Evaluation of Vaginal Drug Levels and Safety of a Locally Administered Glycerol Monolaurate Cream in Rhesus Macaques

• Published in: Journal of pharmaceutical sciences Vol. 106; no. 7; pp. 1821 - 1827
• Main Authors: Kirtane, Ameya R., Rothenberger, Meghan K., Frieberg, Abby, Nephew, Karla, Schultz-Darken, Nancy, Schmidt, Thomas, Reimann, Thomas, Haase, Ashley T., Panyam, Jayanth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2017
• Subjects: Administration, Intravaginal; Animals; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Cytokines - analysis; drug delivery systems; Female; formulation; global health; HIV Infections - prevention & control; HIV/AIDS; Humans; Laurates - administration & dosage; Laurates - adverse effects; Laurates - pharmacokinetics; Macaca mulatta; Monoglycerides - administration & dosage; Monoglycerides - adverse effects; Monoglycerides - pharmacokinetics; pharmacokinetics; Rheology; Simian Acquired Immunodeficiency Syndrome - prevention & control; Simian Immunodeficiency Virus - drug effects; Vagina - drug effects; Vagina - metabolism; Vagina - microbiology; Vaginal Creams, Foams, and Jellies - adverse effects; Vaginal Creams, Foams, and Jellies - chemistry; HIV/AIDS; global health; pharmacokinetics; formulation; drug delivery systems
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1016/j.xphs.2017.03.030

The human immunodeficiency virus epidemic affects millions of people worldwide. As women are more vulnerable to infection, female-controlled interventions can help control the spread of the disease significantly. Glycerol monolaurate (GML), an inexpensive and safe compound, has been shown to protect against simian immunodeficiency virus infection when applied vaginally. However, on account of its low aqueous solubility, fabrication of high-dose formulations of GML has proven difficult. We describe the development of a vaginal cream that could be loaded with up to 35% GML. Vaginal drug levels and safety of 3 formulations containing increasing concentrations of GML (5%w/w, 15%w/w, and 35%w/w) were tested in rhesus macaques after vaginal administration. GML concentration in the vaginal tissue increased as the drug concentration in the cream increased, with 35% GML cream resulting in tissue concentration of ∼0.5 mg/g, albeit with high interindividual variability. Compared with the vehicle control, none of the GML creams had any significant effect on the vaginal flora and cytokine (macrophage inflammatory protein 3α and interleukin 8) levels, suggesting that high-dose GML formulations do not induce local adverse effects. In summary, we describe the development of a highly loaded vaginal cream of GML, and vaginal drug levels and safety after local administration in macaques.