Assessment of new formulations of nonoxynol-9 coprecipitated with polyvinylpyrrolidone and iodine as possible vaginal contraceptives.

OBJECTIVE: To assess the in vitro spermicidal activity of new formulations of nonoxynol-9, coprecipitated with polyvinylpyrrolidone (PVP) or iodinated PVP, against human spermatozoa via the use of the Sander-Cramer test and the cervical mucus penetration test. DESIGN: Solutions of PVP-nonoxynol-9 and iodinated PVP-nonoxynol-9 containing nonoxynol-9 whole molecule (oligomers 1 to 18) and its isolated fractions (oligomers 8 to 10, 4 to 6, and 1 to 3) at various concentrations (microgram/mL) were prepared via serial dilutions. Spermicidal solutions were mixed with human semen to determine the minimal lethal dose (microgram/mL). In the Sander-Cramer test, the lethal dose was reported as the minimal dose capable of killing spermatozoa within 20 seconds. In the cervical mucus penetration test, the lethal dose was reported as the minimal dose capable of preventing penetration of spermatozoa into cervical mucus beyond the second millimeter length of the capillary. SETTING: Andrology laboratory, University of Kentucky, Lexington, Kentucky. PATIENT(S): Normospermic male donors. MAIN OUTCOME MEASURE(S): Spermicidal lethal dose determination of various nonoxynol-9 preparations containing the whole nonoxynol-9 molecule and its isolated fractions coprecipitated with PVP or iodinated PVP. RESULT(S): The use of PVP increased the aqueous solubility of the nonoxynol-9 formulations containing oligomers 1 to 18 and 8 to 10 slightly. The coprecipitation of the nonoxynol-9 formulations containing nonoxynol-9 oligomers 4 to 6 and 1 to 3 with PVP significantly increased their solubilization and spermicidal action in vitro. Moreover, the incorporation of iodine significantly decreased the minimal nonoxynol-9 dose required for complete killing of spermatozoa in preparations containing nonoxynol-9 oligomers 4 to 6 and 1 to 3. CONCLUSION(S): Incorporation of all three components tested in this study (PVP, nonoxynol-9, and iodine) enhanced the efficiency of the spermicidal preparations, especially for nonoxynol-9 preparations containing nonoxynol-9 oligomers 4 to 6 and 1 to 3.

Comparative spermicidal performance of iodinated and non-iodinated contraceptive formulations of nonoxynol-9 co-precipitated with polyvinylpyrrolidone.

The objective of this study was to evaluate the spermicidal qualities of various combinations of nonoxynol-9 (N-9; whole molecule = oligomers 1-18) and its isolated fractions (oligomers 8-10, 4-6 and 1-3), co-precipitated with non-iodinated and/or iodinated (Io) polyvinylpyrrolidone (PVP) as possible vaginal contraceptives. Spermicidal qualities of known equimolar concentrations of various combinations of PVP/N-9 and PVP-Io/N-9 were tested via a modified Sander-Cramer test (SCT) using human spermatozoa. Spermicidal agents and semen samples were mixed 1:1 (v/v) and evaluated for sperm viability. Spermicidal activity was reported as the minimal concentration (microgram/mL) of spermicide capable of killing all spermatozoa within 20 sec after exposure to the spermicide. The spermicidal activity of PVP/N-9 and PVP-Io/N-9 preparations containing N-9 oligomers 1-18 and/or 8-10 was similar, and these preparations were more efficient in killing the spermatozoa than the ones containing N-9 oligomers 4-6 and 1-3. Polyvinyl-pyrrolidone proved to be an effective vehicle for PVP/N-9 and PVP-Io/N-9 preparations, especially those containing N-9 oligomers 4-6 and 1-3. Incorporation of Io into the spermicidal preparations brought about additional efficacy. The current findings could be of clinical significance in future studies when preparing and delivering those selected co-precipitates vaginally.

