Skip to main content
PMC home page
AAPS PharmSciTech logoLink to AAPS PharmSciTech
. 2001 Apr 6;2(2):4–13. doi: 10.1208/pt020205

GM-144, a novel lipophilic vaginal contraceptive gel-microemulsion

Osmond J D’Cruz 1,✉, Seang H Yiv 2, Fatih M Uckun 4
PMCID: PMC2750471  PMID: 14727880

Abstract

In a systematic effort to develop a dual-function intravaginal spermicide as well as a drug delivery vehicle against sexually transmitted pathogens, a submicron particle size (30–80 nm), lipophilic and spermicidal gel-microemulsion (viz GM-144) containing the pharmaceutical excipients propylene glycol, Captex 300, Cremophor EL, Phospholipon 90G, Rhodigel, Pluronic F-68, and sodium benzoate was formulated. GM-144 completely immobilized sperm in human or rabbit semen in less than 30 seconds. Therefore, thein vivo contraceptive potency of intravaginally applied GM-144 was compared in the standard rabbit model to those of the detergent spermicide, nonoxynol-9 (N-9)-containing formulation. Eighty-four ovulated New Zealand White rabbits in subgroups of 28 were artificially inseminated with and without intravaginal administration of GM-144 or 2% N-9 (Gynol II) formulation and allowed to complete term pregnancy. GM-144 showed remarkable contraceptive activity in the rigorous rabbit model. When compared with control, intravaginal administration of GM-144 and Gynol II resulted in 75% and 70.8% inhibition of fertility (P<.0001 versus control, Fisher’s exact test), respectively. Thus, GM-144 as a vaginal contraceptive was as effective as the commercially available N-9 gel. In the rabbit vaginal irritation test, none of the 6 rabbits given daily intravaginal application of spermicidal GM-144 for 10 days developed epithelial ulceration, edema, leukocyte influx, or vascular congestion characteristic of inflammation (total score = 5). Therefore, GM-144 has the potential to become a clinically useful safe vaginal contraceptive and a vehicle for formulating lipophilic drugs used in reducing the risk of heterosexual transmission of sexually tranmitted diseases.

Keywords: Contraceptives, Gel-microemulsion, Intravaginal, Microbicide, Nonoxynol-9, Spermicide

Full Text

The Full Text of this article is available as a PDF (169.0 KB).

