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.     

Potential of polymeric nanoparticles in AIDS treatment and prevention

Importance of the field: Acquired immunodeficiency syndrome (AIDS) remains one of the greatest challenges in public health. The AIDS virus is now responsible for > 2.5 million new infections worldwide each year. Despite significant advances in understanding the mechanism of viral infection and identifying effective treatment approaches, the search for optimum treatment strategies for AIDS remains a major challenge. Recent advances in the field of drug delivery have provided evidence that engineered nanosystems may contribute to the enhancement of current antiretroviral therapy.

Areas covered in this review: This review describes the potential of polymeric nanoparticle-based drug delivery systems in the future treatment of AIDS. Polymeric nanoparticles have been developed to improve physicochemical drug characteristics (by increasing drug solubility and stability), to achieve sustained drug release profile, to provide targeting to the cellular and anatomic human immunodeficiency virus (HIV) latent reservoirs and to be applied as an adjuvant in anti-HIV vaccine formulations.

What the reader will gain: The insight that will be gained is knowledge about the progress in the development of polymeric nanoparticle-based drug delivery systems for antiretroviral drugs as alternative for AIDS treatment and prevention.

Take home message: The advances in the field of targeted drug delivery can result in more efficient strategies for AIDS treatment and prevention.     

Vaginal drug delivery: strategies and concerns in polymeric nanoparticle development

Introduction: Vaginal infection is widespread and > 80% of females encounter such infections during their lives. Topical treatment and prevention of vaginal infection allows direct therapeutic action, reduced drug doses and adverse effects, convenient administration and improved compliance. The advent of nanotechnology results in the use of nanoparticulate vehicle to control drug release, to enhance dosage form mucoadhesive properties and vaginal retention, and to promote mucus and epithelium permeation for both extracellular and intracellular drug delivery.

Areas covered: This review discusses the conflicting formulation requirements on polymeric nanoparticles in order to have them mucoadhesive and retentive in vaginal tract, while able to penetrate through mucus to reach adherent mucus layer or epithelium surfaces to prolong extracellular drug release, or facilitate mucosal permeation and intracellular drug delivery.

Expert opinion: Nanoscale systems are potentially useful in topical vaginal drug delivery. A thorough understanding of their mucus penetration and retention behavior as a function of their formulation, size and surface properties, biorecognition, pH, temperature or other stimuli responsiveness is essential for design of therapeutically effective nanomatrices.     

The development of rectal microbicides for HIV prevention

Introduction: Individuals practicing unprotected receptive anal intercourse are at particularly high risk of HIV infection. Men who have sex with men in the developed and developing world continue to have disproportionate and increasing levels of HIV infection. The last few years have seen important progress in demonstrating the efficacy of oral antiretroviral pre-exposure prophylaxis, vaginal microbicides, and treatment as prevention, but there has also been significant progress in the development of rectal microbicides for HIV prevention.

Areas covered: The purpose of this review is to summarize the status of rectal microbicide research and to identify opportunities, challenges, and future directions in this important field of HIV prevention research. The design of completed and ongoing Phase I rectal microbicide studies that include the generation of comprehensive pharmacokinetic/pharmacodynamic data may allow for more rational decisions about which rectal microbicides should be advanced to later stage development.

Expert opinion: There is a strong rationale for the development of rectal microbicides for HIV prevention. Preclinical data provide supportive evidence for the feasibility of this approach, and there is significant interest in rectal microbicide development from communities at risk of HIV acquisition through unprotected receptive anal intercourse in both the developed and developing world. Demonstration of sustained safety, acceptability, and product adherence in the MTN-017 Phase II study of tenofovir 1% gel will be an important step in rectal microbicide development and will hopefully lead to Phase III effectiveness testing of this novel HIV prevention strategy.     

Innovations in bioadhesive vaginal drug delivery system

Introduction: Vagina, due to its anatomical position and physiological characteristics is increasingly being explored as a site for drug delivery in recent years. This route coupled with bioadhesion phenomena has born fruitful results in delivering drugs both locally as well as systemically.

Areas covered: Bioadhesive vaginal drug delivery system has been used for the treatment of local diseases affecting the vagina like candidiasis, STD, vaginal dryness, and so on. Also, research has demonstrated that drugs can be successfully delivered to systemic circulation via vaginal mucosa for treatment of various diseases like migraine and osteoporosis. Besides, this vaginal route has also been used for uterine targeting of drugs. This review focuses on these recent innovations that have been patented in the area of bioadhesive vaginal drug delivery systems. The review also highlights certain physicochemical characteristics of bioadhesive polymers that affect drug delivery through this route.

Expert opinion: An in-depth study of this review will give an insight into the potential areas that can be explored while designing a bioadhesive vaginal drug delivery system. Also, the in vitro and in vivo experimental results discussed in the review will help stimulate research in development and optimization of newer formulations.     

Topical drug delivery systems: a patent review

Introduction: Topical administration is the favored route for local delivery of therapeutic agents due to its convenience and affordability. The specific challenge of designing a therapeutic system is to achieve an optimal concentration of a certain drug at its site of action for an appropriate duration.

