Relative bioavailability enhancement of simvastatin via dry emulsion systems: Comparison of spray drying and fluid bed layering technology.

Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3% vs 71.5%), encapsulation efficiency (80.0% vs 68.4%), relative one month product stability (93.8% vs 85.5%), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115% relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms.

The Potential of Macroporous Silica-Nanocrystalline Cellulose Combination for Formulating Dry Emulsion Systems with Improved Flow Properties: A DoE Study.

The objective of this study was to explore the possible use of a new combination of two excipients, i.e., nanocrystalline cellulose (NCC) and macroporous silica (MS), as matrix materials for the compounding of dry emulsion systems and the effects these two excipients have on the characteristics of dry emulsion powders produced by the spray drying process. A previously developed liquid O/W nanoemulsion, comprised of simvastatin, 1-oleoyl-rac-glycerol, Miglyol 812 and Tween 20, was employed. In order to comprehend the effects that these two matrix formers have on the spray drying process and on dry emulsion powder characteristics, alone and in combination, a DoE (Design of Experiment) approach was used. The physicochemical properties of dry emulsion samples were characterised by atomic force microscopy, scanning electron microscopy, mercury intrusion porosimetry, energy-dispersive X-ray spectroscopy and laser diffraction analysis. Additionally, total release and dissolution experiments were performed to assess drug release from multiple formulations. It was found that the macroporous silica matrix drastically improved flow properties of dry emulsion powders; however, it partially trapped the oil-drug mixture inside the pores and hindered complete release. NCC showed its potential to reduce oil entrapment in MS, but because of its rod-shaped particles deposited on the MS surface, powder flowability was deteriorated.

Preparation, Physicochemical Characterisation and DoE Optimisation of a Spray-Dried Dry Emulsion Platform for Delivery of a Poorly Soluble Drug, Simvastatin.

In the presented study, insight into the development and optimisation of the dry emulsion formulation and spray drying process is provided. The aim was to facilitate the dissolution of the poorly soluble, highly lipophilic drug, simvastatin, by forming spray-dried dry emulsion particles having adequate powder flow properties, while assuring sufficient drug content. Simvastatin and a mixture of caprylic, capric triglyceride and 1-oleoyl-rac-glycerol were employed as a model drug and solubilising oils, respectively. A matrix of the dry emulsions was composed at a fixed ratio mixture of mannitol and HPMC. Tween 20 was used in low amounts as the primary emulsion stabiliser. To facilitate process optimisation, a DoE surface response design was used to study the influence of formulation and process parameters on the particle size distribution, powder bulk properties, emulsion reconstitution ability, drug stability and process yield of spray-dried products. Two-fluid nozzle geometry was identified, studied and confirmed to be important for most product critical quality attributes. Models obtained after the study showed acceptable coefficients of determination and provided good insight in the relationship governing the process and product characteristics. Five model optimised products showed adequate process yield, suitable particle size distribution, good reconstitution ability and improved dissolution profile, when compared to a non-lipid-based tablet and the pure drug. However, the obtained dry emulsion powders exhibited poor flow character according to the Carr index. The optimised product was further analysed with NMR during lipolysis to gain insight into the species formed during digestion and the kinetics of their formation.

A redispersible dry emulsion system with simvastatin prepared via fluid bed layering as a means of dissolution enhancement of a lipophilic drug.

The purpose of the study was to develop a redispersible dry emulsion, containing a lipophilic, poorly water soluble model drug simvastatin, by employing fluid bed coating technology. The presented dry emulsion manufacturing approach produces pellets in a way, where a layer of the dry emulsion is applied to a neutral core. In the preliminary formulation development phase 1-oleoyl-rac-glycerol was chosen as the oily lipid phase, based on the high drug solubility and potential bioavailability enhancement capability. Mannitol, HPMC and Tween 20 were selected as the solid carriers and surfactant, respectively. The design of experiments, specifically the mixture design approach, was used to obtain the optimal formulation composition. The emulsion reconstitution ability and stability were the main responses, used as the decisive parameters for formulation optimisation. Optimised formulations showed narrow droplet size distribution upon reconstitution, high stability, suitable drug loading and enhanced dissolution profile, compared to a non-lipid based tablet and the pure drug. The scanning electron microscopy, Raman spectroscopy and image analysis disclosed a uniform morphology of the applied layer with separated droplets with simvastatin and uniform size distribution and a circular shape of coated pellets. The study represents the proof of concept of designing redispersible dry emulsions using a fluid bed layering approach.