While the Stokes-Einstein ͑SE͒ equation predicts that the diffusion coefficient of a solute will be inversely proportional to the viscosity of the solvent, this relation is commonly known to fail for solutes, which are the same size or smaller than the solvent. Multiple researchers have reported that for small solutes, the diffusion coefficient is inversely proportional to the viscosity to a fractional power, and that solutes actually diffuse faster than SE predicts. For other solvent systems, attractive solute-solvent interactions, such as hydrogen bonding, are known to retard the diffusion of a solute. Some researchers have interpreted the slower diffusion due to hydrogen bonding as resulting from the effective diffusion of a larger complex of a solute and solvent molecules. We have developed and used a novel micropipette technique, which can form and hold a single microdroplet of water while it dissolves in a diffusion controlled environment into the solvent. This method has been used to examine the diffusion of water in both n-alkanes and n-alcohols. It was found that the polar solute water, diffusing in a solvent with which it cannot hydrogen bond, closely resembles small nonpolar solutes such as xenon and krypton diffusing in n-alkanes, with diffusion coefficients ranging from 12.5ϫ 10 −5 cm 2 / s for water in n-pentane to 1.15ϫ 10 −5 cm 2 / s for water in hexadecane. Diffusion coefficients were found to be inversely proportional to viscosity to a fractional power, and diffusion coefficients were faster than SE predicts. For water diffusing in a solvent ͑n-alcohols͒ with which it can hydrogen bond, diffusion coefficient values ranged from 1.75ϫ 10 −5 cm 2 / s in n-methanol to 0.364ϫ 10 −5 cm 2 / s in n-octanol, and diffusion was slower than an alkane of corresponding viscosity. We find no evidence for solute-solvent complex diffusion. Rather, it is possible that the small solute water may be retarded by relatively longer residence times ͑compared to non-H-bonding solvents͒ as it moves through the liquid.

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbit and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a TAF dose of 10 μg/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. The level of inflammation in the primates was markedly lower in the placebo group than in the active-implant group. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve a sustained target dose, we observed an unacceptable inflammatory response locally at the implant tissue interface.

The Epstein Plesset equation has recently been shown to accurately predict the dissolution of a pure liquid microdroplet into a second immiscible solvent, such as oil into water. Here, we present a series of new experiments and a modification to this equation to model the dissolution of a two-component oil-mixture microdroplet into a second immiscible solvent, in which the two materials of the droplet have different solubilities. The model is based upon a reduced surface area approximation and the assumption of ideal homogenous mixing: Mass0.16667emfluxdmidt=AfraciDifalse(ci-csfalse){1R+1πDit}, where Afraci is the area fraction of component I; ci and cs are the initial and saturation concentrations of the droplet material in the surrounding medium; R is the radius of the droplet; t is time; and Di is the coefficient of diffusion of component I in the surrounding medium. This new model has been tested by use of a two-chamber micropipette-based method, which measured the dissolution of single individual microdroplets of mutually-miscible liquid mixtures (ethyl acetate/butyl acetate, and butyl acetate/amyl acetate) into water. We additionally measured the diffusion coefficient of the pure materials: ethyl acetate, butyl acetate, and amyl acetate, in water at 22 deg C. Diffusion coefficients for the pure acetates in water were: 8.65 x 10−6, 7.61 x 10−6, and 9.14 x 10−6 cm2/s respectively. This model accurately predicts the dissolution of microdroplets for the ethyl acetate/butyl acetate and butyl acetate/amyl acetate systems given the solubility and diffusion coefficients of each of the individual components in water as well as the initial droplet radius. The average mean squared error was 8.96%. The dissolution of a spherical ideally mixed multi-component droplet closely follows the modified Epstein Plesset model presented here.

Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV. Permeability studies demonstrated that TDF, but not TFV, entered cells by passive diffusion. TDF uptake was energy independent but its accumulation followed nonlinear kinetics, and excess unlabeled TDF inhibited radiolabeled TDF uptake in competition studies. The carboxylesterase inhibitor bis-nitrophenyl phosphate reduced TDF uptake, suggesting saturability of intracellular carboxylesterases. In contrast, although TFV uptake was energy dependent, no competition between unlabeled and radiolabeled TFV was observed, and the previously identified transporters, organic anion transporters ( T opical preexposure prophylaxis (PrEP) with tenofovir (TFV)-based drugs could provide a female-initiated method for the prevention of HIV and genital herpes simplex virus (HSV) infections in women (1). Pericoital dosing with 1% vaginal TFV gel reduced HIV acquisition by 39% overall and by 54% in highly adherent women (2, 3) and reduced HSV-2 acquisition by 51% in the CAPRISA 004 trial (4). However, the same gel did not provide protection against HIV in the Vaginal and Oral Interventions to Control the Epidemic (VOICE) and Follow-On Consortium for Tenofovir Studies (FACTS) 001 phase 3 trials, presumably reflecting low adherence (5, 6). Women with detectable TFV in their plasma at the first quarterly visit were less likely to acquire HIV than women with no drug detected (adjusted hazard ratio, 0.34; 95% confidence interval [CI], 0.13 to 0.87; P ϭ 0.02) in a secondary analysis of VOICE data, but the interpretation of this is complex, as women at highest risk for HIV acquisition were less likely to be adherent (5). These findings underscore the need for drugs and delivery systems that mitigate the difficulties associated with adherence.Intravaginal rings (IVRs) designed to deliver TFV and tenofovir disoproxil fumarate (TDF) are currently in early clinical development (7,8). A TDF ring completely protected macaques against 16 weekly intravaginal challenges with simian HIV (8) and also was highly protective in more susceptible, medroxyprogesteronetreated animals (9). Nonhuman primate challenge studies with the TFV IVR have not been published. Consistent with in vitro antiviral studies, 0.3% TDF gel provided significantly greater protection than 1% TFV gel in mice challenged intravaginally with HSV-2 (10). Moreover, the 0.3% TDF gel demonstrated significantly greater protection than 1% TFV gel in mice transgenic for human CD4, CCR5, and cyclin T1 against HIV and HSV-2 (11). These findings may reflect differences in drug pharmacokinetics (PK).The mechanisms of TFV and TDF cellular tran...