Intrauterine Drug Delivery System – Intra Uterine Devices

Intrauterine Drug Delivery System

Intra Uterine Devices

CONTENTS

v  Introduction

Ø  Contraception

Ø  Anatomy
of uterus

Ø  Menstrual
cycle

Ø  Desirable
features of intra vaginal DDS

v  IUD’S

v  Development
of IUD’s

v  Types
of IUD’s

1)      non
medicated

2)      medicated         

a) Copper bearing IUD

              b)
Hormone releasing IUD

TERMS

CONTRACEPTION: (def)

Ø  It
is the method which results into temporary or permanent loss of capability to
reproduce or conceive a young one.

Ø  In
simple words it is the opposite of conception.

Ø  There
are 2 types of contraception: Temporary and permanent.

Ø  Temporary
contraception: It is a method or lifestyle that ensures reversible
infertility for stipulated period of time depending on the subject. e.g. IUD’s,
oral contraceptive pills, condoms etc

Ø  Permanent
contraception: It is the method or technique adopted to give lifelong
acquired inability to reproduce, but it is not the loss of sense or loss of
sexual desire.

Ø  e.g.
ovarectomy, uterectomy, vasectomy, etc.

Anatomy of uterus

l 
The
uterus is a pear shaped, thick-walled, muscular organ suspended in the anterior
wall of pelvic cavity.

l 
In its
normal state, it measures about 3 inches long and 2 inches wide.

l 
Fallopian
tubes enter its upper portion, one on each side, and the lower portion of the
uterus projects into the vagina.

l 
The
uterine cavity is normally triangular in shape and flattened anterio-posteriorly.

The wall of the uterus consists of 3 layers:

1. Endometrium– Inner
coat of the uterine wall and is a mucous membrane. It consists of epithelium lining
and connective tissue.  Epithelium
consists of non-cornified stratified sqamous epithelium, and lamina propria.

Squamous epithelium sub-divided into 4 layers:  Superficial – large, flat cells.

Intermediate – larger flatter nucleated cells Parabasal –
polyhedral cells

Monolayer – cuboidal basal cells closely opposed to basement
membrane.

Connective tissue consists of two types of arteries which
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.

MENSTRUAL CYCLE

Human female’s fertility period, extends from puberty at
about 13 years to about 45-50 years. The menstrual cycle consists of 3 phases:

l  Follicular
or proliferating phase

l  Luteal
or secretory phase

l  Menstrual
or bleeding phase

FOLLICULAR PHASE

1. It
   lasts for 14 days.
2. Follicle
   stimulating hormone (FSH) stimulates the growth of ovarian follicle and
   maturation of the primary oocyte in this follicle.
3. FSH
   stimulates the follicles to secrete estradiol which on attaining a certain
   concentration in blood inhibits FSH secretion and stimulates Leuteinising
   hormone (LH) secretion.

4. The LH induces
   the Graafian follicle to burst and eject its eggs into the fallopian
   tube,a process called ovulation.

5. Estradiol
   also stimulates the uterus to prepare for the implantation nourishment of
   the foetus likely to arrive after ovulation.
6. Vascularization
   of uterus increases and the lining of fallopian tubes is thickened. The
   ciliary movements also increase and prepare the fallopian tubes to convey
   the ovum to the uterus.

LUTEAL PHASE

1. It
   lasts for 10 days
2. High
   levels of LH and prolactin hormone stimulate follicular cells of empty
   graafian follicle to form yellow colour body called corpus luteum, which
   in turn secretes progesterone.

3. Progesterone
   regulates the hypertropy of endometrium for proper implantation of foetus.

4. Luteal
   phase stimulates the endometrial glands to secrete a nutriant fluid for
   the foetus, hence it is called the secretory phase.

MENSTRUAL PHASE

1. If
   fertilization does not occur, high concentration of progesterone in blood
   inhibits the release of LH.
2. Reduction
   in LH levels leads to the degeneration of corpus luteum and a consequent
   fall in progesterone level in blood.
3. The
   uterine lining dies due to deficiency of progesterone and is sloughed off.
   Blood vessels rupture, causing bleeding, this process is called the
   menstrual flow and continues for 3-5 days.
4. The
   basal part of the endometrium remains intact for next cycle.
5. Lowered
   levels of progesterone and estradiol due to degeneration of corpus luteum
   causes the release of FSH which initiates new cycle.

DESIRABLE FEATURES OF
VAGINAL D D S

l  Functionally
effective and aesthetically pleasing to the patient.

l  The
system must be non-irritant and non-interfering with normal physiological
processes.

l  Sustained
release for chronic treatment.

l  Commercially,
cost should be low and manufacturing should be easy.

