An insight to osmotic drug delivery

In a typical therapeutic regimen the drug dose and the dosing interval are optimized to maintain drug concentration within the therapeutic window, thus ensuring efficacy while minimizing toxic effects. For many decades treatment of acute disease or a chronic illness has been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms. The immediate release conventional dosage form does not provide the proper plasma concentration of drug for prolonged period. This results in the development of various controlled drug delivery system. Among which the osmotic drug delivery systems (ODDS) are gaining importance as these systems deliver the drug at specific time as per the path physiological need of the disease, resulting in improved patient therapeutic efficacy and compliance. They work on the principle of osmotic pressure for controlling the delivery of the drug. Osmotic drug delivery systems with their versatility and their highly predictable drug release rates offer various biomedical advantages when given parenterally like reduced dose, targeting of site, avoiding gastrointestinal stability, hepatic bypass of drug molecule and follows zero order kinetics. Osmosis is an aristocratic phenomenon that seizes the attention for its exploitation in zero-order drug delivery systems. The release of the drug is independent of pH and physiological factors of the GIT to a large extent. Optimizing semi-permeable membrane characteristics and osmotic agent can modulate delivery of drug from the system. This review highlights the theoretical concept of drug delivery, history, types of oral osmotic drug delivery systems, factors affecting the drug delivery system, advantages and disadvantages of this delivery system, theoretical aspects, applications, and the marketed status.     

Drug delivery systems 5A. Oral drug delivery

The two main advantages of controlled drug delivery systems are: maintenance of therapeutically optimum drug concentrations in the plasma through zero-order release without significant fluctuations; and elimination of the need for frequent single dose administrations. The oral and other therapeutic systems in human use have validated the concept that controlled continuous drug release can minimize the daily dose of a drug required to maintain the required therapeutic effect, while minimizing unwanted pharmacological effects. By minimizing patient intervention, a design feature of therapeutic systems, compliance is automatically enhanced. Oral drug delivery systems, in particular, have required innovation in materials science to provide materials biocompatible during prolonged contact with body tissues, bioengineering to develop drug delivery modules, and clinical pharmacology for elucidation of drug action under conditions of continuous controlled drug administration. Recent work in advanced oral delivery has been primarily focused on liposome technology and the concept that substances that are normally destroyed by the stomach can be protected long enough before they could be absorbed downstream. For cost and patient convenience, oral delivery certainly would be an attractive method. The nature of biologic substances, however, with their unique technical problems, will probably limit greatly those that can be delivered orally. Besides, where delivery rate control is critical, oral delivery, even when possible, would probably be insufficiently precise. Oral delivery would also limit the substance to bloodstream delivery to the disease site. Even so, oral controlled drug delivery systems will likely find primary usefulness in specific carefully controlled therapies and prophylactic situations with due regard for drug interactions. This system represents a potentially very significant therapeutic modality. These delivery systems will find usefulness primarily in certain well-defined and well-controllable areas with due regard for individual patient variations. The purpose of the present article is to review oral controlled-release drug delivery systems, with particular emphasis on the practical aspects of testing and fabricating these systems and the underlying mechanisms by which control over drug release rate is accomplished.     

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.     

Innovations in drug delivery to the central nervous system

The theoretical goal of the ideal drug - to localize specifically and directly to its intended target, have a high therapeutic index and achieve therapeutic efficacy without side effects - is becoming feasible through improved drug delivery and targeting. The clinical advantages of improved drug delivery include continuously therapeutic drug levels, decreased drug dose, improved patient compliance, increased viability of short-lived pharmaceuticals like peptides and proteins, less invasive routes of administration, reduced drug side effects and simplified dosing. Innovative techniques include antibody-mediated drug release, feedback-responsive delivery systems, manipulation of carrier-mediated transport, microspheres composed of polymers and liposomes, permeabilizers, selective delivery to localized sites and vectors to penetrate the blood-brain barrier. Several delivery systems have been approved and more are in clinical trials. Drug delivery system research has greatly influenced the management of brain tumors, central nervous system infections, chronic pain, drug addiction, epileptic disorders, migraine headaches, neurodegenerative diseases, schizophrenia, spasticity and stroke. For many disorders, optimization of drug delivery will continue to be the therapeutic focus for a long while.     

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.     

