INTRAUTERINE DRUG DEVICES

1. PRINCE SATTAM BIN ABDUL AZIZ UNIVERSITY COLLEGE OF PHARMACY INTRAUTERINE DRUG DEVICES • PHARMACEUTICS- IV • (PHT 414 ) • Dr. ShahidJamil

2. INTRODUCTION CONTRACEPTION: • Contra-opposite/ prevent • Ception- conception (union of male & female gamates to reproduce new ones) • It is the method or technique or process which results into temporary or permanent loss of capability to reproduce or conceive a young one. • Three most popular methods of contraception: • Oral contraceptive pills • Condoms or diaphragms • Intrauterine device (IUD)

3. Intra-uterine devices • DEFINITION IUD’s are medicated devices intended to release a small quantity of drug into uterus in a sustained manner over prolonged period of time.

4. TYPES OF IUD’S • NON MEDICATED: • Ring shaped iud’s made of stainless steel which haven used by 50 millions women in china . • Plastic IUDS : Fabricated from polyethylene or polypropylene which are sold in Asia, south Africa ,south America. • Lippes loop iud & Saf -T-coil is still available commercially in US. • MEDICATED: • Copper bearing IUD E.g. cu 7, CuT-380 • Progesterone releasing IUDS e.g., Progestasert

5. Development of iud’s • 1920- First generation IUD’s • Constructed from silkworm gut & flexible metal wire Eg. Grafenberg star & Ota ring • Decline in popularity- • Difficulty in insertion • Need for frequent removal- pain & bleeding • Other serious complications

6. Development of iud’s • Then- • Several Plastic based IUD’s of varying sizes & shapes were prepared using inert biocompatible polymers like- • Polyethylene • Polypropylene • Ethylene-vinyl acetate copolymers • Silicon Elastomer

7. Development of iud’s • Modern Era- development of • Margulies- Plastic spirals • Lippes- Loop • Dalkon shield IUD • Efficacy of these IUD’s was proportional to their surface area that is in direct contact with endometrium. • Larger IUD’s were more effective but expulsion rate is high as these produce- • Endometrial Compression • Myocardial Distention • Uterine cramps • Bleeding

8. Development of iud’s • Tatum & Zipper (1967) develop T- Shaped polyethylene device. • This significantly reduce side effects • Pregnancy rate become to 18% • Good Uterine tolerance • Non-medicated IUD’s- • Act through mechanical contact with endometrium • Size is important factor • Large size produce irritation & other side effects • High expulsion rate • No improvement in contraception efficacy. • Starting of new era- • As this devices acts as carrier of choice for intrauterine delivery of contraceptive agents.

9. Development of medicated (copper bearing) iud’s • 1969 • Zipper et. al. reported- copper attached to an IUD markedly enhanced the effectiveness. • T-shaped polyethylene device wound with 30 mm2 copper wire (Cu-T-30) • The pregnancy rate was reduced to 5% from 18%. • Additional clinical evaluations with larger surface area of copper wire • 200 mm2 – found maximum contraceptive efficiency.

10. Copper bearing iuds: • The device is made of T shaped polyethylene plastic. • This device uses copper wire wound to the stem of T. • Grades as per the surface area of wire • Cu-T-30, • Cu-T-200, • Cu-T-380.

11. Anti-fertility action of copper • Cytotoxic, Spermatocidal & spermato-depressive action • Competitive inhibitor of steroid-receptor interaction. Eg. Cupric ions –Potent inhibitor • 17 estradiol & Progesterone binding to their receptors. • Progesterone receptors were more susceptible. • Progestational proliferation severely inhibited. • Cu taken up by endometrial epithelium & stromata. • Cu conc. in uterine cytoplasm –1.4 x 10-6 M • Little effect on sperm mobility.

