Current Drug Delivery - Volume 1, Issue 4, 2004

In this work, the development of a gel reservoir for a timolol (TM) transdermal iontophoretic delivery system is investigated. TM gel is prepared using hydroxypropyl cellulose (HPC) and the permeability of TM from the gel through an artificial membrane (Polyflux®) and pig stratum corneum (SC) is studied. For a constant TM donor concentration, the TM transport across the Polyflux® membrane alone decreases when the concentration of the gel increases due to increase of the gel viscosity. For constant gel concentration, however, the TM permeation across the membrane increases when the TM donor concentration increases. In addition, no effect of the electrical current (iontophoresis, current density 0.5 mA cm-2) on the TM permeation is found. For the combination of the Polyflux® membrane with pig SC, the TM transport is much lower than for the membrane alone and the SC fully controls the TM delivery. In this case, the application of electrical current enhances the TM delivery 13-15 times in comparison to passive (no current) transport. According to our estimation, the daily TM dose (10- 60 mg) can be delivered by an iontophoretic patch with Polyflux® membrane area of 6 - 36 cm2 containing 20 % (w / w) HPC gel and 15 mg cm-3 of TM.

The preparation, properties and potential applications in drug delivery of biocompatible and biodegradable PLA-PEG and PLGA-PEG nanoparticles are discussed. PLA-PEG and PLGA-PEG nanoparticles have been produced by emulsification-solvent evaporation, solvent displacement and salting out methods. The nanoparticles can be stored as freeze-dried powders, but an adequate amount of a suitable lyoprotectant should be added prior lyophilisation to prevent nanoparticle aggregation and retain nanoparticle redispersibility. The nanoparticles have a core-shell structure with a PLA core and a PEG coating. Their basic colloidal properties and degradation depend on copolymer composition. The PLAPEG and PLGA-PEG nanoparticles exhibit prolonged blood circulation following intravenous administration to animals. The composition of the nanoparticles determine their biodistribution properties, probably through its effects on the effectiveness of the PEG steric barrier and the size of the nanoparticles. The ability of the PLA-PEG and PLGA-PEG nanoparticles to evade rapid phagocytocis has extended the range of sites within the body that the nanoparticles can reach, which has significant implications with regard to their application in controlled drug delivery and targeting. The PLAPEG and PLGA-PEG nanoparticles can be loaded with a variety of bioactive agents achieving satisfactory loading, especially in the case of hydrophobic drugs. The nanoparticles have been investigated for the treatment of infectious diseases and cancer, the intravenous and mucosal delivery of proteins, and oligonucleotide and gene delivery. The results have been encouraging and PLA-PEG and PLGA-PEG nanoparticle formulations, improving the therapeutic potential of both established and new drugs, may be expected to be available in the near future.

Cancers can adapt several evasive functions including apoptosis evasion, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replication potential, tissue invasion and metastasis. The invariable hurdle for development of therapies against such aberrant conditions requires both selective and potent cytotoxicity. Analysis of HIV-1 Vpr's apoptotic and anti-proliferative activity have revealed potentially important implications for cancer therapy. Accordingly, we have reviewed the properties of Vpr that will likely contribute to its efficacious function as an anti-tumor agent. Among these are its ability to induce cell cycle arrest, inhibit inflammation, provoke p53 independent apoptosis, and selective killing of rapidly dividing cells.

Quinone bioreductive prodrugs were developed to target the hypoxic or the reductase- rich population of solid tumours. The mechanism of their selective activation is based on their ability to convert the quinone sub-structure to their activated semiquinone or hydroquinone species affording the active species. Recent studies on their biochemical activation process have resulted in their development as delivery agents that can effectively release a potent (but not necessarily a cytotoxic) agent under hypoxic / reductive conditions. This technology platform is currently being used to design / identify, and synthesise novel quinone bioreductive delivery agents to target cancer and other diseses where hypoxia and / or reductive enzymes play a major pathophysiological role.

Cyclodextrins are oligosaccharides having outer hydrophilic surface and central hydrophobic cavity. These agents form inclusion complexes with poorly water-soluble drugs; hence they show an important implication for use in ophthalmics because of their applications in solubilising and stabilising the ocular drugs. Most of the drugs being used in ophthalmics were not tailor-made for the eye and considering the poor bioavailability of <1% from the corneal surface, presentation of the drug in a soluble form and at high concentration is important. Provision of a high drug concentration at the corneal surface increases the percent drug permeation indicating the usefulness of cyclodextrins as penetration enhancers. A decrease in irritation potential of some drugs upon incorporation of cyclodextrins is also reported. Polymercyclodextrin multicomponent systems further extend the role of cyclodextrins in improving the solubility and bioavilability of ocular drugs. Large hydrophilic cyclodextrins like hydroxypropyl-β-cyclodextrin and sulphobutylether-β- cyclodextrin are safe for the use in aqueous eye drop solutions especially since they do not cross the lipophilic cornea. Various aspects about the applications of cyclodextrins in ophthalmics, the formulation considerations and expected toxicity of cyclodextrins (especially if high concentration is used) is discussed in this review. Strategies like use of polymers to reduce the effective concentration of cyclodextrin required without compromising solubility are also included. Further the concept of incorporating the drug-cyclodextrin complexes into liposomes or niosomes for a better targeting of the drug at appropriate tissue destination is discussed as a possible future option.

