Effect of the pulmonary deposition and in vitro permeability on the prediction of plasma levels of inhaled budesonide formulation.

The growing interest in the inhalable pharmaceutical products requires advanced approaches to safe and fast product development, such as in silico tools that can be used for estimating the bioavailability and toxicity of developed formulation. GastroPlus™ is one of the few available software packages for in silico simulation of PBPK profile of inhalable products. It contains a complementary module for calculating the lung deposition, the permeability and the systemic absorption of inhalable products. Experimental values of lung deposition and permeability can also be used. This study aims to assess the efficiency of simulation by applying experimental permeability and deposition values, using budesonide as a model substance. The lung deposition values were obtained from the literature, the lung permeability data were experimentally determined by culturing Calu-3 cells under air-liquid interface and submersed conditions to morphologically resemble bronchial and alveolar epithelial cells, respectively. A two-compartment PK model was created for i.v. administration and used as a background for the in silico simulation of the plasma profile of budesonide after inhalation. The predicted plasma profile was compared with the in vivo data from the literature and the effects of experimental lung deposition and permeability on prediction were assessed. The developed model was significantly improved by using realistic lung deposition data combined with experimental data for peripheral permeability.

Self-emulsification of Lipidic Drug Delivery System in Pure Water and in Concentrated Glycerol Solution.

Self-emulsifying drug delivery systems (SEDDS), often intended for oral delivery, are normally explored in biorelevant aqueous media. The high complexity of these multi-component systems leaves the understanding of self-emulsification poor, hindering formulation rationalization. In this work, we aimed to fill this gap by studying the effects of glycerol on the self-emulsification of a ternary component formulation made of 20% w/w Tween 80, 15% w/w Span 80, and 65% w/w Captex 300 Low C6. The behavior of SEDDS in pure water and a binary mixture of water and glycerol (58.8% w/w) were investigated by optical microscopy, SAXS (small angle X-ray scattering), dynamic light scattering, and surface tension measurements. The presence of glycerol, at 58.8% w/w, altered the self-emulsification behavior by suppressing the formation of lamellar structures observed in the presence of water, reducing the droplet mean diameter from 0.2 to 0.1 µm and changing the mechanism of self-emulsification. As co-surfactant, glycerol may intercalate within the polyoxyethylene chains of the surfactant at the palisade layer, increasing the interface flexibility and expanding it. Since no free water is available at the investigated glycerol concentration, glycerol, which is also a co-solvent, may additionally modify long-range interactions by reducing Van-der-Waals attractions or giving rise to repulsive surface-solvent mediated forces of entropic origin. These effects could be exploited to rationalize SEDDS formulations, widening their use within the pharmaceutical industry.

An in vitro and in silico study of the impact of engineered surface modifications on drug detachment from model carriers.

In silico modeling was used to predict the impact of carrier surface modifications on the in vivo plasma concentration of an active pharmaceutical ingredient (API) and as a tool to support formulation development. In vitro fine particle fraction (FPF) and mass median aerodynamic diameter (MMAD) of salbutamol sulphate delivered from Cyclocaps®, detached from unmodified and surface engineered glass beads were measured using a Next Generation Impactor (NGI). Surface roughness was chosen to classify surface modification/engineering and it was evaluated via scanning electron microscopy (SEM) and image analysis. An in silico pharmacokinetic (PK) model was built and the quality confirmed with available literature data. Plasma profiles were generated combining the PK model with in silico deposition models for salbutamol sulphate released from Cyclocaps®, unmodified and surface engineered glass beads. The increased roughness of the surface of engineered beads resulted in a FPF 1.36 times higher than that of untreated beads. Cmax from the in silico plasma profile of salbutamol released from the surface engineered beads was 1.20 fold higher than that from untreated beads. Increasing the surface roughness was found to augment the amount of drug loading and detaching from the carrier both in vitro and in silico.

Measurements of Deposition, Lung Surface Area and Lung Fluid for Simulation of Inhaled Compounds.

