Vaginal gel drug delivery systems: understanding rheological characteristics and performance.

INTRODUCTION: Vaginal gels are used for a wide range of clinical and pharmaceutical applications. Gel performance in vivo, including spreading ability, retention and drug release behavior, is closely related to rheological properties. Hence, a comprehensive rheological characterization of candidate gel formulations is important in screening and designing appropriate vaginal gels to achieve optimal clinical performance. AREAS COVERED: In this review, the basic destructive (flow) and non-destructive (oscillation and creep) techniques, commonly used in the assessment of gels, are introduced. The main rheological properties discussed in this work include viscosity, storage modulus, loss modulus, loss tangent and strain growth under small stress loads. In particular, this paper reviews the rheological methods used in characterizing vaginal gels and discusses the factors that may influence rheological performance. Recent advances in rheological methods, the use of advanced rheological methods and the challenges facing formulation scientists are also reviewed. EXPERT OPINION: The complex and dynamic environment of the vagina requires a comprehensive understanding of the rheological performance of vaginal gels. The establishment of suitable rheological tests to appropriately define such characteristics may facilitate the selection of a gel that avoids leakage. The ideal gel platform must provide adequate coating with minimal leakage. This is extremely difficult to obtain as it requires the formulation of a gel with a suitable viscoelastic balance.

Development of a microbicide-releasing diaphragm as an HIV prevention strategy.

Contraceptive diaphragms offer a discreet method of pregnancy protection that women can use when needed with no side effects. Incorporating antiretroviral HIV microbicides into such devices may also provide protection against HIV infection. The paper gives a brief outline of the work being conducted by PATH, CONRAD and QUB on the development of a microbicide-releasing SILCS diaphragm. The design, engineering and manufacturing challenges that have been encountered will be discussed, as well as the potential impact such a device could have in the developing world.

Drug delivery systems for photodynamic therapy.

Photodynamic therapy (PDT) is a medical treatment in which a combination of a photosensitizing drug and visible light causes destruction of selected cells. Over the past two decades, photodynamic therapy has enjoyed a period of intense investigation, both in the laboratory and in the clinic. Although still widely considered to be an experimental technique, its status and value within modern clinical practice continues to grow. The PDT field has, to date, been dominated by a small number of pharmaceutical companies and inhabited almost exclusively by clinicians and those involved in fundamental scientific research. True pharmaceutical formulation development has been limited, to some extent, by financial constraints. If PDT is to realise its undoubted potential in clinical practice it is important that awareness of the need for appropriate photosensitizer delivery systems is raised. Accordingly, this article deals with the innovations pertaining to drug delivery systems for photodynamic therapy as disclosed in recent patent literature.

Designing photosensitizers for photodynamic therapy: strategies, challenges and promising developments.

Photodynamic therapy (PDT) and photodynamic antimicrobial chemotherapy (PACT) are techniques that combine the effects of visible light irradiation with subsequent biochemical events that arise from the presence of a photosensitizing drug (possessing no dark toxicity) to cause destruction of selected cells. Despite its still widespread clinical use, Photofrin(®) has several drawbacks that limit its general clinical use. Consequently, there has been extensive research into the design of improved alternative photosensitizers aimed at overcoming these drawbacks. While there are many review articles on the subject of PDT and PACT, these have focused on the photosensitizers that have been used clinically, with little emphasis placed on how the chemical aspects of the molecule can affect their efficacy as PDT agents. Indeed, many of the PDT/PACT agents used clinically may not even be the most appropriate within a given class. As such, this review aims to provide a better understanding of the factors that have been investigated, while aiming at improving the efficacy of a molecule intended to be used as a photosensitizer. Recent publications, spanning the last 5 years, concerning the design, synthesis and clinical usage of photosensitizers for application in PDT and PACT are reviewed, including 5-aminolevulinic acid, porphyrins, chlorins, bacteriochlorins, texaphyrins, phthalocyanines and porphycenes. It has been shown that there are many important considerations when designing a potential PDT/PACT agent, including the influence of added groups on the lipophilicity of the molecule, the positioning and nature of these added groups within the molecule, the presence of a central metal ion and the number of charges that the molecule possesses. The extensive ongoing research within the field has led to the identification of a number of potential lead molecules for application in PDT/PACT. The development of the second-generation photosensitizers, possessing shorter periods of photosensitization, longer activation wavelengths and greater selectivity for diseased tissue provides hope for attaining the ideal photosensitizer that may help PDT and PACT move from laboratory investigation to clinical practice.