12. Kinetics of Release of copper • Continuous release by ionization & chelation process. • Diameter of wire was reduce with time by corrosion & flacking of metal • Cu-7 284 deliver Cu at a rate of following expression- Dosage (mg)=0.3 * month + 3.79 • Release 9.87 µg/day • Linear relationship between cumulative copper release with the duration • Reduction in copper release due to formation of- • Corrosion layer- of protein • Encrustation layer- of calcium (impermeable)

13. Cu-7 • Mfg by G.D. Searle & Co. • First device approved by US- FDA for 3 yrs of use. • Polypropylene plastic device shaped like 7 • 89 mg copper wire around vertical limb with surface area of 200 sq. mm • Release 9.87µg/day for 40 months • Smaller volume (0.09 cm3) than Cu-T (0.16 cm3)- easily inserted in nulliparous women. • No need of cervical dilation • Removal is painless.

14. New developments • Efficacy improved when copper wire is located on the transverse arm as in close contact with upper portion of uterine cavity. • Cu-T-380A (US approval -1980) • Two collars of Cu on transverse arm • Each collar provides additional surface are of 30 sq. mm. • Cu-T-200C • Seven copper sleeves of Copper on both arms • Efficious same as Cu-T-380A • Retain physical integrity for 15-20 yrs. • Long acting- beneficial to population in which medical care not readily available.

15. New developments • Multiload Cu IUD: MLCu-250 • Combination of Cu-T & Dalkon Shield without central plastic membrane. • Blunt apex of device fits in to vault of uterine cavity without penetrating endometrial walls • Two teeth-studded side arms adapt to the contours of the uterine cavity • During uterine contraction Fundus presses against upper edge of IUD, results in bending of arms. • Pregnancy rate- 0.3% only • Expulsion- 1% only • Other Devices- • MLCu-250, • MLCu-325 • MLCu-250 mini

16. HORMONE RELEASING IUD’S • Use of hormone in IUD- initiated by Doyle & Clewe • Then Croxatto et al showed that a progestin released at a controlled rate from a silicone capsule inserted in rabbit uterine cavity, prevent implantation. • 1970- Scommegna & coworkers affix progesterone containing silicone capsules to modified Lippes loop. Granted US-patent. • Early models had high expulsion rates or side effects. • T-shaped progesterone releasing IUD were developed, improvement in efficacy. • Release rate of 65 µg/day was found to produce contraception & selected as final design of IUD.

17. HORMONE RELEASING IUD’SAnti-fertility action of progesterone • Secretion of secretary phase is hormonally controlled • Optimum amt. of estrogen & progesterone required for proper development. • Implantation of blastocyst takes place on secretary endometrium. • Decidual reaction- after implantation • Stromal cells enlarge & grow as polyhedral cells rich in glycogen & lipids. These changes takes place in presence of implanted blastocysts. • Once decidual reaction occurred, implantation of blastocyst cannot takes place again. • Endometrial hyper-maturation is unfavorable for implantation. • Maturation of endometrium is associated with decidual formation which is induced by Progesterone.

19. Types of IUD Drug delivery devices • Membrane Controlled Reservoir type D.D.Ds- Polymeric membrane encapsulates the drug & also controls the release. • Two types • Single Component System • Multiple Component System Cont.

20. Membrane Controlled Reservoir type D.D.D • Single Component System • Drug in solid form encapsulated in capsule of biocompatible polymeric material • Polymer- Silicone elastomer / Polyethylene • E.g. Scommegna’s silicone-based IUD • Drug release- zero order kinetics • Silicone elastomer widely used previously as polymer- do not posses required tensile strength or elastic modulus. • To overcome drawbacks- copolymers of Poly(dimethylsiloxone) with polycarbonate or polyurethane were prepared. Cont.

21. Multi component System- • Encapsulation of liquid medium saturated with excess of drug in rate controlling polymeric membrane. • E. g. Progestasert (Alza Corp.) • Membrane- Ethylene vinyl acetate copolymer • 38 mg of Progesterone suspended in silicone oil • Release at constant rate of 65 µg/day • Zero order release rate till drug solution become unsaturated • 60% of loading dose in reservoir compartment depleted during first year. • Useful life is 1 yr.

