PRELIMINARY RESULTS WITH A NEW SOFT PLIABLE DOG INTRAOCULAR IMPLANT: THE CANI/JAG

Abstract

New ocular drug delivery systems are currently 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, and also in part 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 ocular delivery systems extend the duration of drug action by enhancement of corneal absorption; these include soluble gels and emulsions, hydrophilic ocular inserts, ion-pair associations, prodrugs, and liposomes. Other delivery systems provide for a controlled release of drugs; they can be based on any of several different mechanisms and include both erodible and nonerodible matrices. The delivery systems are described in this review, along with their mechanisms, limitations, and the therapeutic rationale for their use.     

Advances in hydrogels applied to degenerative diseases

Hydrogels are currently applied in the treatment of numerous degenerative diseases because of their three dimensional (3D) nature, high water content and wide range of polymers that can be used for their fabrication. Hydrogels have been investigated and commercialized, for example, as soft contact lens-based ophthalmic drug delivery systems. These novel devices improved the bioavailability of ophthalmic drugs and their residence time. Hydrogels are also being investigated to facilitate and augment targeted delivery of chemotherapeutic agents. This approach minimizes significantly the side effects associated with conventional administration of anti-cancer therapeutics. The application of hydrogels as 3D scaffold has recently gained momentum because they can mimic key features of the extracellular matrix. For this reason, hydrogels are representing a viable alternative to traditional tumor xenograft in cancer biology studies. This review highlights recent advances in the development of hydrogels that are applied in degenerative diseases such as ocular, cancer, spine and cartilage degenerative pathologies.     

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.     

Ophthalmic drug design based on the metabolic activity of the eye: Soft drugs and chemical delivery systems

Despite its apparent easy accessibility, the eye is, in fact, well protected against the absorption of foreign materials, including therapeutic agents, by the eyelids, by the tear-flow, and by the permeability barriers imposed by the cornea on one side and the blood-retinal barrier on the other. Most existing ophthalmic drugs were adapted from other therapeutic applications and were not specifically developed for the treatment of eye diseases; hence, they are not well suited to provide eye-specific effects without causing systemic side effects. A real breakthrough in the area of ophthalmic therapeutics can be achieved only by specifically designing new drugs for ophthalmic applications to incorporate the possibility of eye targeting into their chemical structure. Possibilities provided along these lines by designing chemical delivery systems (CDSs) and soft drugs within the framework of retrometabolic drug design are reviewed here. Both are general concept applicable in almost any therapeutic area. This review will concentrate on beta-adrenergic agonists and anti-inflammatory corticosteroids, where clinical results obtained with new chemical entities, such as betaxoxime, adaprolol, loteprednol etabonate, and etiprednol dicloacetate, exist to support the advantages of such metabolism-focused, ophthalmic-specific drug design approaches.     

Nanomedicines for ocular NSAIDs: safety on drug delivery

The eyes are among the most readily accessible organs in terms of location in the body, yet drug delivery to eye tissues is particularly problematic. Poor bioavailability of drugs from ocular dosage forms is mainly due to precorneal loss factors (e.g., tear dynamics, nonproductive absorption, transient residence time in the cul-de-sac, and relative impermeability of the corneal epithelial membrane). There is a clear need for effective topical formulations capable of promoting drug penetration and maintaining therapeutic levels with a reasonable frequency of application—a strategy that can also result in enhancement of side effects that probably would not be acceptable. Delivery of a drug via a nanotechnology-based product fulfills three main objectives: enhancement of drug permeation, controlled release, and targeting. The inflammatory response of the ocular tissues is a common side effect associated with ophthalmic surgery. Together with steroidal agents, nonsteroidal anti-inflammatory drugs are used in eye surgery. In this review we focus on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as formulations incorporating anti-inflammatory drugs for ophthalmic application.From the Clinical EditorThis review focuses on microemulsions, polymeric nanoparticles, liposomes, solid lipid nanoparticles, and drug nanocrystals as novel high efficiency delivery systems of anti-inflammatory drugs in ophthalmic applications.     

Hydrogels in ophthalmic applications

More and more people worldwide are affected by severe eye diseases eventually leading to visual impairment or blindness. In most cases, the treatment involves the application of ophthalmic dosage forms such as eye drops, suspensions or ointments. Unfortunately, some of the therapeutic approaches have major shortcomings, especially in the treatment of the posterior segment of the eye, where many vision-threatening diseases originate. Therefore, research focuses on the development of new materials (e.g., for vitreous substitution) and more advanced drug delivery systems. Hydrogels are an extremely versatile class of materials with many potential applications in ophthalmology. They found widespread application as soft contact lenses, foldable intraocular lenses, in situ gelling formulations for ophthalmic drug delivery and ocular adhesives for wound repair; their use as vitreous substitutes and intravitreal drug delivery systems is currently under investigation. In this article, we review the different applications of hydrogels in ophthalmology with special emphasis placed on the used polymers and their suitability as ocular drug delivery systems.     

Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle

Approximately 90% of all ophthalmic drug formulations are now applied as eye-drops. While eye-drops are convenient and well accepted by patients, about 95% of the drug contained in the drops is lost due to absorption through the conjunctiva or through the tear drainage. A major fraction of the drug eventually enters the blood stream and may cause side effects. The drug loss and the side effects can be minimized by using disposable soft contact lenses for ophthalmic drug delivery. The essential idea is to encapsulate the ophthalmic drug formulations in nanoparticles, and disperse these drug-laden particles in the lens material. Upon insertion into the eye, the lens will slowly release the drug into the pre lens (the film between the air and the lens) and the post-lens (the film between the cornea and the lens) tear films, and thus provide drug delivery for extended periods of time. This paper focuses on dispersing stabilized microemulsion drops in poly-2-hydroxyethyl methacrylate (p-HEMA) hydrogels. The results of this study show that the p-HEMA gels loaded with a microemulsion that is stabilized with a silica shell are transparent and that these gels release drugs for a period of over 8 days. Contact lenses made of microemulsion-laden gels are expected to deliver drugs at therapeutic levels for a few days. The delivery rates can be tailored by controlling the particle and the drug loading. It may be possible to use this system for both therapeutic drug delivery to eyes and the provision of lubricants to alleviate eye problems prevalent in extended lens wear.     

Biodegradable microspheres for vitreoretinal drug delivery.

Vitreoretinal disorders are one of the major causes of blindness in the developed world. Treatments of these pathologies often include repeated intravitreous injections to achieve intraocular drug levels within the therapeutical range. However, the risks of complications increase with the frequency of intravitreous injections. Controlled drug delivery formulations, offer an excellent alternative to multiple administrations. These systems are capable of delivering drugs over longer time periods than conventional formulations. Currently, several kinds of polymer devices for drug delivery to the posterior segment of the eye are under clinical use, or under investigation. Among these devices, microparticulates, such as microspheres, provide an alternative to multiple injections to obtain sustained release of the drug with a single administration. Among the polymers used to make the injectable microparticles, the most commonly used are poly(lactic acid), poly(glycolic acid) and copolymers of lactic and glycolic acids because they are biocompatible and degrade to metabolic products that are easily eliminated from the body. This article reviews the literature of biodegradable polymeric microspheres loaded with drugs, that have been investigated for delivery by intravitreous injection to treat diverse vitreoretinal diseases.     

Solubility enhancers for oral drug delivery

With recent progress in high throughput screening of potential therapeutic agents, the number of poorly water-soluble drug candidates has risen sharply and formulating for poorly water-soluble compounds for oral delivery now presents one of the most frequent and greatest challenges to scientists in the pharmaceutical industry. Many new drugs and potential therapeutic compounds under investigation possess high lipophilicity, poor water solubility, and low oral bioavailability. Furthermore, development of improved oral dosage forms for currently marketed drugs can also enhance their therapeutic value. Oral delivery systems designed for poorly water-soluble drugs include micelles with surfactants, microemulsions, self-emulsifying/microemulsifying drug delivery systems (SEDDS/SMEDDS), solid dispersions, microspheres and cyclodextrin inclusion complexes. These delivery systems have been shown to enhance oral bioavailability and therapeutic effects of poorly water-soluble drugs mainly by improving the poor solubility. As a consequence of extensive research, various oral delivery systems for poorly water-soluble agents are being developed in clinical phases worldwide. New formulation technologies and multidisciplinary expertise may lead to development of advanced and effective oral drug delivery systems applicable to a wide range of poorly water-soluble drugs in the near future.     

Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery

Topical dosing of ophthalmic drugs to the eye is a widely accepted route of administration because of convenience, ease of use, and non-invasiveness. However, it has been well recognized that topical ocular delivery endures a low bioavailability due to the anatomical and physiological constraints of the eye which limit drug absorption from the pre-corneal surface. Nonionic surfactants as versatile functional agents in topical ocular drug delivery systems are uniquely suited to meet the challenges through their potential ability to increase bioavailability by increasing drug solubility, prolonging pre-corneal retention, and enhancing permeability. This review attempts to place in perspective the importance of polyoxyethylated nonionic surfactants in the design and development of topical ocular drug delivery systems by assessing their compatibility with common ophthalmic inactive ingredients, their impact on product stability, and their roles in facilitating ocular drugs to reach the target sites.     

