Transcript INTRAUTERINE DRUG DELIVERY SYSTEMS Dr. Basavaraj K. Nanjwade M. Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnatka, India. E-mail: [email protected] Cell No: 00919742431000 KLE College of.

INTRAUTERINE DRUG DELIVERY
SYSTEMS
Dr. Basavaraj K. Nanjwade M. Pharm., PhD
KLE University College of Pharmacy
BELGAUM-590010, Karnatka, India.
E-mail: [email protected]
Cell No: 00919742431000
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CONTENTS
 Anatomy of uterus.
 Development of IUDs.
 Types of IUDs.
 Copper bearing IUDs.
 Hormone releasing IUDs.
 References
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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.
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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.
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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.
bearing IUDs, such as Cu – 7, and
progesterone releasing IUDs, such as Progestasert
(approve by US FDA in 1976), thus evolved.
 Copper
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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.
Medicated IUDs:

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.
2. Hormone releasing IUDs.
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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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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
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 :





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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.
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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.
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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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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
1.1
120
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 Controlled Drug
Delivery, Vol-I, pg.no.365-370.
 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: [email protected]
Cell No: 00919742431000
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KLE College of Pharmacy, Nipani
28th December2012