An Intravaginal Ring for the Sustained Delivery of Antibodies

Human monoclonal antibodies (mAbs) based on IgG and IgA have shown promise as topical microbicide candidates to protect women from HIV infection. Application of mAbs has been limited, however, by the inability of vaginal gels and conventional intravaginal ring (IVR) designs, the predominant vaginal product formulations, to effectively deliver biomolecules in a coitally independent fashion with retention of bioactivity. We have developed a novel pod‐IVR platform that delivers ovine IgG (ov‐IgG) as a model for IgG and IgA human mAbs. In vitro release of ov‐IgG from the pod‐IVRs was sustained for 14 days. Facile control of release rate was achieved by changing the size of delivery channels in the ring structure, and the feasibility of ov‐IgG delivery in the range 0.5–30 mg day⁻¹ from a 10‐pod IVR was demonstrated. The activity of ov‐IgG in pod‐IVR formulations was maintained as confirmed by ELISA binding assay. Pod‐IVRs delivering ov‐IgG show promise for the effective sustained topical delivery of antibody‐based microbicides. This significantly broadens the range of microbicides that can be delivered in a sustained fashion from IVRs and enables a new arsenal of topical biologic microbicide candidates beyond small molecule antiretrovirals. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3611–3620, 2014     

Compartmental Transport Model of Microbicide Delivery by an Intravaginal Ring

Topical antimicrobials, or microbicides, are being developed to prevent HIV transmission through local, mucosal delivery of antiviral compounds. While hydrogel vehicles deliver the majority of current microbicide products, intravaginal rings (IVRs) are an alternative microbicide modality in preclinical development. IVRs provide a long-term dosing alternative to hydrogel use, and might provide improved user adherence. IVR efficacy requires sustained delivery of antiviral compounds to the entire vaginal compartment. A two-dimensional, compartmental vaginal drug transport model was created to evaluate the delivery of drugs from an intravaginal ring. The model utilized MRI-derived ring geometry and location, experimentally defined ring fluxes and vaginal fluid velocities, and biophysically relevant transport theory. Model outputs indicated the presence of potentially inhibitory concentrations of antiviral compounds along the entire vaginal canal within 24 h following IVR insertion. Distributions of inhibitory concentrations of antiviral compounds were substantially influenced by vaginal fluid flow and production, while showing little change due to changes in diffusion coefficients or ring fluxes. Additionally, model results were predictive of in vivo concentrations obtained in clinical trials. Overall, this analysis initiates a mechanistic computational framework, heretofore missing, to understand and evaluate the potential of IVRs for effective delivery of antiviral compounds. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3514–3521, 2010     

Characterization of silicone elastomer vaginal rings containing HIV microbicide TMC120 by Raman spectroscopy

Silicone elastomer vaginal rings are currently being pursued as a controlled-release strategy for delivering microbicidal substances for the prevention of heterosexual transmission of HIV. Although it is well established that the distribution of drugs in delivery systems influences the release characteristics, in practice the distribution is often difficult to quantify in-situ. Therefore, the aim of this work was to determine whether Raman spectroscopy might provide a rapid, non-contact means of measuring the concentrations of the lead candidate HIV microbicide TMC120 in a silicone elastomer reservoir-type vaginal ring. Vaginal rings loaded with TMC120 were manufactured and sectioned before either Raman mapping an entire ring cross-section (100 microm resolution) or running line scans at appropriate time intervals up to 30 h after manufacture. The results demonstrated that detectable amounts of TMC120, above the silicone elastomer saturation concentration, could be detected up to 1 mm into the sheath, presumably as a consequence of permeation and subsequent reprecipitation. The extent of permeation was found to be similar in rings manufactured at 25 and 80 degrees C.     

阴道环给药系统在医药领域中的应用研究进展

阴道环（intravaginal ring,IVR）给药系统是一种柔软的、环形的、具有弹性的药物输送装置,可向阴道提供长期、持续、控制的物质释放,实现局部给药或全身给药。其已经用于类固醇避孕和雌激素替代疗法,近几年发现将其应用于预防人类免疫缺陷病毒（human immunodeficiency virus,HIV）的杀微生物剂的递送具有很好的疗效,多种杀微生物剂的阴道环目前正在进行临床研究中。自从1970年有关阴道环的专利申请之后,很多的阴道环产品已经上市,例如Estring^®、Nuvaring^®、Progering^®、Annovera^®等,另外还有很多阴道环正在临床研究中。在2002年上市的Nuvaring^®阴道环出现之前制备阴道环的载体材料只局限于硅橡胶（silicone,也叫硅酮）,然而由聚乙烯醋酸乙烯酯（ethylene vinyl acetate,EVA）制备的Nuvaring^®阴道环的出现给人们以启示,热塑性材料应用于阴道环的制备也表现出巨大的潜力,如今热塑性弹性体聚氨酯（polyurethane,PU）也已经用于阴道环的制备。     

Advances in microbicide vaginal rings

Vaginal ring devices capable of providing sustained/controlled release of incorporated actives are already marketed for steroidal contraception and estrogen replacement therapy. In recent years, there has been considerable interest in developing similar ring devices for the administration of microbicidal compounds to prevent vaginal HIV transmission. Intended to be worn continuously, such coitally independent microbicide rings are being developed to maintain effective vaginal microbicide concentrations over many weeks or months, thereby overcoming issues around timing of product application, user compliance and acceptability associated with more conventional semi-solid formulations. In this article, an overview of vaginal ring technologies is presented, followed by a review of recent advances and issues pertaining to their application for the delivery of HIV microbicides. This article forms part of a special supplement on presentations covering intravaginal rings, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.     