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.     

Drug targeting to the colon with lectins and neoglycoconjugates

Targeting of drugs to specific sites of action provides several advantages over non-targeted drugs. These include the prevention of side effects of drugs on healthy tissues and enhancement of drug uptake by targeted cells. This review will cover traditional approaches of colon drug targeting as well as the use of lectins and neoglycoconjugates for the targeted delivery. Direct and reverse targeting strategies, potential molecular targets and targeting moieties for colon drug delivery, targeted drug delivery systems (DDS) for colon delivery, anticancer DDS targeted to colon cancer are examined. Directions of future development are discussed.     

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.     

New generation of liposomal drugs for cancer

This review is focused on liposomes as a delivery system for anticancer agents and more specifically on the advantages of using liposomes as drug nanocarrier in cancer chemotherapy. The main advantages of liposomal drugs over the non-encapsulated drugs include: (1) improved pharmacokinetics and drug release, (2) enhanced intracellular penetration, (3) tumor targeting and preventing adverse side effects and (4) ability to include several active ingredients in one complex liposomal drug delivery system (DDS). The review also includes our recent data on advanced liposomal anticancer drug delivery systems. As a conclusion we propose a novel liposomal DDS which includes inhibitors of pump resistance combined in one liposomal drug delivery system with an inhibitor of antiapoptotic cellular defense, an apoptosis inducer (a traditional anticancer drug) and a targeting moiety. The proposed drug delivery system utilizes a novel three tier approach, simultaneously targeting three molecular targets: (1) extracellular receptors or antigen expressed on the surface of plasma membrane of cancer cells in order to direct the whole system specifically to the tumor, preventing adverse side effects on healthy tissues; (2) drug efflux pumps in order to inhibit them and enhance drug retention by cancer cells, increasing intracellular drug accumulation and thereby limiting the need for prescribed high drug doses that cause adverse drug side effects; and (3) intracellular controlling mechanisms of apoptosis in order to suppress cellular antiapoptotic defense.     

Ocular disposition, pharmacokinetics, efficacy and safety of nanoparticle-formulated ophthalmic drugs

Ophthalmic drugs are delivered to ocular tissues predominantly via relatively simple formulations, such as topically dosed water-soluble drug solutions and water-insoluble drug suspensions in ointments. An ideal topical drug delivery system should possess certain desirable properties, such as good corneal and conjunctival penetration, prolonged precorneal residence time, easy instillation, non-irritative and comfortable to minimize lachrymation and reflex blinking, and appropriate rheological properties. In general, ocular efficacy is closely related to ocular drug bioavailability, which may be enhanced by increasing corneal drug penetration and prolonging precorneal drug residence time. To improve ocular bioavailability of topically dosed ophthalmic drugs, a variety of ocular drug delivery systems, such as hydrogels, microparticles, nanoparticles, microemulsions, liposomes and collagen shields, have been designed and investigated. These newer systems may, to some extent, control drug release and maintain therapeutic levels in ocular tissues over a prolonged period of time. This review focuses on the in vitro, ex vivo and in vivo studies of ophthalmic drugs formulated in nanoparticles published over the past two decades. The progress and development issues relating to ocular disposition, pharmacokinetics, efficacy and safety of the nanoparticle-formulated ophthalmic drugs are specifically addressed. Information and discussions summarized in this review are helpful for pharmaceutical scientists to develop better ophthalmic therapeutics.     

Cyclodextrins in ophthalmic drug delivery

Most ocular diseases are treated by topical drug application in the form of aqueous eye drop solutions. Recent studies have shown that cyclodextrins are useful additives in ophthalmic formulations for increasing the aqueous solubility, aqueous stability and bioavailability of ophthalmic drugs, and to decrease drug irritation. However, these studies have also shown that there are some basic differences between ophthalmic administration of cyclodextrins and administration of cyclodextrins via other routes. These differences have induced some limitations in the ophthalmic application of these most recently developed pharmaceutical excipients. The objective of this review is to summarize recent findings and applications of various cyclodextrins in ophthalmic drug delivery. Their mechanism of action in aqueous eye drop formulations is also discussed. Finally, the formulation of a couple of cyclodextrin containing eye drop solutions is described.     

