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Pharma Department of Pharmaceutics, KLE university, Belgaum CONTENT : CONTENT Introduction Contraception Need of Contraceptives Anatomy of uterus Types of contraception Introduction of IUDs Intra Uterine Devices- Types of IUDs Advantages of IUDs Disadvantages of IUDs Design of IUDs Development of medicated IUDs Copper bearing IUDs Hormone releasing IUDs Comparative efficacy of medicated & non-medicated IUDs New development References Slide 3: 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. Need of contraceptives : Need of contraceptives 1975- United state From approximately 27 million couples of child baring age 76.3% expressed desire to prevent conception either temporarily or Permanently. Anatomy of uterus : Anatomy of uterus Pear shaped, thick-walled muscular organ suspended in the anterior wall of pelvic cavity. Shape: triangular, flattened antero-posteriorly. Dimensions: (in normal state) Length- 3 inches Width- 2 inches Parts- Fundus Body (Uterine Cavity, Isthmus) Cervix (Cervical canal, Internal Os, External Os) Openings- Superior- fallopian tubes Inferior- Vagina (mouth of Uterus) Wall of uterus : Wall of uterus Endometrium – inner coat of uterine wall made up of simple columnar epithelium, areolar connective tissue & endometrial glands. Stratum Functionalis- innermost, sloughed off during menstruation Stratum Basalis- permanent, gives new s. functionalis. Myometrium – Thick, muscular middle layer made up of 3 layers of smooth muscles (Middle thick circular & other two longitudinal) Peritoneum – External surface of uterus which attaches uterus to pelvic cavity by ligaments Menstruation cycle : Menstruation cycle During reproductive ages nonpregnant woman exihibit cyclic changes in ovaries & uterus, called as Menstrual cycle. Typically of 28 days & divided into 4 phases- Menstrual Phase (5 days) Pre-ovulatory phase / Follicular phase (6-13 days) Ovulatory phase (on 14th day) Post-ovulatory phase / Leutial phase (14-28 days) Key points- : Key points- Menstrual phase- (5 days) Decrease in levels of estrogen & progesterone Stimulates release of prostaglandins Produce arteriole constriction, decrease blood supply to s. functionalis Cells starts to die & s. functionalis sloughed off. Bleeding takes place for about 5 days. Follicular phase- ( up to 13th day) Estradiole is secreted from ovaries by secondary follicle Secondary follicle is converted in graffian follicle. Estrogen restores blood supply to endometrium & stimulates formation of s. functionalis from s. basalis. S. functionalis starts to grow and become 3-4 mm thick. Endometrial glands increase in length & tortuosity. Key points- : Key points- Ovulation-( on 14th day) Release of oocyte outside of ovaries into fallopian tube. Takes place at the day of 14 of M.C. under the influence of Leutinizing hormone (LH) & Gonadotropin releasing hormone (GnRH) Released oocyte remain viable for 2 days. Leutial phase-(15-28 day) In ovary graffian follicle collapse to form corpus luteum. It release progesterone & estrogen. In uterus, these hormones promote growth, thickning & coiling of endometrium. Glycogen is secreted by glands. Fertilization- changes remain constant No fertilization- corpus luteum disappear, decrease in level of estrogen & progesterone. Menstruation occurs. Intra-uterine devices : 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. 3 most popular methods of contraception: Oral contraceptive pills Condoms or diaphragms Intrauterine device TYPES OF IUD’S : 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 Development of iud’s : 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 Development of iud’s : 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 Development of iud’s : 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 Development of medicated iud’s : Development of medicated 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. Development of copper bearing iud’s : Development of 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. Slide 18: 18 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. Anti-fertility action of copper : 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. Kinetics of Release of copper : 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) Clinical effectiveness of Cu-bearing IUD : Clinical effectiveness of Cu-bearing IUD Cu-7 : 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. Clinical effectiveness of Cu-T and Cu-7 : Clinical effectiveness of Cu-T and Cu-7 New developments : 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. New developments : 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 HORMONE RELEASING IUD’S : 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. HORMONE RELEASING IUD’SAnti-fertility action of progesterone : 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. Clinical efficacy of Progesterone releasing IUD’s : Clinical efficacy of Progesterone releasing IUD’s Dependant upon daily dose of progesterone released Potential development : Potential development 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. Membrane Controlled Reservoir type D.D.D : 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. Slide 31: 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. Potential development : Potential development 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 Polymer-matrix Diffusion-Controlled D.D.D : 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. Slide 34: 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 Potential developments : Potential developments 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. Potential developments : Potential developments 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. Comparative efficacy of medicated and non medicated IUDs : 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. Slide 38: 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. Slide 39: 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. Slide 40: 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. Slide 41: 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. DISADVANTAGES OF IUD’s : 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. Reference : 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. Slide 44: Thank you… You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.