Current Drug Delivery - Volume 12, Issue 4, 2015

One approach to improve the vaccine quality is the incorporation of immunomodulators and/or adjuvants with modified delivery systems. The use of delivery systems especially chemical carriers is a promising strategy in the prevention and treatment of infections, cancers, allergies and autoimmune diseases. These systems are able to elicit an effective immune response as well as stability and safety in vaccine development. Synthetic microparticles, liposomes, chitosan, virus like particle, polymeric nanogel, phytosome, noisome, and micro/ nanospheres have been applied as carriers, providing a broad variety of immunomodulatory effects in vaccines. The potency and nature of immune responses rely on the physicochemical properties of the vaccine constructs (e.g., size and charge), the route of injection, the biochemical characteristics and the amount of antigen. Three main steps are necessary for vaccine efficiency such as targeting, activation and transfection/ antigen presentation. These systems can generally influence the type and direction of immune responses. This review describes different vaccine delivery systems developed to generate immunomodulatory effects.

Scientists have always been interested in the use of natural polymers for drug delivery. Chitosan, being a natural cationic polysaccharide has received a great deal of attention in the past few years. It is obtained by deacetylation of chitin and is regarded as the second most ubiquitous polymer subsequent to cellulose on earth. Unlike other natural polymers, the cationic charge possessed by chitosan is accountable for imparting interesting physical and chemical properties. Chitosan has been widely exploited for its mucoadhesive character, permeation enhancing properties and controlled release of drugs. Moreover it’s non-toxic, biocompatible and biodegradable properties make it a good candidate for novel drug delivery system. This review provides an insight on various chitosan based formulations for drug delivery. Some of the current applications of chitosan in areas like ophthalmic, nasal, buccal, sublingual, gastro-retentive, pulmonary, transdermal, colon-specific and vaginal drug delivery have been discussed. In addition, active targeting of drugs to tumor cells using chitosan has been described. Lastly a brief section covering the safety aspects of chitosan has also been reviewed.

Anti-allergic agents are used to treat a great variety of diseases which usually involve an inflammation reaction. These compounds act by inhibiting the release and the effects of inflammatory mediators (e.g. histamine) in the target tissue. The purpose of anti-allergy therapy is to deliver the drug to its local of action in a therapeutic concentration, minimizing the undesired side effects. In order to solve some of the anti-allergic agents’ physicochemical drawbacks and the limitations associated to conventional pharmaceutical formulations (e.g. poor solubility and absorption, skin permeation, stability), novel drug delivery systems, such as cyclodextrins, liposomes, micelles, microemulsions, nano and microparticles, have been developed. Depending on the allergic condition, several administration routes are used to deliver anti-allergic agents, each with its own disadvantages to overcome. In the literature, there are a vast number of papers concerning novel delivery systems for anti-allergic agents, making it difficult to evaluate the information and the promising outcomes. The aim of the present review article is to compile the recent (i.e. in the new millennium) improvements of novel drug delivery technology focusing on the achievement of anti-allergic therapeutic delivery. The potential intrinsic benefits of these systems will reflect an increased therapeutic adherence and better patients’ life quality. A critical prospect of future clinical trial directions will also be discussed.

Targeted drug delivery has been the interest of many researchers to improve drug efficiency and reduce side effects. Because of the potential toxicity and contamination problems of the current gelatin capsules, plant derived materials are selected for the developments of capsules for drug delivery systems. The objective of this work is to develop a target drug delivery system using zein and pectin. Different ratios of zein and pectin were used to achieve target delivery in stomach and small intestine. Zein-pectin capsule for colon-specific delivery was also developed. In vitro performance of zeinpectin capsules was examined and their structural morphology was characterized using scanning electron microscopy (SEM). Chemical interactions between zein and pectin were analyzed using Fourier transform infrared spectroscopy equipped with attenuated total reflectance (FTIR-ATR). Zein and pectin formed complex by hydrogen bonding. The swelling behavior of pectin was suppressed by zein in the zein-pectin interacted complex. By adjusting the ratio of zein to pectin, the drug release from the capsule in simulated gastric solution for 2 hours can be controlled in the range of 0% to 38%. Zein-pectin capsule for colon-specific delivery had no release in gastric and intestinal solutions while gradual release from zein-pectin capsule was observed in colonic solution, finally reaching about 80% release. Zein-pectin capsule has a potential in developing targeted drug delivery system.

