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AAPS PharmSciTech. 2003 September; 4(3): 10–17.
Published online 2003 June 6. doi:  10.1208/pt040330
PMCID: PMC2750623

Coprecipitation of nonoxynol-9 with polyvinylpyrrolidone to decrease vaginal irritation potential while maintaining spermicidal potency


The aim of this study was to test the hypothesis that polyvinylpyrrolidone (PVP) would increase the critical micelle concentration (CMC) of nonoxynol-9 (N-9), providing a reduction in its irritation potential, while maintaining essential spermicidal activity. Solid coprecipitates of N-9 with PVP were manufactured with the use of a modified lyophilization process. The irritation potential of N-9 was estimated by an in vitro assay, monitoring the extent of hemolysis of red blood cells. CMCs of N-9 were measured in the presence of various concentrations of PVP. A modified Sander-Cramer assay was implemented to measure the spermicidal activity of N-9 and the N-9/PVP coprecipitates. With the use of the lyophilization process and more suitable solvents, solid coprecipitates of N-9/PVP were manufactured with no residual organic solvents. The irritation potential of N-9 was reduced when in the presence of PVP-50% hemolysis values increased from 0.054mM to more than 0.2mM. N-9 CMC values increased in the presence of PVP from 0.085mM (0% PVP) to 0.110mM (3.5% PVP) and 0.166mM (10% PVP). However, spermicidal activities ranged from 0.213mM to 0.238mM, N-9 remaining steady regardless of the amount of PVP. By use of N-9/PVP coprecipitates, the self-association properties and irritation potentials of N-9 were altered. This result suggests a process to produce a spermicidal product that reduces the detrimental implications to the vaginal epithelium while maintaining the essential spermicidal activity.

