Current Drug Delivery - Volume 6, Issue 4, 2009

The Australian Chapter of the Controlled Release Society (AUS-CRS) is dedicated to broadening the awareness, application and appeal of controlled release of bioactive molecules and technology within the academic and industrial community. Another important purpose of the Chapter is to support young researchers in the field of drug delivery and formulation. Successful delivery of a high quality annual scientific meetings and workshops provides the principal means for achieving these aims. Our 2nd AUS-CRS Annual Meeting was held in conjunction with Australasian Pharmaceutical Science Association (APSA) Conference on Sunday 7th of December 2008 at the Australian National University in Canberra. Created in July 2007, AUSCRS is only a young chapter of the main international CRS organization, yet the quality of the program was clearly excellent. Outstanding plenary lectures were given by highly recognized drug delivery scientists.

The aim of this study was to investigate the potential for coating drug particles with liquid crystalline lipids with a view to modifying drug dissolution behaviour in the particle form. Firstly, dissolution of a simple salicylic acid layer on a microscope slide, as a model system was shown to be hindered by the liquid crystal layer and was sensitive to the type of liquid crystal nanostructure present. Particles of sodium salicylate (hydrophilic) and triamcinolone acetonide (hydrophobic) were produced, and lipids applied to the drug surface using either mechanofusion or co-spray drying approaches. The coated sodium salicylate particles dissolved extremely rapidly. Triamcinolone acetonide particles on the other hand dissolved very slowly compared to uncoated triamcinolone acetonide particles, which indicated that the coating was in fact intact, and that drug solubility in the aqueous channels likely controlled the transport of drug into the dissolution medium. Whilst more investigation is required, these initial studies demonstrate a potentially useful strategy for controlling drug dissolution for applications such as intravitreal steroid injections.

Porous CaCO3 microparticles were fabricated by colloidal crystallization. Two oppositely charged polyelectrolytes, poly (styrene sulfonate, PSS) and poly (allylamine hydrochloride, PAH) were adsorbed layer-by-layer on the CaCO3 templates. Polyelectrolyte microcapsules were then obtained by removing the CaCO3 core. Scanning electron microscopy (SEM), energy-dispersion X-ray analysis (EDX), laser diffraction particle sizing and Raman spectroscopy were employed to characterize the physico-chemical properties of the constructed microcapsules. In vitro drug release studies were conducted using the model water-soluble drug Rhodamine B. Factors such as the number of polyelectrolyte layers and pH were investigated. SEM micrographs revealed uniform CaCO3 microparticles, nearly spherical in shape with pronounced surface roughness, and highly developed interior porous structure. The surface of polyelectrolyte coated particles became rougher than the initial CaCO3 microparticles. The acquired SEM micrographs of the (PSS/PAH)n microcapsules indicated that the number of layers affected the morphology of the microcapsules. The (PSS/PAH)3 microcapsules revealed a very porous network with many holes resembling the initial morphology of CaCO3 microparticles. Raman spectra showed peaks at 1125 cm-1 (S=O bond) and 1600 cm-1 (aromatic ring stretching) which represented the PSS molecule. The thickness of each layer was about 10 to 20 nm and it can be tailored to such nanometer level by controlling the number of adsorbed layers. The in vitro release of Rhodamine B was dependent on both the number of wall bilayers as well as the pH of the release media. These systems provide an opportunity for the development of controlled release dosage forms with greater effectiveness in the treatment of chronic conditions.

Gene delivery research has come a long way in recent years but there are still a number of barriers preventing therapeutic gene-based drugs reaching the market. Dendrimers or multi-component carriers may provide a means to overcome the issues of gene degradation and transport to the target site by employing different entities in the same carrier. We will discuss some recent approaches to gene delivery using modified dendrimers. We also discuss our work to deliver oligonucleotides and genes using dendritic peptide-based carriers.

Influenza virus remains a significant threat to humanity despite the discovery of novel anti-viral therapies and the continuing development of seasonal vaccines. The reason for this ongoing concern is that the development of drug resistance to anti-virals has rapidly occurred and the currently developed vaccines are typically only effective against a specific influenza virus strain. The continual emergence of new influenza virus strains that may lead to the next human pandemic has inspired much research into a better understanding of the virus, particularly the role(s) of carbohydrates in the virus' lifecycle. Much of this research is directed towards next generation anti-influenza drugs. Important advances in the interrogation of influenza virus' surface glycoprotein haemagglutinin by NMR spectroscopy have been made in recent times. An overview of some of these advances is provided.

Although most commercial vaccines are delivered by injection, there is an increasing interest in needle-free vaccine delivery for reasons including the ability to elicit immune responses at mucosal surfaces, ease of administration, and the ability to administer vaccines without the need for trained medical professionals. This review summarizes strategies and technologies that are being used to improve oral vaccine absorption. Peptides and proteins, which comprise important vaccine components, exhibit unfavorable physicochemical properties including degradation in the gastrointestinal tract, and poor transport across the intestinal wall, which hinder oral vaccine development. Approaches to overcome these obstacles aim to provide new vaccines and delivery systems that are capable of eliciting protective immune responses, and are making an impact on current vaccine development.