Pharmacokinetics and Tolerability of a Novel 17β-Estradiol and Progesterone Intravaginal Ring in Sheep

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-naïve 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.     

Segmented polyurethane intravaginal rings for the sustained combined delivery of antiretroviral agents dapivirine and tenofovir

Dual segment polyurethane intravaginal rings (IVRs) were fabricated to enable sustained release of antiretroviral agents dapivirine and tenofovir to prevent the male to female sexual transmission of the human immunodeficiency virus. Due to the contrasting hydrophilicity of the two drugs, dapivirine and tenofovir were separately formulated into polymers with matching hydrophilicity via solvent casting and hot melt extrusion. The resultant drug loaded rods were then joined together to form dual segment IVRs. Compression testing of the IVRs revealed that they are mechanically comparable to the widely accepted NuvaRing^® IVR. Physical characterization of the individual IVR segments using wide angle X-ray scattering and differential scanning calorimetry determined that dapivirine and tenofovir are amorphous and crystalline within their polymeric segments, respectively. In vitro release of tenofovir from the dual segment IVR was sustained over 30 days while dapivirine exhibited linear release over the time period. A 90 day accelerated stability study confirmed that dapivirine and tenofovir are stable in the IVR formulation. Altogether, these results suggest that multisegment polyurethane IVRs are an attractive formulation for the sustained vaginal delivery of drugs with contrasting hydrophilicity such as dapivirine and tenofovir.     

Drug delivery in multiple indication (multipurpose) prevention technologies: systems to prevent HIV-1 transmission and unintended pregnancies or HSV-2 transmission

INTRODUCTION: The development of multiple indication (multipurpose) prevention technologies (MIPTs) is driven by overlapping relationships in the area of female reproductive health. AREAS COVERED: 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. EXPERT OPINION: 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.     

Drug delivery in multiple indication (multipurpose) prevention technologies: systems to prevent HIV-1 transmission and unintended pregnancies or HSV-2 transmission

Introduction: The development of multiple indication (multipurpose) prevention technologies (MIPTs) is driven by overlapping relationships in the area of female reproductive health.

Areas covered: 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.

Expert opinion: 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.     

pH-sensitive Eudragit nanoparticles for mucosal drug delivery

Drug delivery via vaginal epithelium has suffered from lack of stability due to acidic and enzymatic environments. The biocompatible pH-sensitive nanoparticles composed of Eudragit S-100 (ES) were developed to protect loaded compounds from being degraded under the rigorous vaginal conditions and achieve their therapeutically effective concentrations in the mucosal epithelium. ES nanoparticles containing a model compound (sodium fluorescein (FNa) or nile red (NR)) were prepared by the modified quasi-emulsion solvent diffusion method. Loading efficiencies were found to be 26% and 71% for a hydrophilic and a hydrophobic compound, respectively. Both hydrophilic and hydrophobic model drugs remained stable in nanoparticles at acidic pH, whereas they are quickly released from nanoparticles upon exposure at physiological pH. The confocal study revealed that ES nanoparticles were taken up by vaginal cells, followed by pH-responsive drug release, with no cytotoxic activities. The pH-sensitive nanoparticles would be a promising carrier for the vaginal-specific delivery of various therapeutic drugs including microbicides and peptides/proteins.     

The importance of the vaginal delivery route for antiretrovirals in HIV prevention

The HIV/AIDS pandemic continues to be a global health priority, with high rates of new HIV-I infections persisting in young women. One HIV prevention strategy is topical pre-exposure prophylactics or microbicides, which are applied vaginally or rectally to protect the user from HIV and possibly other sexually transmitted infections. Vaginal microbicide delivery will be the focus of this review. Multiple nonspecific and specific antiretroviral microbicide products have been clinically evaluated, and many are in preclinical development, The events of HIV mucosal transmission and dynamics of the cervicovaginal environment should be considered for successful vaginal microbicide delivery. Beyond conventional vaginal formulations, intravaginal rings, tablets and films are employed as platforms in the hope to increase the likelihood of microbicide use. Furthermore, combining multiple antiretrovirals within a given formulation, combining a microbicide product with a vaginal device and integrating novel drug-delivery strategies within a microbicide product are approaches to successful vaginal-microbicide delivery.     

