Pharmaceutical composition for emergency contraception

Abstract

The invention relates to pharmaceutical compositions for emergency contraception, to the use of levonorgestrel in combination with COX inhibitors for the preparation of pharmaceutical compositions for the stated purpose, and to a method for preparing these pharmaceutical compositions.

Claims

1. A pharmaceutical composition, comprising (a) 50-900 ?g levonorgestrel, (b) a COX inhibitor selected from: 50-600 mg indomethacin and 40-50 mg diclofenac; and (c) a pharmaceutically acceptable excipient, wherein the pharmaceutical composition is adapted for oral emergency contraception in a single dose to prevent pregnancy.

2. The pharmaceutical composition as claimed in claim 1, characterized in that the levonorgestrel is in a range of 100-360 ?g.

3. The pharmaceutical composition as claimed in claim 1, wherein the levonorgestrel is in a range of 150-300 ?g.

4. A method for emergency contraception comprising administering to a patient in need thereof a composition comprising the composition of claim 1.

5. The method of claim 4, wherein the pharmaceutical composition is administered in a single dose within 72 hours post coitus.

Description

EXAMPLE 1

Ovulation Inhibition Test on Rats

(1) The rat is an especially suitable animal model for demonstration of ovulation-inhibiting substances, since it ovulates spontaneously and the menstrual cycle can be easily monitored using vaginal smears.

(2) In the following test, female rats weighing between 200 and 220 g were used. The animals were housed in macrolon cages in rooms under controlled lighting conditions (12 hours of darkness, 12 hours of light), were fed a standard diet and had access to water ad libitum.

(3) Levonorgestrel was dissolved in benzyl benzoate/castor oil (1+4 v/v), and the daily dose was given by s.c. administration in a volume of 1 ml/kg body weight.

(4) The COX inhibitors were suspended in a carrier liquid (85 mg of MyrjR53 (2-hydroxyethyl octadecanoate; CAS no. 9004-99-3) in 100 ml of 0.9% w/v NaCl solution), and the daily dose corresponding to the treatment group was administered orally in a volume of 2 ml/kg body weight.

(5) Two cycles were monitored using vaginal smears before the start of the test. Only animals with a regular 4-day cycle were entered in the test. The allocation to the treatment groups was randomized. Starting in the metestrus, the test substance was administered for 4 days (days 1-4) and the cycle continued to be monitored. On day 3 of treatment (proestrus), a retrobulbar blood sample was taken at 9.00 h and from 18.30 h in order to determine the luteinizing hormone (LH). On day 4 (after administration), the animals with vaginal smears showing them in estrus or metestrus underwent unilateral ovariectomy under anaesthetic. Crush preparations were made from the tubes and were examined under a microscope for the presence of oocytes. On day 5, all the animals (the intact animals and those having undergone unilateral ovariectomy) were sacrificed, and the tubes of the animals in estrus and metestrus were prepared and examined in the same way. The tests that were carried out show that a low dose of levonorgestrel, although not itself inhibiting ovulation, does provide increased suppression of ovulation when combined with COX inhibitors, and, in the case of piroxicam, almost complete suppression of ovulation can be achieved. By contrast, the COX inhibitors on their own provide only partial suppression of ovulation.

(6) The results of the study, i.e. the combined effect of levonorgestrel plus COX inhibitors on ovulation, are summarized in Table 4:

(7) TABLE-US-00004 TABLE 4 Ovulation Ovulation count, count, Treatment group absolute mean Vehicle 42 8.4 ? 0.5 LNG 0.01 mg s.c. 35 7.0 ? 2.0 Meloxicam 2 mg p.o. 28 5.6 ? 2.5 Piroxicam 2 mg p.o. 9 1.8 ? 0.4 LNG (0.01 mg) + Priox 3 0.6 ? 1.3 (only 1 (2 mg) animal ovulated 3 oocytes) LNG (0.01 mg) + Melox 18 3.6 ? 3.3 (2 mg)

EXAMPLE 2

(8) The test set-up corresponds to the one described in Example 1.

