Vaginal distribution and retention of a multiparticulate drug delivery system, assessed by gamma scintigraphy and magnetic resonance imaging

Mehta, Samata; Verstraelen, Hans; Peremans, Kathelijne; Villeirs, Geert; Vermeire, Simon; Vos, Filip De; Mehuys, Els; Remon, Jean Paul; Vervaet, Chris

doi:10.1016/j.ijpharm.2012.01.006

Cited by 30 publications

(15 citation statements)

References 26 publications

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“…This is an interesting result considering that the time-averaged daily TFV release from the IVR, as determined by residual drug extraction, was less than one-half of the daily TFV gel dose. The percentage of dosed TFV absorbed following TFV 1% vaginal gel administration has not been reported, but it is likely that a significant fraction is not absorbed because the gel leaks out of the vaginal tract (2,33). The gel more rapidly achieved high TFV vaginal and systemic concentrations and therefore may be advantageous for coitally dependent, intermittent use when it is applied just prior to sex (similar to CAPRISA 004 dosing).…”

Section: Fig 7 Proximal and Distal Tfv Vaginal Tissue Concentrations mentioning

confidence: 99%

“…The vaginal microflora species and vaginal fluid pH of sheep and women are generally different, although large variation in both variables exists in both populations (29,31,57). Another limitation of sheep is their seasonal breeding and shorter estrous cycle (approximately 17 days) compared to women, a difference which may potentially alter drug pharmacokinetics via changes in vaginal epithelium thickness and permeability (33,39). The estrous cycle was not monitored or controlled in this study, and future studies may be justified to understand whether or not this variable significantly alters local or systemic drug pharmacokinetics.…”

Section: Fig 7 Proximal and Distal Tfv Vaginal Tissue Concentrations mentioning

confidence: 99%

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A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

Johnson

Clark

Albright

et al. 2012

Antimicrob Agents Chemother

117

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A vaginal gel containing the antiretroviral tenofovir (TFV) recently demonstrated 39% protection against HIV infection in women. We designed and evaluated a novel reservoir TFV intravaginal ring (IVR) to potentially improve product effectiveness by providing a more controlled and sustained vaginal dose to maintain cervicovaginal concentrations. Polyurethane tubing of various hydrophilicities was filled with a high-density TFV/glycerol/water semisolid paste and then end-sealed to create IVRs. In vitro, TFV release increased with polyurethane hydrophilicity, with 35 weight percent water-swelling polyurethane IVRs achieving an approximately 10-mg/day release for 90 days with mechanical stiffness similar to that of the commercially available NuvaRing. This design was evaluated in two 90-day in vivo sheep studies for TFV pharmacokinetics and safety. Overall, TFV vaginal tissue, vaginal fluid, and plasma levels were relatively time independent over the 90-day duration at approximately 10 4 ng/g, 10 6 ng/g, and 10 1 ng/ml, respectively, near or exceeding the highest observed concentrations in a TFV 1% gel control group. TFV vaginal fluid concentrations were approximately 1,000-fold greater than levels shown to provide significant protection in women using the TFV 1% gel. There were no toxicological findings following placebo and TFV IVR treatment for 28 or 90 days, although slight to moderate increases in inflammatory infiltrates in the vaginal epithelia were observed in these animals compared to naïve animals. In summary, the controlled release of TFV from this reservoir IVR provided elevated sheep vaginal concentrations for 90 days to merit its further evaluation as an HIV prophylactic. R ecent progress in antiretroviral HIV prevention research has advanced the field from concept toward medical practice (46). The CAPRISA 004 study demonstrated that a vaginal gel containing the reverse transcriptase inhibitor tenofovir (TFV) was partially effective in preventing HIV transmission in women (1), with significant protection observed in women who maintained preventative TFV concentrations of at least 1,000 ng/ml in vaginal fluid (23). However, the overall effectiveness (39%) was likely reduced by poor user adherence to the inconvenient before-andafter-sex dosing regimen. The correlation of adherence and TFV vaginal fluid concentrations to protection was a key finding (23,24), indicating the need for vaginal drug delivery systems that attain and maintain elevated user adherence and vaginal drug concentrations. More recently, the VOICE trial tested the same TFV 1% gel formulation as CAPRISA 004 but with a once-daily dosage regimen and failed to show any effectiveness in women. Here, as well, low adherence may have contributed to the gel's inability to prevent HIV transmission (54). As a result, we (6, 21) and others (4,35,36,44,49) aim to develop TFV drug delivery systems to provide sustained protective vaginal tissue concentrations and potentially increase user adherence.The micromolar anti-HIV activity of TFV motivated sel...