Keywords: micelle, HIV, red blood cell assay, hemolysis, Sander-Cramer assay

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Selected References

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1. Gerbase A, Rowley J, Mertens T. Global epidemiology of sexually transmitted diseases. Lancet. 1998;351:2–4. doi: 10.1016/S0140-6736(98)90001-0. [PubMed] [Cross Ref]
2. Ebrahim S, Peterman T, Zaidi A, Kamb M. Mortality related to sexually transmitted diseases in US women—1973 through 1992. Am J Public Health. 1997;87:938–944. [PubMed]
3. Elias C, Heise L. Challenges for the development of female-controlled vaginal microbicides. AIDS. 1994;8:1–9. doi: 10.1097/00002030-199401000-00002. [PubMed] [Cross Ref]
4. Bourinbaiar A, Lee-Huang S. Comparative in vitro study of contraceptive agents with anti-HIV activity: gramicidin, nonoxynol-9 and gossypol. Contraception. 1994;49:131–137. doi: 10.1016/0010-7824(94)90088-4. [PubMed] [Cross Ref]
5. Walter B, Hawi A, Zavos P, Digenis G. Solubilization and in vitro spermicidal assessment of nonoxynol-9 and selected fractions using rabbit spermatozoa. Pharm Res. 1991;8(3):403–408. doi: 10.1023/A:1015818220894. [PubMed] [Cross Ref]
6. Walter B, Digenis G. High-performance liquid chromatographic (HPLC) analysis of oligomeric components of the spermicide nonoxynol-9. Pharm Res. 1991;8:409–411. doi: 10.1023/A:1015870304964. [PubMed] [Cross Ref]
7. Barwicz J, Christian S, Gruba I. Effects of the aggregation state of amphotericin B on its toxicity to mice. Antimicrob Agents Chemother. 1992;36(10):2310–2315. [PMC free article] [PubMed]
8. Yamashita K, Janout V, Bernard E, Armstrong D, Regen S. Micelle/monomer control over the membrane-disrupting properties of an amphiphilic antibiotic. J Am Chem Soc. 1995;117:6249–6253. doi: 10.1021/ja00128a011. [Cross Ref]
9. Barwicz J, Gareau R, Audet A, Morisset A, Villiard J, Gruda I. Inhibition of the interaction between lipoproteins and amphotericin B by some delivery systems. Biochim Biophys Res Comm. 1991;181(2):722–728. doi: 10.1016/0006-291X(91)91250-G. [PubMed] [Cross Ref]
10. Aramwit P, Yu B, Kwon G. The effects of serum albumin on the aggregation state and toxicity of amphotericin B. Proceed Int_1 Symp Control Rel Bioact Mater. 1998;25:669–670.
11. Ladipo O, Castro M, Filho L, et al. A new vaginal antimicrobial contraceptive formulation: phase I clinical pilot studies. Contraception. 2000;62(2):91–97. doi: 10.1016/S0010-7824(00)00138-4. [PubMed] [Cross Ref]
12. Gagne N, Cormier H, Omar R, et al. Protective effect of a thermoreversible gel against the toxicity of nonoxynol-9. Sex Transm Dis. 1999;26(3):177–183. doi: 10.1097/00007435-199903000-00009. [PubMed] [Cross Ref]
13. Stafford M, Ward H, Flanagan A, et al. Safety study of nonoxynol-9 as a vaginal microbicide: evidence of adverse effects. J Acquir Immune Defic Syndr Hum Retrovirol. 1998;17(4):327–331. [PubMed]
14. Roddy RE, Cordero M, Cordero C, Fortney JA. A dosing study of nonoxynol-9 and genital irritation. Int J STD AIDS. 1993;4(3):165–170. [PubMed]
15. Phillips D, Taylor C, Zacharopoulos V, Maguire R. Nonoxynol-9 causes rapid exfoliation of sheets of rectal epithelium. Contraception. 2000;62(3):149–154. doi: 10.1016/S0010-7824(00)00156-6. [PubMed] [Cross Ref]
16. Niruthisard S, Roddy RE, Chutivongse S. The effects of frequent nonoxynol-9 use on the vaginal and cervical mucosa. Sex Transm Dis. 1991;18:176–179. [PubMed]
17. Robinson B, Sullivan F, Borzelleca J, Schwartz S. PVP: A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone. Chelsea, MI: Lewis Publishers; 1990.
18. Digenis G, Nosek D, Mohammadi F, Darwazeh N, Anwar H, Zavos P. Novel vaginal controlled-delivery systems incorporating coprecipitates of nonoxynol-9. Pharm Dev Tech. 1999;4(3):421–430. doi: 10.1081/PDT-100101378. [PubMed] [Cross Ref]
19. Digenis G, Digenis A. High-energy coprecipitates of nonoxynol-9 oligomers, PVP and iodine having contraceptive and potent anti-HIV properties. US patent 5 380 523. January 10, 1995.
20. Digenis G, Digenis A. Coated products with potent anti-HIV properties. US patent 5 492 692. February 20, 1996.
21. Elbary A, Nour S. Correlation between the spermicidal activity and the haemolytic index of certain plant saponins. Pharmazie. 1979;34(9):560–561. [PubMed]
22. Agha B, Garbolas G, Digenis G. Preparation of (131I) iodinated nonoxynol-9. J Labelled Comp Radiopharm. 1984;21(9):821–831. doi: 10.1002/jlcr.2580210906. [Cross Ref]
23. Lard S, Hastings K, Feigal D. Considerations in the development of vaginal products intended to prevent the sexual transmission of HIV. Washington, DC: United States Government Printing Office; 1994.
24. Pape W, Hoppe U. In vitro methods for the assessment of primary local effects of topically applied preparations. Skin Pharmacol. 1991;4(3):205–212. doi: 10.1159/000210950. [PubMed] [Cross Ref]
25. Pape W, Pfannenbecker U, Hoppe U. Validation of the red blood cell test system as in vitro assay for the rapid screening of irritation potential of surfactants. Mol Toxicol. 1987;1(4):525–536. [PubMed]
26. Sander F, Cramer S. A practical method for testing the spermicidal action of chemical contraceptives. Hum Fertil. 1941;6(5):134–137.
27. WHO Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction. 3rd ed. New York, NY: Cambridge University Press; 1992.
28. Goldsworthy T, Monticello T, Morgan K, et al. Examination of potential mechanisms of carcinogenicity of 1,4-dioxane in rat nasal epithelial cells and hepatocytes. Arch Toxicol. 1991;65(1):1–9. doi: 10.1007/BF01973495. [PubMed] [Cross Ref]
29. Kasraian K, DeLuca P. Thermal analysis of the tertiary butyl alcohol-water system and its implications on freeze-drying. Pharm Res. 1995;12(4):484–490. doi: 10.1023/A:1016233408831. [PubMed] [Cross Ref]
30. Kasraian K, DeLuca P. The effect of tertiary butyl alcohol on the resistance of the dry product layer during primary drying. Pharm Res. 1995;12(4):491–495. doi: 10.1023/A:1016285425670. [PubMed] [Cross Ref]
31. Ben-David A, Gavendo S. The protective effect of polyvinylpyrrolidone and hydroxyethyl starch on noncryogenic injury to red blood cells. Cryobiology. 1972;9:192–197. doi: 10.1016/0011-2240(72)90031-4. [PubMed] [Cross Ref]
32. Zavos PM, Correa JR, Nosek D, Mohammadi F, Digenis GA. Assessment of new formulations of nonoxynol-9 coprecipitated with polyvinylpyrrolidone and iodine as possible vaginal contraceptives. Fertil Steril. 1996;66(5):729–733. [PubMed]
33. Zavos PM, Correa JR, Nosek D, Mohammadi F, Digenis GA. Comparative spermicidal performance of iodinated and noniodinated contraceptive formulations of nonoxynol-9 coprecipitated with polyvinylpyrrolidone. Contraception. 1996;54:39–41. doi: 10.1016/0010-7824(96)00118-7. [PubMed] [Cross Ref]
34. Pandit N, Kanjia J. Phase behavior of nonionic surfactant solutions in the presence of polyvinylpyrrolidone. Int J Pharm. 1996;141:197–203. doi: 10.1016/0378-5173(96)04637-6. [Cross Ref]
35. Wolfinbarger, L. Process for cleaning large bone grafts and bone grafts produced thereby. US Patent 5 977 432. November 2, 1999.

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