ECTS: 15
Vejleder: René Holm
Background of the project
The administration of drugs via the oral route is preferable due to good patient convenience and hence, better compliance (Mu et all., 2013). Even though the oral route is most favorable, it presents some challenges when administering poorly water-soluble drugs, which an increasing number of new drug candidates are. Many of these drugs are characterized as class II drugs according to the Biopharmaceutics Classification System (BCS), due to their good permeability across the intestinal membrane, but poor aqueous solubility. The aqueous solubility is therefore often the rate limiting step for the intestinal absorption of these compounds, which consequently may lead to a reduced bioavailability if administered in a conventional dosage form.
The use of lipid-based drug delivery systems can be one of the strategies to overcome the problem of poor drug solubility in the gastrointestinal tract after oral administration. Lipids in a pharmaceutical context are excipients with a hydrophobic or at least partly hydrophilic character, such as triglycerides (TG), and excipients with amphiphilic properties such as surfactants. During lipid digestion TG are hydrolyzed to diglycerides, monoglycerides and free fatty acids. The presence of lipids and lipid digestive products in the small intestine stimulates the secretion of bile salts (BS) and phospholipids (PL) from the gall bladder and pancreatic fluids from the pancreas. Together with lipid digestion products the BS and PL are able to form colloidal structures including vesicles and mixed micelles. These colloidal structures help to improve the solubility of the poorly-water soluble drugs in the small intestine.
Lipid-based formulations have typically been based on drug solutions, however, the lack of aqueous solubility does not equal to a high solubility in lipids. A much less but even interesting approach could be the use of lipid suspensions, i.e. a formulation system where the compound is suspended in the lipid excipient or a mixture of excipients. Studies have shown that oral administrations of poorly-water soluble drugs suspended in lipids have a higher bioavailability compared to an aqueous suspension (Bloedow and Hayton, 1976; Carrigan and Bates, 1973; Dahan and Hoffman, 2007). Furthermore, an in vitro study by Kaukonen et al. (2004) showed that drugs with poor aqueous and lipid solubility, administered as lipid suspensions proved beneficial, as the solubilization capacity of the colloidal phases was likely to be greater for lipid suspensions than lipid solutions. Altogether this suggests that lipid suspensions may be an option to increase the bioavailability in the situations where the aqueous solubility and lipid solubility are insufficient (Mu et al., 2013), however, to the best of our knowledge limited information is available about the physical stability of lipid suspensions and also the biopharmaceutical influence of different particle sizes in the suspension.
Problem formulation
What is the influence of particle size on lipid suspension stability and bioavailability?
Methods
The study will involve the selection and characterization of model drugs and lipid excipients, followed by the formulation and evaluation of supersaturated lipid based formulations with various classes lipids.
Analytical techniques including polarized light microscopy (PLM), laser diffraction, X-ray diffraction (XRD) and potential in vivo studies combined with bioanalysis dependent upon the time.
Guidance
There will be scheduled meetings every two weeks where the student is expected to present results, interpretations and what is subsequently planned – and from here a professional discussion is taken. In addition, there will always be the possibility of ad hoc guidance meeting.
References
Mu, H., R. Holm, and A. Mullertz, Lipid-based formulations for oral administration of poorly water-soluble drugs. Int J Pharm, 2013. 453(1): p. 215-24
Bloedow, D.C. and W.L. Hayton, Effects of lipids on bioavailability of sulfisoxazole acetyl, dicumarol, and griseofulvin in rats. J Pharm Sci, 1976. 65(3): p. 328-34.
Carrigan, P.J. and T.R. Bates, Biopharmaceutics of drugs administered in lipid-containing dosage forms. I. GI absorption of griseofulvin from an oil-in-water emulsion in the rat. J Pharm Sci, 1973. 62(9): p. 1476-9.
Dahan, A. and A. Hoffman, The effect of different lipid based formulations on the oral absorption of lipophilic drugs: the ability of in vitro lipolysis and consecutive ex vivo intestinal permeability data to predict in vivo bioavailability in rats. Eur J Pharm Biopharm, 2007. 67(1): p. 96-105.
Kaukonen, A.M., et al., Drug solubilization behavior during in vitro digestion of suspension formulations of poorly water-soluble drugs in triglyceride lipids. Pharm Res, 2004. 21(2): p. 254-60.