Kinematics of shoulder, trunk, pelvis, and hip while reaching forward to progressively distant targets.

INTRODUCTION: Information on the normal contribution of various body regions to forward reaching provides a basis for assessing the maneuver. The purpose of this study was to describe the kinematics of the shoulder, trunk, pelvis, and hip of healthy young males while they stood and reached toward a target at arm's length and 5%, 10%, 15%, and 20% of body height beyond. METHOD: Twelve healthy adult males were marked with 22 spherical reflective markers. Two trials of unilateral forward reaching were performed towards a target placed at five target distances. Motion was captured via reflective markers and an infrared camera system. RESULTS: Sagittal and transverse plane motions demonstrated high reliability between trials at each target distance (ICC = 0.716 trunk flexion to 0.977 shoulder flexion). Shoulder flexion and horizontal abduction were major contributors to forward reaching with components of trunk flexion and left trunk rotation at all target distances. Hip flexion, pelvic tilt, left pelvis rotation, and hip external rotation made notable contributions at the furthest targets. All motions became more pronounced as target distance increased (P ≤ .001). CONCLUSION: Kinematic analysis demonstrated that right forward reaching requires composite movements at the shoulder, trunk, pelvis, and hip. The contribution of each body region to forward reaching became more pronounced as the target became more distant. These findings may be helpful when identifying localized movement impairments contributing to limited forward reach in a clinical population, although clinical validation is needed.

Controlling the hydration rate of a hydrophilic matrix in the core of an intravaginal ring determines antiretroviral release.

Intravaginal ring technology is generally limited to releasing low molecular weight species that can diffuse through the ring elastomer. To increase the diversity of drugs that can be delivered from intravaginal rings, we designed an IVR that contains a drug matrix encapsulated in the core of the IVR whereby the mechanism of drug release is uncoupled from the interaction of the drug with the ring elastomer. We call the device a flux controlled pump, and it is comprised of compressed pellets of a mixture of drug and hydroxypropyl cellulose within the hollow core of the ring. The pump orifice size and chemistry of the polymer pellets control the rate of hydration and diffusion of the drug-containing hydroxypropyl cellulose gel from the device. A mechanistic model describing the hydration and diffusion of the hydroxypropyl cellulose matrix is presented. Good agreement between the quantitative model predictions and the experimental studies of drug release was obtained. We achieved controlled release rates of multiple antiretrovirals ranging from µg/d to mg/d by altering the orifice design, drug loading, and mass of pellets loaded in the device. This device could provide an adaptable platform for the vaginal drug delivery of many molecules.

An Intravaginal Ring for the Simultaneous Delivery of an HIV-1 Maturation Inhibitor and Reverse-Transcriptase Inhibitor for Prophylaxis of HIV Transmission.

Nucleocapsid 7 (NCp7) inhibitors have been investigated extensively for their role in impeding the function of HIV-1 replication machinery and their ability to directly inactivate the virus. A class of NCp7 zinc finger inhibitors, S-acyl-2-mercaptobenzamide thioesters (SAMTs), was investigated for topical drug delivery. SAMTs are inherently unstable because of their hydrolytically labile thioester bond, thus requiring formulation approaches that can lend stability. We describe the delivery of N-[2-(3,4,5-trimethoxybenzoylthio)benzoyl]-ß-alaninamide (SAMT-10), as a single agent antiretroviral (ARV) therapeutic and in combination with the HIV-1 reverse-transcriptase inhibitor pyrimidinedione IQP-0528, from a hydrophobic polyether urethane (PEU) intravaginal ring (IVR) for a month. The physicochemical stability of the ARV-loaded IVRs was confirmed after 3 months at 40°C/75% relative humidity. In vitro, 25 ± 3 mg/IVR of SAMT-10 and 86 ± 13 mg/IVR of IQP-0528 were released. No degradation of the hydrolytically labile SAMT-10 was observed within the matrix. The combination of ARVs had synergistic antiviral activity when tested in in vitro cell-based assays. Toxicological evaluations performed on an organotypic EpiVaginal(™) tissue model demonstrated a lack of formulation toxicity. Overall, SAMT-10 and IQP-0528 were formulated in a stable PEU IVR for sustained release. Our findings support the need for further preclinical evaluation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:3426-3439, 2015.

Engineering a segmented dual-reservoir polyurethane intravaginal ring for simultaneous prevention of HIV transmission and unwanted pregnancy.