Org 45697 (MW 600.7, clogP 7.92, soybean oil solubility 50 mg/g) and Org 46035 (MW 601.6, clog P 8.46, soybean oil solubility 40 mg/g) are two poorly water soluble (<0.1μg/ml), highly lipophilic drug candidates with immunomodulator activity and highly analogous chemical structures. After oral administration to conscious ambulatory rats in an aqueous-based methylcellulose/Tween® 80 suspension, the bioavailability of both compounds was low (< 2% of administered dose). However, bioavailability was significantly increased (> 5 fold) after oral administration in a long chain triglyceride lipid (olive oil) formulation. Subsequent studies have explored the potential for solubilising formulations, including lipid-based formulations, to enhance the oral bioavailability of Org 45697 and Org 46035 and secondly to explore the potential contribution of intestinal lymphatic transport to intestinal absorption. The experimental data show that solubilising formulations may provide for significant increases in oral bioavailability for Org 45697 and Org 46035 and that after co-administration with lipid, 35-50% of the absorbed dose may be transported to the systemic circulation via the intestinal lymph. Interestingly, the lymphatic transport of the less lipid soluble analogue, Org 46035 was approximately 40% lower than that of Org 45697 suggesting that relatively subtle differences in lipid solubility can have significant impact on the extent of lymphatic transport.

The dermal delivery characteristics of hydrophilic silica nanoparticle coated medium chain triglyceride oil-inwater emulsions are reported and correlated with the physicochemical and interfacial properties of the emulsion based drug carriers. The synergistic drug/stabiliser/nanoparticle interactions are demonstrated to be a function of the charge and concentration of the initial emulsion stabiliser; charge and initial loading phase of nanoparticles and physicochemical properties of the drug molecule. The improved physical stability of the emulsions and the chemical stability of two model lipophilic agents (all-trans-retinol and acridine orange 10-nonyl bromide) confirmed that engineered nanoparticle layers can enhance the shelf-life of liable lipophilic agents. Nanoparticle coatings are shown to control the in-vitro release of active agents from emulsions and significantly promote skin retention. The lipophilic agents distributed into the deeper viable skin layers without permeation through full-thickness skin and hence systemic exposure. Nanoparticle-coated submicron oil-in-water emulsions can serve as novel dermal carriers with controlled release kinetics and targeted drug delivery.

Converting drugs from the crystalline to the amorphous state has gained increasing interest in the past decades as a potential method to overcome solubility issues of poorly water soluble drugs. A variety of techniques exist to convert the crystalline state of a drug to its amorphous form, including solution based, heat based and solid - solid conversion based methods. Inherent to the amorphous state, regardless of its preparation technique, is its physical instability and tendency to recrystallize. In this study, quench-cooled and cryo-milled simvastatin were compared with regards to their configurational thermodynamic parameters (entropy, enthalpy and Gibbs free energy) and mobility (relaxation times calculated using the Adam-Gibbs and Kohlrausch-Williams-Watts method). Stability studies showed quench-cooled simvastatin to be more stable than cryo-milled simvastatin. This was reflected in the calculated parameters although their absolute values did not agree with the stability behaviour. Relaxation time parameters of τ = 6.9·104 s for quench-cooled and τ = 1.7·104 s for cryo-milled simvastatin were calculated. The results from this study suggested that differences in the physical stability of amorphous forms prepared by different techniques are reflected in their mobility and thermodynamic parameters. Even though the predictive capabilities of these parameters for a set of different drugs may be limited, they can serve as a predictive tool for physical stability assessment if differently prepared amorphous forms of the same drug are investigated.

Currently there is a lack of new active pharmaceutical ingredients (APIs) appearing on the veterinary market. In the short term this problem can be offset by developing controlled release drug delivery technologies to extend the commercial life of existing drugs. However, such a commercial opportunity does not come without its challenges. These generally revolve around financial factors, which include limited budgets assigned to conduct veterinary R&D, the costcompetitive amount that can be charged for the finished product and the expensive time-consuming registration process. In addition, the gap between the perceived and actual market needs makes the return on investment hard to defend. It is not surprising therefore that few controlled release products appear on the market for farmed animals, despite their potential advantages to that sector. The landscape for an academic veterinary pharmaceutical scientist is quite different from that of the industrial one. When you remove the commercial requirement associated with product development, there are numerous fundamental and applied research opportunities, with the outcome of demonstrating the potential worth, or otherwise, of an approach being sufficient to achieve the major goal of academics, publication in peer-reviewed journals. A further opportunity arises when controlled release dosage forms are used as research tools to forward knowledge in the area of animal science. The aim of this review is to provide a perspective of the current animal health industry through examination of the commercial challenges per se, along with the potential for academic collaboration that lie within this demanding area of pharmaceutical science.