The brain is protected and isolated from the general circulation by a highly efficient blood-brain barrier. This is characterised by relatively impermeable endothelial cells with tight junctions, enzymatic activity and active efflux transport systems. Consequently the blood-brain barrier is designed to permit selective transport of molecules that are essential for brain function. This creates a considerable challenge for the treatment of central nervous system diseases requiring therapeutic levels of drug to enter the brain. Some small lipophilic drugs diffuse across the blood-brain barriersufficiently well to be efficacious. However, many potentially useful drugs are excluded. This review provides an insight into the current research into technologies to target small molecules, peptides and proteins to the brain. A brief review of the nature of the blood-brain barrier and its transport mechanisms is provided. Strategies to target and improve transport across the blood-brain barrier include the prodrug-lipidisation approach, sequential metabolism chemical delivery systems, drug-vectors, liposomes and nanoparticles. Included is the discussion of techniques to minimise clearance from the circulation by the reticuloendothelial system in order to extend circulation residence time and optimise the opportunity for interaction between the drug delivery system and the blood-brain barrier.

Water-soluble polymers have been used in the last two decades to modify the pharmacokinetics and physicochemical properties of targeted therapeutic agents. Non-invasive imaging techniques such as nuclear imaging can be used to assess the drug delivery efficiency of novel formulations in a cost-effective fashion and thereby facilitate their development process. Polymeric radiopharmaceuticals have also been investigated on their own right as potential nuclear imaging agents. Clinical applications of polymeric radiopharmaceuticals include blood-pool imaging and targeted molecular imaging. In the latter case, water-soluble polymers are often used to modify the pharmacokinetics and biodistribution pattern of ligands that target receptors or antigens at disease sites. As advances are continue to be made in the emerging field of molecular imaging, nuclear imaging will play an increasingly important role in the development of polymeric drug delivery systems. Similarly, polymer technology will also be integrated into the development of molecularly targeted radiopharmaceuticals. Here, we review various aspects of polymeric radiotracers and their applications in nuclear imaging.

The mucosal administration of vaccines is an area currently receiving a high level of interest due to potential advantages offered by this technique. These advantages include the ability to administer vaccines without need for needles, thus improving patient compliance with vaccination schedules, and the capacity to induce immune responses capable of preventing infections at the site of acquisition. Despite these advantages a number of limitations exist which currently inhibit our ability to successfully develop new mucosal vaccines. As such, much research is currently focused on developing new adjuvants and delivery systems to overcome these difficulties. However, despite high levels of interest in this area, relatively few mucosal vaccine candidates have successfully progressed to human clinical trials. In the review that follows, we aim to provide the reader with an overview of the immune system with respect to induction of mucosal immune responses. Furthermore, the review provides an overview of a number of microbial (bacterial toxins, CpG DNA, cytokines / chemokines, live vectors, and virus like particles) and synthetic (microspheres, liposomes, and lipopeptides) strategies that have been investigated as adjuvants or delivery systems for mucosal vaccine development, with a focus on the delivery of vaccines via the oral route.

Skin perturbation with ethanol followed by application of β-chloroalanine (β-CA) or atorvastatin (AVN) was employed for delaying the recovery of sphingosine (a precursor of ceramide) and cholesterol, respectively in epidermis of rats. Dose optimization studies revealed 600 μg of β-CA and 750 μg of AVN significantly (p < 0.05) inhibited the synthesis of sphingosine and cholesterol, respectively and prevented their replenishment to normal levels till 48 hr in viable rat skin. Co-application of calcium chloride (0.1 mM) inhibited the synthesis of both micro constituents of epidermis to a greater magnitude, whereas verapamil reduced this effect. The in vitro permeation of levodopa across treated skin portions was directly correlated with percentage of sphingosine and cholesterol inhibited by the treatments. The in vitro permeation of levodopa across skin excised after treatment with β-CA or AVN was enhanced 3-fold. Effective plasma concentration (1.58 μg / ml) of levodopa in rats was achieved within 2 hr and maintained till 12 hr after AVN treatment, and increased to 36 hr with the co-application of calcium chloride. However, when the skin was treated with β-CA, C eff was achieved after 4 hr and was maintained till 36 hr. The inclusion of calcium chloride maintained C eff for 48 hr. Hence, synthesis inhibition of skin lipids seems to offer a feasible means to enhance the systemic delivery of polar drugs like levodopa.

The main objective of these studies was to investigate whether the nanoparticle delivery has any immunopotentiation effect at modest doses of a few micro- or nanograms of CpG oligodeoxynucleotide (CpG ODN) and what would be the influence on T cell responses at such low doses. Various doses (5 to 0.05 μg) of a model CpG ODN adjuvant (#1826) along with 2 Lf tetanus toxoid (TT) were formulated in either nanoparticles using poly(D,L-lactic-coglycolic acid) (PLGA) 50:50 co-polymer, or saline. Strong antigen specific ex vivo T cell proliferation was observed for the Balb / c mice receiving immunogens in nanoparticles. At 5 μg dose of CpG ODN, the T cell stimulation index (SI) was 241 as compared with 74 for the same dose when given in saline. Comparable SI value of 78 was observed at 100-fold lower dose (0.05 μg) using nanoparticles. Similarly, significantly higher (P<0.01) cytokine secretion was observed for nanoparticles groups. A ten-fold lower dose (0.5 μg instead of 5 μg) of CpG ODN in nanoparticles was adequate to obtain levels of IFN-γ, TNF-α, and IL-2 comparable to those observed following immunisations in saline. The immunopotentiation effect of the particulate delivery on antibody response (total IgG and subtypes) was not so marked. These studies emphasise that antigen delivery in biodegradable nanoparticles can facilitate induction of strong T cell responses, particularly of the Th1 type, at extremely lower doses of CpG ODN. Such reduction in the effective dose would be advantageous for minimising the potential side effects of these novel adjuvants.