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.     

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.     

药物传递系统（DDS）Ⅳ腔道给药传递系统

腔道给药是能起全身作用、避开肝首过代谢作用、患者便于自用的非损伤性给药途径。本文着重介绍影响鼻腔、阴道给药药物吸收的生物因素和剂型因素及正在开发的腔道给药传递系统。     

阴道给药制剂的研究进展

目的　介绍近年来阴道给药制剂的研究进展,为新型药物制剂的开发提供参考。方法　通过1998～2003年国内外相关文献的分析,总结各种阴道给药制剂的特点及其优点与不足。结果和结论　阴道给药制剂有良好的开发前景。     

Novel drug delivery systems for steroidal hormones

There are two main goals in the development of steroid containing drug delivery systems (DDS); firstly, to enhance the therapeutic value of the resulting systems versus standard dosage forms such as peroral tablets or injections. And secondly to manage the life cycle of drug substances which are going off patents. An example of an important development is patient friendly transdermal delivery systems (TDS) for oestrogen replacement therapy, which requires application intervals of once-a-week only, despite the fact that the biological half-life of the delivered oestradiol is ~ 20 min. Even more impressive are the achievements in the classes of intrauterine systems (IUS) and implants where the application intervals can be up to 5 years, throughout which low dosages of levonorgestrel are constantly released with high precision and reproducibility. Novel system developments also include steroid loaded vaginal rings for fertility control. On the basis of the technologies already available in the aforementioned areas of TDS, IUS, implants and vaginal rings, many efforts currently concentrate on expanding the therapeutic value of these system types via integrated technological and clinical development activities. Main targets are fertility control, hormone replacement therapy, treatment of gynaecological conditions (e.g. menorrhagia) and andropause (male hormone replacement therapy).     

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.     

Nanoparticle-based vaginal drug delivery systems for HIV prevention

Importance of the Field: Several strategies are being investigated for the prevention of heterosexual transmission of HIV. Of these, topical vaginal drug delivery systems, microbicides, are being actively pursued. HIV prevention by means of a topical microbicide has several drug delivery challenges. These challenges include the vaginal mucosal barriers and potential degradation of the drugs in the vaginal lumen due to pH and enzymes present. Also, new drugs being evaluated as microbicides have specific mechanisms of action, which in some cases require drug targeting to a specific site of action. Nanoparticles provide a delivery strategy for targeted or controlled delivery to the vagina which can be applied in the field of HIV prevention.

Areas covered in the review: This review summarizes nanoparticulate systems and their use in mucosal delivery to date. The sexual transmission of HIV along with the various targets to prevent transmission are discussed as well as the potential opportunities, challenges and advantages in using a nanoparticle-based approach for microbicidal drug delivery.

What the reader will gain: This review provides a general understanding of vaginal drug delivery, its challenges, and nanoparticulate delivery systems. Additionally, insight will be gained as to the limited existing application of this technology to the field of HIV prevention.

Take home message: To date, few studies have been published that exploit nanoparticle-based microbicidal delivery to the vagina. The use of nanoparticles for vaginal drug delivery provides an approach to overcome the existing barriers to success.     

微凝胶的制备及其在药物缓控释系统中的应用

微凝胶是一种具有分子内交联网状结构,粒径在0.1~100 μm之间的功能性聚合物,具有粒径小、载药量高、环境响应性灵敏、生物相容性好等特点,在药物缓控释系统中的应用具有独特优势。笔者在查阅近年国内外文献的基础上综述了微凝胶的基本特性、制备方法、制备材料及在药物缓控释系统中的应用。     

壬苯醇醚阴道用缓释凝胶的研制

目的制备壬苯醇醚阴道用缓释凝胶并优化其处方与工艺。方法采用正交试验设计 ,考察了聚卡波菲用量、卡波沫用量、pH值、甘油用量、液体石蜡用量、山嵛酸甘油酯用量及不同工艺对释放度的影响 ,与国外产品进行残差平方和、拟合度、区分因子和相似因子比较 ,确定壬苯醇醚阴道用缓释凝胶的处方工艺 ,并考察了其初步稳定性。结果优化所得处方工艺为 :聚卡波菲用量0 5 % (w) ,卡波沫用量 1% (w) ,甘油用量为 5 % (w) ,液体石蜡用量为 5 % (w) ,山嵛酸甘油酯用量为 1% (w) ,pH值为 4 5 ,选用工艺 1。 结论按优化处方工艺制得的壬苯醇醚阴道用缓释凝胶稳定 ,与国外产品比较具有相似的释放度 ,且以复合模式释放。     