A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases

Intravitreal implantable device technology utilizes engineered materials or devices that could revolutionize the treatment of posterior segment eye diseases by affording localized drug delivery, responding to and interacting with target sites to induce physiological responses while minimizing side‐effects. Conventional ophthalmic drug delivery systems such as topical eye‐drops, systemic drug administration or direct intravitreal injections do not provide adequate therapeutic drug concentrations that are essential for efficient recovery in posterior segment eye disease, due to limitations posed by the restrictive blood‐ocular barriers. This review focuses on various aspects of intravitreal drug delivery such as the impediment of the blood‐ocular barriers, the potential sites or intraocular drug delivery device implantation, the various approaches employed for ophthalmic drug delivery and includes a concise critical incursion into specialized intravitreal implantable technologies for the treatment of anterior and posterior segment eye disease. In addition, pertinent future challenges and opportunities in the development of intravitreal implantable devices is discussed and explores their application in clinical ophthalmic science to develop innovative therapeutic modalities for the treatment of various posterior segment eye diseases. The inherent structural and functional properties, the potential for providing rate‐modulated drug delivery to the posterior segment of the eye and specific development issues relating to various intravitreal implantable drug delivery devices are also expressed in this review. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2219–2239, 2010     

Biodegradable Implants for Sustained Drug Release in the Eye

The safety and effectiveness of systemic and topical medical therapies for ocular disorders are limited due to poor ocular drug uptake, nonspecificity to target tissues, systemic side effects, and poor adherence to therapy. Intravitreal injections can enhance ocular drug delivery, but the need for frequent retreatment and potential injection-related side effects limit the utility of this technique. Sustained-release drug delivery systems have been developed to overcome these limitations; such systems can achieve prolonged therapeutic drug concentrations in ocular target tissues while limiting systemic exposure and side effects and improving patient adherence to therapy. A critical factor in the development of safe and effective drug delivery systems has been the development of biocompatible polymers, which offer the versatility to tailor drug release kinetics for specific drugs and ocular diseases. Ocular implants include nonbiodegradable and biodegradable designs, with the latter offering several advantages. The polymers most commonly used in biodegradable delivery systems are synthetic aliphatic polyesters of the poly-α-hydroxy acid family including polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid. The characteristics of these polymers for medical applications as well as the pharmacological properties, safety, and clinical effectiveness of biodegradable drug implants for the treatment of ocular diseases are reviewed herein.     

Transdermal treatment options for neurological disorders: impact on the elderly

As people grow old, their need for medications increases dramatically because of the higher incidence of chronic pain, diabetes mellitus, cardiovascular and neurological diseases in the elderly population. Furthermore, the elderly require special consideration with respect to drug delivery, drug interactions and adherence. In particular, patients with chronic neurological diseases often require multiple administration of drugs during the day to maintain constant plasma medication levels, which in turn increases the likelihood of poor adherence. Consequently, several attempts have been made to develop pharmacological preparations that can achieve a constant rate of drug delivery. For example, transdermal lisuride and apomorphine have been shown to reduce motor fluctuations and duration of 'off' periods in advanced Parkinson's disease, while rotigotine allows significant down-titration of levodopa without severe adverse effects. Thus, parkinsonian patients with long-term levodopa syndrome or motor disorders during sleep could benefit from use of transdermal lisuride and apomorphine. Moreover, transdermal dopaminergic drugs, particularly rotigotine, seem the ideal treatment for patients experiencing restless legs syndrome or periodic limb movement disorder during sleep, disorders that are quite common in elderly people or in association with neurodegenerative diseases. Unlike dopaminergic drugs, transdermal treatments for the management of cognitive and behavioural dysfunction in patients with Parkinson's disease and Alzheimer's disease have inconsistent effects and no clearly established role. Nevertheless, because of their favourable pharmacological profile and bioavailability, the cholinesterase inhibitors tacrine and rivastigmine are expected to show at least the same benefits as oral formulations of these drugs, but with fewer severe adverse effects. Transdermal delivery systems play an important role in the management of neuropathic pain. The transdermal lidocaine (lignocaine) patch is recommended as first-line therapy for the treatment of postherpetic neuralgia. Furthermore, in patients with severe persistent pain, transdermal delivery systems using the opioids fentanyl and buprenorphine are able to achieve satisfactory analgesia with good tolerability, comparable to the benefits seen with oral formulations. Transdermal administration is the ideal therapeutic approach for chronic neurological disorders in elderly people because it provides sustained therapeutic plasma levels of drugs, is simple to use, and may reduce systemic adverse effects. Several transdermal delivery systems are currently under investigation for the treatment of Parkinson's disease, Alzheimer's disease and neuropathic pain. Although most transdermal delivery systems treatments cannot be considered as first-line therapy at present, some of them provide clear advantages compared with other routes of administration and may become the preferred treatment in selected patients. In general, however, most transdermal treatments still require long-term evaluation in large patient groups in order to optimise dosages and evaluate the actual incidence of local and systemic adverse effects.