In this work a thorough characterization of the GM1 micelle-Amphotericin B (AmB) interaction was performed. The micelle formation as well as the drug loading occurs spontaneously, although influenced by the physicochemical conditions, pH and temperature. The chromatographic profile of GM1-AmB complexes at different molar ratios shows the existence of two populations. The differential absorbance of GM1, monomeric and aggregate AmB, allowed us to discriminate the presence of all of them in both fractions. Thus, we noted that at higher proportion of AmB in the complex, increases the larger population which is composed mainly of aggregated AmB. The physical behavior of these micelles shows that both GM1- AmB complexes were stable in solution for at least 30 days. However upon freeze-thawing or lyophilization-solubilization cycles, only the smallest population, enriched in monomeric AmB, showed a complete solubilization. In vitro, GM1-AmB micelles were significantly less toxic on cultured cells than other commercial micellar formulations as Fungizone, but had a similar behavior to liposomal formulations as Ambisome. Regarding the antifungal activity of the new formulation, it was very similar to that of other formulations. The characterization of these GM1-AmB complexes is discussed as a potential new formulation able to improve the antifungal therapeutic efficiency of AmB.

An injectable hydrogel based on the inclusion complexation of polymerized β-cyclodextrin (pβ-CD) and cholesterol terminated poly(ethylene glycol) (PEG-chol) was developed and used as a delivery system for both macromolecules and small drugs. The hydrogel was characterized by different analyses including X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. The effects of pβ-CD/PEG-chol ratio and PEG-chol architecture on the hydrogel properties were also investigated. Cytotoxicity of the hydrogel was evaluated in NIH 3T3 fibroblasts using MTS assay. The hydrogel had an elastic behavior even at high temperature since the gelation temperature was observed at 68 °C. The highest hydrogel strength and stability were observed for the 8-armed PEG-chol at a pβ-CD/PEG-chol ratio of 1:1, w/w. Hydrogel degradation in phosphate buffered saline occurred by gradual erosion over the course of two months. IgG, a model hydrophilic macromolecule and riluzole, a model hydrophobic small drug were incorporated into the hydrogel and quantitatively released in a sustained fashion. The released IgG maintained its bioactivity confirming the absence of deleterious effects on protein structure during loading and release. The hydrogels showed no toxicity on NIH 3T3 fibroblasts confirming their biocompatibility. These results confirm the potential of pβ-CD/PEG-chol hydrogel as a versatile delivery system for drugs of different molecular weights and nature.

The purpose of this study is to formulate and develop tablets dosage form containing Metronidazole which has swelling and floating properties as a gastroretentive controlled-release drug delivery system to improve drug bioavailability. Fifteen different formulations of effervescence-forming floating systems were designed using HPMC K15M, xanthan gum, co-povidone, Eudragit® RL PO, pluronic® F-127 and/or polypropylene foam powder as swelling agents and sodium bicarbonate with/ without citric acid as gas-forming agents at different compositions. Six out of these 15 formulations which have satisfactory tablet floating behaviour were further studied with the incorporation of Metronidazole. The tablets were evaluated based on tablet physicochemical properties, floating behaviour, swelling ability and drug dissolution studies which were carried out using 0.1M HCl at 37°C for 8 hours. Furthermore, evaluation of the powder mixtures using Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC) and scanning electron microscope (SEM) were investigated. Most of the tablets show good physicochemical properties except for F11 which contains pluronic® F-127 as its release-retarding matrix-forming polymer. Other formulations show high swelling capacity, ability to float for at least 8 hours in vitro and have sustained drug release characteristics. Data obtained indicated that F3 which contains HPMC (12.5%w/w), xanthan gum (25%w/w), co-povidone (12.5%w/w) and sodium bicarbonate (31.7%w/w) is a suitable formulation with short floating lag time, good floating behaviour and sustained drug release for at least 8 hours in vitro with a zero order kinetic. Combinations of HPMC K15M and xanthan gum as swelling agents show synergistic effect in retarding drug release and are suitable in providing the most sustained drug release system.