(9) The results for the progesterone concentrations in proestrus at 19.00 h are summarized in Table 5:

(10) TABLE-US-00005 TABLE 5 Progesterone in proestrus at Treatment group 19.00 hmean ? SD (n = 10) Vehicle 254 ? 88 Piroxicam 0.5 mg p.o. 237 ? 49 Piroxicam 1 mg p.o. 183 ? 67 Piroxicam 2 mg p.o. 122 ? 94

EXAMPLE 3

(11) Substances can influence fertility by reducing the fertilizability of oocytes or cumulus-oocyte complexes. In order to investigate such effects, substances can be administered in vivo and, after ovulation from cumulus/oocyte complexes, can be subjected to in vitro fertilization. The in vitro fertilization rate, with no further test substance being added, allows conclusions to be drawn regarding the in vivo effects of the test substances.

(12) Immature female mice (strain: B6D2F1, Charles River, Suelzfeld, age: 19-25 days) were housed in macrolon cages in rooms under controlled lighting conditions (12 hours of darkness, 12 hours of light), were fed a standard diet and had access to water ad libitum. The mice were primed with PMSG (Pregnant Mare Serum Gonadotropin) (10 IU/animal i.p.). After 48 hours, an ovulation-triggering stimulus was induced in the animals by administration of 10 IU/animal i.p. The COX inhibitors were suspended in a carrier liquid (85 mg MyrjR53 (2-hydroxyethyl octadecanoate; CAS no. 9004-99-3) in 100 ml of 0.9% w/v NaCl solution), and the daily dose corresponding to the treatment group (n=5 animals per group) was administered in a volume of 0.2 ml p.o. 8 hours before and together with hCG. Fourteen hours after hCG administration, the animals were sacrificed. Ovulated oocytes and cumulus-oocyte complexes were recovered from the ovarian bursa and/or oviduct and subjected to in vitro fertilization, with a sperm count of 40,000 sperm/0.5 ml for 1 hour being used for the fertilization. Twenty-four hours after incubation with the sperm, the number of fertilized oocytes was established and the percentage fertilization rate determined.

(13) The results show that piroxicam has an effect on the fertilizability of ovulated cumulus-oocyte complexes.

(14) The results of the study of the effect of piroxicam on the fertilization rate of ovulated cumulus-oocyte complexes are summarized in Table 6:

(15) TABLE-US-00006 TABLE 6 Fertilization Treatment group rate (% ? SD) Vehicle 55 ? 16 Piroxicam 12 ? 7 (2 ? 0.5 mg/animal p.o.) Piroxicam 14 ? 18 (2 ? 0.3 mg/animal p.o.) Piroxicam 19 ? 8 (2 ? 0.15 mg/animal p.o.)

EXAMPLE 4

Method for Producing a Tablet for Emergency Contraception

(16) Tablets having a total weight of 200 mg per tablet and being of the composition shown in Table 7

(17) TABLE-US-00007 TABLE 7 Levonorgestrel, micronized 0.25 mg Piroxicam, micronized 20.00 mg Lactose monohydrate 107.75 mg Maize starch 36.00 mg Modified starch 24.00 mg Polyvinylpyrrolidone 25000 10.00 mg Magnesium stearate 2.00 mg
were produced by filling a fluidized bed granulator with 31.68 kg of maize starch, 21.12 kg of modified starch, 0.22 kg of levonorgestrel (micronized), 17.6 kg of piroxicam (micronized) and 94.82 kg of lactose monohydrate and by activating the fluidized bed. An aqueous solution of 8.8 kg of polyvinylpyrrolidone 25000 in 50 kg of purified water was sprayed continuously onto the fluidized bed, and the mixture was dried at the same time by heating the air stream of the fluidized bed. At the end of the process, 1.76 kg of magnesium stearate were introduced into the fluidized bed granulator and mixed with the resulting granules with the fluidized bed running. The granulate thus formed was pressed in a rotary tablet press into the shape of a tablet with an 8 mm diameter.

