Publications by authors named "Agnes Taillardat-Bertschinger"

5 Publications

  • Page 1 of 1

Use of in vitro lipid digestion data to explain the in vivo performance of triglyceride-based oral lipid formulations of poorly water-soluble drugs: studies with halofantrine.

J Pharm Sci 2004 May;93(5):1110-21

Department of Pharmaceutics, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.

The relative oral bioavailability (BA) of halofantrine base (Hf) was assessed in male beagle dogs after administration of a medium chain triglyceride (MCT), a long chain triglyceride (LCT), and a blended LCT/MCT lipid solution formulation of Hf (Study 1) and after administration of suspensions of Hf base and Hf. HCl in LCT (Study 2). A series of in vitro lipid digestion experiments were also performed in an attempt to clarify the data obtained. In vitro drug solubilization profiles were markedly dependent on the mass of lipid employed in lipid digestion experiments. At high lipid masses ( approximately 25 mg triglyceride/mL), MCT formulations gave maximal benefit, whereas at low lipid concentrations ( approximately 5 mg triglyceride/mL), LCT formulations provided improved solubilization capacity. The in vitro digestion and solubilization data at lower lipid masses were consistent with the in vivo data where the BA of Hf after oral administration of the LCT solution > LCT/MCT blend > MCT solution. The second BA study showed similar, albeit variable, exposure after oral administration of a suspension of Hf base or Hf. HCl in LCT and this trend was broadly consistent with in vitro results. This study demonstrates the potential utility of in vitro digestion models to assess and rank order the in vivo performance of lipid solution and suspension formulations of poorly water-soluble drugs such as Hf.
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http://dx.doi.org/10.1002/jps.20039DOI Listing
May 2004

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant.

J Pharm Sci 2003 Nov;92(11):2217-28

Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.

Recent studies in a conscious dog model demonstrated intestinal lymphatic transport to be a significant contributor to the bioavailability of the highly lipid-soluble free-base of halofantrine (Hf), and surprisingly, also the poorly lipid-soluble hydrochloride salt (Hf. HCl). Partial conversion of solubilized Hf. HCl to Hf base within the intestinal lumen prior to the lymphatic uptake seemed to be the most likely explanation for these results. This hypothesis was supported by studies exploring the partitioning behavior of Hf. HCl between soybean oil (SBO) and aqueous micellar solutions containing different ionic and nonionic surfactants. Mixed micelles prepared from sodium taurodeoxycholate (NaTC) and lecithin (PC) were chosen to represent fed-state intestinal fluids. The apparent ionization constants derived from the partitioning versus pH profiles showed marked shifts when compared with the likely aqueous pK(a) value. In the present paper, the apparent pK(a) values of Hf in aqueous micellar phases, without a coexisting oil phase, were investigated to further probe the mechanisms underlying the effect of micellar media on the apparent ionization equilibrium, and subsequently, on its partitioning behavior in the triphasic systems. Another aim of this study was to further evaluate the aqueous pK(a) value of Hf. The results indicate that the aqueous pK(a) of Hf is most probably in the range approximately 8-9, and that the ionization equilibrium is highly dependent on the solution environment. For example, marked pK(a) shifts of several units were observed for Hf in the presence of different micellar species and SBO. The apparent ionization equilibrium depends not only on interaction of Hf with the micelles, but also on its partitioning into the oil phase.
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http://dx.doi.org/10.1002/jps.10479DOI Listing
November 2003

Immobilized artificial membrane HPLC in drug research.

J Med Chem 2003 Feb;46(5):655-65

Institut de Chimie Thérapeutique, Section de Pharmacie, Université de Lausanne, CH-1015 Lausanne, Switzerland.

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http://dx.doi.org/10.1021/jm020265jDOI Listing
February 2003

Molecular factors influencing retention on immobilized artifical membranes (IAM) compared to partitioning in liposomes and n-octanol.

Pharm Res 2002 Jun;19(6):729-37

Institut de Chimie, Thérapeutique, Section de Pharmacie, Université de Lausanne, Switzerland.

Purpose: To assess the effect of molecular factors influencing retention on immobilized artificial membrane (IAM) high-performance liquid chromatography columns compared to liposomal partitioning and traditional n-octanol/water partition coefficients.

Methods: IAM capacity factors were measured at pH 7.0 on an IAM.PC.DD2 stationary phase. Liposomal partitioning at pH 7.0 and n-octanol/water partition coefficients were measured using the pH metric method. Partitioning in egg-phosphatidylcholine (PhC) liposomes was also measured by equilibrium dialysis for a series of beta-blockers.

Results: For the ionized beta-blockers, potentiometry and equilibrium dialysis yielded consistent partitioning data. For relatively large bases. IAM retention correlated well with PhC liposome partitioning, hydrophobic forces being mainly involved. For more hydrophilic compounds and for heterogeneous solutes, in contrast, the balance between electrostatic and hydrophobic interactions was not the same in the two systems. Hydrogen bonding, an important factor in liposomes partitioning, played only a minor role in IAM retention.

Conclusions: Partitioning in immobilized artificial membranes depends on size, hydrophobicity, and charge. When hydrophobic interactions dominate retention, IAM capacity factors are well correlated with liposomal partitioning. On the contary, for hydrophilic solutes, the two systems do not yield the same information and are not interchangeable.
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http://dx.doi.org/10.1023/a:1016156927420DOI Listing
June 2002

The relative partitioning of neutral and ionised compounds in sodium dodecyl sulfate micelles measured by micellar electrokinetic capillary chromatography.

Eur J Pharm Sci 2002 Mar;15(2):225-34

Institut de Chimie Thérapeutique, Section de Pharmacié Universitéde Lausanne, CH-1015 Lausanne, Switzerland.

The rational use of micelles in quantitative structure-activity and quantitative structure-permeation relationships implies a good knowledge of the nature of recognition forces underlying solute-micelle association. The aims of this study were to unravel the intermolecular interaction forces responsible for the association of neutral and ionised compounds with negatively charged sodium dodecyl sulfate (SDS) micelles, using micellar electrokinetic capillary chromatography (MEKC). The MEKC capacity factors (log k(MEKC)) of 36 neutral model solutes were analysed by linear solvation free-energy relationships (LSERs). The results indicate that the size and H-bond acceptor strength of solutes are mainly responsible for their MEKC retention. Compared to n-octanol, the SDS micelles are more cohesive and stronger H-bond donors. Strong attractive electrostatic interactions govern solute-micelle association for positively charged compounds and micelles of the opposite charge, whereas repulsive electrostatic interactions occur between negatively charged solutes and micelles of the same charge. The capacity factors measured for the ionised forms of the acids and bases under study (log k(MEKC)(I)) indeed lie on two distinct plateau, about -1.0 for the former and about 2.0 for the latter and depend on the solute's charge more than on its chemical structure. Thus, the derivation of a diff(log k(MEKC)(N-I)) value, defined as the difference between the log k(MEKC) values of the neutral and charged species, strongly correlates with the respective log k(MEKC)(N) value and does not afford additional information.
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http://dx.doi.org/10.1016/s0928-0987(02)00004-0DOI Listing
March 2002
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