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Section: Fig 7 Proximal and Distal Tfv Vaginal Tissue Concentrations mentioning

confidence: 99%

Section: Fig 7 Proximal and Distal Tfv Vaginal Tissue Concentrations mentioning

confidence: 99%

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

Johnson

Clark

Albright

et al. 2012

Antimicrob Agents Chemother

117

View full text Add to dashboard Cite

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“…In a sheep model characterized as a good model for the human vagina, 32–34 we explored the use of OCT to measure vaginal epithelial thickness after the application of vaginal products and noninvasively monitored changes in the vaginal epithelial thickness over time. Whereas prior studies have focused on developing a scoring system for noninvasive assessment of epithelial disruption, the current study focuses on noninvasive longitudinal measurement of epithelial thickness, comparing OCT to histology findings.…”

Section: Introductionmentioning

confidence: 99%

Monitoring vaginal epithelial thickness changes noninvasively in sheep using optical coherence tomography

Vincent

Vargas

Wei

et al. 2013

American Journal of Obstetrics and Gynecology

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Objective High-resolution optical coherence tomography (OCT), can be used noninvasively to evaluate vaginal morphologic features, including epithelial thickness, to assess this protective barrier in transmission of sexually transmitted infections and to monitor tissue response to topical medications and hormonal fluctuations. We examined the utility of OCT to measure epithelial thickness noninvasively before and after topical treatment with a drug that causes epithelial thinning. Study Design Twelve female sheep were treated with intravaginal placebo (n=4) or nonoxynol-9 (n=8). Vaginal OCT images were obtained before and 24 hours after treatment. Four sheep in the nonoxynol-9 group were also examined on days 3 and 7. Vaginal biopsies were obtained on the last exam day. Epithelial thickness was measured in OCT images and in H&E-stained histological sections from biopsies. Statistical analysis was performed using ANOVA (significance p<0.05). Results Baseline OCT epithelial thickness measurements were similar (85±19 μm placebo, 78±20 μm nonoxynol-9; p=0.52). Epithelial thinning was significant after nonoxynol-9 (32±22 μm) compared to placebo (80±15 μm) 24 hours after treatment (p<0.0001). In the four nonoxynol-9-treated sheep followed for 7 days, epithelial thickness returned to baseline by day 3, and increased significantly on day 7. Epithelial thickness measurements from histology were not significantly different than OCT (p=0.98 N-9, p=0.93 HEC). Conclusion Drug-induced changes in the epithelium were clearly detectable using OCT imaging. OCT and histology epithelial thickness measurements were similar, validating OCT as a noninvasive method for epithelial thickness measurement, providing an important tool for quantitative and longitudinal monitoring of vaginal epithelial changes.

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“…Exploratory treatments for restoring the healthy vaginal environment and preventing BV infection include oral/vaginal administration of probiotics and vaginal acidification [49–52]. However, current intra vaginal gel formulations show poor retention in the vagina and are hence ineffective due to insufficient concentrations of the active agent in the vagina [25–27]. Therefore, the present study aims at developing PEG-based hydrogels: (1) for the controlled release of lactic acid to maintain vaginal acidity for a prolonged period of time, and (2) with viscoelastic properties to prevent leakage and improve vaginal retention.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials of semi-solid gel microbicides suggest that one of the reasons for their poor in vivo performance might be the inadequate retention of the gel itself resulting in insufficient concentrations of active agents in the vagina. Semi-solid gels have been reported to leak from the vagina within a few hours of application [25–27]. In fact, BufferGel and Acidform are currently being evaluated for contraceptive use and BufferGel has been shown to be effective only when used in combination with a diaphragm [28, 29].…”

Section: Introductionmentioning

confidence: 99%

Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment

Rajan

Turovskiy

Singh

et al. 2014

Journal of Controlled Release

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Women with bacterial vaginosis (BV) display reduced vaginal acidity, which make them susceptible to associated infections such as HIV. In the current study, poly(ethylene glycol) (PEG) nanocarrier-based degradable hydrogels were developed for the controlled release of lactic acid in the vagina of BV-infected women. PEG-lactic acid (PEG-LA) nanocarriers were prepared by covalently attaching lactic acid to 8-arm PEG-SH via cleavable thioester bonds. PEG-LA nanocarriers with 4 copies of lactic acid per molecule provided controlled release of lactic acid with a maximum release of 23% and 47% bound lactic acid in phosphate buffered saline (PBS, pH 7.4) and acetate buffer (AB, pH 4.3), respectively. The PEG nanocarrier-based hydrogels were formed by cross-linking the PEG-LA nanocarriers with 4-arm PEG-NHS via degradable thioester bonds. The nanocarrier-based hydrogels formed within 20 min under ambient conditions and exhibited an elastic modulus that was 100-fold higher than the viscous modulus. The nanocarrier-based degradable hydrogels provided controlled release of lactic acid for several hours; however, a maximum release of only 10%–14% bound lactic acid was observed possibly due to steric hindrance of the polymer chains in the cross-linked hydrogel. In contrast, hydrogels with passively entrapped lactic acid showed burst release with complete release within 30 min. Lactic acid showed antimicrobial activity against the primary BV pathogen Gardnerella vaginalis with a minimum inhibitory concentration (MIC) of 3.6 mg/ml. In addition, the hydrogels with passively entrapped lactic acid showed retained antimicrobial activity with complete inhibition G. vaginalis growth within 48 h. The results of the current study collectively demonstrate the potential of PEG nanocarrier-based hydrogels for vaginal administration of lactic acid for preventing and treating BV.

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Vaginal distribution and retention of a multiparticulate drug delivery system, assessed by gamma scintigraphy and magnetic resonance imaging

Cited by 30 publications

References 26 publications

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

Monitoring vaginal epithelial thickness changes noninvasively in sheep using optical coherence tomography

Poly(ethylene glycol) (PEG)-lactic acid nanocarrier-based degradable hydrogels for restoring the vaginal microenvironment

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