Spomenka Simovic

Self-ordered nanopore and nanotube platforms for drug delivery applications

The application of nanotechnology to medicine termed as ‘nanomedicine’ is recognised as an emerging field with enormous potential for developing new therapeutic concepts. A range of nanoscale materials have been explored in the last few years for drug delivery to address the problems associated with conventional drug therapies such as limited drug solubility, poor biodistribution, lack of selectivity and unfavourable pharmacokinetics. Among them, nanoporous materials with ordered and controlled pore structures, high surface area and pore volume, attracted great attention, particularly for implantable drug delivery systems. This review presents the recent progress in this field focused on electrochemically engineered nanopores/nanotube materials such as nanoporous alumina and nanotubular titania. The basic concept of fabrication of these unique materials using a self-ordering process, description of their structural properties, biocompatibility and recent applications for therapeutic implants is presented.

Silica-lipid hybrid (SLH) microcapsules: a novel oral delivery system for poorly soluble drugs.

A silica-lipid hybrid (SLH) microcapsule system for oral delivery of poorly water-soluble drugs is reported for the first time. For the model drug celecoxib (CEL), SLH microcapsules composed of medium-chain triglycerides, lecithin and silica nanoparticles; with an internal porous matrix structure, were shown to offer several physicochemical and biopharmaceutical advantages in comparison with unmodified drug, lipid emulsion, dry emulsion and the commercial product, Celebrex. DSC and XRD analyses confirmed non-crystalline CEL in SLH microcapsules and verified medium term physical stability. Dissolution under sink conditions revealed a 2- to 5-fold increase in dissolution efficiencies (%DE) and significantly reduced t(50%) (> or =50-fold) for CEL formulated as SLH microcapsules. Orally dosed in vivo studies in rats demonstrated superior pharmacokinetics for SLH microcapsules. Specifically, the fasted-state bioavailability (F) was statistically higher (p<0.05) than for aqueous suspension, lipid solution, o/w emulsion and a maltodextrin-stabilised dry emulsion, and was greater than for Celebrex. SLHs showed the highest maximum plasma concentration (C(max)) among all tested formulations (p<0.05). Linear correlations were observed between %DE and the pharmacokinetic parameters (F and C(max)). It is postulated that SLH microcapsules improve CEL oral absorption via dissolution enhancement, potentially in conjunction with other unexplored mechanisms, hence offering the possibility of dose reduction for improved therapeutic efficacy and cost-effectiveness of poorly soluble drugs.

Controlled drug release from porous materials by plasma polymer deposition.

In this communication, we present a novel approach for control of drug release from porous materials. The method is based on deposition of a plasma polymer layer with controlled thickness which reduces a pore diameter and, hence, defines the rate of drug release.

Dry Hybrid Lipid−Silica Microcapsules Engineered from Submicron Lipid Droplets and Nanoparticles as a Novel Delivery System for Poorly Soluble Drugs

We report on the fabrication and characterization of dry hybrid lipid-silica nanoparticle based microcapsules with an internal porous matrix structure for encapsulation of poorly soluble drugs, and their delivery properties (in vitro release and lipolysis and in vivo pharmacokinetics demonstrated for indomethacin as a model drug). Microcapsules were prepared by spray drying of Pickering o/w emulsions containing either negatively or positively charged lipophilic surfactant in the oil phase and hydrophilic silica nanoparticles in the aqueous phase. Effective microcapsule formation is critically dependent on the interfacial structure of the nanoparticle containing emulsions, which are in turn controlled by the surfactant charge and the nanoparticle to lipid ratio. Microcapsules (containing 50-85% oil) can be prepared with 10 times fewer silica nanoparticles when a droplet-nanoparticle charge neutralizing mechanism is operative. Cross-sectional SEM imaging has confirmed the internal porous matrix structure and identified pore sizes in the range 20-100 nm, which is in agreement with BET average pore diameters determined from gas adsorption experiments. Differential scanning calorimetry and X-ray diffraction analysis have confirmed that the model drug indomethacin remains in a noncrystalline form during storage under accelerated conditions (40 degrees C, 75% RH). Dissolution studies revealed a 2-5-fold increase in dissolution efficiency and significantly reduced the time taken to achieve 50% of drug dissolution values (> or =2- or 10-fold) for indomethacin formulated as microcapsules in comparison to o/w submicron emulsions and pure drug, respectively. Orally dosed in vivo studies in rats have confirmed superior pharmacokinetics for the microcapsules. Specifically, the fasted state absolute bioavailability (F) was statistically higher (93.07 +/- 5.09%) (p < 0.05) than for aqueous suspension (53.54 +/- 2.91%) and o/w submicron emulsion (64.57 +/- 2.11%). The microcapsules also showed the highest maximum plasma concentration (C(max)) among the investigated formulations (p < 0.05). In vitro lipolysis showed statistically higher (p < 0.05) fasted digestion (75.8% after 5 min) and drug solubilization (98% after 5 min) in digestive products for microcapsules than o/w emulsions. The hybrid lipid-silica microcapsules improve oral absorption by enhancing lipolysis and drug dissolution.

