nanjwadebk@gmail.com
Cell No: 00919742431000
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KLE College of Pharmacy, Nipani

28th December2012