Pharmacosomes: the lipid-based new drug delivery system

Lipid-based drug delivery systems have been investigated in various studies and shown their potential in controlled and targeted drug delivery. Pharmacosomes are amphiphilic phospholipid complexes of drugs bearing active hydrogen that bind to phospholipids. Pharmacosomes impart better biopharmaceutical properties to the drug, resulting in improved bioavailability. Pharmacosomes have been prepared for various non-steroidal anti-inflammatory drugs, proteins, cardiovascular and antineoplastic drugs. Developing the pharmacosomes of the drugs has been found to improve the absorption and minimize the gastrointestinal toxicity. This article reviews the potential of pharmacosomes as a controlled and targeted drug delivery system and highlights the methods of preparation and characterization.     

Permeation enhancer strategies in transdermal drug delivery

Abstract

Today, ～74% of drugs are taken orally and are not found to be as effective as desired. To improve such characteristics, transdermal drug delivery was brought to existence. This delivery system is capable of transporting the drug or macromolecules painlessly through skin into the blood circulation at fixed rate. Topical administration of therapeutic agents offers many advantages over conventional oral and invasive techniques of drug delivery. Several important advantages of transdermal drug delivery are prevention from hepatic first pass metabolism, enhancement of therapeutic efficiency and maintenance of steady plasma level of the drug. Human skin surface, as a site of drug application for both local and systemic effects, is the most eligible candidate available. New controlled transdermal drug delivery systems (TDDS) technologies (electrically-based, structure-based and velocity-based) have been developed and commercialized for the transdermal delivery of troublesome drugs. This review article covers most of the new active transport technologies involved in enhancing the transdermal permeation via effective drug delivery system.     

Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

Topical iontophoretic delivery

At present, transdermal iontophoresis is used in the topical delivery of local anesthetics and anti-inflammatory agents. The treatment of hyperhidrosis and the diagnosis of cystic fibrosis are other clinical applications of iontophoresis. Also, a glucose-monitoring device has been developed utilizing the principle of reverse iontophoresis. Commercial iontophoretic systems that would continuously deliver therapeutic agents into the systemic circulation, corresponding to the passive transdermal patches, do not exist at the moment; however, Alza Corporation has announced that it has received an approvable letter from the US FDA regarding a new drug application for Ionsys®, an iontophoretic, fentanyl-containing, transdermal analgesic. There is currently a lot of interest in the potential of closed-loop systems, which not only sense changes in the concentration of the analyte in the skin and in the subdermal tissues, but also administer a drug in response to the fluctuating concentration/need. Thus, self-regulated or patient-regulated systems that allow medication to be administered at home would enable controlled therapy, while accounting for the individual needs of the patient. Predictable and controlled non-invasive drug delivery on the one hand, and putative adverse effects on the other, determine the success of topical iontophoretic systems and methods. The often unavoidable skin sensitization/irritation and other adverse reactions have to be related to the therapeutic benefit(s) of (bio)molecule administration; for example, the potential for skin irritation associated with pain control medication is quite different (in terms of acceptability) to skin irritation associated with cancer treatment. An additional obstacle in the path to successful transdermal delivery is the stability issue of the (bio)molecule in the drug delivery system, skin, and target tissue.     

The impact of nanobiotechnology on the development of new drug delivery systems

Nanotechnology, or systems/devices manufactured at the molecular level, is a multidisciplinary scientific field undergoing explosive development. A part of this field is the development of nanoscaled drug delivery devices. Nanoparticles have been developed as an important strategy to deliver conventional drugs, recombinant proteins, vaccines and more recently nucleotides. Nanoparticles and other colloidal drug delivery systems modify the kinetics, body distribution and drug release of an associated drug. Other effects are tissue or cell specific targeting of drugs and the reduction of unwanted side effects by a controlled release. Therefore nanoparticles in the pharmaceutical biotechnology sector improve the therapeutic index and provide solutions for future delivery problems for new classes of so called biotech drugs including recombinant proteins and oligonucleotides. This review discusses nanoparticular drug carrier systems with the exception of liposomes used today, and what the potential and limitations of nanoparticles in the field of pharmaceutical biotechnology are.     

