The development of vaginal microbicides for the prevention of sexual transmission of HIV is becoming an increasingly important strategy in the battle against the AIDS epidemic. Several first generation microbicide candidates are entering Phase III efficacy trials, and several other candidates are in earlier stages of clinical development. The capacity to make accurate clinical assessments of the safety and efficacy of microbicide formulations is critical. Since microbicide trials will rely on a blinded, randomized, placebo-controlled design, it is important to employ a placebo formulation that does not distort either safety or efficacy assessments. Efficacy of the microbicide would be underestimated if the placebo itself provided a degree of protection. Conversely, a placebo with epithelial toxicity that increased susceptibility would cause an overestimation of microbicide efficacy. To address these issues, a hydroxyethylcellulose (HEC) placebo formulation has been developed and has been adopted for use in clinical evaluations of investigational microbicides as a "universal" placebo. In this report, the chemical and physical properties of this formulation are described, as well as its in vitro and in vivo effects on safety and efficacy. The results show that this "universal" placebo has adequate physical properties, is sufficiently stable as a vaginal gel formulation, and is safe and sufficiently inactive for use in the clinical study of investigational microbicides.

Alkyl betaines and alkyl dimethylamine oxides have been shown to have pronounced antimicrobial activity when used individually or in combination. Although several studies have been conducted with these compounds in combinations, only equimolar concentrations of the C 12 /C 12 and C 16 /C 14 chain lengths for the betaine and the amine oxide, respectively, have been investigated. This study investigates the antimicrobial activity of a wide range of chain lengths (C 8 to C 18 ) for both the betaine and amine oxide and attempts to correlate their micelle-forming capabilities with their biological activity. A broth microdilution method was used to determine the MICs of these compounds singly and in various molar ratio combinations. Activity against both Staphylococcus aureus and Escherichia coli was investigated. Antimicrobial activity was found to increase with increasing chain length for both homologous series up to a point, exhibiting a cutoff effect at chain lengths of approximately 16 for betaine and 14 for amine oxide. Additionally, the C 18 oleyl derivative of both compounds exhibited activity in the same range as the peak alkyl compounds. Critical micelle concentrations were correlated with MICs, inferring that micellar activity may contribute to the cutoff effect in biological activity.As more resistant organisms continue to emerge in society, the identification of additional antimicrobial agents becomes increasingly more important. Compounds such as surfactants are an area to be investigated. Betaines and amine oxides, two types of amphoteric surfactants, have been shown to exhibit antimicrobial activity against a variety of microorganisms (7,16,18,25). Although each of these compounds has shown pronounced activity alone, they have also been used in combination to exhibit a synergistic effect (6).An equimolar mixture of N-alkyl betaine and N-alkyl-N,Ndimethylamine oxide was patented in 1978 in a compound called C31G (17). With chain lengths ranging from C 8 to C 18 and buffered in a citrate buffer, C31G was first shown to have pronounced wound healing and deodorizing effects, as well as antimicrobial sensitivity. Further studies showed C31G has exhibited pronounced activity not only against bacteria, but also against yeasts, fungi, sperm, and enveloped viruses (4,6,14,23). Although several studies have been published about this compound in reference to the extent of antimicrobial activity, little work has been conducted with any other chain lengths besides the following two chain-length combinations: (i) C 12 betaine-C 12 amine oxide and (ii) C 16 betaine-C 14 amine oxide. Additionally, only an equimolar ratio of the two components has been investigated.The structures of these two components are shown in Fig. 1. The variation in length of the long hydrocarbon tail is thought to influence the extent of antimicrobial activity. Like most other surfactants, they are believed to be membrane perturbants, disrupting the cell membrane of the microorganism (26). It is believed that interaction with the surface of th...

BackgroundThe objective of this study is to identify the critical formulation parameters controlling distribution and function for the rectal administration of microbicides in humans. Four placebo formulations were designed with a wide range of hydrophilic characteristics (aqueous to lipid) and rheological properties (Newtonian, shear thinning, thermal sensitive and thixotropic). Aqueous formulations using typical polymers to control viscosity were iso-osmotic and buffered to pH 7. Lipid formulations were developed from lipid solvent/lipid gelling agent binary mixtures. Testing included pharmaceutical function and stability as well as in vitro and in vivo toxicity.ResultsThe aqueous fluid placebo, based on poloxamer, was fluid at room temperature, thickened and became shear thinning at 37°C. The aqueous gel placebo used carbopol as the gelling agent, was shear thinning at room temperature and showed a typical decrease in viscosity with an increase in temperature. The lipid fluid placebo, myristyl myristate in isopropyl myristate, was relatively thin and temperature independent. The lipid gel placebo, glyceryl stearate and PEG-75 stearate in caprylic/capric triglycerides, was also shear thinning at both room temperature and 37°C but with significant time dependency or thixotropy. All formulations showed no rectal irritation in rabbits and were non-toxic using an ex vivo rectal explant model.ConclusionsFour placebo formulations ranging from fluid to gel in aqueous and lipid formats with a range of rheological properties were developed, tested, scaled-up, manufactured under cGMP conditions and enrolled in a formal stability program. Clinical testing of these formulations as placebos will serve as the basis for further microbicide formulation development with drug-containing products.

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