INTRA UTERINE DIVICES
(IUD’s)

DEFINITION

l  IUD’s
are medicated devices intended to release a small quantity of drug intouterus
in a sustained manner over prolonged period of time.

3 most popular methods:

l  Oral
contraceptive pills

l  Condoms
or diaphragms

l  Intrauterine
device

An Intrauterine Device (IUD) 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.

IUD’s can show pharmacological efficacy for about 1-10
years.

M O A: 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.

Development of IUD’s

Development of IUD’s began in the 1920s, with the first
generation of IUD’s 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 IUD’s of varying shapes and sizes were
made available.

Various inert, biocompatible, polymeric materials — such as
polyethylene and silicone elastomer — were widely used to construct IUD’s.

These devices cause more endometrial compression and
myometrial distension, leading to uterine cramps, bleeding, and expulsion of
IUD’s.

Researchers developed IUD’s 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 IUD’s to minimize 
the bleeding and pain.

Tatum developed a T – shaped device to confirm to the better
contours of uterus. This reduced side effects significantly.

Zipper 1968 added contraceptive metals (Cu) and Doyle and
Clewedeveloped progestin – releasing IUD’s.

This development initiated a new era of R & D for long
term I.U

•       contraception,
leading to generation of recent IUD’s– the medicated

•       IUD’s.

Copper bearing IUD’s, such as Cu – 7 and progesterone
releasing IUD’s such as Progestasert thus evolved.

LOCATION OF IUD

TYPES OF IUD

a) Non-medicated IUD’s:

These IUD’s 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 IUD’s plastic IUD’s, lippes loop, Dalkon
shield, Saf-  T-Coil.

b) Medicated IUD’s:

These IUD’s are capable of delivering pharmacologically
active antifertility agents.

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

Non – medicated IUD’s

These IUD’s do not contain any therapeutically active agent.

These prominantly make use of metal or plastic rings and
coils.

e.g. Dalkon shield, Lippes loop, Saf – T- coil.

Rings of stainless steel have mechanical effects on the
uterus leading to contraception.

Plastic rings also act as mechanical barrier for sperms and
eggs so they don’t fuse.

Plastic rings are made from sterile materials such as
polyethylene and polypropylene

Non medicated IUD’s
have vanished from market.  Because of
one or more following reasons:

l  Newer
devices that are safer and effective.

l  Irregularities
in menstrual bleeding.

l  Discomfort
and lower patient compliance

l  Cases
of pelvic inflammatory diseases (PID).

l  They
show higher rates of pregnancies.

Medicated IUD’s:

v  Copper
bearing IUD’S

v  Hormone
releasing IUD’S

1) COPPER BEARING IUD’s

•       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, Cu-T-380

•       Cytotoxic

•       Low
conc.- Spermatocidal & Spermatodepressive

•       Contraceptive
Effectiveness is more.

•       Pregnancy
rate –reduced to 5%

•       e.g.        cu –T-200, cu-T-30, cu-T-380, Cu-T-220

•       Copper
wire thickness –0.2-0.4 mm

Mechanism of action

Clinical effectiveness of
Cu-T and Cu-7

Antifertility Action of Copper

l  In
high concentration copper is cytotoxic. It enhance the spermatocidal and
spermato- depressive action of an IUD.

l  Cupric
ion (Cu++) is a competitive inhibitor of progesterone and to lesser effect
estrogen.

l  Evoke
sterile inflammatory response in the endometrium.

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.

•       e.g.
Cu-T-380A

•       It
has a surface area of 380 sq.mm

•       Composed
of 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 differs only at Cu has Ag core that slows the corrosion rate.

Side effects

n  Menstrual
problems. About 12% of women have the Copper T 380-A IUD removed because of
increased menstrual bleeding or cramping.

n  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.

n  Expulsion.
About 2% to 10% of IUD’s 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 (a woman who has never given birth to a child
before).

2) HORMONE
RELEASING IUD’s

n  Doyle and Clewe first initiated the use of
hormone releasing IUD’s.

n  Scommegna et al in 1970 carried human testing
using conventional IUD having
contraceptive steroids.

n  A T-shaped progesterone releasing IUD having
vertical limb embedded with drug-containing silicone capsule was evolved.

n  Coated with polymer for achieving slower
release.

Objectives

n  Enhance
uterine retension

n  Show
slowly releasing steroids

n  e.g.
Melengestrol acetate.

Formulation:

n  Suspension
of Progesterone microcrystal àSilicon
medial fluid à Ethylene-
Vinyl acetate copolymer (EVA)

n  Release
rate-65 mg/ day for one year.