Preparation of multiparticulate vaginal tablet using glyceryl monooleate for sustained progesterone delivery

Most of the sustained release vaginal formulations are in the form of bioadhesive gels and tablets. Though proved efficient, their presence in the vagina for a longer time as a bulk produces discomfort and interference with body functioning including sexual activities. Hence, they lack complete patient compliance. In this study, multiparticulate vaginal tablets were prepared by utilizing progesterone (PRO) loaded dry powder precursor of cubic phase (DPPCP) of glyceryl monooleate (GMO). DPPCP were obtained by spray drying GMO with magnesium trisilicate (MTS) and have presented PRO sustained release in simulated vaginal fluid (SVF) for 14 hours. The effect of hydrophilic and hydrophobic tableting excipients on compression, phase, bioadhesion and drug release properties of prepared tablets was evaluated. The effervescent hydrophilic tablet (EHT) prepared with hydrophilic excipients showed rapid disintegration but, diminished sustaining ability owing to transformation into lamellar phase whereas the multiparticulate hydrophobic tablet (MHT) obtained from hydrophobic excipients presented both rapid disintegration and sustained release in SVF by virtue of cubic phase retention. During bioadhesivity testing, fast disintegration of MHT with formation of uniform and viscous bioadhesive layer on cow mucosa was observed even with a small volume of SVF. As MHT may not produce discomfort and interference, it will be preferred over bioadhesive gel or tablet.     

Preparation of Multiparticulate Vaginal Tablet Using Glyceryl Monooleate for Sustained Progesterone Delivery

Most of the sustained release vaginal formulations are in the form of bioadhesive gels and tablets. Though proved efficient, their presence in the vagina for a longer time as a bulk produces discomfort and interference with body functioning including sexual activities. Hence, they lack complete patient compliance. In this study, multiparticulate vaginal tablets were prepared by utilizing progesterone (PRO) loaded dry powder precursor of cubic phase (DPPCP) of glyceryl monooleate (GMO). DPPCP were obtained by spray drying GMO with magnesium trisilicate (MTS) and have presented PRO sustained release in simulated vaginal fluid (SVF) for 14 hours. The effect of hydrophilic and hydrophobic tableting excipients on compression, phase, bioadhesion and drug release properties of prepared tablets was evaluated. The effervescent hydrophilic tablet (EHT) prepared with hydrophilic excipients showed rapid disintegration but, diminished sustaining ability owing to transformation into lamellar phase whereas the multiparticulate hydrophobic tablet (MHT) obtained from hydrophobic excipients presented both rapid disintegration and sustained release in SVF by virtue of cubic phase retention. During bioadhesivity testing, fast disintegration of MHT with formation of uniform and viscous bioadhesive layer on cow mucosa was observed even with a small volume of SVF. As MHT may not produce discomfort and interference, it will be preferred over bioadhesive gel or tablet.     

The Effect of Drug Content Reduction on the In Vitro and In Vivo Properties of Levonorgestrel-Releasing Intravaginal Rings

Intravaginal rings (IVRs) are an option for continuous administration of drugs in women. However, a considerable amount of excess drug often remains in the ring upon removal. The current study focuses on comparing 2 IVRs releasing levonorgestrel (LNG). Both formulations were designed to release 40 μg of LNG daily, however, with a significant difference in the total amount of drug (10.6 vs. 176.9 mg). Numerical simulations and in vitro release rate testing were utilized in designing the IVRs and confirming the similarity of drug release. Moreover, a pharmacokinetic (PK) study was performed in 13 healthy Japanese women to investigate both formulations during the intended wearing period of 28 days. The primary PK metrics was the average concentration of LNG in plasma at defined time points under stable conditions. Statistical evaluation of the ratio of the main PK metrics indicated values almost in the bioequivalence range. Furthermore, drug content determinations for used and unused IVRs were analyzed for confirming the expected drug delivery in vivo. In summary, it was shown that with proper design, even major differences in the total drug content of IVR formulations might not result in significant effects in the in vitro and in vivo release properties.     

Vaginal microbicides and their delivery platforms

Introduction: HIV type 1 infection, despite having fallen by one-third over the past decade, remains a global health concern affecting millions of individuals worldwide. A focal point in contemporary research aimed at global HIV prevention has been the development of safe and efficacious coitally dependent and coitally independent anti-HIV microbicides to curb heterosexual HIV transmission. Despite extensive research efforts to develop novel vaginal antiretroviral (ARV) formulations and intravaginal ring delivery systems, the clinical advancement of microbicides with improved safety, efficacy and tolerability has significantly lagged behind.

Areas covered: This review focuses on the current status of both coitally dependent and coitally independent delivery platforms designed to increase user acceptability and clinical effectiveness of anti-HIV microbicides. The clinical failure of several vaginal microbicide candidates has propelled the field to mechanism-based ARV candidates that act more specifically on viral receptors, viral enzymes and host proteins. Consequently, improved vaginal microbicide delivery strategies that achieve uniform drug distribution with enhanced solubility, sustained drug release, improved product adherence with reduced dosing frequency and lack of effect on the vaginal mucosa and microbiota are being sought.

Expert opinion: Clinical success with vaginal microbicides may best be achieved through the combined effects of ARV compounds that exhibit different mechanisms of action with potent activity against multidrug-resistant HIV and efficacious delivery systems.