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Objectives To evaluate pharmacokinetics (PK) of a single dose of an investigational 2% clindamycin phosphate vaginal gel in healthy women by assessment of plasma and vaginal clindamycin concentrations over 7 days, and assess safety. Methods Single-centre, Phase 1, single-dose PK study. Blood and vaginal samples were collected daily and safety was evaluated through to Day 7. Results Twenty-one subjects were enrolled; 20 completed the study. Plasma clindamycin concentrations demonstrated quantifiable values in all subjects through to 24 h post-dose, remaining above the limits of quantification (LOQ) through to 48 h for the majority of subjects. Systemic exposure (AUC0–t) was 1179 (range 62–3822) h·ng/mL. Arithmetic mean AUC0–24 was 818 (range 51–3287) h·ng/mL. Vaginal clindamycin phosphate levels were relatively high 24 h following administration in 15/21 subjects (6 subjects had values >400 µg/g and 9 had values of 100–400 µg/g). The levels dropped in most participants to below the LOQ 2 days following dosing. In a few participants, levels remained elevated for several days. Maximal amounts of vaginal clindamycin occurred on Day 2 with a mean value of 30.3 µg. One treatment-emergent adverse event (TEAE) of moderate-severity headache not related to study drug was reported and resolved on Day 1. No TEAEs were related to physical examinations, pelvic examinations, laboratory values or vital signs. Conclusions The vaginal concentrations of clindamycin phosphate plus the clindamycin plasma profile over time are consistent with release of drug from the investigational gel over 24 to 72 h. A single dose was well tolerated.

This study reports the preparation, in vitro release, pharmacokinetics, and local tolerability of novel ethylene-vinyl acetate intravaginal rings (IVRs) delivering 17β-estradiol (E2) and progesterone (P), in drug-naive ovariectomized female Dorset crossbred sheep. After preparation and assessment of in vitro release of E2 and P, animals were randomized to treatment groups 1 or 2 (comparator rings releasing 50 or 100 μg/d E2, respectively), groups 3 or 4 (ethylene-vinyl acetate IVRs, 160 μg/d E2 with 4 [160/4 IVR] or 8 mg/d P [160/8 IVR], respectively), or group 5 (160 μg E2 and 10 mg P administered intravenously). IVRs were placed on day 1 and remained in place through day 29. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on groups 1-4 were macroscopic and microscopic evaluations, including irritation scoring and histopathology. IVRs were retained over 28 days in all but 1 animal (group 4). In all animal groups, clinical observations showed no significant abnormal findings. Pharmacokinetic analysis in the animals showed sustained release of E2 and P over a 28-day period. Irritation scores and microscopic assessments were consistent with foreign object placement. A novel 2-drug IVR delivery system was well tolerated in a sheep model and pharmacokinetic release was as expected over a 28-day release period. These results will guide future human clinical studies.

The objectives of this work were to evaluate the in vitro release and in vivo pharmacokinetics and local tolerability of a novel, segmented ethylene-vinyl acetate (EVA) intravaginal ring (IVR) delivering progesterone (P) in drug-naive ovariectomized female Dorset crossbred sheep. Following preparation and assessment of in vitro release of P, animals were randomized into one of six treatment groups: group 1 Crinone® 8% gel (90 mg); group 2 Prometrium® 200-mg capsules; group 3 placebo IVR; group 4 progesterone (P) IVR 4 mg/day; group 5 P IVR 8 mg/day; or group 6 P IVR 12 mg/day. Crinone 8% gel and Prometrium capsules were administered once daily for 28 days. IVRs were inserted vaginally on day 1 and remained in place through day 14; a new ring was administered on day 15 and was removed at day 28. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on all IVR groups included vaginal irritation, macroscopic, and microscopic evaluations, including irritation scoring and histopathology. Intravaginal rings were retained over 28 days in all animals. Clinical observations showed no significant abnormal findings in any group. Pharmacokinetic analysis in animals showed sustained release of P over from days 0 through 14 of ring use. Irritation scores and microscopic assessments were consistent with the IVRs being well tolerated. These results will guide future human clinical studies to ultimately develop an IVR for use in women for the prevention of preterm birth.

The development of pericoital (on demand) vaginal HIV prevention technologies remains a global health priority. Clinical trials to date have been challenged by nonadherence, leading to an inability to demonstrate product efficacy. The work here provides new methodology and results to begin to address this limitation. We created validated scales that allow users to characterize sensory perceptions and experiences when using vaginal gel formulations. In this study, we sought to understand the user sensory perceptions and experiences (USPEs) that characterize the preferred product experience for each participant. Two hundred four women evaluated four semisolid vaginal formulations using the USPE scales at four randomly ordered formulation evaluation visits. Women were asked to select their preferred formulation experience for HIV prevention among the four formulations evaluated. The scale scores on the Sex-associated USPE scales (e.g., Initial Penetration and Leakage) for each participant's selected formulation were used in a latent class model analysis. Four classes of preferred formulation experiences were identified. Sociodemographic and sexual history variables did not predict class membership; however, four specific scales were significantly related to class: Initial Penetration, Perceived Wetness, Messiness, and Leakage. The range of preferred user experiences represented by the scale scores creates a potential target range for product development, such that products that elicit scale scores that fall within the preferred range may be more acceptable, or tolerable, to the population under study. It is recommended that similar analyses should be conducted with other semisolid vaginal formulations, and in other cultures, to determine product property and development targets.

Vaginal microbicide gels containing tenofovir have proven effective in HIV prevention, offering the advantage of reduced systemic toxicity. We studied the vaginal distribution and effect on mucosal permeability of a gel vehicle. Six premenopausal women were enrolled. In Phase 1, a spreading gel containing (99m)technetium-DTPA ((99m)Tc) radiolabel and gadolinium contrast for magnetic resonance imaging (MRI) was dosed intravaginally. MRI was obtained at 0.5, 4, and 24 h, and single photon emission computed tomography with conventional computed tomography (SPECT/CT) at 1.5, 5, and 25 h postdosing. Pads and tissues were measured for activity to determine gel loss. In Phase 2, nonoxynol-9 (N-9), containing (99m)Tc-DTPA, was dosed as a permeability control; permeability was measured in blood and urine for both phases. SPECT/CT showed the distribution of spreading gel throughout the vagina with the highest concentration of radiosignal in the fornices and ectocervix; signal intensity diminished over 25 h. MRI showed the greatest signal accumulation in the fornices, most notably 1-4 h postdosing. The median (interquartile range) isotope signal loss from the vagina through 6 h was 29.1% (15.8-39.9%). Mucosal permeability to (99m)Tc-DTPA following spreading gel was negligible, in contrast to N-9, with detectable radiosignal in plasma, peaking at 8 h (5-12). Following spreading gel dosing, 0.004% (0.001-2.04%) of the radiosignal accumulated in urine over 12 h compared to 8.31% (7.07-11.01%) with N-9, (p=0.043). Spreading gel distributed variably throughout the vagina, persisting for 24 h, with signal concentrating in the fornices and ectocervix. The spreading gel had no significant effect on vaginal mucosal permeability.

Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups, however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form.

Endometriosis and uterine fibroids (also known as uterine leiomyomas) are serious medical conditions affecting large numbers of women worldwide. Many women are asymptomatic but those with symptoms require medical intervention to relieve chronic pain and dysmenorrhea and to address infertility. Drug delivery has played a role in reducing some of the symptoms associated with endometriosis and uterine fibroids. Use of drug delivery systems for both conditions can roughly be divided into two categories: (1) existing systems designed for other indications such as contraception for symptomatic relief and (2) development of novel systems aimed at addressing some of the underlying biochemical changes associated with endometriosis and uterine fibroids such as oxidative stress, angiogenesis, and matrix degradation. The latter drug delivery approaches rely heavily on nanotechnology. Existing systems that deliver estrogens and/or progestins include vaginal rings, transdermal patches, and intrauterine systems. Long-acting implantable contraceptives such as Implanon® and injectables such as Depo-Provera® have found use in treating endometriosis. Similarly, long-acting GnRH products (e.g., Lupron Depot®) are used to treat endometriosis. Other drugs formulated in long-acting formulations include intravaginal rings capable of delivering selective progesterone receptor modulators, androgens such as danazol, and aromatase inhibitors (e.g., anastrozole). Nanoparticles composed of silica, poly(lactic-co-glycolic acid), cerium oxide, dendrimers, and chitosan/polyethyleneamine have all been investigated to improve treatment of endometriosis and to a lesser extent, uterine fibroids.

Vaginal rapidly disintegrating tablets (RDTs) containing tenofovir (TFV) or TFV and emtricitabine (FTC) were evaluated for safety and pharmacokinetics in pigtailed macaques. Two separate animal groups ( n = 4) received TFV (10 mg) or TFV-FTC (10 mg each) RDTs, administered near the cervix. A third group ( n = 4) received 1 ml TFV gel. Blood plasma, vaginal tissue biopsy specimens, and vaginal fluids were collected before and after product application at 0, 0.5, 1, 4, and 24 h. A disintegration time of 4 to 10 5 ng/g (147 to 571 μM) and 10 6 ng/g (12 to 34 mM), respectively, at 1 to 4 h postdose. At 24 h, however, TFV vaginal tissue levels were more sustained after RDT dosing, with median TFV concentrations being approximately 1 log higher than those with gel dosing. FTC pharmacokinetics after combination RDT dosing were similar to those of TFV, with peak median vaginal tissue and fluid levels being on the order of 10 4 ng/g (374 μM) and 10 6 ng/g (32 mM), respectively, at 1 h postdose with levels in fluid remaining high at 24 h. RDTs are a promising alternative vaginal dosage form, delivering TFV and/or FTC at levels that would be considered inhibitory to simian-human immunodeficiency virus in the macaque vaginal microenvironment over a 24-h period.

The effectiveness of any biomedical prevention technology relies on both biological efficacy and behavioral adherence. Microbicide trials have been hampered by low adherence, limiting the ability to draw meaningful conclusions about product effectiveness. Central to this problem may be an inadequate conceptualization of how product properties themselves impact user experience and adherence. Our goal is to expand the current microbicide development framework to include product "perceptibility," the objective measurement of user sensory perceptions (i.e., sensations) and experiences of formulation performance during use. For vaginal gels, a set of biophysical properties, including rheological properties and measures of spreading and retention, may critically impact user experiences. Project LINK sought to characterize the user experience in this regard, and to validate measures of user sensory perceptions and experiences (USPEs) using four prototype topical vaginal gel formulations designed for pericoital use. Perceptibility scales captured a range of USPEs during the product application process (five scales), ambulation after product insertion (six scales), and during sexual activity (eight scales). Comparative statistical analyses provided empirical support for hypothesized relationships between gel properties, spreading performance, and the user experience. Project LINK provides preliminary evidence for the utility of evaluating USPEs, introducing a paradigm shift in the field of microbicide formulation design. We propose that these user sensory perceptions and experiences initiate cognitive processes in users resulting in product choice and willingness-to-use. By understanding the impact of USPEs on that process, formulation development can optimize both drug delivery and adherence.

Vaginally delivered tamoxifen is being developed as alternative to estrogen-based therapies for the treatment of vulvar and vaginal atrophy (VVA) symptoms in subjects at high risk for breast cancer, undergoing treatment for breast cancer with aromatase inhibitors or are breast cancer survivors. Tamoxifen (1 or 20 mg) was administered intra-vaginally to female rabbits once-daily over a 28-day period to assess its pharmacokinetics, systemic exposure and local vaginal tolerance. Plasma samples were taken to assess concentrations of tamoxifen and its metabolites 4-hydroxytamoxifen and N-desmethyltamoxifen over the first day of vaginal administration and following the last dose on Day 28. In-life observations included evaluation of the vaginal region for signs of irritation. At necropsy, vaginal irritation was assessed by the method of Eckstein which reflect collective histopathological grading of four parameters within the vagina including epithelial morphology, leukocytic infiltration, congestion, and edema. Uterine effects of vaginal tamoxifen were also assessed. Plasma concentrations of tamoxifen were higher following administration of 20 mg tamoxifen compared to 1 mg tamoxifen at both Day 1 and Day 28. The metabolite 4-hydroxytamoxifen could not be detected on Day 1 and concentrations were low at Day 28 at the 1 mg tamoxifen dose. 4-Hydroxytamoxifen concentrations were low, but detectable at Day 1 and 28 following administration of 20 mg tamoxifen. The metabolite N-desmethyltamoxifen was undetectable at the 1 mg and 20 mg doses on Day 1; it remained undetectable at the 1 mg tamoxifen dose at Day 28. N-desmethyltamoxifen was detected over the first 8 h of Day 28 then fell below the quantitation limits. There was little to no vaginal or systemic accumulation of tamoxifen following once-daily dosing for 28 days. Tamoxifen accounted for more than 85% of the total systemic exposure compared to its metabolites, 4-hydroxytamoxifen, and N-desmethyltamoxifen. There was essentially no detectable vaginal irritation evident over the course of the study. At necropsy the individual Eckstein scores (maximum score of 16) of the proximal, mid, and distal vagina of females in the 1 mg and 20 mg dose groups were generally comparable in both groups and ranged from minimal to mild magnitude (1 mg dose group: ranging from 1 to 3 in the proximal vagina, 4 to 5 in the mid vagina, and 3 to 7 in the distal vagina; 20 mg dose group: ranging from 3 to 5 in the proximal vagina, 4 to 7 in the mid vagina, and 4 to 5 in the distal vagina). Overall, tamoxifen was absorbed and metabolized following vaginal administration and vaginal irritation was minimal to none at both doses.

