Monash University
4705594_monash_158656.pdf (26.4 MB)

In-vitro evaluation of factors that affect the performance of lipid-based drug delivery systems

Download (26.4 MB)
posted on 2017-03-01, 05:07 authored by Devraj, Ravi
Development of formulations containing poorly water-soluble drugs (PWSDS) incorporated in lipid-based drug delivery systems (LBDDS) poses a great challenge to scientists (both, at academia and industry) across the globe. To date there are no standard in vitro protocols for formulation scientists which predict their performance in-vivo. This thesis addresses various key issues that are important in development of LBDDS. Chapter 1 sets the work in context by reviewing the published literature. Work carried out in Chapter 2: addressed the issue of "non-completion of lipolysis" as this has been attributed by many authors to be one factor that limits the use of in vitro digestion tests, and limits the degree of in vitro- in vivo correlation (IVIVC) that can be achieved. This study has investigated the effect of increasing calcium and bile salt (BS) concentration on the in vitro digestion of a long-chain triglyceride (soybean oil) in order to understand how these factors will affect the solubility of poorly water-soluble drugs delivered in lipid vehicles. The solubility of two model poorly-water soluble drugs (fenofibrate and Danazol ) in the aqueous phase digests obtained via digestion of a long-chain triglyceride, LCT (soybean oil), increased significantly in each of the conditions (fasting and fed), by comparison with respective controls, irrespective of the molar concentration of calcium employed in the media. Systems containing 40 mM calcium concentration (high levels of calcium used in the study) when compared to that containing 5 mM calcium, had a lower capacity for solubilization of either drug in aqueous phases after digestion, in both fed and fasting conditions. This was thought to be attributed to the formation of large amount of insoluble calcium soaps which were observed (as a precipitate) during our experiments. Formation of calcium soaps has been reported elsewhere (MacGregor et al., 1997, Hu et al., 2010, Zangenberg et al., 2001a). Soap formation may occur upon an interaction of calcium with the bile salt component of the solubilized species (Fatouros et al., 2009) when calcium is in excess. In conclusion, from our data, although high calcium concentration may prove beneficial with respect to bringing the lipolysis to completion, the addition of calcium ions should be conducted with caution because it interferes with the solubilisation of poorly water soluble drugs. Therefore, it can be anticpated that high concentrations of calcium in the system during in vitro lipolysis will result in a poor model for correlation in vivo. A second focus of this thesis is discussed in Chapter 3: describes an investigation of a series of closely related SEDDS viz. Type II and Type IIIA as defined by the Lipid Formulation Classification System (LFCS) (Pouton, 2006b, Pouton, 2000b), all of which contained fenofibrate as model drug. A variety of factors influencing the performance of these systems during in vitro dispersion and digestion tests were studied. The results were interpreted based on the level/extent of supersaturation attained during these in vitro processes to gain an insight into formulation performance and to establish guidelines for formulators. Emphasis was placed on the effects of lipid composition (long-chain vs. medium-chain) and the surfactant type (hydrophilic vs. lipophilic) on the solubilization properties of these formulations during dispersion and digestion. Despite generating diverse formulations by altering the nature of oils and blends of oils which made up the lipid component, the dispersion results showed that Type II formulations (containing Tween 85, a lipophilic surfactant) always supported drug in solubilized form (100%) for at least 4 days (in the absence of digestion), Type III formulations on the other hand were unable to maintain all of the drug in solubilized form on dispersion, though they maintained greater than 70% of drug in solubilized form for 4 days. Most of the loss of drug in the form of precipitate occurred after the initial 4 hours.. The degree of supersaturation generated during dispersion was estimated by determining the solubility of fenofibrate in dispersed formulations. Type III formulations were supersaturated and drug was maintained in this meta-stable state for up to 4 hours and after which drug was lost to some extent in the form of precipitate. Type II systems were not supersaturated. Considering the transit time of all the formulations in the intestine was expected to be 3-4 hours, clearly Type II and Type IIIA formulations, prior to digestion, met the primary performance requirement for drugs meant to be administered orally. After dynamic digestion studies, the ability of each of these formulations (Type II and Type IIIA) to maintain drug in a solubilized state was highly dependent on both, the lipid composition and the choice of surfactant. For example, medium-chain lipids exhibited very good solubilizing properties in the dispersed state, but resulted in a higher degree of supersaturation on digestion, leading to higher susceptibility to drug precipitation. Results from the digestion studies showed that replacing long-chain lipids with medium-chain lipids in Type II and IIIA LBDDS is likely to promote supersaturation on digestion. Utilization of long-chain instead of medium-chain triglycerides in LBDDS prevents the development of sudden and higher degrees of supersaturation and consequently reduces the risk of precipitation (Kossena et al., 2003a). The present digestion studies in Chapter 3: have indicated that this approach alone will not work for all drugs. For fenofibrate, various other strategies needs to be explored to prevent drug precipitation from formulations, such as lowering the drug load (Williams et al., 2012a), employing polymer-based precipitation inhibitors (Anby et al., 2012c), and/or by the careful selection of surfactants (Cuine et al., 2008a). Without careful consideration of drug loading and choice of surfactant in Type II/IIIA medium-chain lipid formulations, there is a high risk of precipitation of drug in the intestine. Critical to the utility of self-emulsifying drug delivery systems (SEDDS) in oral bioavailability enhancement is a capacity to both generate and maintain supersaturation following dispersion and digestion processes in the gastro-intestinal tract. Studies carried out in Chapter 4: investigated the effect of drug-type and drug loading on supersaturation in digested SEDDS consisting of long-chain lipids and a range of chemically diverse nonionic surfactants. Supersaturation is described in terms of the maximum supersaturation ratio (SRM) attained on initiation of digestion. Calculated from the maximum attainable concentration in the test (a function of drug loading) and the drug solubility in the colloidal phases formed by digestion of the SEDDS, SRM defines the maximum supersaturation pressure in the digestion experiment and proves to be a remarkable indicator of performance across a range of formulations. SEDDS containing danazol showed little evidence of precipitation on digestion, even at drug loads approaching saturation in the formulation. In contrast, fenofibrate extensively crystallized on digestion of the same SEDDS. The performance differential of danazol and fenofibrate-containing SEDDS however could be rationalized by the much higher SRM values generated by fenofibrate. And on further analysis of formulations containing various fenofibrate loads, a threshold SRM of ~2.6 was identified in 6 of the 7 SEDDS above which supersaturation could not be maintained. Near this threshold, performance became increasingly variable and most sensitive to surfactant-type, though overall, the SRM attained on digestion was most predictive of performance.


Campus location


Principal supervisor

Colin Pouton

Year of Award


Department, School or Centre

Pharmaceutical Biology

Degree Type



Faculty of Pharmacy and Pharmaceutical Sciences

Usage metrics

    Faculty of Pharmacy and Pharmaceutical Sciences Theses


    No categories selected


    Ref. manager