Silica nanoparticles to control the lipase-mediated digestion of lipid-based oral delivery systems

We investigate the role of hydrophilic fumed silica in controlling the digestion kinetics of lipid emulsions, hence further exploring the mechanisms behind the improved oral absorption of poorly soluble drugs promoted by silica-lipid hybrid (SLH) microcapsules. An in vitro lipolysis model was used to quantify the lipase-mediated digestion kinetics of a series of lipid vehicles formulated with caprylic/capric triglycerides: lipid solution, submicrometer lipid emulsions (in the presence and absence of silica), and SLH microcapsules. The importance of emulsification on lipid digestibility is evidenced by the significantly higher initial digestion rate constants for SLH microcapsules and lipid emulsions (>15-fold) in comparison with that of the lipid solution. Silica particles exerted an inhibitory effect on the digestion of submicrometer lipid emulsions regardless of their initial location, i.e., aqueous or lipid phases. This inhibitory effect, however, was not observed for SLH microcapsules. This highlights the importance of the matrix structure and porosity of the hybrid microcapsule system in enhancing lipid digestibility as compared to submicrometer lipid emulsions stabilized by silica. For each studied formulation, the digestion kinetics is well correlated to the corresponding in vivo plasma concentrations of a model drug, celecoxib, via multiple-point correlations (R(2) > 0.97). This supports the use of the lipid digestion model for predicting the in vivo outcome of an orally dosed lipid formulation. SLH microcapsules offer the potential to enhance the oral absorption of poorly soluble drugs via increased lipid digestibility in conjunction with improved drug dissolution/dispersion.

An oral delivery system for indomethicin engineered from cationic lipid emulsions and silica nanoparticles

We report on a porous silica-lipid hybrid microcapsule (SLH) oral delivery system for indomethacin fabricated from Pickering emulsion templates, where the drug forms an electrostatic complex with cationic lipid present in the oil phase. Dry SLH microcapsules prepared either by spray drying (approximately 1-5 microm) or phase coacervation (20-50 microm) exhibit a specific internal porous matrix structure with pore diameters in the range of 20 to 100 nm. Dissolution studies under sink conditions and in the presence of electrolytes revealed a decreased extent of dissolution; this confirms the lipophilic nature the drug-lipid complex and its location in the oil phase. Orally dosed in-vivo studies in rats showed complete drug absorption and statistically higher fasted state bioavailability (F) (p<0.05) in comparison to aqueous suspensions and o/w submicron emulsions of indomethacin. It is postulated that the SLH microcapsules improve oral absorption via complete solubilisation of drug-lipid electrostatic complexes during enzymatic lipolysis in the GI track.