Extending on recent progress in control of matter at the nanoscale, functional nanoparticles and drug nanocarriers are being actively developed with the promise of improved delivery of therapeutic agents. Nanotechnology-enabled drug delivery approaches usually aim at reducing the systemic distribution and associated side-effects typically observed with conventional chemotherapeutic molecules as well as increasing the therapeutic index of the active agents. The enhanced permeation and retention effect has been exploited with notable success to passively deliver nanostructured drug carriers and therapeutic nanoparticles in vivo. Strategies aimed at further enhancing the nanocarriers accumulation within tumor tissues are under intensive investigation and could enable, in a not too distant future, the realization of the long sought after goal of chemotherapy without - or with reduced - side-effects. In particular, immunotargeted approaches are widely predicted to offer much greater specificity towards the target cells and tissues. Advancement in molecular biology has indeed made a wealth of information available in biological processes and application of this new knowledge to nanostructured agents, has also generated unprecedented hope of novel molecular diagnostic and therapeutic strategies. Focusing on oncological applications, this review aims to discuss the recent developments in immunotargeting of functional nanoparticles and drug nanocarriers and the integration of these systems into clinically relevant therapeutic applications.

Delivering therapeutic agents to the airways maximizes their concentration in lung tissue, decreasing systemic exposure or facilitating systemic absorption as desired. Many formulations exist for the treatment of respiratory illnesses however, no controlled release inhalation formulation exists to-date. This review is an update of the current advances in controlled release inhalation formulations and evaluation. The major successful particle engineering strategies are discussed along with potential in vitro and in vivo methodologies required for their characterisation. Controlled release formulation has many challenges to overcome, specific to this kind of medicament for inhalation. With small particle size and thus an increase in surface area, it becomes more difficult to achieve an effective controlled release profile. In addition, the physiology of the lung and its impact on resident particles need to be considered. An important issue when developing controlled release inhalation formulation is the toxic, inflammatory and accumulation effects of the release modifying agents used. These effects will need to be scrutinized in much greater detail in order to bring these formulations to the market. Currently, strategies for controlling the release of inhalation therapy include molecular dispersions (liposomal-based systems), solid lipid microparticles, coating or encapsulating drug particles in a lipid outer shield, solid biodegradable (synthetic and natural excipient-based matrices), conjugates and viscous semisolid vehicles. However, the availability of standardized pharmacopoeia methodologies to test the in vitro release rates or in vivo methodologies to evaluate deposition, pharmacokinetics and clearance of controlled release systems are not available. These methodologies are presented and discussed in this review.

In this study, bilosome as a drug delivery system for insulin was studied. Two bilosomal preparations were formulated and assessed. One was prepared using a lipid extract from Soya beans seed (SBE), Palmitic acid (PA) and cholesterol (CH ) in the ratio of 0.25:1:1 w/w designated as BI while the other (BII) contained PA and CH as the lipid entity at the ratio of 1:1 w/w. Each of the preparations contained 0.5% of sodium deoxycholate (SDC) and soluble insulin. BI was given orally only, while BII was administered subcutaneously, intraperitoneally and orally to different groups of streptozotocin-induced diabetic male rats, and the blood glucose levels were measured at predetermined time intervals. The results of the studies showed that oral administration of BI and BII produced blood glucose reduction, which could mimick endogenous release of insulin with prolonged activity, although, less blood sugar lowering compared with parental administration. BI (oral I) containing SBE had greater reduction of blood glucose than BII (oral II) ,showing that SBE increased the bioavailability of insulin. Bilosomal insulin formulation could provide a good oral delivery system for insulin that would affect the entero-insular axis similar to endogenous insulin.

Several methods are being employed to improve the oral bioavailability of lipophilic drugs like using inert lipid vehicles such as Oils, Surfactant dispersions, Self Microemulsifying Drug Delivery Systems (SMEDDS) and Liposomes. SMEDDS is formulated with the help of oil or suitable lipid materials, Surfactants and hydrophilic Co-surfactants. Mixture of above ingredients can be filled in a soft capsule and ingested. When the mixture comes in contact with gastrointestinal fluid it forms a stable O/W Microemulsion. A pseudo ternary phase diagram is used for identifying the efficient Self micro-emulsification region. SMEDDS can be formulated to give sustained release by use of inert polymers. When this polymer comes in contact with GI fluids, it forms gelled polymeric matrix, which releases the micro-emulsified active principle in a continuous and prolonged manner. Physical characterization of SMEDDS should be carried out by droplet size analysis and spontaneity of emulsification. The purpose of this review is to provide a brief out line of the formulation of SMEDDS, possible mode for improving bioavailability, fate and evaluation of the same.