Multipurpose prevention technologies (MPTs) are broadly defined as products capable of simultaneously addressing multiple sexual and reproductive health needs including unintended pregnancy, STIs including HIV-1, and other reproductive tract infections. MPTs have been discussed for a few decades but little product development has occurred. With the recent proof-of-concept that a topically applied antiretroviral (ARV) can effectively reduce sexual transmission of HIV-1 (tenofovir 1% gel) the impetus to develop MPTs is gaining momentum. Products currently in development are broadly categorized as either long-acting or on-demand. Long-acting MPTs include intravaginal rings (IVRs) and long-acting injectable products. Several IVR MPTs are under development including one designed to release tenofovir to prevent transmission of HIV-1 and levonorgestrel (LNG) to prevent unintended pregnancy over a 90-day period. Another MPT IVR under development is designed to release the ARV dapivirine and LNG for 2 months. Long-acting injectable pre-exposure prophylaxis (PrEP) formulations of rilpivirine (TMC278) and GSK1265744 have entered clinical evaluation and could form the basis of long-acting injectable products for HIV-1 prevention and prevention of unintended pregnancy. On-demand products include TFV 1% gel (HIV-1/HSV-2 prevention), a zinc/carrageenan zinc gel (HIV-1/HSV-2 prevention), and the SILCS diaphragm administered with TFV 1% gel. Significant technical, funding, and regulatory hurdles must be overcome to develop most MPTs; however, the significant reproductive health benefits to many women around the world should provide motivation to overcome these hurdles. This article is based on a presentation at the "Product Development Workshop 2013: HIV and Multipurpose Prevention Technologies", held in Arlington, Virginia on February 21-22, 2013. It forms part of a special supplement to Antiviral Research.

The development of topically applied products capable of preventing vaginal and rectal transmission of HIV-1 has been on-going for nearly 20 years. Despite this, only one clinical trial has demonstrated protection against sexual transmission of HIV-1 in women. This review covers the development of microbicides, also referred to as topical pre-exposure prophylaxis (PrEP), through three stages. The first stage focused on nonspecific agents, including surfactants such as nonoxynol-9 (N-9), to prevent HIV-1 transmission. Unfortunately, N-9 enhanced susceptibility to sexual transmission of HIV-1 when evaluated for efficacy. Soon thereafter, other nonspecific agents (polyanions) were quickly moved into large efficacy trials. Due to a lack of coordination among investigators and funders, a large investment was made in a class of compounds shown ultimately to be ineffective, although poor adherence may have contributed to these findings. The second stage involved the assessment of the antiretroviral drug tenofovir, formulated as a vaginal gel, which was found to be modestly effective in a Phase IIb trial (CAPRISA-004) when dosed in a coitally-dependent manner. In another Phase IIb trial, VOICE (MTN-003), tenofovir gel was found to be ineffective when dosed once-daily in a coitally-independent manner. Based on pharmacokinetic data, it was concluded the participants were poorly adherent to this dosing regimen, leading to a lack of efficacy. Tenofovir gel is currently in a Phase III safety and efficacy trial in South Africa (FACTS-001), using the coitally-dependent dosing regimen employed in CAPRISA-004. We are now in the third stage of microbicide research. The antiretroviral drug dapivirine is currently in two Phase III safety and efficacy studies formulated as a vaginal ring. It is hoped that the once-monthly dosing regimen will lead to higher adherence than found in the VOICE study. It is now clear that product adherence could be the greatest challenge to demonstrating topical (and to a similar extent oral) PrEP. Novel dosage forms should play a role in creating products that women will use correctly.

Multipurpose Prevention Technologies (MPTs) are designed to address two or more indications from a single product. The overall goal is to prevent unintended pregnancy and transmission of one or more STIs including HIV-1.The topics covered herein are advances in over the past three years. Advances include development of novel intravaginal rings capable of releasing microbicides to prevent transmission of HIV-1 and unintended pregnancy. These rings include the potential to prevent transmission of more than one STI and unintended pregnancy. There are also gels that can potentially accomplish the same thing. Finally, combination of a drug and barrier device are also covered.There has been considerable advance in this field over the past three years. There is one ring currently in a Phase I clinical trial and others are soon to follow. Some of these drug delivery systems are by necessity rather complicated and hence could be prohibitively expensive in the developing world. Conducting multiple clinical trials to support regulatory approval of two or more indications represents a significant barrier. It remains unclear that women will be more motivated to use MPT products than has been observed in recent microbicide-only clinical trials. Despite these challenges, the need for MPTs remain acute hopefully ensuring they will continue to be developed over the coming years.

