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. KLE College of Pharmacy, Nipani 28th December2012

The wall of the uterus consists of 3 layers 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. 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. 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 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

Location of IUD KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

Development of IUDs These devices cause more endometrial compression and myometrial distension, leading to uterine cramps, bleeding,expulsion of IUDs. 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 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. KLE College of Pharmacy, Nipani 28th December2012

Types of IUDs Medicated IUDs: Copper bearing 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:- Copper bearing IUDs. Hormone releasing IUDs. KLE College of Pharmacy, Nipani 28th December2012

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, Cu- T-380. 28th December2012 KLE College of Pharmacy, Nipani

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 inflammatory response in the endometrium. KLE College of Pharmacy, Nipani 28th December2012

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) KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

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. 16 28th December2012 KLE College of Pharmacy, Nipani

Cu-T-200 and Cu-T-380A: Difference being Cu located in the transverse arm, which is in close contact with fundus. 17 28th December2012 KLE College of Pharmacy, Nipani

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. KLE College of Pharmacy, Nipani 28th December2012

Multi load Cu IUD KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

Antifertility action of progesterone releasing IUDs They diminish sperm transport through the cervix to the oviduct by increasing the thickness of the cervical mucous. Steroid releasing devices induce progestational changes that result in endometrial gland atrophy and inhibit further development of the ova. KLE College of Pharmacy, Nipani 28th December2012

Antifertility action of progesterone releasing IUDs 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. 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. KLE College of Pharmacy, Nipani 28th December2012

Clinical effectiveness Contraceptive efficacy was related with daily dose of progesterone release from device. Dose mcg/day % pregnancy 10 5.2 25 2.7 65 1.1 120 0.6 27 28th December2012 KLE College of Pharmacy, Nipani

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. KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

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. KLE College of Pharmacy, Nipani 28th December2012

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 KLE College of Pharmacy, Nipani 28th December2012

E-mail: nanjwadebk@gmail.com Cell No: 00919742431000 KLE College of Pharmacy, Nipani 28th December2012