Passive transdermal drug delivery systems

The skin has evolved as a formidable barrier against invasion by external microorganisms and against the prevention of water loss. Notwithstanding this, transdermal drug delivery systems have been designed with the aim of providing continuous controlled delivery of drugs via this barrier to the systemic circulation. There are numerous systems now available that effectively deliver drugs across the skin. These include reservoir devices, matrix diffusion-controlled devices, multiple polymer devices, and multilayer matrix systems. This review article focuses on the design characteristics and composition of the main categories of passive transdermal delivery device available. Mechanisms controlling release of the active drug from these systems as well as patch size and irritation problems will be considered. Recent developments in the field are highlighted including advances in patch design as well as the increasing number of drug molecules now amenable to delivery via this route. From the early complex patch designs, devices have now evolved towards simpler, matrix formulations. One of the newer technologies to emerge is the delivery-optimized thermodynamic (DOT) patch system, which allows greater drug loading to be achieved in a much smaller patch size. With the DOT technology, drug is loaded in an acrylic-based adhesive. The drug/acrylic blend is dispersed through silicone adhesive, creating a semi-solid suspension. This overcomes the problem with conventional drug-in-adhesive matrix patches, in which a large drug load in the adhesive reservoir can compromise the adhesive properties or necessitate a large patch size. Transdermal drug delivery remains an attractive and evolving field offering many benefits over alternative routes of drug delivery. Future developments in the field should address problems relating to irritancy and sensitization, which currently exclude a number of therapeutic entities from delivery via this route. It is likely that further innovations in matrix composition and formulation will further expand the number of candidate drugs available for transdermal delivery.     

Disposition of nanoparticle-based delivery system via inner ear administration

The inner ear is difficult to access by conventional systemic drug delivery due to formidable physiological and anatomic barriers. There is an increasing interest in the treatment of inner ear disorders by topical application of drugs to the inner ear. One of the most important issues to overcome before full clinical application is the development of smart delivery systems for drugs to the target sites and controlled release in the inner ear. This is an area where nanoparticles will play an extremely important role. These submicron particles have exhibited improved biocompatibility, in vivo stability, target specificity, and cell/tissue uptake and internalization of the encapsulated therapeutic agents, leading to a decrease in the dose required and a decrease in side effects. This unique combination of properties makes nanoparticles a novel delivery device, which fulfils the requirements for inner ear application. This review will summarize recent findings and applications of various nanoparticle-based systems like poly (D, L-lactic/glycolic acid) nanoparticles, magnetic nanoparticles, lipid nanoparticles, liposomes, polymersomes, hydroxyapatite nanoparticles, and silica nanoparticles in the field of inner ear drug delivery. Moreover, the review will provide an insight into the future strategies of nanoparticle-based cochlear drug delivery. In conjunction, physiological considerations related to inner ear administration will be highlighted. The routes and applications for local inner-ear drug delivery will also be mentioned. In closing, this review will give an overview of the potential future development in inner ear administration with nanoparticles.     

Cutting-edge technologies in colon-targeted drug delivery systems

Oral colon-targeted drug delivery systems have gained enormous attention among researchers in the last two decades. The significance of this site-specific drug delivery system can be measured by its usefulness for delivering a variety of therapeutic agents, both for the treatment of local diseases or for systemic therapies. With the arrival of newer innovations, a large number of breakthrough technologies have emerged for targeting a drug molecule to the colon. Researchers have attempted various approaches in the development of these formulation technologies, such as pH-dependent, time-dependent and microflora-activated systems. Recently, a number of approaches have been proposed that utilize a novel concept of di-dependent drug delivery systems, that is, the systems in which the drug release is controlled by two factors: pH and time, and pH and microflora of the colon. This Editorial article is not intended to offer a comprehensive review on drug delivery, but shall familiarize the readers with the formulation technologies that have been developed for attaining colon-specific drug delivery.     