References

  • 1.Digenis GA, Nosek D, Mohammadi F, Darwazeh NB, Anwar HS, Zavos PM. Novel vaginal controlled-delivery systems incorporating coprecipitates of nonoxynol-9. Pharm Dev Technol. 1999;4:421–430. doi: 10.1081/PDT-100101378. [DOI] [PubMed] [Google Scholar]
  • 2.Furuse K, Ishizeki C, Iwahara S. Studies on spermicidal activity of surfactants. I. Correlation between spermicidal effect and physicochemical properties of p-methanylphenyl polyoxyethylene (8.8) ether and other surfactants. J Pharmacobiodyn. 1983;6:359–372. doi: 10.1248/bpb1978.6.359. [DOI] [PubMed] [Google Scholar]
  • 3.OTC Panel Vaginal contraceptive drug products for over-the-counter human use. Federal Register. 1980;45:82014–82019. [Google Scholar]
  • 4.Chantler E. Vaginal spermicides: some current concerns. Brit Fam Plann. 1992;17:118–119. [Google Scholar]
  • 5.Mendez F, Castro A, Ortega A. Use effectiveness of a spermicidal suppository containing benzalkonium chloride. Contraception. 1986;34:353–362. doi: 10.1016/0010-7824(86)90088-0. [DOI] [PubMed] [Google Scholar]
  • 6.Schill WB, Wolf HH. Ultrastructure of human spermatozoa in the presence of the spermicide nonoxynol-9 and a vaginal contraceptive containing nonoxynol-9. Andrologia. 1981;13:42–49. doi: 10.1111/j.1439-0272.1981.tb00006.x. [DOI] [PubMed] [Google Scholar]
  • 7.Wilburn WH, Hahn DW, McGuire JJ. Scanning electron microscopy of human spermatozoa after incubation with the spermicide nonoxynol-9. Fertil Steril. 1983;39:717–719. doi: 10.1016/s0015-0282(16)47074-3. [DOI] [PubMed] [Google Scholar]
  • 8.D’Cruz OJ, Shih M-J, Yiv SH, Chen C-L, Uckun FM. Synthesis, characterization and preclinical formulation of a dual-action phenyl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) with potent anti-HIV and spermicidal activities. Mol Hum Reprod. 1999;5:421–432. doi: 10.1093/molehr/5.5.421. [DOI] [PubMed] [Google Scholar]
  • 9.D’Cruz OJ, Venkatachalam TK, Uckun FM. Structural requirements for potent human spermicidal activity of dual-function aryl phosphate derivative of bromo-methoxy zidovudine (compound WHI-07) Biol Reprod. 2000;62:37–44. doi: 10.1095/biolreprod62.1.37. [DOI] [PubMed] [Google Scholar]
  • 10.D’Cruz OJ, Uckun FM. Novel derivatives of phenethyl-5-bromopyridylthiourea (PBT) and dihydroalkoxybenzyloxopyrimidine (DABO) are dual-function spermicides with potent anti-HIV activity. Biol Reprod. 1999;60:1419–1428. doi: 10.1095/biolreprod60.6.1419. [DOI] [PubMed] [Google Scholar]
  • 11.D’Cruz OJ, Venkatachalam TK, Uckun FM. Novel thiourea compounds as dual-function microbicides. Biol Reprod. 2000;63:196–205. doi: 10.1095/biolreprod63.1.196. [DOI] [PubMed] [Google Scholar]
  • 12.Klebanoff SJ. Effects of the spermicidal agent nonoxynol-9 on vaginal microbial flora. J Infect Dis. 1992;165:19–25. doi: 10.1093/infdis/165.1.19. [DOI] [PubMed] [Google Scholar]
  • 13.Uckun FM, D’Cruz OJ. Prophylactic contraceptives for HIV/AIDS. Hum Reprod Update. 1999;5:506–514. doi: 10.1093/humupd/5.5.506. [DOI] [PubMed] [Google Scholar]
  • 14.Nurithisard SR, Roddy E, Chutivongse S. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sex Transm Dis. 1991;18:176–179. doi: 10.1097/00007435-199107000-00010. [DOI] [PubMed] [Google Scholar]
  • 15.Rekart ML. The toxicity and local effects of the spermicide nonoxynol-9. J Acquir Immune Defic Syndr. 1992;5:425–427. [PubMed] [Google Scholar]
  • 16.Roddy RE, Cordero M, Cordero C, Fortney JA. A dosing of nonoxynol-9 and genital irritation. Int J STD HIV. 1993;4:165–170. doi: 10.1177/095646249300400308. [DOI] [PubMed] [Google Scholar]
  • 17.Weir SS, Roddy RE, Zekeng L, Feldblum PJ. Nonoxynol-9 use, genital ulcers, and HIV infection in a cohort of sex workers. Genitourin Med. 1995;71:78–81. doi: 10.1136/sti.71.2.78. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Hooten TM, Hillier S, Johnson C, Roberts PL, Stamm WE. Escherichia coli bacteriuria and contraceptive method. JAMA. 1991;265:64–69. doi: 10.1001/jama.265.1.64. [DOI] [PubMed] [Google Scholar]