Tenofovir (TFV) 1% gel has proven effective in preclinical and clinical studies in preventing sexual transmission of HIV-1. The impact of changing the current gel formulation to reduce its osmolality was evaluated using pharmacokinetic assessments and local tissue effects in the rabbit. Following vaginal administration of TFV 1% gel and reduced-glycerin TFV 1% gel, TFV was measured in plasma, vaginal tissues, vaginal fluids, and iliac lymph nodes. After a single dose, plasma C(max) and AUC(0-4h) were significantly higher in the TFV 1% gel group compared with the reduced-glycerin TFV 1% gel group. After 14 days of once-daily dosing, differences in these parameters were insignificant. Vaginal fluid concentrations were ∼100 μg/ml following the first dose and up to a mean of about 500 μg/ml after 14 once-daily doses. Mean (and median) cranial TFV tissue concentrations were generally in excess of 100 μg/g following a single dose and 14 once-daily doses of both gels; concentrations in the caudal vaginal tissues were comparatively lower, although in nearly all cases mean values exceeded 10 μg/g. Treatment of tissues with phosphatase to liberate TFV from its diphosphate and monophosphate metabolites increased recovery of TFV by 60-120%. Median TFV concentrations in iliac lymph nodes ranged from 44 ng/g to 196 ng/g; differences between iliac lymph node TFV concentrations following dosing of the two gels were insignificant. There were no differences observed in histological evaluation in the cranial vagina following 14 days of once-daily dosing of either gel. There was an apparent impact of TFV on rabbit vaginal epithelium (increased secretory depletion and increased cellular vacuolization) independent of formulation. These data indicate that the reduced-glycerin TFV 1% gel may be a suitable alternative to TFV 1% gel.

In vitro testing and quantitative analysis of a matrix, hydrophilic polyether urethane (HPEU) intravaginal ring (IVR) for sustained delivery of the anti-HIV agent tenofovir (TFV) are described. To aid in device design, we employed a pseudo-steady-state diffusion model to describe drug release, as well as an elastic mechanical model for ring compression to predict mechanical properties. TFV-HPEU IVRs of varying sizes and drug loadings were fabricated by hot-melt extrusion and injection molding. In vitro release rates of TFV were measured at 37 °C and pH 4.2 for 30 or 90 days, during which times IVR mechanical properties and swelling kinetics were monitored. Experimental data for drug release and mechanical properties were compared to model predictions. IVRs loaded with 21% TFV (w/w) released greater than 2mg TFV per day for 90 days. The diffusion model predicted 90 day release data by extrapolating forward from the first 7 days of data. Mechanical properties of IVRs were similar to NuvaRing, although the matrix elastic modulus decreased up to three-fold following hydration. This is the first vaginal dosage form to provide sustained delivery of milligram quantities of TFV for 90 days. Drug release and mechanical properties were approximated by analytical models, which may prove useful for the continuing development of IVRs for HIV prevention or other women's health indications.

Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day⁻¹) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology.

HIV continues to be a problem worldwide. Topical vaginal microbicides represent one option being evaluated to stop the spread of HIV. With drug candidates that have a specific action against HIV now being studied, it is important that, when appropriate and based on the mechanism of action, the drug permeates the tissue so that it can be delivered to specific targets which reside there. Novel formulations of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) and the nonnucleoside reverse transcriptase inhibitor UC781 have been developed and evaluated here. Gels with three distinct rheological properties were prepared. The three gels released both UC781 and TFV under in vitro conditions at concentrations equal to or above the reported 50% effective concentrations (EC 50 s). The drug concentrations in ectocervical tissues were well in excess of the reported EC 50 s. The gels maintain ectocervical viability and prevent infection of ectocervical explants after a HIV-1 challenge. This study successfully demonstrates the feasibility of using this novel combination of antiretroviral agents in an aqueous gel as an HIV infection preventative.

Objectives: Coital use of 1% tenofovir gel was shown to be modestly effective at preventing HIV transmission when applied vaginally in the CAPRISA 004 trial. Because the gel is hyperosmolar, which would reduce the integrity of the epithelium and induce fluid movement into the lumen, rectal use may not be acceptable. This study evaluated the pre-clinical safety and efficacy of a reformulated (reduced osmolality) tenofovir gel product. Methods: Reduced glycerine (RG)-tenofovir gel was compared with the original tenofovir gel for physiochemical characteristics, product safety and anti-HIV-1 activity. Results: The formulations were similar in all characteristics except for osmolality and spreadability/firmness. The RG-tenofovir gel had a 73% lower osmolality, a 29.6% increase in spreadability and a 27% decrease in firmness as compared with the original tenofovir gel. When applied to epithelial cell monolayers, tenofovir gel showed a transient reduction in the transepithelial resistance while the RG-tenofovir gel did not. Both gels retained ectocervical and colorectal explant viability. However, tenofovir gel treatment resulted in epithelial stripping that was absent after RG-tenofovir gel treatment of the polarized explants. Anti-HIV-1 activity was confirmed by lack of HIV-1 infection in polarized explants treated with either gel as compared with the control explants. Conclusions: Reducing the osmolality of the tenofovir gel resulted in improved epithelial integrity, which suggests better safety upon rectal use. The improved gel safety did not compromise drug release or anti-HIV-1 activity. These data support the use of this gel as a dual compartment microbicide.

Vaginal rings are currently being investigated for delivery of HIV microbicides. However, vaginal rings are currently manufactured form hydrophobic polymers such as silicone elastomer and polyethylene vinyl acetate (PEVA), which do not permit release of hydrophilic microbicides such as the nucleotide reverse transcriptase inhibitor tenofovir. Biodegradable polymers such as polylactide (PLA) may help increase release rates by controlling polymer degradation rather than diffusion of the drug through the polymer. However, biodegradable polymers have limited flexibility making them unsuitable for use in the manufacture of vaginal rings. This study demonstrates that by blending PLA and PEVA together it is possible to achieve a blend that has flexibility similar to native PEVA but also allows for the release of tenofovir.

The development of multiple indication (multipurpose) prevention technologies (MIPTs) is driven by overlapping relationships in the area of female reproductive health.In this review, the basis for MIPTs is detailed. The current state of the field for the use of drug delivery in novel MIPTs is covered. Of particular interest is the application of intravaginal rings (IVRs) for the delivery of two drugs simultaneously, to prevent one STI and pregnancy, or two STIs. IVRs are currently available commercially for contraception and have been developed for release of microbicides to prevent sexual transmission of HIV-1. Novel IVRs capable of releasing relatively large amounts of drugs such as tenofovir are discussed, along with those that contain independent delivery elements, such as pods, that can be used to release drugs at independent rates. The vaginal administration of macromolecules (antibodies and vaccines) is also reviewed in the context of MIPTs.The field of MIPTs remains one of potential. There is yet to be a proven microbicide effective at preventing sexual transmission of HIV-1. Development of MIPTs in the near term will proceed under the assumption that one or more antiretroviral (ARV) drugs will eventually be proven successful. IVRs have already demonstrated success in the area of contraception. Prevention of sexual transmission of HIV-1 and herpes simplex virus-2 (HSV-2) (or suppression of recurrence) remains an attractive MIPT target. In the long term, development of MIPTs will require validation of surrogate end points, particularly for prevention of HIV-1 transmission.