Modern strategies in drug development employ in silico techniques in the design of compounds as well as estimations of pharmacokinetics, pharmacodynamics and toxicity parameters. The quality of the results depends on software algorithm, data library and input data. Compared to simulations of absorption, distribution, metabolism, excretion, and toxicity of oral drug compounds, relatively few studies report predictions of pharmacokinetics and pharmacodynamics of inhaled substances. For calculation of the drug concentration at the absorption site, the pulmonary epithelium, physiological parameters such as lung surface and distribution volume (lung lining fluid) have to be known. These parameters can only be determined by invasive techniques and by postmortem studies. Very different values have been reported in the literature. This review addresses the state of software programs for simulation of orally inhaled substances and focuses on problems in the determination of particle deposition, lung surface and of lung lining fluid. The different surface areas for deposition and for drug absorption are difficult to include directly into the simulations. As drug levels are influenced by multiple parameters the role of single parameters in the simulations cannot be identified easily.

Quality by Design Applied to Ocular Solid Lipid Nanoparticles Containing a Hydrophilic Peptide Prepared via Hot High Pressure Homogeniser.

BACKGROUND: Quality by Design (QbD) is an approach encouraged by regulatory bodies and applied by pharmaceutical industries to improve the quality of the final product. The objective of this paper is to describe via a QbD approach the available knowledge on the formulation and manufacturing of solid lipid nanoparticles (SLN) for ocular applications using hot high pressure homogeniser (HPH). METHODS: The formulation of SLN for the ocular delivery of a hydrophilic peptide is discussed based on a QbD perspective, where the knowledge is gathered from literature references. RESULTS: The Quality Target Product Profile (QTPP) is defined, followed by a description of the Critical Quality Attributes (CQA) and Critical Material Attributes (CMA). After having described the manufacturing process via hot HPH, the Critical Process Parameters (CPP) are discussed along with the possible control strategies. CONCLUSIONS: The QbD approach for the development of a SLN for ocular application described in this review paper can be used as starting point for similar applications.

The effect of composition and gastric conditions on the self-emulsification process of ibuprofen-loaded self-emulsifying drug delivery systems: a microscopic and dynamic gastric model study.

PURPOSE: To investigate the physical processes involved in the emulsification of self-emulsifying drug delivery systems (SEDDSs) and the use of the Dynamic Gastric Model (DGM) as a characterisation tool. METHODS: SEDDSs based on soybean oil, Tween 80, Span 80 and ibuprofen were prepared and their equilibrium phase diagrams established. The emulsification behaviour in a range of media was studied using polarised light microscopy and particle sizing. The behaviour of the SEDDSs in the DGM and conventional testing equipment was assessed. RESULTS: A range of liquid crystalline mesophases was observed, enhanced in the presence of the drug. Polarised light microscopy showed different emulsification processes in the presence and absence of the drug, which was also manifest in different droplet sizes. The droplet size distribution varied between the DGM and the USP II dissolution apparatus. CONCLUSIONS: The model SEDDS displays complex liquid crystalline behaviour which may be intimately involved in the emulsification process, which in turn may alter particle size on emulsification, although there remains a question as to the in vivo significance of this effect. Furthermore, we demonstrate that the DGM represents a very promising new method of assessing the biological fate of SEDDSs.

Differences between eccentric and rotary tablet machines in the evaluation of powder densification behaviour.

Differences in the dynamics of powder densification between eccentric and rotary machine were pointed out by compressing at different compression pressures microcrystalline cellulose, lactose monohydrate and dicalcium phosphate dihydrate and recovering the corresponding stress/strain data in both machines equipped to monitor punches displacement and compression forces. Heckel plots were then obtained from these stress/strain data. Curves obtained in the rotary machine possess a narrower zone of linearity for the calculation of P(Y) and D(A). The effect of the different compression mechanism of the rotary machine on the shape of the Heckel plot is more noticeable in a non-deforming material such as dicalcium phosphate. The effect of the longer dwell time of the rotary machine on the porosity reduction occurring after the maximum pressure has been reached, is more noticeable in a ductile material such as microcrystalline cellulose. Heckel parameters obtained in the rotary press are in some cases different from those recovered in the eccentric machine because of the longer dwell time, machine deflection and punch tilting occurring in the rotary machine, although theoretically they could better describe the material densification in a high speed production rotary machine.