Active-targeted nanotherapy strategies for prostate cancer

Castration-resistant prostate cancer remains incurable and a major cause of mortality worldwide. The absence of effective therapeutic approaches for advanced prostate cancer has led to an intensive search for novel treatments. Emerging nanomedical approaches have shown promising results, in vitro and in vivo, in improving drug distribution and bioavailability, tumor penetration and in limiting toxicity. Nanoscaled carriers bearing finely controlled size and surface properties such as liposomes, dendrimers and nanoparticles have been developed for successful passive and active tumortargeting. Enhanced pharmacokinetics of nanotherapeutics, through improved target delivery and prolonged tissue halflife provides optimal drug delivery that is tumor-specific. Tumor-targeting may be improved through ligand directed delivery systems binding to tumor-specific surface receptors improving cellular uptake through receptor-mediated endocytosis. Recently published data have provided pre-clinical evidence showing the potential of active-targeted nanotherapeutics in prostate cancer therapy; unfortunately, only a few of these therapies have translated into early phase clinical trials development. Hence, progress of active-targeted nanotherapy improving efficiency of site-specific drug delivery is a critical challenge in future clinical treatment of prostate cancer. Exploring specific prostate cell-surface antigens or receptor overexpression may elaborate promising strategies for future therapeutic design. This review presents an overview of some new strategies for prostate cancer active-targeting nanotherapeutics.     

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.     

Chitosan-based gastroretentive floating drug delivery technology: an updated review

INTRODUCTION: Gastroretentive floating drug delivery systems have emerged as efficient approaches for enhancing the bioavailability and controlled delivery of various therapeutic agents. Significant advancements exploiting chitosan have been made worldwide, in order to investigate these systems according to patient requirements, both in terms of therapeutic efficacy as well as patient compliance. Such systems precisely control the release rate of the target drug to a specific site, which facilitates an enormous impact on health care. AREAS COVERED: Different novel strategies have been undertaken for the development of various gastric floating dosage forms utilizing chitosan as a promising excipient. The present paper is an earnest attempt to provide new insights on various physicochemical and biological characteristics of chitosan, along with its potential applications in a wide array of biomedical approaches. Numerous and significant research findings in the vistas of chitosan-based gastroretentive floating drug delivery technology are also discussed. EXPERT OPINION: Chitosan has been considered as a unique and efficacious agent possessing a myriad spectrum of desired characteristics. It is emphasized that recent scientific advancements in the use of this excipient as a carrier will yield new generation gastroretentive drug delivery systems, with better pharmacotherapeutic interventions. Further studies are required to unveil the hidden beneficial properties of chitosan and its derivatives, to obtain newer delivery systems which may hold tremendous prospects in the near future.     

Colon targeted drug delivery systems--an overview

In the last two decades colon targeted drug delivery has gained increased importance not just for the deliver drugs for the treatment of various colonic diseases but also for its potential for delivery of proteins and therapeutic peptides. In the past various traditional approaches used for colon targeted delivery like prodrugs, pH, time dependent, and microflora activated systems, have achieved limited success. For successful colon targeted drug delivery, the drug needs to be protected from absorption and/or the environment of the upper gastrointestinal tract and then be abruptly released into the colon. Hence continuous efforts have been made on designing colon targeted drug delivery systems with improved site specificity and versatile drug release kinetics to fulfill different therapeutic needs. In last couple of years few new systems have been developed for colon targeted drug delivery such as pressure dependent systems, CODES technology, microsponges, pectin and galactomannan coating, microbially triggered osmotic systems, lectins and neoglyconjugated etc. which are reported to have better in-vivo site specificity and design rationale than the earlier approaches. This review article gives an overview of various approaches for colonic targeted drug delivery with emphasis on newer systems, their merits and demerits, in vitro/ in-vivo evaluation and market status of such delivery systems.     

Therapeutic potential of controlled drug delivery systems in neurodegenerative diseases

Several compounds that exhibit a therapeutic effect in experimental models of neurodegenerative diseases have been identified over recent years. Safe and effective drug delivery to the central nervous system is still one of the main obstacles in translating these experimental strategies into clinical therapies. Different approaches have been developed to enable drug delivery in close proximity to the desired site of action. In this review, we describe biodegradable polymeric systems as drug carriers in models of neurodegenerative diseases. Biomaterials described for intracerebral drug delivery are well tolerated by the host tissue and do not exhibit cytotoxic, immunologic, carcinogenic or teratogenic effects even after chronic exposure. Behavioral improvement and normalization of brain morphology have been observed following treatment using such biomaterials in animal models of Parkinson's, Alzheimer's and Huntington's diseases. Application of these devices for neuroactive drugs is still restricted due to the relatively small volume of tissue exposed to active compound. Further development of polymeric drug delivery systems will require that larger volumes of brain tissue are targeted, with a controlled and sustained drug release that is carefully controlled so it does not cause damage to the surrounding tissue.     

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.