PHARMACEUTICS- PHARMACEUTICS- IVIV

(PHT 414 ) (PHT 414 )

Dr. Shahid JamilDr. Shahid Jamil

PRINCE SATTAM BIN ABDUL AZIZ UNIVERSITY

COLLEGE OF PHARMACY

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INTRODUCTIONINTRODUCTIONCONTRACEPTION:

• 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)

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DEFINITIONDEFINITIONIUD’s are medicated devices intended to release a small quantity of drug into uterus in a sustained manner over prolonged period of time.

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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

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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

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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

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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

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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.04/21/23 8

1969Zipper 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 wire200 mm2 – found maximum contraceptive

efficiency.

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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.

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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.04/21/23 11

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)

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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.

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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 armEach collar provides additional surface are of 30 sq. mm.

Cu-T-200C Seven copper sleeves of Copper on both armsEfficious same as Cu-T-380ARetain physical integrity for 15-20 yrs.Long acting- beneficial to population in which medical

care not readily available.

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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

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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.

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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.

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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.

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Single Component SystemDrug in solid form encapsulated in capsule of

biocompatible polymeric materialPolymer- Silicone elastomer / Polyethylene E.g. Scommegna’s silicone-based IUDDrug release- zero order kineticsSilicone 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.04/21/23 20

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.

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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

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Retrievable Matrix Device-Retrieved or removed after termination of

treatmentPreparation-

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.

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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

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Sandwich-type D.D.D.Hybrid of polymer membrane permeation with polymer

matrix diffusionThin 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.

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Estriole Releasing IUD’sSynthesis 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.

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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.

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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.

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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.

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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.04/21/23 32

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.

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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.

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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.

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