Areas covered: This review summarizes innovations from the past 3 years (2012–2015) in the field of topical drug delivery for the treatment of local infections of the vagina, nose, eye and skin. The review also throws some light on the anatomy and physiology of these organs and their various defensive barriers which affect the delivery of drugs administered topically.

Expert opinion: Topical administration has been gaining attention over the last few years. However, conventional topical drug delivery systems suffer from drawbacks such as poor retention and low bioavailability. The successful formulation of topical delivery products requires the careful manipulation of defensive barriers and selection of a soluble drug carrier. Extensive research is required to develop newer topical drug delivery systems aiming either to improve the efficacy or to reduce side effects compared to current patented systems.     

Small molecule HIV entry inhibitors: Part II. Attachment and fusion inhibitors: 2004 – 2010

Introduction: The first US FDA approved HIV entry inhibitor drug Enfuvirdine belongs to the fusion inhibitor category. Earlier efforts in this area were focused on peptides and monoclonal antibodies; recently, the focus has shifted towards the development of small molecule HIV attachment and fusion inhibitors. They can be used for prophylactic purposes and also hold potential for the development of HIV microbicides.

Areas covered: In a previous paper (‘Small molecule HIV entry inhibitors: Part I’), we reviewed patents and patent applications for small molecule chemokine receptor antagonists from major pharmaceutical companies. In this paper, the development of small molecule HIV attachment and fusion inhibitors is discussed in detail. It covers patents and patent applications for small molecule HIV attachment and fusion inhibitors published between 2004 and 2010 and related literature with a focus on recent developments based on lead generation and lead modification.

Expert opinion: To augment the potency of currently available antiretroviral drug combinations and to fight drug-resistant virus variants, more effective drugs which target additional steps in the viral replication cycle are urgently needed. HIV attachment and fusion processes are such targets. Inhibitors of these targets will provide additional options for the treatment of HIV drug-resistant strains. Small molecule HIV attachment inhibitors such as BMS-378806 and analogs from Bristol Myers Squibb, N-aryl piperidine derivatives from Propharmacon, and NBD-556 and NBD-557 from New York Blood Center may have potential as vaginal microbicidal agents and can be an economical alternative to monoclonal antibodies.     

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.     

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.     

Preventing mucosal HIV transmission with topical microbicides: challenges and opportunities

A combination of prevention and treatment modalities will be needed to successfully control the global spread of HIV. Microbicides, drug products topically applied to mucosal surfaces to prevent HIV infection, are one of these biomedical interventions that hold great promise. In order to be efficacious, microbicides must overcome several challenges imposed by the mucosal microenvironment they intend to protect and the mischievous human immunodeficiency virus with its enormous capacity to adapt. Recent data, however, supports the establishment of the primo-infection by only a small number of founder viruses, which are highly vulnerable to microbicidal intervention at the initial stages of mucosal invasion. The biological foundation of these challenges and opportunities in microbicide development is explored in this review. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.     

Pickering emulsions: challenges and opportunities in topical delivery

ABSTRACT

Introduction: Topical drug delivery is a challenging area with many advantages such as avoidance of first passage effect, stabilization of blood concentrations and attainment of local therapeutic effect with fewer side effects. Despite all these advantages, topical drug delivery remains limited to few molecules, since skin acts as a barrier to the delivery of many therapeutic molecules. To overcome this obstacle, a favored strategy relies on selecting suitable vehicles for dermatologic therapy, such as emulsions, gels and, more recently, nanoparticulate systems.

Areas covered: Particle-stabilized emulsions, also known as Pickering emulsions, have garnered interest in recent years. Although most of the investigation on Pickering emulsions has been based on model systems with inorganic or organic solid particles, recent advances have been made regarding the application of nanocarriers, protein-based particles or cyclodextrins for this purpose. This review reports the latest advances in Pickering emulsions technical challenges, and discusses the potential benefits and drawbacks of using these formulations for topical pharmaceutical and cosmetic applications as an alternative to conventional surfactant-based systems.

Expert opinion: Pickering emulsions appear as a multifunctional dosage form with endless advantages. A great deal of progress is expected in this area, which might represent a renewed vision for the pharmaceutical and cosmetic industry.     

A drug evaluation of 1% tenofovir gel and tenofovir disoproxil fumarate tablets for the prevention of HIV infection

Introduction: More than a million people acquire HIV infection annually. Pre-exposure prophylaxis (PrEP) using antiretrovirals is currently being investigated for HIV prevention. Oral and topical formulations of tenofovir have undergone preclinical and clinical testing to assess acceptability, safety and effectiveness in preventing HIV infection.

Areas covered: The tenofovir drug development pathway from compound discovery, preclinical animal model testing and human testing were reviewed for safety, tolerability and efficacy. Tenofovir is well tolerated and safe when used both systemically or applied topically for HIV prevention. High drug concentrations at the site of HIV transmission and concomitant low systemic drug concentrations are achieved with vaginal application. Coitally applied gel may be the favored prevention option for women compared with the tablets, which may be more suitable for prevention in men and sero-discordant couples. However, recent contradictory effectiveness outcomes in women need to be better understood.