Ethylene vinyl acetate intravaginal rings (IVRs) were prepared by hot-melt compounding and injection moulding. The IVRs contained various levels of the antiretroviral drug UC781 and the contraceptive hormone levonorgestrel. The IVRs were assayed for drug content and related substances, characterized for physical properties, in vitro drug-elution kinetics, photostress stability, and 3-month accelerated storage stability under ICH conditions. UC781 degrades on exposure to light and during thermal processing. UC22 is the major degradant of UC781. Drug release rates were proportional to drug loading, independent of the other drug in combination with IVRs, and were stable for 3 M at 40°C/75% RH despite changes in the appearance of the IVRs which is tentatively ascribed to crystallization of UC781 at or near the surface of the IVRs. The behavior of UC781 poses a substantial barrier to the commercial development of these IVRs.

Intravaginal rings (IVRs) are a dosage form used to locally or systemically deliver drugs in the vagina. They are capable of releasing one or more drugs over an extended period of time (from several weeks to a year or longer). Contraceptive IVRs are currently gaining popularity due to the success of the contraceptive product NuvaRing®. Delivery of contraceptives from IVRs should promote compliance/adherence, and they also provide effective cycle control and symptom relief (menorrhagia, dysmenorrheal, and polycystic ovarian syndrome). Vaginal delivery of proteins from IVRs was first explored in an attempt to deliver IgG2a antibody intravaginally to neutralize herpes simplex virus 2. More recently, IVRs capable of releasing antibodies and recombinant proteins potentially along with low molecular weight microbicides are under investigation for prevention of HIV-1 transmission. Vaginal delivery of microbicides has been studied with several drugs most notably the non-nucleoside reverse transcriptase inhibitor dapivirine. Another drug capable of blocking transmission of HIV-1 when released from IVRs is tenofovir. Finally, combinations of drugs with different indications (i.e., multipurpose prevention technologies) are actively being pursued.

A significant number of women, especially in developing countries, need protection against more than one sexually transmitted infection (STIs), for instance HIV-1 and HSV-2, and family planning methods to prevent unwanted pregnancies. Dual protection technologies (DPTs; also known as multipurpose technologies) are designed to address two different indications with one product. Examples of DPTs are vaginal products capable of preventing transmission of HIV-1 in women while simultaneously providing contraceptive properties and a vaginal product capable of reducing HIV-1 transmission while preventing transmission of a second STI. DPTs can be categorized into three main approaches: 1) physical barriers, 2) chemical barriers, and 3) a combination of physical and chemical barriers. Examples of physical barriers are male and female condoms, diaphragms and cervical caps. Chemical barriers include use of a single drug with two mechanisms of action (viz., dual-activity compounds with microbicidal and contraceptive properties or activity against HIV-1 and a second STI pathogen such as HSV-2) or a combination of two drugs each targeted against separate mechanisms for achieving contraception and inhibition of HIV-1. Combinations of chemical and physical barriers are based on physical barriers such as a diaphragm along with a microbicide. Examples of each approach and current prototypes (such as vaginal gels and intravaginal rings) under development are described in this paper. Challenges facing development and regulatory approval of DPTs are also reviewed. This article forms part of a special supplement on a presentation covering DPTs, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.

Develop a preclinical in vitro algorithm enabling de novo design of semisolid vaginal drug delivery gels, by using biomechanical modeling of gel spreading in the vaginal canal and empirically relating gel composition to mechanical properties and predicted performance. Gel performance was defined through a multivariate objective function constructed from gels’ mechanical properties and selected performance criteria for gel spreading within the vaginal canal. Mixture design of experiment was used to establish a semi-empirical relationship linking composition-property and property-performance relationships for gels with varying concentrations of hydroxyethylcellulose and Carbopol 974P. This permits definition of a local optimum for gel composition and volume of administration, within a defined gel composition space. Rheological behavior and, consequently, the value of the objective function varied broadly with composition. The algorithm indicated a 3.0 wt% HEC gel as the near optimal composition for a 3.5 mL applied volume for gels designed to spread throughout the vagina. The algorithm introduced herein is a novel tool that facilitates an understanding of the composition-property-performance relationship for vaginal semisolid drug delivery gels. This approach has promise as a scientific methodology for evaluation and optimization of vaginal gels prior to in vivo investigations.

In this work, we evaluated the chemical stability profiles of UC781 based solutions to identify excipients that stabilize the microbicidal agent UC781. When different antioxidants were added to UC781 in sulfobutylether-beta-cyclodextrin (SBE-beta-CD) solutions and subjected to a 50 degrees C stability study, it was observed that EDTA was a better stabilizing agent than sodium metabisulfite, glutathione or ascorbic acid. Some antioxidants accelerated the degradation of UC781, suggesting metal-catalyzed degradation of UC781. Furthermore, we observed substantial degradation of UC781 when stored in 1% Tween 80 and 1% DMSO solutions alone or in those with 10mM EDTA. On the other hand, improved stability of UC781 in the presence of 100 and 200mM of EDTA was observed in these solutions. The addition of both EDTA and citric acid in the stock solutions resulted in recovery of more than 60% of UC781 after 12 weeks. Generally, 10% SBE-beta-CD in the presence of EDTA and citric acid stabilized UC781 solutions: the amount of UC781 recovered approaching 95% after 12 weeks of storage at 40 degrees C. We also showed that the desulfuration reaction of the UC781 thioamide involves oxygen by running solution stability studies in deoxygenated media. Improved stability of UC781 in the present study indicates that the incorporation of EDTA, citric acid and SBE-beta-CD and the removal of oxygen in formulations of this drug will aid in increasing the stability of UC781 where solutions of the drug are required.

The field of controlled release has contributed significantly to female reproductive health and in particular the prevention of unintended pregnancy. For at least 50years, there have been significant advances in controlled release dosage forms used for contraception. These advances have been driven by the need to provide women a wide array of products that address adherence problems noted with oral contraceptives. The first long-acting injectable product (Depo-Provera®) was approved in the US in 1959. Since then, there has been an emphasis on development of long-acting reversible contraceptives. These products include implants, intrauterine systems, and vaginal rings. A shorter acting contraceptive option is the transdermal patch. Despite these advances there are still a large number of unplanned pregnancies around the world. New controlled release technologies will be needed to continue providing women safe and easy to use contraceptive products.