LITERATURE

(18) 1. Swahn M L. Effect of post-coital contraceptive methods on the endometrium and the menstrual cycle. Acta Obstet Gynecol Scand 1996; 75:738-44. 2. Ling W Y. Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. Fertil Steril 1979; 32:297-302. 3. Rowlands S. A possible mechanism of action of danazol and an ethinylestradiol/norgestrel combination used as postcoital contraceptive agents. Contraception 1986; 33:539-45. 4. Croxatto H B. Effects of the Yuzpe regimen, given during the follicular phase, on ovarian function. Contraception 2002; 65:121-8. 5. Kubba A A. The biochemistry of human endometrium after two regimens of postcoital contraception: a dl-norgestrel/ethinylestradiol combination or danazol. Fertil Steril 1986:45:512-6. 6. Ling W Y. Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. II. Effect of postovulatory administration on ovarian function and endometrium. Fertil Steril 1983; 39:292-7. 7. Yuzpe A A. Post coital contraceptiona pilot study. J Reprod Med 1974; 13:53-8. 8. Taskin O. High doses of oral contraceptives do not alter endometrial ?1 and ???3integrins in the late implantation window. Fertil Steril 1994; 61:850-5. 9. Raymond E G. Effect of the Yuzpe regimen of emergency contraception on markers of endometrial receptivity. Hum Reprod 2000; 15:2351-5. 10. Ling W Y. Mode of action of dl-norgestrel and ethinylestradiol combination in postcoital contraception. III. Effect of preovulatory administration following the luteinizing hormone surge on ovarian steroidogenesis. Fertil Steril 1983; 40:631-6. 11. Croxatto H B. Mechanism of action of hormonal preparations used for emergency contraception: a review of the literature. Contraception 2001; 63:111-21. 12. Croxatto H B. Mechanisms of action of emergency contraception. Steroids 2003; 68:1095-8. 5 13. Glasier A. Emergency postcoital contraception. N Engl J Med 1997; 337:1058-64. 14. Trussell J, Raymond E G. Statistical evidence concerning the mechanism of action of the Yuzpe regimen of emergency contraception. Obstet Gynecol 1999; 93:872-6. 15. Hapangama D. The effects of peri-ovulatory administration of levonorgestrel on the menstrual cycle. Contraception 2001; 63:123-9. 16. Durand M. On the mechanisms of action of short-term levonorgestrel administration in emergency contraception. Contraception 2001; 64:227-34. 17. Marions L. Emergency contraception with mifepristone and levonorgestrel: mechanism of action. Obstet Gynecol 2002; 100:65-71. 18. Marions L, Cekan S Z, Bygdeman M, Gemzell-Danielsson K. Effect of emergency contraception with levonorgestrel or mifepristone on ovarian function. Contraception 2004; 69:373-7. 19. Croxatto H B. Pituitary-ovarian function following the standard levonorgestrel emergency contraceptive dose or a single 0.75-mg dose given on the days preceding ovulation. Contraception 2004; 70:442-50. 20. Okewole I A. Effect of single administration of levonorgestrel on the menstrual cycle. Contraception 2007; 75:372-7. 21. Durand M. Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle. Contraception 2005; 71:451-7. 22. Nascimento J A. In vivo assessment of the human sperm acrosome reaction and the expression of glycodelin-A in human endometrium after levonorgestrel emergency contraceptive pill administration. Hum Reprod 2007; 22:2190-5. 23. Kesser? E. The hormonal and peripheral effects of dnorgestrel in postcoital contraception. Contraception 1974; 10:411-24. 24. Trussell J. Plan B and the politics of doubt. J Am Med Assoc 2006; 296:1775-8. 25. M?ller A L. Postcoital treatment with levonorgestrel does not disrupt postfertilization events in the rat. Contraception 2003; 67:415-19. 26. Ortiz M E. Postcoital administration of levonorgestrel does not interfere with post-fertilization events in the new-world monkey Cebus apella. Hum Reprod 2004; 19:1352-6. 27. Hatcher R A, Trussell J. Emergency Contraception: The Nation's Best Kept Secret. Decatur Ga.: Bridging the Gap Communications, 1995. 28. Teichmann Empf?ngnish?tung: eine vergleichende ?bersicht aller Methoden, Risiken and Indikationen, published by Georg Thieme Verlag (1996) 29. Moore C, Carol W, Gr?ser T et al. in Clin Drug Invest 18, 271-8 (1999) Influence of dienogest on ovulation in young fertile women 30. R. Druckmann; contraception 79 (2009) 272-281: Profile of progesterone derivative chlormadinone acetatePharmacodynamic properties and therapeutic applications 31. Fertility control Stephen L. Corson, Richard J. Derman, Louise B. Tyrer Edition: 2, illustrated. Publishers Taylor & Francis, 1994 ISBN 096979780X, 9780969797807 514 pages 32. Bazin B, Thevenot R, Bursaux C and Paris J (1987) Effect of nomegestrol acetate, a new 19 nor-progesterone derivative, on pituitary-ovarian function in women. Br J Obstet Gynaecol 94, 1199-1204 33. Schindler A. E. et al (2003) Classification and pharmacology of progestins Maturitas 46, S1, 7-16