眼部给药系统的研究进展

由于眼部特殊的生理结构与诸多屏障的存在,传统的眼用制剂存在生物利用度低、眼内保留时间短以及刺激性强等问题,常常难以达到预期治疗效果。近年来,各种新技术如纳米技术、植入技术、接触镜片的研究和应用,使得眼部给药有了长足的发展。其中纳米材料具有尺寸小、可降解、靶向性强以及对生物组织刺激性小等特点,多种纳米载体如聚合物胶束、纳米粒、纳米混悬液、脂质体与纳米乳等,已被广泛用于眼部给药系统。目前以上多种新技术在眼部给药系统中显示出良好的应用前景。笔者就近年来这方面的研究与应用作一综述,以期为眼部给药系统的研发提供参考。     

Polymeric nanofibers: targeted gastro-retentive drug delivery systems

Background: Conventional oral dosage forms exhibit poor/low bioavailability due to incomplete release of drug and short residence time at the absorption site. Gastro-retentive drug delivery system (GRDDS) is particularly used to improve bioavailability of the drugs, which have narrow absorption window down in the levels of gastrointestinal tract and also to treat local disorders.

Purpose: The purpose of this review is to describe the utility of the nanofibers as gastro-retentive dosage form. From last few decades, formulation scientists have put extensive efforts to develop suitable gastro-retentive drug delivery system, which is appropriate for commercialization. Current approaches used for preparation of gastro-retentive drug delivery system offers limited functional features to control the floating behavior. Recently, an extensive research has been developed to improve the gastric residence time by using nanofibers, which ultimately leads to the increased bioavailability of the drug. Multiple functional features and unique properties of nanofibers improve its gastro retention.

Conclusion: Nanofiber system provides stomach-specific drug release for longer duration; moreover, increased local action of the drug due to prolonged contact time with the gastric mucosa. Thus, the nanofiber system promises to be the potential approach for gastric retention drug delivery system.     

Drug release kinetics and physicochemical characteristics of floating drug delivery systems

Introduction: Absorption of drugs through the gastrointestinal tract poses a variety of limitations, making the in vivo performance of drug delivery systems uncertain. Following on from recent advances, in a time of increased consideration of floating drug delivery systems, it is as important as ever to continue the progress by studying different aspects of these systems. Moreover, it seems imperative to gain a deeper insight into drug release mechanisms, in order to design a more systematic and intellectual floating system.

Areas covered: This paper summarizes current approaches in the research and development of ideal floating drug delivery systems, from recent literature. Also, in order to have predictability and reproducibility in designing an efficient floating dosage form, some kinetic studies are mentioned, and the drug release mechanism from floating drug delivery systems is discussed.

Expert opinion: Developing an efficient floating dosage form is reliant on a better understanding of the relation between formulation variables and performance of the floating systems. Generally, the combination of two buoyancy mechanisms and gas-generating systems with swellable polymers would be beneficial for obtaining an appropriate floating lag time and duration of buoyancy, which in turn guarantees optimum efficiency of the pharmaceutical dosage form.     

Ophthalmic drug delivery systems

New ophthalmic drug delivery systems are curently receiving increased attention, in part because of the expected emergence of new drugs with short biological half-lives whose usefulness may depend on a more continuous drug supply than eyedrops can provide, but also because of the potential of some delivery systems to reduce the side effects of the more potent drugs recently introduced or presently under investigation. Some ophthalmic delivery systems extend the duration of drug action by enhancement of corneal absorption; these systems include soluble gels and emulsions, hydrophilic ocular inserts, ion-pair associations, prodrugs, and liposomes. Since these systems enhance the “pulse entry” of the drug, they are limited to use with drugs whose dose-related side effects are not serious. Other delivery systems provide for a controlled release of drugs and therefore minimize the pulse entry with which side effects are associated. They can be based on any of several different mechanisms and include both erodible and nonerodible matrices. The various delivery systems that have recently been developed and those that are currently known to be under investigation are described in this paper, along with some observations regarding the future outlook of ophthalmic drug delivery systems.     

Stimuli-sensitive drug delivery systems for site-specific antibiotic release

Site-specific delivery of antibiotics has always been a high-priority area in pharmaceutical research. Conventionally used antibiotics suffer several limitations, such as low accumulation and penetration in diseased cells/tissues, limited bioavailability of drugs, drug resistance, and off-target toxicity. To overcome these limitations, several strategies have been exploited for delivering antibiotics to the site of infection, such as the use of stimuli-responsive antibiotic delivery systems, which can release antibiotics in a controlled and timely fashion. These stimuli can either be exogenous (light, magnetism, ultrasound, and electrical) or endogenous (pH, redox reactions, and enzymatic). In this review, we present a summary of recent developments in the field of stimuli-based targeted drug delivery systems for the site-specific release of antibiotics.     