Nanoparticle Coated Submicron Emulsions: Sustained In-vitro Release and Improved Dermal Delivery of All-trans-retinol

PurposeThe aim of this research is to investigate the dermal delivery of all-trans-retinol from nanoparticle-coated submicron oil-in-water emulsions as a function of the initial emulsifier type, the loading phase of nanoparticles, and the interfacial structure of nanoparticle layers.MethodsThe interfacial structure of emulsions was characterized using freeze-fracture-SEM. In-vitro release and skin penetration of all-trans-retinol were studied using Franz diffusion cells with cellulose acetate membrane, and excised porcine skin. The distribution profile was obtained by horizontal sectioning of the skin using microtome-cryostat and HPLC assay.ResultsThe steady-state flux of all-trans-retinol from silica-coated lecithin emulsions was decreased (up to 90%) and was highly dependent on the initial loading phase of nanoparticles; incorporation from the aqueous phase provided more pronounced sustained release. For oleylamine emulsions, sustained release effect was not affected by initial location of nanoparticles. The skin retention significantly (p ≤ 0.05) increased and was higher for positive oleylamine-stabilised droplets. All-trans-retinol was mainly localized in the epidermis with deeper distribution to viable skin layers in the presence of nanoparticles, yet negligible permeation (∼1% of topically applied dose) through full-thickness skin.ConclusionsSustained release and targeted dermal delivery of all-trans-retinol from oil-in-water emulsions by inclusion of silica nanoparticles is demonstrated.

Silica microcapsules from diatoms as new carrier for delivery of therapeutics

AIM This study explores the use of natural silica-based porous material from diatoms, known as diatomaceous earth, as a drug carrier of therapeutics for implant- and oral-delivery applications. MATERIALS & METHODS To prove this concept, two drugs models were used and investigated: a hydrophobic (indomethacin) and hydrophilic (gentamicin). RESULTS & DISCUSSION Results show the effectiveness of diatom microcapsules for drug-delivery application, showing 14-22 wt% drug loading capacity and sustained drug release over 2 weeks. Two steps in the drug release from diatom structures were observed: the first, rapid release (over 6 h is attributed to the surface deposited drug) and the second, slow and sustained release over 2 weeks with zero order kinetics. CONCLUSION These results confirm that natural material based on diatom silica can be successfully applied as a drug carrier for both oral and implant drug-delivery applications, offering considerable potential to replace existing synthetic nanomaterials.

Silica Materials in Drug Delivery Applications

In this review article we collect and analyse preparation, chemistry and properties of silica materials relevant for drug delivery applications. We review some of the most relevant milestones in the research of silica materials for implantable, oral, intravenous and dermal drug delivery systems. Preparation, chemistry and drug delivery characteristics of fumed silica nanoparticles (oral and dermal delivery route), silica xerogels (implant delivery), mesoporous silica materials (implant and oral delivery) and mesoporous silica spheres (intravenous delivery) with particular emphasis on their role in anticancer therapy and the design of stimuli responsive drug delivery systems are analysed. Recent progress in the research of silica materials for controlled drug delivery, namely, biocompatibility aspects, research on hybrid materials, anticancer and stimuli-responsive mesoporous silica materials are particularly emphasized.

Chemical stability and phase distribution of all-trans-retinol in nanoparticle-coated emulsions

The influence of silica nanoparticle coating on the chemical stability and phase distribution of all-trans-retinol in submicron oil-in-water emulsions is reported. The chemical stability was studied as a function of UVA+UVB irradiation, and storage temperature (4 degrees C, ambient temperature, and 40 degrees C) for emulsions stabilised with lecithin and oleylamine as the initial emulsifier with and without silica nanoparticle layers. The chemical stability of all-trans-retinol was highly dependent on the emulsifier type and charge, with negligible influence of the initial loading phase of silica nanoparticles. A significant stability improvement (approximately 2-fold increase in the half-life of the drug) was observed by nanoparticle incorporation into oleylamine-stabilised droplets (i.e. electrostatically coated), with no considerable effect for partially coated lecithin-stabilised droplets. The chemical stability of all-trans-retinol incorporated into nanoparticle-coated emulsions was well-correlated to the phase distribution of the active agent, and the interfacial structure of emulsions as determined by freeze fracture-SEM. Specifically engineered nanoparticle layers can be used to enhance the chemical stability of active ingredients in emulsion carriers.