Abstract
Triglycerides (TG) are one of the most common excipients used in oral lipid-based formulations. The chain length of the TG plays an important role in the oral bioavailability of the co-administered drug. Fatty acid (FA) chain-length specificity of porcine pancreatic lipase was studied by means of an in vitro lipolysis model under bio-relevant conditions at pH 6.80. In order to determine the total extent of lipolysis, back-titration experiments at pH 11.50 were performed. Results suggest that there is a specific chain length range (C2–C8) for which pancreatic lipase shows higher activity. This specificity could result from a combination of physicochemical properties of TGs, 2-monoglycerides (2-MGs) and FAs, namely the droplet size of the TGs, the solubility of 2-MGs within mixed micelles, and the relative stability of the FAs as leaving groups in the hydrolysis reaction. During experimentation, it was evident that an optimisation of lipolysis conditions was needed for tighter control over pH levels so as to better mimic in vivo conditions. 1M NaOH, 3.5mL/min maximum dosing rate, and 3μL/min minimum dosing rate were the optimised set of conditions that allowed better pH control, as well as the differentiation of the lipolysis of different lipid loads.
Highlights
Since the advent of high throughput techniques and development of combinatorial chemistry in the early 1990s, the number of potential drug candidates has significantly increased [1]
Maleate, sodium taurocholate hydrate (98% w/w), L-a-lecithin ($60% pure L-a-phosphatidylcholine, from egg yolk), pancreatin powder from porcine pancreas (8 Â United States Pharmacopeia specifications activity), glyceryl triacetate (P99.9%), glyceryl trioctanoate (P99%), and peanut oil were all purchased from Sigma– Aldrich (Dorset, UK)
Regardless of carbon chain length, all pH–time profiles showed an initial drop of pH as a result of the delay between the pH-stat titrator detecting the first ionised Fatty acid (FA) and the subsequent addition of NaOH solution for the titration
Summary
Since the advent of high throughput techniques and development of combinatorial chemistry in the early 1990s, the number of potential drug candidates has significantly increased [1]. Physical properties of the new chemical entities have changed towards higher molecular weight, higher melting point, increased H-bonding capacity, and increased lipophilicity, leading to poorer solubility in aqueous media [2]. It was estimated that in 2005 40% of the top 200 oral marketed oral drugs were poorly water-soluble [3]. Exhibited poor aqueous solubility [4]. Since low aqueous solubility can be associated with poor absorption and poor bioavailability, it is clear that one of the main challenges for pharmaceutical scientists is finding novel formulations capable of improving the intraluminal solubility of poorly soluble drugs
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