Cyclodextrins (CDs) are carrier molecules produced by cyclization of α-1,4-glucans by Cyclodextrin Glycosyl Transferase (CGTase). These torus shaped molecules have hydrophobic cavity and hydrophilic shell making them useful in pharmaceutical, food, textile, pesticide and cosmetic industries. In this study, culture conditions for the production of CGTase by organism belonging to Arthrobacter genus obtained from a paddy field soil were optimized by single parameter mode. Soluble starch, yeast extract and magnesium sulphate played an important role in CGTase production. Percentage increase in CGTase yield under optimized conditions was 396.77%. The enzyme precipitated by 60% ammonium sulphate was purified using DEAE-sepharose. The molecular weight of the purified protein as determined by SDS-PAGE was 75 kDa. Purified CGTase was thermostable and stable over a wide pH range. Dissolution studies on β -cyclodextrin-Irbesartan complex revealed that β -CDs formed were useful in preparing immediate release oral dosage forms.

Boswellia carterii (BC) Birdwood oleogum resin is an ancient remedy of inflammation processes known since Ancient Egyptian time. Of boswellic acids, 3-acetyl-11-keto-β-boswellic acid (AKBA) is the most potent anti-inflammatory active principle. Liquisolid systems of the biologically active fraction of BC oleogum resin were prepared for improving dissolution properties using low dose oral delivery to achieve enhanced anti-inflammatory activity, in comparison with the standard oral anti-inflammatory; Indomethacin. AKBA was assayed, employing an accurate and sensitive HPLC method. Detection was carried out at 210 nm using UV/Vis detector. A solubility study for the bioactive fraction was conducted. Microcrystalline cellulose and Aeroperl®300 Pharma were used as carrier and coating materials. Angle of slide, liquid load factor and Carr’s flow index were estimated. Six systems were prepared using polyethylene glycol 400, solvent and two drug loading concentrations; 20 and 40 %. For each concentration, three carrier: coat ratios were dispensed; 20:1, 10:1, and 5:1. Dissolution study was performed and two systems were selected for characterization and in vivo evaluation by investigating upper GIT ulcerogenic effect and anti-inflammatory efficacy in rats. Results indicate absence of ulcers and significantly higher and prolonged anti-inflammatory efficacy for formulations F1 and F2, with carrier: coat ratio, 5:1 and drug loads of 20 and 40 %, respectively, compared with standard oral indomethacin. We conclude higher efficacy of BC bioactive fraction liquisolids compared with Indomethacin with greater safety on GIT, longer duration of action and hence better patient compliance.

Invasive pulmonary aspergillosis is a life threatening fungal infection mainly caused by Aspergillus species. Available treatment strategy against pulmonary aspergillosis is having very limited applicability, due to its toxicity and low circulation half-life. Pulmonary drug delivery is one of the strategies that can minimize these pitfalls. In the present study, polymeric and lipidic nanoparticles of amphotericin B were prepared by spray drying technique using hydroxypropylmethylcellulose (HPMC) and stearylamine with oleic acid respectively. Formulations were characterized for particle size, zeta potential, entrapment efficiency, in-vitro release studies, uptake analysis and in-vivo bio distribution studies. Developed polymeric and nanostructured lipid carriers (NLCs) were found in submicron size (600-700nm) and spherical in shape. Studies suggested that NLCs have better entrapment efficiency (77.1±5.5 %) as compared to HPMC carrier (71.28±5.22 %). Both formulations provided sustained drug release (HPMC, 82.05% releases up to 32 hrs and NLC, 88.2 % up to 40 hrs) and reduced dose dumping that may be helpful to reduce the toxicity and improve patient compliance. In-vitro antifungal studies suggested that stearylamine formulations exhibited better antifungal activity over control and HPMC formulations. Pharmacokinetic and organ distribution studies also support our hypothesis i.e. localized drug delivery for prolong period, improving the therapeutic effectiveness of the encapsulated drug against pulmonary aspergillosis. Studies suggested that drug delivery by pulmonary route is beneficial for local action in lungs.