Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.     

Lipid implants as drug delivery systems

The parenteral controlled delivery of acid-labile drugs (e.g., proteins) is difficult, because the standard polymer poly(lactic-co-glycolic acid) used to control drug release upon parenteral administration degrades into shorter chain acids, creating acidic microclimates. Lipid implants do not show this disadvantage. The objective of this article is to give an overview on the present state of the art and to highlight the advantages and drawbacks of the different types of systems reported in the literature. The major preparation techniques for lipid implants, underlying mass transport mechanisms, biocompatibility and in vivo performance of the most interesting systems are described. Lipid implants offer a great potential as parenteral controlled drug delivery systems, especially for protein-based drugs. A broad spectra of release patterns can be provided and acidic microclimates avoided.     

Parenteral drug delivery: a review

The parenteral route of administration is the most effective route for the delivery of the active pharmaceutical substances with narrow therapeutic index, poor bioavailability especially for those drugs, prescribed to unconscious patients. To maintain a therapeutic effective concentration of the drug, it requires frequent injections which ultimately lead to patient discomfort. In parenteral drug delivery, major progress has been done in the field of formulation technologies so as to provide a targeted and sustained release of drug in predictable manner. The present article reviews recent patents and major advancements in parenteral drug delivery systems along with general introduction. This article also deals with importance of novel systems in drug delivery to overcome the problems associated with conventional parenteral drug delivery systems.     

Lipid implants as drug delivery systems

The parenteral controlled delivery of acid-labile drugs (e.g., proteins) is difficult, because the standard polymer poly(lactic-co-glycolic acid) used to control drug release upon parenteral administration degrades into shorter chain acids, creating acidic microclimates. Lipid implants do not show this disadvantage. The objective of this article is to give an overview on the present state of the art and to highlight the advantages and drawbacks of the different types of systems reported in the literature. The major preparation techniques for lipid implants, underlying mass transport mechanisms, biocompatibility and in vivo performance of the most interesting systems are described. Lipid implants offer a great potential as parenteral controlled drug delivery systems, especially for protein-based drugs. A broad spectra of release patterns can be provided and acidic microclimates avoided.     

Getting into the colon: approaches to target colorectal cancer

Colorectal cancer (CRC) is the third most common cancer in the world and the second most common cause of cancer related deaths. Conventional treatment of CRC is comprised of drug (chemotherapeutic agents) administration by parenteral route, which delivers the drug to both normal as well as cancerous tissues, thus leading to numerous undesirable effects. Enormous research is going on worldwide for designing an alternative route of administration, among which oral colon-targeted drug delivery systems have gained immense attention amongst scientific community. Direct delivery of drugs at the site of action leads to an increase in the availability of drugs at the targeted region. This causes a reduction in the amount of drug required to exert same therapeutic effect, thus reducing the incidents of adverse effects. Various maneuvers (pH-dependent, time-dependent and microflora-activated systems) have been attempted by researchers for targeting drugs successfully to the colonic region by circumventing the upper part of gastrointestinal tract. This Editorial article aims to put forth an overview of the formulation technologies that have been developed for attaining colon specific drug delivery for the treatment of CRC.     

Intraoral drug delivery

The oral availability of many drugs is poor because of the pH of the stomach, the presence of enzymes, and extensive first-pass metabolism. Traditionally, these drugs have been administered as parenteral drug delivery systems, which invariably leads to poor patient compliance. This has made the pharmaceutical industry look for alternative routes of drug delivery. One possible route is via the oral cavity. This review compares the many different and novel drug delivery systems that have been developed for absorption through the oral cavity as well as those that undergo quick disintegration or dissolution in the oral cavity. Systems for oral delivery include mucoadhesive patches, films and tablets, as well as quick-disintegrating wafers, tablets and films. There are many examples of drugs that have been formulated into intraoral absorptive drug delivery systems as well as quick-disintegrating drug delivery systems. The fact that most of the research being conducted on intraoral drug delivery systems is driven by pharmaceutical manufacturers demonstrates the need for such drug delivery systems. As we begin to discover more about oral mucosal drug delivery, and develop much more sophisticated drug delivery systems, many more drugs will be formulated as intraoral systems. There is no doubt that the need for these systems is real, and many classes of drugs could benefit from this noninvasive type of drug delivery. The challenge now is to synthesize drug moieties that exhibit increased absorption across the oral mucosa and are more potent in their action. Intraoral drug delivery systems are possibly one of the very few drug delivery systems that seem to be ahead of the development of new drug compounds that are effectively absorbed across tissue membranes.     

Biodegradable microspheres for parenteral delivery

Nowadays, emphasis is being laid to development of controlled release dosage forms. Interest in this technology has increased steadily over the past few years. Although oral administration of drugs is a widely accepted route of drug delivery, bioavailability of drug often varies as a result of gastrointestinal absorption, degradation by first-pass effect, and hostile environment of gastrointestinal tract. Transdermal administration for percutaneous absorption of drug is limited by the impermeable nature of the stratum corneum. Ocular and nasal delivery is also unfavorable because of degradation by enzymes present in eye tissues and nasal mucosa. Hence, the parenteral route is the most viable approach in such cases. Of the various ways of achieving long-term parenteral drug delivery, biodegradable microspheres are one of the better means of controlling the release of drug over a long time. Because of the lipidic nature of liposomes, problems such as limited physical stability and difficulty of freeze-drying are encountered. Similarly, for emulsions, stability on long-term basis and in suspensions, rheological changes during filling, injecting, and storage poses limitation. Also, in all these systems, the release rate cannot be tailored to the needs of the patient. Parenteral controlled-release formulations based on biodegradable microspheres can overcome these problems and can control the release of drug over a predetermined time span, usually in the order of days to weeks to months. Various FDA-approved controlled-release parenteral formulations based on these biodegradable microspheres are available on the market, including Lupron Depot Nutropin Depot and Zoladex. This review covers various molecules encapsulated in biodegradable microspheres for parenteral delivery.     

Nasal route: an alternative approach for antiemetic drug delivery

INTRODUCTION: Antiemetic drugs are used in the treatment of nausea and emesis. Development of novel delivery systems for antiemetic drugs, as an alternative to conventional preparations, is important in terms of good patient compliance and improving bioavailability. The nasal route offers unique superiorities, such as fast and high drug absorption, and high patient compliance. Therefore, a considerable amount of research has been carried out on the development of nasal delivery systems for antiemetic drugs. AREAS COVERED: This review deals with the importance of nasal delivery of antiemetic drugs and the studies performed on this subject. The first part of this review summarizes the properties of the nasal route, its advantages and limitations, parameters affecting drug absorption through nasal mucosa, nasal passage pathways and general approaches to improve nasal transport. The second part reviews the studies conducted on the development of nasal delivery systems. EXPERT OPINION: Due to its superiorities, the nasal route could be considered as an attractive alternative to oral and parenteral routes. To overcome the barrier properties of the nasal epithelium and to enhance transport of antiemetic drugs, several approaches, including permeation enhancers, in situ gel formulations and micro- and nanoparticulate systems, have been evaluated. The results obtained are promising and indicate that nasal formulations of some antiemetic drugs may enter the market in the near future.     

Delivery strategies for macromolecular drugs in cancer therapy

With the development of biotherapy, biomacromolecular drugs have gained tremendous attention recently, especially in drug development field due to the sophisticated functions in vivo. Over the past few years, a motley variety of drug delivery strategies have been developed for biomacromolecular drugs to overcome the difficulties in the druggability, e.g., the instability and easily restricted by physiologic barriers. The application of novel delivery systems to deliver biomacromolecular drugs can usually prolong the half-life, increase the bioavailability, or improve patient compliance, which greatly improves the efficacy and potentiality for clinical use of biomacromolecular drugs. In this review, recent studies regarding the drug delivery strategies for macromolecular drugs in cancer therapy are summarized, mainly drawing on the development over the last five years.     

Advances in lipid nanodispersions for parenteral drug delivery and targeting

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application of these lipid systems in parenteral drug delivery, however, particularly with new chemical entities, has been limited due primarily to the following reasons: a) only a small number of parenteral lipid excipients are approved, b) there is increasing number of drugs that are partially or not soluble in conventional oils and other lipid solvents, and c) the ongoing requirement for site-specific targeting and controlled drug release. Thus, there is growing need to expand the array of targetable lipid-based systems to deliver a wide variety of drugs and produce stable formulations which can be easily manufactured in a sterile form, are cost-effective and at least as safe and efficacious as the earlier developed systems. These advanced parenteral lipid-based systems are at various stages of preclinical and clinical development which include nanoemulsions, nanosuspensions and polymeric phospholipid micelles. This review article will showcase these parenteral lipid nanosystems and discuss advances in relation to formulation development, processing and manufacturing, and stability assessment. Factors controlling drug encapsulation and release and in vivo biodistribution will be emphasized along with in vitro/in vivo toxicity and efficacy case studies. Emerging lipid excipients and increasing applications of injectable lipid nanocarriers in cancer chemotherapy and other disease indications will be highlighted and in vitro/in vivo case studies will be presented. As these new parenteral lipid systems advance through the clinic and product launch, their therapeutic utility and value will certainly expand.     

Drug delivery to the posterior segment of the eye

Delivery of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains of the eye. There is an increasing need for managing rapidly progressing posterior eye diseases, such as age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. Drug delivery to the posterior segment of the eye is therefore compounded by the increasing number of new therapeutic entities (e.g. oligonucleotides, aptamers and antibodies) and the need for chronic therapy. Currently, the intravitreal route is widely used to deliver therapeutic entities to the retina. However, frequent administration of drugs via this route can lead to retinal detachment, endophthalmitis and increased intraocular pressure. Various controlled delivery systems, such as biodegradable and non-biodegradable implants, liposomes and nanoparticles, have been developed to overcome such adverse effects, with some success. The periocular route is a promising alternative, owing to the large surface area and the relatively high permeability of the sclera. Yet, the blood-retinal barrier and efflux transporters hamper the transport of therapeutic entities to the retina. As such, the efficient delivery of drugs to the posterior eye remains a major challenge facing the pharmaceutical scientist. In this review, we discuss the barriers of the posterior eye drug delivery and the various drug-delivery strategies used to overcome these barriers.     

Recent advances in slow and sustained drug release for retina drug delivery

ABSTRACT

Introduction: Striking recent advance has occurred in the field of medical retina, greatly because intraocular drugs have been developed, enhancing their clinical efficacy while avoiding systemic side-effects. However, the burden of repeated intraocular administration makes limits the optimal efficacy of treatments, prompting the development of new drugs with prolonged half-life or of sustained drug delivery systems.

Area covered: In this review, we describe the various drugs and drug delivery systems that have reached the clinical stage and those that are in clinical development and we discuss the limitations to clinical translation.

Expert opinion: Substantial fundamental work is still required to build guidelines on optimal animal models for ocular pharmacokinetics and safety studies depending on the target disease site and the on the type of therapeutic compounds. The effects of a drug administered as a bolus at high concentration in the vitreous might differ from those resulting from the sustained release of a lower concentration, and no delivery platform can be simply adapted to any drug. For the treatment of retinal diseases, development of therapeutic compounds should integrate from its early conception, the combination of an active drug with a specific drug delivery system, administered by a specific route.     

Nasal route: an alternative approach for antiemetic drug delivery

Introduction: Antiemetic drugs are used in the treatment of nausea and emesis. Development of novel delivery systems for antiemetic drugs, as an alternative to conventional preparations, is important in terms of good patient compliance and improving bioavailability. The nasal route offers unique superiorities, such as fast and high drug absorption, and high patient compliance. Therefore, a considerable amount of research has been carried out on the development of nasal delivery systems for antiemetic drugs.

Areas covered: This review deals with the importance of nasal delivery of antiemetic drugs and the studies performed on this subject. The first part of this review summarizes the properties of the nasal route, its advantages and limitations, parameters affecting drug absorption through nasal mucosa, nasal passage pathways and general approaches to improve nasal transport. The second part reviews the studies conducted on the development of nasal delivery systems.

Expert opinion: Due to its superiorities, the nasal route could be considered as an attractive alternative to oral and parenteral routes. To overcome the barrier properties of the nasal epithelium and to enhance transport of antiemetic drugs, several approaches, including permeation enhancers, in situ gel formulations and micro- and nanoparticulate systems, have been evaluated. The results obtained are promising and indicate that nasal formulations of some antiemetic drugs may enter the market in the near future.     

Colloidal soft matter as drug delivery system

Growing interest is being dedicated to soft matter because of its potential in delivering any type of drugs. Since hydrophilic, lipophilic, small and big molecules can be loaded into these colloidal systems and administered through the parenteral or nonparenteral route, soft matter systems have been used to solve many biomedical and pharmaceutical problems. In fact, they make possible to overcome difficulties in the formulation and delivery of poorly water-soluble drug molecules, settle some stability issues typical of biological drug molecules, design parenteral sustained release forms and provide functionalized soft particles that are very effective in drug targeting. This review deals with the important role that colloids play in the drug delivery and targeting, with particular attention to the more currently used systems such as microemulsions, organogels, liposomes, micelles, and dendrimers. Though significant progress has been made in drug targeting, some challenges still remain. Further efforts will be required to better understand the characteristics of targets and to discover new ones. In-depth knowledge of the physico-chemical structure and properties of the systems used for targeting is fundamental for understanding the mechanism of interaction with the biological substrate and the consequent drug release.     

Tight junction modulators: promising candidates for drug delivery

Recent advances in genomic drug development and high-throughput technologies, such as combinatorial chemistry, high throughput screening and in silico screening, are making it easier to screen compounds with pharmaceutical activity. Drugs developed by genomic and throughput technologies traverse the epithelial and endothelial membranes. Although the paracellular pathway is a potent drug delivery route for these drugs, few strategies for their delivery have been developed because tight junctions (TJs), which exist between adjacent cells, strictly regulate the movement of solutes. Recent progress in biology of TJs has provided new insights into the biochemical and functional structure of TJs, and into the roles that occludin, claudins and tricellulin play in regulating TJ barriers. Novel strategies based on TJ-components for delivering drugs through the paracellular pathway have been developed. In this review, we discuss drug delivery through the paracellular route within the context of biology of TJs, as well as future directions of TJ-component-based drug delivery systems.     

Nanoencapsulation II. Biomedical applications and current status of peptide and protein nanoparticulate delivery systems

The concept of polymeric nanoparticles for the design of new drug delivery systems emerged a few years ago, and recent rapid advances in nanotechnology have offered a wealth of new opportunities for diagnosis and therapy of various diseases. Recent progress has made possible the engineering of nanoparticles to allow the site-specific delivery of drugs and to improve the pharmacokinetic profile of numerous compounds with biomedical applications such as peptide and protein drugs. Biologically active peptides and their analogues are becoming an increasingly important class of drugs. Their use for human and animal treatment is problematic, however, because some of these drugs are generally ineffective when taken orally and thus have been administered chiefly by the parenteral route. This review covers some of the historical and recent advances of nanotechnology and concludes that polymeric nanoparticles show great promise as a tool for the development of peptide drug delivery systems.     

Use of transdermal drug formulations in the elderly

Transdermal drug delivery systems are pharmaceutical forms designed to administer a drug through the skin to obtain a systemic effect. They ensure a constant rate of drug administration and a prolonged action. Several different types of transdermal delivery devices are available on the market. They are either matrix or reservoir systems and their main current uses are to treat neurological disorders, pain and coronary artery disease, and as hormone replacement therapy.Transdermal drug administration has a number of advantages compared with the oral route: it avoids gastrointestinal absorption and hepatic first-pass metabolism, minimizes adverse effects arising from peak plasma drug concentrations and improves patient compliance. Compared with the parenteral route, transdermal administration entails no risk of infection. For elderly people, who are often polymedicated, transdermal drug delivery can be a good alternative route of administration.Transdermal absorption depends on passive diffusion through the different layers of the skin. As skin undergoes many structural and functional changes with increasing age, it would be useful to know whether these alterations affect the transdermal diffusion of drugs. Studies have shown that age-related changes in hydration and lipidic structure result in an increased barrier function of the stratum corneum only for relatively hydrophilic compounds. In practice, no significant differences in absorption of drugs from transdermal delivery systems have been demonstrated between young and old individuals. The need for dose adaptation in elderly patients using transdermal drug delivery systems is therefore not related to differences in skin absorption but rather to age-related cardiovascular, cerebral, hepatic and/or renal compromise, and to ensuing geriatric pharmacokinetic and pharmacodynamic changes.     

Nasal drug delivery: new developments and strategies

The use of the nasal route for the delivery of challenging drugs has created much interest in recent years in the pharmaceutical industry. Consequently, drug delivery companies are actively pursuing the development of novel nasal drug-delivery systems and the exploitation of these for administration of conventional generic drugs and peptides, both in-house and with partners in the pharmaceutical industry. This review sets out to discuss some new developments and strategies in nasal drug delivery. An exiting discovery that drugs can be transported directly from nose to brain via the olfactory pathway is discussed and examples of proof-of-concept in man are given.