Proliposome Powders for the Generation of Liposomes: the Influence of Carbohydrate Carrier and Separation Conditions on Crystallinity and Entrapment of a Model Antiasthma Steroid

Formulation effects on the entrapment of beclometasone dipropionate (BDP) in liposomes generated by hydration of proliposomes were studied, using the high-density dispersion medium deuterium oxide in comparison to deionized water (DW). Proliposomes incorporating BDP (2 mol% of the lipid phase consisting of soya phosphatidylcholine (SPC) and cholesterol; 1:1) were manufactured, using lactose monohydrate (LMH), sorbitol or D-mannitol as carbohydrate carriers (1:5 w/w lipid to carrier). Following hydration of proliposomes, separation of BDP-entrapped liposomes from the unentrapped (free) BDP at an optimized centrifugation duration of 90 min and a centrifugation force of 15,500g were identified. The dispersion medium was found to have a major influence on separation of BDP-entrapped liposomes from the unentrapped drug. Entrapment efficiency values were higher than 95% as estimated when DW was used. By contrast, the entrapment efficiency was 19.69 ± 5.88, 28.78 ± 4.69 and 34.84 ± 3.62% upon using D2O as a dispersion medium (for LMH-, sorbitol- and D-mannitol-based proliposomes, respectively). The similarity in size of liposomes and BDP crystals was found to be responsible for co-sedimentation of liposomes and free BDP crystals upon centrifugation in DW, giving rise to the falsely high entrapment values estimated. This was remedied by the use of D2O as confirmed by light microscopy, nuclear magnetic resonance ((1)HNMR), X-ray diffraction (XRD) and entrapment studies. This study showed that carrier type has a significant influence on the entrapment of BDP in liposomes generated from proliposomes, and using D2O is essential for accurate determination of steroid entrapment in the vesicles

A geometrical approach to the PKPD modelling of inhaled bronchodilators

The present work introduces a new method to model the pharmacokinetics and pharmacodynamics (PKPD) of an inhaled dose of bronchodilator. This method provides an alternative approach to classic compartmental representations or computational fluid dynamics. A five compartment lung model comprising the upper airways, bronchial tree mucosa, bronchial muscles, alveoli and plasma has been modified to take into account anatomical, geometrical features such as bronchial branching and smooth muscle distribution. Many anatomical and physiological features of the bronchial tree depend, as a first approximation, on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which work together in determining the local response to the inhaled dose; integrating these local responses over the whole bronchial tree allows an approximation of total broncodilator response, particularly with respect to airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part substitutes a simplified geometrical and functional description of the bronchial tree for the typical PD models of effect, leading to the direct computation of the approximate FEV1. In the present work the construction of the model is detailed, and literature data are used to derive the anatomical approximations used. Simulation of two asthmatic subjects is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and effect of an inhaled dose of bronchodilator. The relevance of formulation diffusivity on therapeutic efficacy is discussed and conclusions regarding the applicability of the model in interpreting single-subject and population experiments are drawn