22. Types of IUD Drug delivery devices • Polymer-matrix Diffusion-Controlled D.D.Ds- Homogenously dispersing drug particles in a cross linked polymeric matrix • Two types • Retrievable Matrix Device • Biodegradable Matrix Device

23. Polymer-matrix Diffusion-Controlled D.D.D • Retrievable Matrix Device- • Retrieved or removed after termination of treatment • Preparation- • Mix drug powder with a semisolid silicone elastomer vulcanization at room / low temp. • Mix drug powder with low density polyethylene particles  Melt & extrude • Drug release is linearly proportional to square root of time Cont.

24. Biodegradable matrix device: • No need of retrieving at the termination of treatment. • Preparation – Dissolve drug + Biodegradable polymer e.g. Poly(lactic acid)  in common organic solvent  Melt pressing at elevated temp. after flashing off solvent • Drug release is combination of polymer hydrolysis & drug diffusion

25. Types of IUD Drug delivery devices • Sandwich-type D.D.D. • Hybrid of polymer membrane permeation with polymer matrix diffusion • Thin rate controlling membrane encapsulates a high permeable drug dispersing matrix. • Release rate can be improved by coating porous support with silicone elastomer. • E.g. Nova-T (Leiras Pharmaceuticals, Finland) • Drug Levonorgesterel (more potent progesterone analog) • T shaped polyethylene support by a sandwich type silicone based drug reservoir • Daily release – 20 µg • Lifetime- more than 5 yrs.

27. Types of IUD Drug delivery devices • Estriole Releasing IUD’s • Synthesis of estradiole dependant uterine RNA is essential for implantation • Estriole binds with uterine receptors & compete with estradiole. But incapable of inducing uterine growth. • It interfere with synthesis of estradiole induced uterine RNA, preventing implantation. • Release rate of 1.25 µg/day effectively inhibits development & implantation of blastocyst.

29. ADVANTAGES OF iud’s • The copper IUD prevents ectopic pregnancies. • This contraceptive is very cost effective (inexpensive) over time. • Use of an IUD is convenient, safe & private. • 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.

30. DISADVANTAGES OF IUD’s • There may be cramping, pain after insertion. • The number of bleeding days is slightly higher than normal • Somewhat increased menstrual cramping. • If bleeding pattern is bothersome, contact the doctor. • The IUD provides no protection against sexually transmitted infections. • There is a higher initial cost of insertion. However, after 2 years, it is the most cost-effective contraceptive method. • The IUD must be inserted by a doctor, nurse or physician’s assistant.

31. Comparative efficacy of medicated and non medicated IUDs • Use of Cu -7 group was declined due to the problem of excessive bleeding . • Irregular bleeding was higher in Cu – 7 group (13.4%) than in progestasert group (7.5%). • But progestasert has a limited life span of one year which is disadvantageous as compared to three year users life of Cu -7. Cont.

32. Changes in enzymatic activity- • Copper bearing IUD produce significant variations in secretary phase of the endometrium with two fold increase in total enzyme activity. • Progesterone releasing IUD induced no (or only small ) change in activity of lysosomal enzymes and increased the stability of lysosomal membrane during secretary phase. • The changes in activities and sub cellular distribution of lysosomal enzymes induced by non medicated placebo IUD were found to be quantitatively small and of limited biological significance . Cont.

33. Changes in endometrium- • The plain and copper bearing spring coil IUDs the cyclic patterns of endometrium was preserved . • Progesterone releasing IUDs produce the histological changes that made endometrium unsuitable for implantation . • Mestranol releasing deviceproduces proliferative or hyperplastic changes in both glandular & stromal cells with prevention of secreatory changes in endometrium which become unreceptive to ova Cont.

34. Changes in menstrual bleeding- • Insertion of copper bearing IUDs has resulted in increased in menstrual blood loss and decreased in Hb compared to pre insertion cycle • Insertion of progesterone releasing IUDs yielded either no change or reduction in menstrual blood loss & no significant variation in Hb conc.

35. Reference • Y.W. Chien. Novel Drug Delivery System, 2nd edition, Marcel Decker , page no.- 585-630 • Advanced in controlled & novel drug delivery-N.K.Jain. • Remington-the science & practice of pharmacy vol.1&2. • www.google.com.

36. Thank you…