Progesteron releasing IUDs

Progestesert :

n  A novel progesterone (pg) releasing IUD.

n  The
device has a solid poly EVA (ethyl vinyl acetate) side arms core in the silicone oil with BaSo4.

n  Dimensions-0.25mm
thick, pg is released by diffusion through rate limiting membrane.

n  Loaded
with 38mg of Pg, release rate is 65 mcg/day

n  Approved
by USFDA in 1975 for 12 month contraceptive use

n  Preg.
Rate 1.8/100 for parous and 2.5/100 for nulliparous.

n  Does
not inhibit ovulation but interfere with implantation in endometrium,
thickening of cervical mucus.

n  Intrauterine
administration was compared with oral delivery and sub-cutanous injection.
Progesterone administered I U shows 45 times greater bioavailability than the
other 2 routes.

n  Apparently
the endometrium tissue is extremely effective for progesterone absorption.

Advantages:

Increased effectiveness, lower menstrual blood flow, and
decreased dysmenorrhea.

Disadvantages:

Need to be replaced yearly, intermenstrual bleeding, ectopic
pregnancies?

38 mg of
progesterone microcrystals (and barium sulfate) suspended in silicone oil

Antifertility action of progesterone
releasing IUDs:

They diminish sperm transport through the cervix to the
oviduct by increasing the thickness of the cervical mucus.

Steroid releasing devices induce progesteronal changes that
result in endometrial gland atrophy and inhibit further development of the ova.

Endometrial hypermaturation is unfavorable for implantation
of a blastocyst. This is associated with decidual formation induced by
progesterone.

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.

Levonorgesterol releasing
IUD

n  These
carry levonorgesterol releasing device. It is an intrauterine system that has
sleeves of levonorgesterol 52 mg around its stem.

n  It
is composed of a polyethylene stem covered by matrix Silastin: LNg (2:1).

n  Releasing
20 mcg/day and lasting for at least 5 years. Initial fast release then at 60 %
drug release rate reduces to 16mcg/day.

n  Suppresses
endometrium and ovulation.

n  Also,
unlike other IUDs, it may reduce the risk of (PID).

Mode of action :

n  Prevents
fertilization by damaging or killing sperm and making the mucus thick and
sticky, so sperm can’t get through to the uterus.

n  It
also keeps endometrium from growing very thick, making lining a poor place for
a fertilized egg to implant and grow.

n  It
may relieve irregular menstrual bleeding and cramping.

Disadvantages of LNg IUD

n  It
may cause noncancerous (benign) growths called ovarian cysts, which usually go
away on their own.

n  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.

Contraindications

•         
pregnancy

•         
puerperal sepsis or immediate post septic  abortion

•         
distorted uterine cavity (congenital or
acquired)

•         
unexplained vaginal bleeding

•         
suspected genital malignancy

•         
genital tuberculosis

•         
active Pelvic Inflammatory Disease (PID)

WHAT ARE THE ADVANTAGES OF
AN IUD?

•         
Copper T 380 A IUD (ParaGard) is effective for
at least 12 year

•         
Copper T IUD (ParaGard) and Levonorgestetrel IUD
(Mirena) are the two most effective reversible methods of birth control.

• Only
  1 out of 100 women using a Copper T for 12 years will become pregnant.

• The
  copper IUD prevents ectopic pregnancies.
• This
  contraceptive is very cost effective (inexpensive) over time.
• Use
  of an IUD is convenient, safe & private.
• All
  you have to do is check for the strings each month.
• The
  ParaGard IUD may be used by women who cannot use estrogen–containing birth
  control pills, patches or vaginal ring including breastfeeding women.
• The
  IUD may be inserted immediately following the delivery of a baby or
  immediately after an abortion.
• Some
  studies of IUDs have shown a decreased risk for uterine cancer. There is
  also some evidence that IUDs protect against cervical cancer.

WHAT ARE THE DISADVANTAGES OF AN IUD?

l  There
may be cramping, pain or spotting after insertion.

l  The
number of bleeding days is slightly higher than normal and you may have
somewhat increased menstrual cramping. If your bleeding pattern is bothersome
to you, contact your doctor. There are medications which may give you a more
acceptable pattern of bleeding and cramping.

l  The
IUD provides no protection against sexually transmitted infections. Use condoms
if there is any risk.

l  There
is a higher initial cost of insertion. However, after 2 years, it is the most
cost-effective contraceptive method.

l  The
IUD must be inserted by a doctor, nurse practitioner, nurse midwife or
physician’s assistant.

l  A
very small percentage of women are allergic to copper.

l  A
small percentage of IUDs may be expelled by a woman’s body within the first few
months due to an improper fit.

For Image Based Detailed PDF Notes Click on Download Button