Expert opinion: Emerging evidence has brought new hope that antiretrovirals can potentially change the course of the HIV epidemic when used as early treatment for prevention, as topical or oral PrEP. Although some trial results appear conflicting, behavioral factors, adherence to dosing and pharmacokinetic properties of the different tenofovir formulations and dosing approaches offer plausible explanations for most of the variations in effectiveness observed in different trials.     

Topical delivery for the treatment of psoriasis

Importance of the field: Psoriasis is one of the most common human skin diseases. Topical therapy forms the cornerstone in the management of mild-to-moderate psoriasis. Topical therapies are also used as adjunctive to systemic therapy in moderate and severe forms of the disease.

Areas covered in this review: In this review, an overview of psoriasis pathogenesis, new topical medications for psoriasis, new targets and molecules, combination topical therapies and combination of topical and phototherapy is provided. Over the past decade several efficacious and acceptable treatment options have emerged from the age-old therapies. The development of sophisticated formulation options has led to an enhancement in the rate and extent of drug delivery across the skin, increasing therapeutic value and improving patient compliance.

What the reader will gain: Readers will learn about monotherapy and combination topical products as well as new topical drug delivery technology to achieve optimal clinical outcomes. This review will highlight the need to generate more dermal pharmacokinetic data for better understanding of the impact of formulation change on skin pharmacokinetics to help design improved topical drug delivery systems.

Take home message: New topical formulations have the potential to achieve better efficacy with improved safety profile.     

Topical drug delivery using chitosan nano- and microparticles

Introduction: Topical drug delivery offers important benefits for improving the therapeutic effect and reducing systemic side effects of the administered compounds. In addition, utilization of biopolymeric material-based systems can play a key role in developing new topical dosage forms and their applications. This review describes the advances that have been made, new strategies and as well as possible challenges of particular systems of chitosan used in topical drug delivery, including challenging innovations in topical usage of these systems that can make significant impact on clinical practice.

Areas covered: The main area covered is hypothesis that particulate carriers based on chitosan and its derivatives can penetrate the topical barriers from the body. For this reason, the novel studies described emphasize the fact that chitosan-based particular systems are popular that can be tailor-made according to in vitro and in vivo characterization. Such parameters, which are known to influence their in vivo performance, can be modulated by adjusting the formulation conditions of the chitosan-based particular systems for topical application.

Expert opinion: The topical application of drugs with particulate systems comprising a natural polymer, chitosan, is one of the most popular drug delivery routes. The aim of topical use of chitosan particles is to improve the drug bioavailability by prolonging the residence time of drugs applied topically or by enhancing the passing of drugs through the epithelial cells by opening the tight junctions between epithelial cells and also to reduce the side effects of the drugs.     

Pharmacogenomics-based RNA interference nanodelivery: focus on solid malignant tumors

Introduction: RNA interference represents one of the most promising strategies in fighting disease. However, small RNA interference faces substantial challenges for in vivo application due to the inherent instability of the RNA interference molecule. Among the nonviral gene delivery carriers, nanoparticles have attracted interest due to their success in various model systems. Nanomaterials have unique properties compared to conventional bulk materials that may be applicable in this setting. The nanoparticle complex carrying small interference RNA can undergo surface modification to achieve targeted modification for tissue-specific delivery. However, toxicity issues of the delivery systems need to be addressed and they require a pharmacogenomic profile of their own.

Areas covered: The authors review pharmacogenomics, toxicogenomics, nanoparticle-based drug delivery, and small interference RNA, with a focus on how logically engineered nanoparticle delivery systems can be used for personalized medicine in malignant tumors.

Expert opinion: Pharmacogenomics may be helpful in addressing possible individualized drug response for both the gene silencing capability of the delivered siRNA and the nanoparticle drug delivery system as both complete and distinct units. This may be done by assessing variations in gene expressions and single nucleotide polymorphisms. Patient profiling may be key as patient noncompliance due to toxicity plays a major role in treatment failure.     

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.     

An update on multipurpose prevention technologies for the prevention of HIV transmission and pregnancy

ABSTRACT

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.     

Development and characterisation of a self-microemulsifying drug delivery systems (SMEDDSs) for the vaginal administration of the antiretroviral UC-781

UC-781 is highly selective and potent against HIV-1. However, its hydrophobic nature (log P 5.1) and lack of aqueous solubility have limited its development as a HIV microbicide. Self-microemulsifying drug delivery systems (SMEDDSs) have been developed to enhance the water solubility and bioavailability of hydrophobic drugs, such as UC781. In this study, we show the development of UC781-loaded SMEDDS and their enhanced release of UC781 from hard gelatine capsules, when compared to UC781 powder only. The majority of antiretrovirals being evaluated as potential HIV microbicides are hydrophobic. Therefore, a SMEDDS formulation offers an alternative approach to enhancing the vaginal absorption of these microbicidal candidates.