UC781 is a potent and poorly water-soluble nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide for preventing sexual transmission of HIV-1. This study was designed to evaluate the in vivo release and pharmacokinetics of UC781 delivered from matrix-type intravaginal ring segments in rabbits. Three polymer matrices (polyurethane, ethylene vinyl acetate copolymer, and silicone elastomer) and two drug loadings (5 and 15 mg/segment) were evaluated in at least one of two independent studies for up to 28 days in vivo. Inter-study comparison of in vivo release, vaginal tissue, and plasma concentrations for similar formulations demonstrated good reproducibility of the animal model. Mean estimates for a 28-day in vivo release ranged from 0.35 to 3.17 mg UC781 per segment. Mean proximal vaginal tissue levels (adjacent to the IVR segment) were 8–410 ng/g and did not change significantly with time for most formulations. Distal vaginal tissue levels of UC781 were 6- to 49-fold lower than proximal tissue levels. Mean UC781 plasma levels were low for all formulations, at 0.09–0.58 ng/mL. All formulations resulted in similar UC781 concentrations in vaginal tissue and plasma, except the low loading polyurethane group which provided significantly lower levels. Loading dependent release and pharmacokinetics were only clearly observed for the polyurethane matrix. Based on these results, intravaginal ring segments loaded with UC781 led to vaginal tissue concentrations ranging from below to approximately two orders of magnitude higher than UC781’s EC50 under in vitro conditions (2.8 ng/mL), with little influence by polymer matrix or UC781 loading. Moreover, these findings support the use of rabbit vaginal pharmacokinetic studies in preclinical testing of microbicide intravaginal rings.

This study describes the preclinical development of a matrix-type silicone elastomer vaginal ring device designed to provide controlled release of UC781, a non-nucleoside reverse transcriptase inhibitor. Testing of both human- and macaque-sized rings in a sink condition in vitro release model demonstrated continuous UC781 release in quantities considered sufficient to maintain vaginal fluid concentrations at levels 82–860-fold higher than the in vitro IC50 (2.0 to 10.4 nM) and therefore potentially protect against mucosal transmission of HIV. The 100-mg UC781 rings were well tolerated in pig-tailed macaques, did not induce local inflammation as determined by cytokine analysis and maintained median concentrations in vaginal fluids of UC781 in the range of 0.27 to 5.18 mM during the course of the 28-day study. Analysis of residual UC781 content in rings after completion of both the in vitro release and macaque pharmacokinetic studies revealed that 57 and 5 mg of UC781 was released, respectively. The pharmacokinetic analysis of a 100-mg UC781 vaginal ring in pig-tailed macaques showed poor in vivo–in vitro correlation, attributed to the very poor solubility of UC781 in vaginal fluid and resulting in a dissolution-controlled drug release mechanism rather than the expected diffusion-controlled mechanism.

UC781 is a potent nonnucleoside reverse transcriptase inhibitor being investigated as a potential microbicide to prevent transmission of HIV-1 both vaginally and rectally. This study was designed to investigate the in vitro drug release, in vitro permeability/safety, and in vivo pharmacokinetics in rabbits of a vaginal gel prepared with micronized or nonmicronized UC781 (UC781m and UC781nm, respectively). Gels prepared with UC781m had greater in vitro release rates (Franz cells) and permeability/tissue-associated UC781 concentrations than gels prepared with UC781nm (EpiVaginal tissues). Both gels were well tolerated under in vitro conditions compared with controls using EpiVaginal tissues. Following intravaginal administration of both gels to rabbits, tissue concentrations typically ranged from 1,000 to over 10,000 ng/g regardless of dosing regimen (single dose or 7 days once daily dosing) and sampling times (2 and 24 h post-dose). Tissue-associated concentrations were highly variable, and no statistically significant differences were found between test conditions. Plasma levels were generally low after vaginal administration: following a single dose, the concentrations were between 0.5 and 1.0 ng/mL. After 7 days repeated once daily dosing, UC781 concentrations were slightly higher ranging from below 1.0 to about 2 ng/mL, although none of the differences were statistically significant. Based on these results, gels prepared with either form of UC781 led to tissue concentrations well in excess of UC781’s EC50 under in vitro conditions (~3 ng/mL).

UC781 is potent, hydrophobic, non-nucleotide reverse transcriptase inhibitor (NNRTI) against the human immunodeficiency virus (HIV). UC781 is currently being investigated for use as a potential HIV microbicide. A study in rhesus macaques demonstrated that a 100-mg UC781-loaded silicone elastomer vaginal ring released limited amounts of UC781 into the vaginal fluid and tissue after 28 days. The reason for this was due to the hydrophobic nature and limited aqueous solubility of UC781. This study describes the manufacture of UC781-loaded polyethylene vinyl acetate (PEVA) vaginal rings, which have an improved in vitro release rate of UC781 when compared to UC781-loaded silicone elastomer vaginal rings. The study demonstrates that the UC781 in the PEVA rings is mostly in its amorphous form due to the rings being manufactured above UC781’s melting point. Furthermore, the rings do not show any signs of UC781 degradation, such as the presence of UC22.

Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored.

Background The Woman's Condom is a new female condom that uses a dissolvable polyvinyl alcohol capsule to simplify vaginal insertion. This preclinical study assessed the feasibility to incorporate an antiviral drug, UC781, into the Woman's Condom capsule, offering a unique drug delivery platform. Study design UC781 capsules were fabricated using methods from the development of the Woman's Condom capsules as well as those used in vaginal film development. Capsules were characterized to evaluate physical/chemical attributes, Lactobacillus compatibility, in vitro safety and bioactivity, and condom compatibility. Results Two UC781 capsule platforms were assessed. Capsule masses (mg; mean±SD) for platforms 1 and 2 were 116.50±18.22 and 93.80±8.49, respectively. Thicknesses were 0.0034±0.0004 in and 0.0033±0.0004 in. Disintegration times were 11±3 s and 5±1 s. Puncture strengths were 21.72±3.30 N and 4.02±0.83 N. Water content measured 6.98±1.17% and 7.04±1.92%. UC781 content was 0.59±0.05 mg and 0.77±0.11 mg. Both platforms retained in vitro bioactivity and were nontoxic to TZM-bl cells and Lactobacillus . Short-term storage of UC781 capsules with the Woman's Condom pouch did not decrease condom mechanical integrity. Conclusions UC781 was loaded into a polymeric capsule similar to that of the Woman's Condom product. This study highlights the potential use of the Woman's Condom as a platform for vaginal delivery of drugs relevant to sexual/reproductive health, including those for short- or long-acting HIV prevention. Implications We determined the proof-of-concept feasibility of incorporation of an HIV-preventative microbicide into the Woman's Condom capsule. This study highlights various in vitro physical and chemical evaluations as well as bioactivity and safety assessments necessary for vaginal product development related to female sexual and reproductive health.