The HIV/AIDS pandemic and its impact on women prompt the investigation of prevention strategies to interrupt sexual transmission of HIV. Long-acting drug delivery systems that simultaneously protect womenfrom sexual transmission of HIV and unwanted pregnancy could be important tools in combating the pandemic. We describe the design, in silico, in vitro and in vivo evaluation of a dual-reservoir intravaginal ring that delivers the HIV-1 reverse transcriptase inhibitor tenofovir and the contraceptive levonorgestrel for 90 days. Two polyether urethanes with two different hard segment volume fractions were used to make coaxial extruded reservoir segments with a 100 µm thick rate controlling membrane and a diameter of 5.5 mm that contain 1.3 wt% levonorgestrel. A new mechanistic diffusion model accurately described the levonorgestrel burst release in early time points and pseudo-steady state behavior at later time points. As previously described, tenofovir was formulated as a glycerol paste and filled into a hydrophilic polyurethane, hollow tube reservoir that was melt-sealed by induction welding. These tenofovir-eluting segments and 2 cm long coaxially extruded levonorgestrel eluting segments were joined by induction welding to form rings that released an average of 7.5 mg tenofovir and 21 µg levonorgestrel per day in vitro for 90 days. Levonorgestrel segments placed intravaginally in rabbits resulted in sustained, dose-dependent levels of levonorgestrel in plasma and cervical tissue for 90 days. Polyurethane caps placed between segments successfully prevented diffusion of levonorgestrel into the tenofovir-releasing segment during storage.Hydrated rings endured between 152 N and 354 N tensile load before failure during uniaxial extension testing. In summary, this system represents a significant advance in vaginal drug delivery technology, and is the first in a new class of long-acting multipurpose prevention drug delivery systems.

Multipurpose prevention technologies: products in development.

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.

A 90-day tenofovir reservoir intravaginal ring for mucosal HIV prophylaxis.

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.

Quantitative evaluation of a hydrophilic matrix intravaginal ring for the sustained delivery of tenofovir.

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.

State of the art in intravaginal ring technology for topical prophylaxis of HIV infection.

There is renewed interest in the development of long-term, controlled-release dosage forms for the intravaginal delivery of antiretrovirals for HIV prophylaxis. This interest has catalyzed a renaissance in vaginal drug delivery, increasing the fundamental understanding of determinants of controlled drug delivery in the vagina as well as development of new materials, delivery platforms, and animal models. Our goal in writing this review from the perspective of engineers and pharmaceutical scientists interested in prevention of sexually transmitted infections is to highlight the current state of the art, progress in preclinical programs, new drug-delivery device designs, and to discuss some of the important unknowns in this area of HIV prevention for the general audience involved in HIV research. As far as antiretrovirals are concerned, this review is limited to programs working with antiretrovirals that are supported with an investigational new drug filing. We draw primarily from published papers in the PubMed and CAS databases, however, many of the most recent advances have yet to appear in the peer-reviewed literature and for this class of publications we draw from a recent formulation workshop held by CONRAD as well as from the Microbicides, Controlled Release Society, and CROI meetings.

A hot-melt extruded intravaginal ring for the sustained delivery of the antiretroviral microbicide UC781.

Microbicide intravaginal rings (IVRs) are a promising woman-controlled strategy for preventing sexual transmission of human immunodeficiency virus (HIV). An IVR was prepared and developed from polyether urethane (PU) elastomers for the sustained delivery of UC781, a highly potent nonnucleoside reverse transcriptase inhibitor of HIV-1. PU IVRs containing UC781 were fabricated using a hot-melt extrusion process. In vitro release studies of UC781 demonstrated that UC781 release profiles are loading dependent and resemble matrix-type, diffusion-limited kinetics. The in vitro release methods employed over predicted the in vivo release rates of UC781 in rabbits. Accelerated stability studies showed good chemical stability of UC781 in prototype formulations, but surface crystallization of UC781 was observed following long-term storage at higher UC781 loadings, unless formulated with a polyvinylpyrrolidone/glycerol surface coating. Mechanical stability testing of prototype rings showed moderate stiffening upon storage. The PU and UC781 had minimal to no impact on viability, tissue integrity, barrier function, or cytokine expression in the tissue irritation model, and UC781 was shown to be delivered to and permeate through this tissue construct in vitro. Overall, UC781 was formulated in a stable PU IVR and provided controlled release of UC781 both in vitro and in vivo.

An update on second-generation devices for endometrial ablation.

Menorrhagia is a very common problem. Hysterectomy has been the traditional surgical treatment of choice guaranteeing amenorrhoea. It is 100% effective but is associated with surgical complications, and is more costly in terms of economic impact and recovery time. Minimally invasive procedures to ablate the endometrium reduce complications and recovery time. The newer second-generation endometrial ablation devices negate the need for surgery under direct hysteroscopic vision, thus ensuring that the treatments are not operator dependent. However, they heavily rely on the device themselves to ensure safety and efficacy. There are a variety of these devices currently available on the market. The authors will review these devices and provide the evidence for their suitability in various settings.