叶酸受体介导的靶向纳米给药系统研究进展

叶酸受体在许多恶性肿瘤细胞表面过度表达,而在正常细胞中则几乎不表达或只有少量表达。利用叶酸受体表达的特性,通过将叶酸修饰于药物载体表面,可使药物靶向输送至叶酸受体过度表达的肿瘤细胞中,从而避免对正常细胞产生毒性,提高药物疗效;而纳米给药系统因粒径较小等原因可使药物在肿瘤部位浓集。本文对近年来叶酸受体介导的靶向纳米给药系统进行了综述。     

Thermo-responsive systems for controlled drug delivery

Controlled drug delivery systems represent advanced systems that can be tightly modulated by stimuli in order to treat diseases in which sustained drug release is undesirable. Among the many different stimuli-sensitive delivery systems, temperature-sensitive drug delivery systems offer great potential over their counterparts due to their versatility in design, tunability of phase transition temperatures, passive targeting ability and in situ phase transitions. Thus, thermosensitive drug delivery systems can overcome many of the hurdles of conventional drug delivery systems in order to increase drug efficacies, drug targeting and decrease drug toxicities. In an effort to further control existing temperature-responsive systems, current innovative applications have combined temperature with other stimuli such as pH and light. The result has been the development of highly sophisticated systems, which demonstrate exquisite control over drug release and represent huge advances in biomedical research.     

Advanced and controlled drug delivery systems in clinical disease management

Advanced and controlled drug delivery systems are important for clinical disease management. In this review the most important new systems which have reached clinical application are highlighted.Microbiologically controlled drug delivery is important for gastrointestinal diseases like ulcerative colitis and distally localized Crohn's disease. In cardiology the more classic controlled release systems have improved patient compliance and decreased side effects. In the treatment of intractable pain the spinal and transdermal route is well documented.In neurology the flattened peak-through levels of antiepileptic drugs and anti Parkinson's drugs represents a more predictable kinetic profile.Tracheal delivery of corticosteroids and sympaticomimetics in asthma and Chronic Obstructive Pulmonary Disease is fully accepted in clinical practice: delivery by this route results in better efficacy and a better safety profile.In gynaecology the delivery of pulsatile hormones (LHRH) is used for pregnancy induction, while transdermal oestrogens are promising in the prevention of osteoporosis.In surgical practice the use of antibiotic impregnated bone cement and antibiotic impregnated biodegradable collagens is well established.To prevent infections intravascular catheters coated with heparin or antibiotics are used.In ophthalmology the Ocusert^® systems provide a controlled release of different drugs in the eye.Most spectacular is the clinical introduction of the first liposomal drugs: amfotericine B and daunorubicine. Liposomal formulations of these drugs have enhanced activity and decreased toxicity compared to conventional formulations.     

Expansible thermal gelling foam aerosol for vaginal drug delivery

Vaginal delivery of antimicrobial drugs is the most effective method for the local treatment of the vaginal infections. However, current vaginal drug delivery systems (VDDS), including gel, lotion, aerosol and cream, are suffering from low penetration in the deep vaginal rugae and easy elimination by self-cleaning of vaginal canal. To address these issues, a foam aerosol based on the thermal transformation was designed to improve penetration efficiency and achieve the extended retention. The expansible thermal gelling foam aerosol (ETGFA) consisting of thermal sensitive matrix, silver nanoparticle, adhesive agent and propellant, was optimized by evaluations of precursor viscosity, foam expansion, thermal gelation, gel adhesiveness, antimicrobial effects and tissue irritation. The ETGFA would penetrate to the deep vaginal rugae to cover the infectious sites by foam expansion. Drug leakage was intended to be avoided by the thermal gelation at physiological temperature before foam collapse. The gel could be retained in the vaginal canal for extended time due to its superior adhesiveness when compared to the commercial gel Asimi^®. The ETGFA provided extended drug release for over 4?h and maintained effective drug concentrations at the infectious sites. The ETGFA containing silver nanoparticles showed dose-dependent antimicrobial effects on the vaginal floras and irritation reduction to the vaginal tissues. The results demonstrated that the ETGFA could overcome the limitations of conventional dosage forms, including poor drug penetration, carrier retention and patient compliance and satisfied the requirements for vaginal drug delivery.     

口腔黏膜给药系统研究进展

口腔黏膜给药使药物通过颈内静脉直接进入全身循环,避免胃肠道中的酸水解及肝脏首过效应,具有生物利用度高、患者依从性良好的优点。口腔黏膜给药的主要特点是利用生物粘附现象,即生物膜表面与天然或合成聚合物之间的界面分子粘合力现象,延长制剂在生物黏膜表面上的停留时间,以获得更高、更稳定的药物吸收。对口腔黏膜的结构特征、黏膜生物粘附机制、影响黏膜粘附的因素、口腔黏膜剂型设计以及口腔黏膜给药系统的研究进展进行了介绍。