Inflammatory bowel disease (IBD) is often localized to specific sites in the gastrointestinal tract (GIT). As a result, this disease can be treated with oral site-specific (targeted) drug delivery systems. Targeted delivery systems for treatment of IBD are designed to increase local tissue concentrations of antiinflammatory drugs from lower doses compared with systemic administration. This review addresses the impact disease has or may have on oral targeted delivery for treatment of IBD as well as a number of delivery approaches currently used in marketed products or under investigation. Delivery systems reviewed rely on temporal control, changes in pH along the GIT, the action of local enzymes to trigger drug release, and changes in intraluminal pressure. Dissolution of enteric polymer coatings due to a change in local pH and reduction of azo-bonds to release an active agent are both used in commercially marketed products. Newer approaches showing promise in treating IBD are based on polysaccharides. These materials are most effective when used as compression coatings around core tablets, which contain the active agent. More complex polymeric prodrugs systems are also under investigation. If the dose of the drug is sufficiently low, this approach may also prove useful in improving treatment of IBD.

Oral delivery of drugs to the small intestine is an important topic in the research and development of more effective oral dose forms. This review highlights several important developments in this area. An overriding theme in drug delivery to the small intestine is how to increase the efficiency (ie, how to increase bioavailability) of absorption. The role of P-glycoprotein and intestinal transporters is discussed in this regard. These systems are normally studied under defined in vitro conditions; recent data suggest that this approach, though useful, may not fully represent the in vivo situation. Recent advances and issues in the characterization and prediction of drug absorption from the small intestine are reviewed. These efforts, if successful, will shorten development timelines by eliminating compounds with poor absorption characteristics early in the process. Nanoparticulate delivery systems and those prepared by microfabrication technology are being used to improve bioavailability of poorly absorbed drugs. A relatively new technique (electroporation) has been proposed to enhance oral delivery of macromolecules, still an unrealized objective in drug delivery.

Introduction : Product adherence and its measurement have emerged as a critical challenge in the evaluation of new HIV prevention technologies. Long-acting ARV-based vaginal rings may simplify use instructions and require less user behaviour, thereby facilitating adherence. One ARV-based ring is in efficacy trials and others, including multipurpose rings, are in the pipeline. Participant motivations, counselling support and measurement challenges during ring trials must still be addressed. In previous HIV prevention trials, this has been done largely using descriptive and post-hoc methods that are highly variable and minimally evaluated. We outline an interdisciplinary framework for systematically investigating promising strategies to support product uptake and adherence, and to measure adherence in the context of randomized, blinded clinical trials. Discussion : The interdisciplinary framework highlights the dual use of adherence measurement (i.e. to provide feedback during trial implementation and to inform interpretation of trial findings) and underscores the complex pathways that connect measurement, adherence support and enacted adherence behaviour. Three inter-related approaches are highlighted: 1) adherence support – sequential efforts to define motivators of study product adherence and to develop, test, refine and evaluate adherence support messages; 2) self-reported psychometric measures – creation of valid and generalizable measures based in easily administered scales that capture vaginal ring use with improved predictive ability at screening, baseline and follow-up that better engage participants in reporting adherence; and 3) more objective measurement of adherence – real-time adherence monitoring and cumulative measurement to correlate adherence with overall product effectiveness through innovative designs, models and prototypes using electronic and biometric technologies to detect ring insertion and/or removal or expulsion. Coordinating research along these three pathways will result in a comprehensive approach to product adherence within clinical trials. Conclusions : Better measurement of adherence will not, by itself, ensure that future effectiveness trials will be able to address the most basic question: if the product is used per instructions, will it prevent HIV transmission? The challenges to adherence measurement must be addressed as one component of a more integrated system that has as its central focus adherence as a behaviour emerging from the social context of the user. Keywords: vaginal ring; acceptability; adherence; clinical trial research; HIV prevention; measurement. (Published: 8 September 2014) Citation: MacQueen KM et al. Journal of the International AIDS Society 2014, 17 (Suppl 2):19158 http://www.jiasociety.org/index.php/jias/article/view/19158 | http://dx.doi.org/10.7448/IAS.17.3.19158

Tenofovir gel is being evaluated for vaginal and rectal pre-exposure prophylaxis against HIV transmission. Because this is a new prevention strategy, we broadly assessed its effects on the mucosa. In MTN-007, a phase-1, randomized, double-blinded rectal microbicide trial, we used systems genomics/proteomics to determine the effect of tenofovir 1% gel, nonoxynol-9 2% gel, placebo gel or no treatment on rectal biopsies (15 subjects/arm). We also treated primary vaginal epithelial cells from four healthy women with tenofovir in vitro. After seven days of administration, tenofovir 1% gel had broad-ranging effects on the rectal mucosa, which were more pronounced than, but different from, those of the detergent nonoxynol-9. Tenofovir suppressed anti-inflammatory mediators, increased T cell densities, caused mitochondrial dysfunction, altered regulatory pathways of cell differentiation and survival, and stimulated epithelial cell proliferation. The breadth of mucosal changes induced by tenofovir indicates that its safety over longer-term topical use should be carefully monitored. Clinical trial registration: NCT01232803. DOI: http://dx.doi.org/10.7554/eLife.04525.001, eLife digest Tenofovir is a drug that can stop some viruses—including HIV—from multiplying. It is commonly used in multidrug therapies to control HIV infection. Clinical trials are underway to find out whether using the drug in the form of a gel applied to the vagina or rectum could be an effective way to prevent HIV transmission during sex. Some of the clinical trials carried out so far have produced promising results. However, since the use of gels containing anti-viral drugs is a new strategy for HIV prevention, there are limited data available about the safety of these products. Previous studies have shown that the concentration of tenofovir in the vagina is much higher in individuals using the gel than in those taking the tablet form of the drug. These high concentrations could lead to unexpected effects on the health of the cells exposed to the gel. Here, Hladik, Burgener, Ballweber et al. used a systems biology approach to look at the broad effects of tenofovir gel on tissue from the rectum. Tissue samples taken from the rectums of 15 patients who used tenofovir gel for seven days were compared with tissue samples taken from individuals who used a control gel that did not contain the drug or who did not use any gel. Genes that regulate inflammation were suppressed in the rectal tissue from patients who used tenofovir, as were genes that help these tissues regenerate and produce energy. The tissue from these patients also contained more immune cells, suggesting that their local immune systems were more active. Additionally, Hladik, Burgener, Ballweber et al. observed changes that could potentially lead to the increased growth of cells. Similar differences were also observed in vaginal cells that had been treated with tenofovir in the laboratory. These findings suggest that tenofovir delivered directly to the vagina or rectum may have unintentional local side effects. However, it is important to acknowledge that tenofovir gel has been evaluated in multiple studies that have not observed overt clinical adverse effects. Therefore, the implication of these findings is currently unclear and warrants further study. DOI: http://dx.doi.org/10.7554/eLife.04525.002