PIP: At the University of Kentucky in Lexington, pooled normospermic semen specimens collected after 3-4 days of sexual abstinence were co-precipitated with non-iodinated and/or iodinated (Io) polyvinylpyrrolidone (PVP) to determine the spermicidal qualities of various combinations of nonoxynol-9 (N-9) (oligomers 1-18) and its isolated fractions (oligomers 8-10, 4-6, and 1-3) as possible vaginal contraceptives. The Sander-Cramer test on human spermatozoa was used to test the spermicidal qualities of known equimolar concentrations of various combinations of PVP/N-9 and PVP-Io/N-9. The minimal lethal dose (LD) concentration (mcg/ml) of spermicide capable of killing all spermatozoa within 20 seconds after exposure to the spermicide was the definition of spermicidal activity. The LD of PVP/N-9 and PVP-Io/N-9 spermicidal preparations containing N-9 oligomers 1-18 and/or 8-10 was similar (165-166/mcg/ml for PVP/N-9 and 193-231/mcg/ml for PVP-Io/N-9). These particular preparations were more efficient in destroying spermatozoa than those containing N-9 oligomers 4-6 and 1-3 (p 0.05). PVP appeared to an efficient vehicle for the studied spermicides, particularly those containing N-9 oligomers 4-6 and 1-3. The addition of Io into PVP/N-9 preparations improved spermicidal activity, and significantly so, for N-9 oligomers 4-6 and 1-3 (495 mcg/ml for non-iodinated PVP/N-9 vs. 385 mcg/ml for PVP-Io/N-9; p 0.05). These findings will help future studies when the researchers prepare and deliver spermicides that co-precipitate vaginally.

Synthetic macromolecular inhibitors of human leukocyte elastase. 2. Effect of loading of a peptidyl carbamate inhibitor and molecular size of polymer backbone on its inhibitory capacity.

Several macromolecular inhibitors of human leukocyte elastase (HLE) were prepared by covalently bonding a low molecular weight HLE inhibitor peptidyl carbamate, p-nitrophenyl-N-[succinyl-L-alanyl-L-ananyl-L-prolylmethyl]- N-isopropyl carbamate 1, with the neutral hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide], PHEA 2. These novel polymeric compounds differed in the molecular size of their PHEA polymer backbone and the extent of loading of the peptidyl carbamate, (PC). They were shown to efficiently inhibit HLE (Ki = 97 to 12.8 nM) as intact macromolecular entities and were found to be more stable to hydrolysis than the non-polymer bound low molecular weight inhibitor 1. The inhibition of HLE by the novel macromolecular inhibitors was found to be noncompetitive and reversible, proceeding via slow formation of inhibitor-enzyme complex. The effect of loading of 1 and molecular size of the PHEA 2 polymer on enzymatic parameters Ki, kon and koff is discussed and a possible mechanism of inhibition is presented.

Novel vaginal controlled-delivery systems incorporating coprecipitates of nonoxynol-9.

The purpose of this study was to formulate Nonoxynol-9 (N-9) into a solid coprecipitate form which can be used in preparing pharmaceutically attractive and nonirritating vaginal controlled-release delivery systems (DDSs) such as gelatin capsules (HGC) and tablets. N-9 was coprecipitated with polyvinylpyrrolidone (PVP) with or without iodine to produce solid powders which were incorporated into either (a) bilayer tablet DDSs which possess a fast- (outer) and slow- (inner core) releasing compartment, and (b) HGC DDSs (named Triad HGC) composed of fast- (outer), intermediate- (granules), and slow- (pellets) releasing compartments. The rates of release of iodine and/or [14C]N-9 from the two DDSs were studied in vitro in phosphate buffer at pH 5.0, in human seminal plasma and in vivo after intravaginal administration in rabbits. In all of the above-described release studies, the DDSs were shown to release their N-9 or iodine content rapidly, reaching spermicidal levels within 3 min. This was further substantiated by experiments in which the DDSs were introduced in whole human semen containing live spermatozoa. Complete spermicidal kill was obtained in less than 1 min and in less than 3 min from the bilayer tablet and the Triad HGC, respectively. Furthermore, the release of N-9 from the two DDSs was shown to continue for at least 4 hr in buffers (pH 5.0), human seminal fluid, and after intravaginal administration in rabbits. The resulting powder from the coprecipitation of N-9 and PVP (K-30) can be appropriately formulated into a controlled-released HGC or bilayer tablet to produce vaginal controlled-release DDSs which are nonirritating and have the potential to become effective spermicidal products.