Levonorgestrel release from

A ketene acetal-terminated prepolymer was first prepared from 2 eq of the diketene acetal 3,9-bis(ethylidene-2,4,8,10-tetraoxaspiro-[5,5]undecane) and 1 eq of the diol 3-raethyl-l,5-pentanediol and. then 30 wt% levonorgestrel, 7 wt% Mg(OH)2j and a 30 mole% excess of 1,2,6-hexanetriol mixed into the prepolymer. This mixture was then extruded into rods and cured. Erosion and drug release from these devices was studied by implanting the rod-shaped devices subcutaneously into rabbits, explanting at various time intervals, and measuring weight loss and residual drug (15). 

FIGURE 18 In vivo cumulative weight loss (o) and cumulative release of levonorgestrel (o) from a crossUnked polymer prepared from a 3,9-bis(ethylidene-2,4,8,10-tetraoxaspiro[5,5]undecane)/3-methyl-1,5-pentanediol prepolymer crossUnked with 1,2,6-hexane triol. Polymer rods, 2.4 X 20 mm, containing 30 wt% levonorgestrel and 7.1 mol% Mg(OH)2. Devices implanted subcutaneously in rabbits. (From Ref. 15.)... 

Observational data illustrate a reduction in dysmenorrhea from 60% to 29% with the levonorgestrel-releasing IUD after 3 years.17 As observed with depo-medroxyprogesterone acetate, this reduction is likely secondary to the increasing incidence of amenorrhea in users of this contraceptive device. 

Gardner FJ, Konje JC, Abrams KR, Brown LJ, Khanna S, Al-Azzawi F, Bell SC, Taylor DJ. Endometrial protection from tamoxifen-stimulated changes by a levonorgestrel-releasing intrauterine system a randomised controlled trial. Lancet 2000 356(9243) 1711-7. 

Because a number of contraceptive steroids, and particularly levonorgestrel, have water solubilities of only a few parts per million, the effect of drug water solubility on rate of release from bioerodible polymers into an aqueous medium becomes an important consideration and can, in fact, become rate limiting. 

Implanted Contraceptives. Controlled release of contraceptive progestins also can be accompHshed by incorporating the dmg into an implantable cylinder or rod. The best known implant is Norplant, developed by the Population Council. Norplant is composed of six matchlike silastic cylinders with the progestogen levonorgestrel (11) incorporated on the inside of each cylinder. After implantation under the skin, the product can provide effective contraception for a period of five years (43,44). Since silastic is not biodegradable, the implant can be removed from a patient at any time. 

Controlled release fiber systems based on aliphatic polyesters were investigated by Dunn and Lewis (51-54). The feasibility of hollow fibers spun from poly (L-lactide) and containing the contraceptive steroid levonorgestrel has been demonstrated (55). 

The rate of release of levonorgestrel from films of block copolymers of e-caprolactone and dl-lactic acid (drug load 30%) was shown to be a function of the copolymer composition. The rate was unchanged for compositions of 100% and 88% e-capirolactone, but decreased thereafter as the e-caprolactone content decreased (42). 

FIGURE 15 Long-term release of levonorgestrel from a PCL capsule (reservoir device) implanted (s.c.) in rabbit, showing both blood and excreta levels of the drug and its metabolites. (From Ref. 6.)... 

H., In vitro and in vivo release of levonorgestrel from poly-(ortho esters). II. Crosslinked polymers, J. Control. Rel., 1, 233-238, 1985. 

D.N.Robertson, I.Sivin, H.A.Nash, J.Braun and J.Dinh, Release rates of levonorgestrel from silastic capsules, homogeneous rods and covered rods in humans, Contraception, 27,483 195 (1983). 

FIGURE 6.25 The release of levonorgestrel from a poly(orthoester) slab containing 30% drug and 2% calcium lactate. [Graph reconstructed from data by Heller et al. in Controlled Release of Bioactive Materials, R. W. Baker (Ed.), Academic Press, New York, 1980, p. 1.]... 

Fig. 7 Diagrammatic illustration of the subcutaneous implantation of Norplant implants. The subcutaneous release profile of levonorgestrel in female volunteers for up to 6 years and the resultant plasma profile as compared to those obtained by oral administration. (Adapted from Refs. l)...

Fig. 11 Comparative in vitro release rate profile of levonor-gestrel from a vaginal ring containing a homogeneous dispersion of drug in a silicone-based polymer matrix (O) and from one containing an inert overcoat covering the drug reservoir layer ( and ). The effect of overcoat thickness fijii on the release rate of levonorgestrel is also shown. (From RefP l)...

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