The gastrointestinal tract is structurally and functionally different from the vagina. Thus, the paradigm of topical microbicide development and evaluation has evolved to include rectal microbicides (RMs). Our interest was to create unique RM formulations to safely and effectively deliver antiretroviral drugs to mucosal tissue. RMs were designed to include those that spread and coat all surfaces of the rectum and distal colon rapidly (liquid) and those that create a deformable, erodible barrier and remain localized at the administration site (gel). Tenofovir (TFV) (1%) was formulated as an aqueous thermoreversible fluid and a carbopol-based aqueous hydrogel. Lipid-based liquid and gel formulations were prepared for UC781 (0.1%) using isopropyl myristate and GTCC (Caprylic/Capric Triglycerides), respectively. Formulations were characterized for pH, viscosity, osmolality, and drug content. Pre-clinical testing incorporated ex vivo colonic tissue obtained through surgical resections and flexible sigmoidoscopy (flex sig). As this was the first time using tissue from both sources side-by-side, the ability to replicate HIV-1 was compared. Efficacy of the RM formulations was tested by applying the products with HIV-1 directly to polarized colonic tissue and following viral replication. Safety of the formulations was determined by MTT assay and histology. All products had a neutral pH and were isoosmolar. While HIV-1BaL and HIV-1JR-CSF alone and in the presence of semen had similar replication trends between surgically resected and flex sig tissues, the magnitude of viral replication was significantly better in flex sig tissues. Both TFV and UC781 formulations protected the colonic tissue, regardless of tissue source, from HIV-1 and retained tissue viability and architecture. Our in vitro and ex vivo results show successful formulation of unique RMs. Moreover, the results of flex sig and surgically resected tissues were comparable suggesting the incorporation of both in pre-clinical testing algorithms.

Purpose. This study was performed to examine the use of guar gum to sustain the release of diltiazem under in vitro and in vivo conditions.

Ulcerative colitis and Crohn's colitis are chronic intestinal diseases usually treated with various nonsteroidal antiinflammatory agents to maintain remission. Corticosteroids, while useful in acute treatment of these diseases, present side-effects generally too serious to allow maintenance therapy. Colon-specific drug delivery may permit use of corticosteroids for maintenance therapy if doses can be reduced while maintaining efficacy. In this study, two prodrugs (dexamethasone-beta-D-glucuronide (DXglrd) and budesonide-beta-D-glucuronide (BUDglrd)) were administered by intragastric (i.g.) infusion to conventional and colitic rats. In addition, dexamethasone (DX) and budesonide (BUD) were administered either i.g. or subcutaneously (s.c.) to healthy and colitic rats. Colon-specific delivery was assessed using the drug delivery index (DDI). In conventinal rats, DDIs for DXglrd ranged from about five to as high as 11 in the luminal contents relative to DX administered sc or i.g. DDI values were also elevated in the mucosa of both healthy and colitic rats following i.g. administration of DXglrd. BUD was delivered somewhat less effectively from BUDglrd to the rat large intestine than was DX from DXglrd. The data are consistent with efficacy studies and support the conclusion that local delivery of corticosteroids to the large intestine is due, at least in part, to higher levels of drug delivery into the mucosal tissues.

Background: Colonic delivery of corticosteroids may reduce the side-effects commonly associated with their use. Therefore, we tested the ability of the naturally occurring polysaccharide guar gum to deliver a corticosteroid, dexamethasone, to the colon using pharmacoscintigraphy. Guar gum is metabolized in the colon by resident bacterial enzymes to trigger drug release. Materials: Each subject (eight per group, parallel study design) was administered one of four dexamethasone (9 mg) tablet formulations, radiolabelled with 153Sm using neutron activation, under fasted conditions. One formulation was designed to release drug rapidly following ingestion while the other three formulations were designed to delay release of dexamethasone to varying degrees. Progression of the formulations down the gastrointestinal tract was followed by gamma scintigraphy. Serum concentrations were measured over time to relate disintegration profiles of the tablets with pharmacokinetic observations. Results: The immediate release formulation disintegrated in the stomach, on average, within 20 min of dosing. One of the three delayed release preparations (CD1) began to disintegrate in the small intestine 1.7±1.0 h after dosing. The second and third delayed release preparations (CD2 and CD3) did not begin to disintegrate until 5.8±2.3 and 3.6±1.6 h after dosing, respectively. All three colonic delivery preparations completely disintegrated in the colon ranging from 7.8±2.7 h (CD1) to 12.4±3.2 h (CD2) following oral administration. Pharmacoscintigraphic data indicated that 72–82% of the dexamethasone was delivered into the colon although not all the dexamethasone delivered into the colon was absorbed. Conclusions: Simple guar gum formulations are capable of delivering the corticosteroid dexamethasone to the colon of normal subjects. Locally delivered corticosteroids may be useful in the treatment of ulcerative colitis and Crohn's disease. Pharmacoscintigraphic evaluation is a useful method to discriminate between the in vivo behaviour of colonic delivery systems.