1. PHARMACEUTICS- IV (PHT 414 ) Dr. Shahid Jamil PRINCE SATTAM BIN ABDUL AZIZ UNIVERSITY COLLEGE OF PHARMACY 12/25/2015 1

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) 12/25/2015 2

3.  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. 12/25/2015 3

4.  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 12/25/2015 4

5.  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 12/25/2015 5

6.  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 12/25/2015 6

7.  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 12/25/2015 7

8.  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. 12/25/2015 8

9.  1969  Zipper et. al. reported- copper attached to an IUD markedly enhanced the effectiveness.  T-shaped polyethylene device wound with 30 mm 2 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 mm 2 – found maximum contraceptive efficiency. 12/25/2015 9

10. 10  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. 12/25/2015

11.  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. 12/25/2015 11

12.  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) 12/25/2015 12

13.  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 cm 3 ) than Cu-T (0.16 cm 3 ) - easily inserted in nulliparous women.  No need of cervical dilation  Removal is painless. 12/25/2015 13

14.  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. 12/25/2015 14

15.  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 12/25/2015 15

16.  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. 12/25/2015 16

17.  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. 12/25/2015 17

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19.  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. 12/25/2015 19

20.  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. 12/25/2015 20

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. 12/25/2015 21

22.  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 12/25/2015 22

23.  Retrievable Matrix Device-  Retrieved or removed after termination of treatment  Preparation- 1) Mix drug powder with a semisolid silicone elastomer  vulcanization at room / low temp. 2) Mix drug powder with low density polyethylene particles  Melt & extrude  Drug release is linearly proportional to square root of time Cont. 12/25/2015 23

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 12/25/2015 24

25.  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. 12/25/2015 25

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27.  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. 12/25/2015 27

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29.  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. 12/25/2015 29

30.  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. 12/25/2015 30

31.  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. 12/25/2015 31

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. 12/25/2015 32

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 device produces proliferative or hyperplastic changes in both glandular & stromal cells with prevention of secreatory changes in endometrium which become unreceptive to ova Cont. 12/25/2015 33

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. 12/25/2015 34

35.  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. 12/25/2015 35

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