Microstructured devices for transdermal drug delivery and minimally-invasive patient monitoring.

Transdermal drug delivery offers certain advantages over conventional oral or parenteral administration. However, the excellent barrier function of the skin, accomplished almost entirely by the stratum corneum, restricts the number of drug substances that can be administered transdermally to those with very specific physicochemical properties. Several approaches have been used to enhance the transport of drugs through the stratum corneum. However, in many cases, only moderate success has been achieved and each approach is associated with significant problems. Microstructured devices, consisting of a plurality of microprojections attached to a support, can be used to painlessly bypass the stratum corneum barrier and thus achieve successful transdermal delivery. Moreover, microprojection devices also enable minimally-invasive sampling and monitoring of biological fluids. Much activity is currently focussed in this area. Accordingly, this article deals with the innovations pertaining to microprojection-based devices for transdermal drug delivery and minimally-invasive monitoring as disclosed in recent patent literature.

In vitro release of nonoxynol-9 from silicone matrix intravaginal rings.

The controlled-release characteristics of matrix silicone intravaginal rings loaded with between 100 and 971 mg of nonoxynol-9 have been investigated with a view to developing a ring that may offer a new female-controlled method for the prevention of transmission of sexually transmitted diseases, particularly HIV. Intravaginal rings containing 253, 487 and 971 mg of nonoxynol-9 provided a daily release of 2 mg or more over the 8-day release period, the minimal amount of nonoxynol-9 considered to provide an effective vaginal concentration for the prevention of HIV. Furthermore, the maximum daily release of N9 was about 6 mg, an amount significantly smaller than that observed for other nonoxynol-9 products whose large daily doses may in fact increase the occurrence of HIV by causing epithelial damage to the vaginal tissue. The release mechanism of the liquid nonoxynol-9 from the intravaginal rings has also been investigated and compared to models describing the release of solid drugs from the rings. It has been demonstrated through release studies and surface microscopy that a drug depletion zone is not established in such liquid-loaded intravaginal ring systems, with implications for the release kinetics.

Influence of silicone elastomer solubility and diffusivity on the in vitro release of drugs from intravaginal rings.

The in vitro release characteristics of eight low-molecular-weight drugs (clindamycin, 17beta-estradiol, 17beta-estradiol-3-acetate, 17beta-estradiol diacetate, metronidazole, norethisterone, norethisterone acetate and oxybutynin) from silicone matrix-type intravaginal rings of various drug loadings have been evaluated under sink conditions. Through modelling of the release data using the Higuchi equation, and determination of the silicone solubility of the drugs, the apparent silicone elastomer diffusion coefficients of the drugs have been calculated. Furthermore, in an attempt to develop a quantitative model for predicting release rates of new drug substances from these vaginal ring devices, it has been observed that linear relationships exist between the log of the silicone solubility of the drug (mg x ml(-1)) and the reciprocal of its melting point (K(-1)) (y=3.558x-9.620, R=0.77), and also between the log of the diffusion coefficient (cm(2) s(-1)) and the molecular weight of the drug molecule (g x mol(-1)) (y=-0.0068x-4.0738, R=0.95). Given that the silicone solubility and silicone diffusion coefficient are the major parameters influencing the permeation of drugs through silicone elastomers, it is now possible to predict through use of the appropriate mathematical equations both matrix-type and reservoir-type intravaginal ring release rates simply from a knowledge of drug melting temperature and molecular weight.