  • 19.Stafford MK, Ward H, Flanagan A, et al. A safety study of nonoxynol-9 as a vaginal microbicide: evidence of adverse effects. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;17:327–331. doi: 10.1097/00042560-199804010-00006. [DOI] [PubMed] [Google Scholar]
  • 20.Rosenstein IJ, Stafford MK, Kitchen VS, Ward H, Weber JN, Taylor-Robinson D. Effect of normal vaginal flora of three intravaginal microbicidal agents potentially active against human immunodeficiency virus type 1. J Infect Dis. 1998;177:1386–1390. doi: 10.1086/517820. [DOI] [PubMed] [Google Scholar]
  • 21.Augenbraun MH, McCormack WM. Sexually transmitted diseases in HIV-infected persons. Infect Dis Clin North Am. 1994;8:439–448. [PubMed] [Google Scholar]
  • 22.Kreiss J, Ngugi E, Holmes K, et al. Efficacy of nonoxynol-9 contraceptive sponge use in preventing heterosexual transmission of HIV in Nairobi prostitutes. JAMA. 1992;268:477–482. doi: 10.1001/jama.268.4.477. [DOI] [PubMed] [Google Scholar]
  • 23.Eccleston GM. Microemulsion. In: Swarbrick J, Boylan JC, editors. Encyclopedia of Pharmaceutical Technology. New York: Marcel Dekker; 1992. pp. 375–421. [Google Scholar]
  • 24.Tenjaria S. Microemulsions: an overview and pharmaceutical applications. Crit Rev Ther Drug Carrier Syst. 1999;16:461–521. [PubMed] [Google Scholar]
  • 25.D’Cruz OJ, Zhu Z, Yiv SH, Chen C-L, Waurzyniak B, Uckun FM. WHI-05, a novel bromomethoxy substituted phenyl phosphate derivative of zidovudine, is a dual-action spermicide with potent anti-HIV activity. Contraception. 1999;59:319–331. doi: 10.1016/S0010-7824(99)00041-4. [DOI] [PubMed] [Google Scholar]
  • 26.Eckstein P, Jackson MC, Millman N, Sobrero AJ. Comparison of vaginal tolerance tests of spermicidal preparations in rabbits and monkeys. J Reprod Fertil. 1969;20:85–93. doi: 10.1530/jrf.0.0200085. [DOI] [PubMed] [Google Scholar]
  • 27.Castle PE, Hoen TE, Whaley KJ, Cone RA. Contraceptive testing of vaginal agents in rabbits. Contraception. 1998;58:51–60. doi: 10.1016/S0010-7824(98)00059-6. [DOI] [PubMed] [Google Scholar]
  • 28.Castle PE, Whaley KJ, Hoen TE, Moench TR, Cone RA. Contraceptive effect of spermagglutinating monoclonal antibodies in rabbits. Biol Reprod. 1997;56:153–159. doi: 10.1095/biolreprod56.1.153. [DOI] [PubMed] [Google Scholar]
  • 29.Lundberg BB. A submicron lipid emulsion coated with amphipathic polyethylene glycol for parenteral administration of Paclitaxel (Taxol) J Pharm Pharmacol. 1997;49:16–21. doi: 10.1111/j.2042-7158.1997.tb06744.x. [DOI] [PubMed] [Google Scholar]
  • 30.Woodcock DM, Jefferson S, Linsenmeyer ME, Crowther PJ, Chojnowski GM, William B, Bertoncello I. Reversal of multidrug resistance phenotype with Cremophor EL, a common vehicle for water-insoluble vitamins and drugs. Cancer Res. 1990;5:4199–4203. [PubMed] [Google Scholar]
  • 31.Dreher F, Walde P, Luisi PL, Elsner P. Human skin irritation studies of a lecithin microemulsion gel and of lecithin liposomes. Skin Pharmacol. 1996;9:124–129. doi: 10.1159/000211408. [DOI] [PubMed] [Google Scholar]
  • 32.Katz DH, Marcelletti JF, Khalil MH, Pope LE, Katz LR. Antiviral activity of 1-docosanol, an inhibitor of lipid-enveloped viruses including herpes simplex. Proc Natl Acad Sci U S A. 1991;88:10825–10829. doi: 10.1073/pnas.88.23.10825. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Nerurkar MM, Burton PS, Borchardt RT. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system. Pharm Res. 1996;13:528–534. doi: 10.1023/A:1016033702220. [DOI] [PubMed] [Google Scholar]
  • 34.Murhammer DW, Goochee CF. Sparged animal cell bioreactors: mechanism of cell damage and Pluronic F-68 protection. Biotechnol Prog. 1990;6:391–397. doi: 10.1021/bp00005a012. [DOI] [PubMed] [Google Scholar]
  • 35.de Jong HJ. The safety of pharmaceutical excipients. Therapie. 1999;54:11–14. [PubMed] [Google Scholar]
  • 36.Sutherland IW. Novel and established applications of microbial polysaccharides. Trends Biotechnol. 1998;16:41–46. doi: 10.1016/S0167-7799(97)01139-6. [DOI] [PubMed] [Google Scholar]

Articles from AAPS PharmSciTech are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES