Matrix- and reservoir-based transmucosal delivery systems

Traditionally, per-oral delivery has been the primary route of administration for therapeutic agents targeting systemic delivery. However, oral administration subjects these compounds to extensive presystemic elimination, which may include gastrointestinal degradation, metabolism, or first-pass clearance via the liver, and may ultimately result in poor bioavailability. Parenteral routes, such as intravenous or intramuscular, permit therapeutic agents to gain direct entry into the systemic circulation and, therefore, reach the intended site of action more rapidly. Unfortunately, this mode of drug administration entails numerous disadvantages, including the requirement for close medical supervision and the need for specialized equipment. Transmucosal absorption of nitroglycerin from solutions through the oral cavity was demonstrated in the mid-nineteenth century, and since that time various conventional drug delivery systems for oral mucosal delivery have been proposed and have achieved clinical application. Technologic advances in biomaterials and techniques have resulted in the formulation of novel designs more pertinent to the oral cavity, meeting the challenges of the physicochemical properties of the drug entity itself and achieving the therapeutic aims of the drug delivery system. Issues of patient compliance and convenience have recently resulted in a trend toward once-a-day administration regimens, requiring drugs with high potency and sustained effect. Such drugs usually have a short biologic half-life, exhibit poor permeability and solubility, and are susceptible to enzymatic degradation. However, because of the advantages of delivering a drug through the oral mucosa, these drugs are viable candidates for delivery via this route. Many investigators have studied the potential of transmucosal delivery through the oral cavity, and the oral mucosa is increasingly being considered as a plausible route for many drug classes. Sublingual tablets, oral lozenges, chewing gum systems, and other dosage forms represent potential drug delivery systems for the oral mucosa, but most of the literature has not discussed information on specific drug delivery systems and their challenges. This article examines the anatomy, physiology, and absorption properties of the oral mucosal environment; explores the considerations for a transmucosal system; reviews these types of systems; and evaluates and proposes matrix and reservoir transmucosal applications.     

New developments and opportunities in oral mucosal drug delivery for local and systemic disease

The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.     

Polymer based drug delivery systems for mycobacterial infections

In the last decade, polymer based technologies have found wide biomedical applications. Polymers, whether synthetic (e.g. polylactide-co-glycolide or PLG) or natural (e.g. alginate, chitosan etc.), have the property of encapsulating a diverse range of molecules of biological interest and bear distinct therapeutic advantages such as controlled release of drugs, protection against the premature degradation of drugs and reduction in drug toxicity. These are important considerations in the long-duration treatment of chronic infectious diseases such as tuberculosis in which patient non-compliance is the major obstacle to successful chemotherapy. Antitubercular drugs, singly or in combination, have been encapsulated in polymers to provide controlled drug release and the system also offers the flexibility of selecting various routes of administration such as oral, subcutaneous and aerosol. The present review highlights the approaches towards the preparation of polymeric antitubercular drug delivery systems, emphasizing how the route of administration may influence drug bioavailability as well as the chemotherapeutic efficacy. In addition, the pros and cons of the various delivery systems are also discussed.     

Inhalation of nanoparticle-based drug for lung cancer treatment: Advantages and challenges

Ever since the success of developing inhalable insulin, drug delivery via pulmonary administration has become an attractive route to treat chronic diseases. Pulmonary delivery system for nanotechnology is a relatively new concept especially when applicable to lung cancer therapy. Nano-based systems such as liposome, polymeric nanoparticles or micelles are strategically designed to enhance the therapeutic index of anti-cancer drugs through improvement of their bioavailability, stability and residency at targeted lung regions. Along with these benefits, nano-based systems also provide additional diagnostic advantages during lung cancer treatment, including imaging, screening and drug tracking. Nevertheless, delivery of nano-based drugs via pulmonary administration for lung cancer therapy is still in its infancy and numerous challenges are expected. Pharmacology, immunology, toxicology and large-scale manufacturing (stability and activity of drugs) are some aspects in nanotechnology that should be taken into consideration for the development of inhalable nano-based chemotherapeutic drugs. This review will focus on the current inhalable nano-based drugs for lung cancer treatment.     

Drug delivery by the intravaginal route

The human vagina represents a potential, accessible space that offers a valuable route for drug delivery through the use of specifically designed carrier systems for both local and systemic applications. Intravaginal drug delivery is particularly appropriate for drugs associated with women's health issues but may also have applications in general drug delivery within the female population. A range of drug delivery platforms suitable for intravaginal administration are discussed in this review, including hydrogels, vaginal tablets, pessaries/suppositories, particulate systems, and intravaginal rings. Drug release mechanisms and absorption pathways are reviewed with respect to a range of therapeutic and prophylactic indications for intravaginal delivery.     

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.     

Single-use disposable dry powder inhalers for pulmonary drug delivery

IMPORTANCE OF THE FIELD: The understanding of pulmonary drug delivery and thus its utilization for medical purposes has remarkably advanced over the last decades. It has been recognized that this route of administration offers many advantages and several drug delivery systems have been developed accordingly. Thereby, single-use disposable dry powder inhalers may be considered an economically and therapeutically valuable option for both local and systemic administration of drugs to treat a variety of different disease states. AREAS COVERED IN THIS REVIEW/WHAT THE READER WILL GAIN: This review highlights the required characteristics and potential applications of single-use disposable dry powder inhalers considering advantages as well as limitations of these drug delivery devices. Until now, such drug delivery systems have not become widely accepted. Several devices are available or under development and a few products have reached or completed the clinical phase, but none of them have received market authorization as yet. TAKE HOME MESSAGE: Recent advances in formulation and device design, however, can be considered encouraging and should eventually lead to a wider establishment of single-use disposable dry powder inhalers in pulmonary drug delivery.     

Erythrocyte-based drug delivery

The use of a physiological carrier to deliver therapeutics throughout the body to both improve their efficacy while minimising inevitable adverse side effects, is an extremely fascinating perspective. The behaviour of erythrocytes as a delivery system for several classes of molecules (i.e., proteins, including enzymes and peptides, therapeutic agents in the form of nucleotide analogues, glucocorticoid analogues) has been studied extensively as they possess several properties, which make them unique and useful carriers. Furthermore, the possibility of using carrier erythrocytes for selective drug targeting to differentiated macrophages increases the opportunities to treat intracellular pathogens and to develop new drugs. Finally, the availability of an apparatus that permits the encapsulation of drugs into autologous erythrocytes has made this technology available in many clinical settings and co-mpetitive with other drug delivery systems.     

Absorption of peptides and proteins from the respiratory tract and the potential for development of locally administered vaccine

Since the appearance of the first therapeutic active peptides and proteins produced by genetic engineering, there has been an ever-increasing demand to be able to deliver these drugs by routes other than the parenteral. For most drugs the need for alternative delivery systems is due to short-half lives in the bloodstream, large extents of first pass metabolism, or the possibility of obtaining endogenous-like plasma profiles. A wide variety of drugs have now been tested for bioavailability after respiratory, especially intranasal, administration. A small range of drugs (such as propranolol and progesterone) appears to be absorbed effectively via the nasal route and shows bioavailabilities comparable to the intravenous route. However, most drugs shows a much lower degree of absorption. The present review discusses the critical steps that have to be considered when attempting to deliver drugs effectively via the nasal and pulmonary routes and how it is possible by suitable formulation of delivery systems to overcome some of the most important barriers to drug absorption. Furthermore, the immunological responses to respiratory absorption of exogenous peptides and proteins and the potential for development of locally administered vaccines are reviewed.     

Erythrocyte-based drug delivery

The use of a physiological carrier to deliver therapeutics throughout the body to both improve their efficacy while minimising inevitable adverse side effects, is an extremely fascinating perspective. The behaviour of erythrocytes as a delivery system for several classes of molecules (i.e., proteins, including enzymes and peptides, therapeutic agents in the form of nucleotide analogues, glucocorticoid analogues) has been studied extensively as they possess several properties, which make them unique and useful carriers. Furthermore, the possibility of using carrier erythrocytes for selective drug targeting to differentiated macrophages increases the opportunities to treat intracellular pathogens and to develop new drugs. Finally, the availability of an apparatus that permits the encapsulation of drugs into autologous erythrocytes has made this technology available in many clinical settings and competitive with other drug delivery systems.     

The Hypotonic Environmental Changes Affect Liposomal Formulations for Nose-to-Brain Targeted Drug Delivery

Systemic administration of drugs is ineffective in the treatment of central nervous system disorders because of the blood-brain barrier. Nasal administration has been suggested as an alternative administration route as drugs absorbed in the olfactory epithelium bypass the blood-brain barrier and reach the brain within minutes. However, the nasal mucosa properties (e.g., tonicity, pH) are not constant because of physiological and environmental factors, and this might limit the therapeutic outcome of nanocarrier-based formulations. To shine light on the impact of environmental ionic strength on nanocarrier-based formulations, we have studied how liposomal formulations respond to the change of tonicity of the external environment. Large unilamellar vesicles loaded with 6 different drugs were exposed to different hypotonic environments, creating an osmotic gradient within the inner core and external environment of the liposomes up to 650 mOsm/kg. Both size and polydispersity of liposomes were significantly affected by tonicity changes. Moreover, the release kinetics of hydrophilic and lipophilic drugs were largely enhanced by hypotonic environments. These results clearly demonstrate that the environmental ionic strength has an impact on liposomal formulation stability and drug release kinetics and it should be considered when liposomal formulations for nose-to-brain targeted drug delivery are designed.     

RETRACTED: Pulmonary route of administration is instrumental in developing therapeutic interventions against respiratory diseases

Pulmonary route of drug delivery has drawn significant attention due to the limitations associated with conventional routes and available treatment options. Drugs administered through pulmonary route has been an important research area that focuses on to developing effective therapeutic interventions for asthma, chronic obstructive pulmonary disease, tuberculosis, lung cancer etc. The intravenous route has been a natural route of delivery of proteins and peptides but associated with several issues including high cost, needle-phobia, pain, sterility issues etc. These issues might be addressed by the pulmonary administration of macromolecules to achieving an effective delivery and efficacious therapeutic impact. Efforts have been made to develop novel drug delivery systems (NDDS) such as nanoparticles, microparticles, liposomes and their engineered versions, polymerosomes, micelles etc to achieving targeted and sustained delivery of drug(s) through pulmonary route. Further, novel approaches such as polymer-drug conjugates, mucoadhesive particles and mucus penetrating particles have attracted significant attention due to their unique features for an effective delivery of drugs. Also, use of semi flourinated alkanes is in use for improvising the pulmonary delivery of lipophilic drugs. Present review focuses on to unravel the mechanism of pulmonary absorption of drugs for major pulmonary diseases. It summarizes the development of interventional approaches using various particulate and vesicular drug delivery systems. In essence, the orchestrated attempt presents an inflammatory narrative on the advancements in the field of pulmonary drug delivery.     

An update on the application of physical technologies to enhance intradermal and transdermal drug delivery

A large number of biopharmaceuticals and other macromolecules are being developed for therapeutic applications. Conventional oral delivery is not always possible due to first-pass metabolism and degradation in the GI tract. Parenteral delivery is invasive and has poor patient compliance. Transdermal delivery provides one attractive route of administration. Transdermal administration can achieve the continuous and non-invasive delivery of drugs. However, passive transdermal delivery is restricted to small lipophilic molecules. Active physical-enhancement technologies are being investigated to increase the scope of transdermal delivery to hydrophilic molecules and macromolecules. Recent developments in transdermal technologies, such as microporation, iontophoresis and sonophoresis can enable therapeutic delivery of many drug molecules, biopharmaceuticals, cosmeceuticals and vaccines. This review provides an update of recent developments in transdermal delivery focusing on physical-enhancement technologies.     

Exploring novel approaches to vaginal drug delivery

Vaginal route serves as a potential site of drug administration for local and systemic absorption of a variety of therapeutic agents. Despite being a non- invasive route of drug administration, the vagina has not been extensively explored as compared to other routes. Intravaginal drug delivery has been traditionally restricted to delivery of antinfectives to the local vaginal cavity. Concerted efforts have been made in the recent past to rediscover the vaginal route as a potential route for the delivery of therapeutically important molecules, proteins, peptides, small interfering RNAs, oligonucleotides, antigens, vaccines and hormones. The understanding of vaginal physiology has led to the design of specific intravaginal drug delivery systems to reach the systemic circulation. To overcome the limitations of conventional dosage forms administered through vaginal route various novel approaches like the use of mucoadhesive or bioadhesive polymers, pH- or temperature-sensitive polymers, liposomes, nanoemulsions, nanoparticles, vaginal inserts, multiple emulsions and hydrogels have been designed which enable controlled and prolonged release of drugs. The present article is a comprehensive review of the research and patents encompassing conventional dosage forms used for vaginal drug delivery with emphasis on newer platform technologies pertaining to intravaginal administration.     

Polymeric nanoparticles for oral delivery of drugs and vaccines: a critical evaluation of in vivo studies

Oral drug delivery is the preferred route of administration of drugs. Because of their versatility, nanoparticles often have been investigated for the delivery of a wide number of drugs by this route. This article first examines the physicochemical, pharmaceutical and technological aspects that make nanoparticles a potential oral delivery system for drugs and active biomolecules. Next, upon consideration of in vivo studies, the pharmacokinetic, pharmacological and therapeutic aspects of orally administered nanoparticles are described. Special emphasis is placed on improvement of oral bioavailability of drugs incorporated into nanoparticles. Two main mechanisms involved in enhancing drug absorption are discussed: the protection of drug by nanoparticles against harsh conditions in the gut and the prolongation of gastrointestinal transit of nanoparticles by using bioadhesive polymers. Furthermore, nanoparticle uptake by intestinal cells and oral vaccination by these colloidal carriers are also covered. In this context, the immune responses elicited as well as the protection against pathogens induced by antigen-loaded nanoparticles administered by the oral route are presented. Finally, the main limitations and perspectives of these colloidal carriers as oral drug delivery systems are discussed.     

Nanotechnology and pulmonary delivery to overcome resistance in infectious diseases

Used since ancient times especially for the local treatment of pulmonary diseases, lungs and airways are a versatile target route for the administration of both local and systemic drugs. Despite the existence of different platforms and devices for the pulmonary administration of drugs, only a few formulations are marketed, partly due to physiological and technological limitations.Respiratory infections represent a significant burden to health systems worldwide mainly due to intrahospital infections that more easily affect immune-compromised patients. Moreover, tuberculosis (TB) is an endemic infectious disease in many developing nations and it has resurged in the developed world associated with the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic.Currently, medicine faces the specter of antibiotic resistance. Besides the development of new anti-infectious drugs, the development of innovative and more efficient delivery systems for drugs that went off patent appears as a promising strategy pursued by the pharmaceutical industry to improve the therapeutic outcomes and to prolong the utilities of their intellectual property portfolio. In this context, nanotechnology-based drug delivery systems (nano-DDS) emerged as a promising approach to circumvent the limitations of conventional formulations and to treat drug resistance, opening the hypothesis for new developments in this area.     

肺部吸入给药制剂及临床应用

目的:分析和综述肺吸入制剂的分类、现状及其临床用药。方法:收集国内外发表出版的相关论文及专著,对肺部吸入给药的特点及临床药物制剂进行了分析总结。结果与结论:肺部吸入给药是防治哮喘、慢性阻塞性肺病等呼吸道疾病的首选给药方式。常见的吸入给药制剂包括定量吸入气雾剂、干粉吸入剂和雾化吸入剂,所用药物主要为β2受体激动剂、抗胆碱药物、吸入性糖皮质激素及复方药物等。     

Drug delivery systems. 6. Transdermal drug delivery

Transdermal drug delivery system has been in existence for a long time. In the past, the most commonly applied systems were topically applied creams and ointments for dermatological disorders. The occurrence of systemic side-effects with some of these formulations is indicative of absorption through the skin. A number of drugs have been applied to the skin for systemic treatment. In a broad sense, the term transdermal delivery system includes all topically administered drug formulations intended to deliver the active ingredient into the general circulation. Transdermal therapeutic systems have been designed to provide controlled continuous delivery of drugs via the skin to the systemic circulation. The relative impermeability of skin is well known, and this is associated with its functions as a dual protective barrier against invasion by micro-organisms and the prevention of the loss of physiologically essential substances such as water. Elucidation of factors that contribute to this impermeability has made the use of skin as a route for controlled systemic drug delivery possible. Basically, four systems are available that allow for effective absorption of drugs across the skin. The microsealed system is a partition-controlled delivery system that contains a drug reservoir with a saturated suspension of drug in a water-miscible solvent homogeneously dispersed in a silicone elastomer matrix. A second system is the matrix-diffusion controlled system. The third and most widely used system for transdermal drug delivery is the membrane-permeation controlled system. A fourth system, recently made available, is the gradient-charged system. Additionally, advanced transdermal carriers include systems such as iontophoretic and sonophoretic systems, thermosetting gels, prodrugs, and liposomes. Many drugs have been formulated in transdermal systems, and others are being examined for the feasibility of their delivery in this manner (e.g., nicotine antihistamines, beta-blockers, calcium channel blockers, non-steroidal anti-inflammatory drugs, contraceptives, anti-arrhythmic drugs, insulin, antivirals, hormones, alpha-interferon, and cancer chemotherapeutic agents). Research also continues on various chemical penetration enhancers that may allow delivery of therapeutic substances. For example, penetration enhancers such as Azone may allow delivery of larger-sized molecules such as proteins and polypeptides.     

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.     

Local strategies and delivery systems for the treatment of malignant gliomas

Abstract

Glioma is one of the most common type of malignant tumours with high morbidity and mortality rates. Due to the particular features of the brain, such as blood–brain barrier or blood–tumour barrier, therapeutic agents are ineffective by systemic administration. The tumour inevitably recurs and devitalises patients. Herein, an overview of the localised gliomas treatment strategies is provided, including direct intratumoural/intracerebral injection, convection-enhanced delivery, and the implant of biodegradable polymer systems. The advantages and disadvantages of each therapy are discussed. Subsequently, we have reviewed the recent developments of therapeutic delivery systems aimed at transporting sufficient amounts of antineoplastic drugs into the brain tumour sites while minimising the potential side effects. To treat gliomas, localised and controlled delivery of drugs at their desired site of action is preferred as it reduces toxicity and increases treatment efficiency. Simultaneously, various drug delivery systems (DDS) have been used to enhance drug delivery to the brain. Use of non-conventional DDS for localised therapy has greatly expanded the spectrum of drugs available for the treatment of malignant tumours. Use smart DDS via localised delivery strategies, in combination with radiotherapy and multiple drug loading would serve as a promising approach to treat gliomas.