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Thursday, 28 February 2013 14:25

Paradigm Shift in Lipid-Based Drug Delivery?

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Typical experimental set-up for in vitro lipolysis Typical experimental set-up for in vitro lipolysis

Lipid-based drug delivery systems have become a popular approach for the delivery of poorly water-soluble drugs. The limitations associated with this formulation strategy have been the drug solubility in the delivery systems and the lack of characterization techniques predicting the in vivo performance. Solid state characterization of the in vitro digestion products has provided new insights that scrutinize current paradigms in the development of lipid-based drug delivery systems.

Lipid-based drug delivery

Lipid-based drug delivery systems take advantage of poorly water-soluble drugs being presented in the dissolved state, thereby avoiding the often limiting dissolution rate of solid, crystalline drugs [1]. The current development of lipid-based delivery systems, in particular self-nanoemulsifying drug delivery systems (SNEDDS), involves the assessment of drug solubility in excipients and mixtures [2]. The construction of a phase diagram and dispersion of water-free SNEDDS pre-concentrates help identify mixtures capable of generating nano-emulsions upon contact with aqueous medium under gentle stirring [3]. Thereafter, the identified SNEDDS are subjected to dynamic in vitro lipolysis. In essence, the in vitro digestion model simulates the physiological degradation of lipids by pancreatic lipase and co-lipase in the gastrointestinal tract (Fig. 1a). Samples collected during in vitro lipolysis are quantified for drug in the aqueous phase and in the pellet obtained after a centrifugation step (Fig. 1b).

Until recently the common notion was that only the drug solubilized in the aqueous phase was available for absorption. Conversely, the presence of precipitated drug in the pellet has been considered as undesired in the development of SNEDDS. The rationale behind this notion was that the limited dissolution rate of solid compound would be re-introduced with precipitation, compensating the initial advantage of the dissolved drug present in the pre-concentrate [5-7]. However, this implies that the drug precipitates in a crystalline form. That this is not necessarily the case has been shown by Sassene et al. who investigated the isolated pellet obtained after in vitro lipolysis by X-ray powder diffraction (XRPD) and polarizing light microscopy (PLM) [8]. In fact, the authors observed that cinnarizine precipitated in an amorphous form. Moreover, the dissolution rate of the precipitated cinnarizine was substantially increased compared with the crystalline starting material. So far the possible implications of this finding for the absorption in vivo were not known.

Supersaturated SNEDDS

Pre-concentrates loaded with amounts of simvastatin exceeding the drugs' solubility in the pre-concentrates (i.e. supersaturated SNEDDS, or super-SNEDDS, Fig. 2) were developed and subjected to dynamic in vitro lipolysis according to the accepted digestion protocol established in Copenhagen [9, 10].

Precipitation of simvastatin during in vitro lipolysis was evident and, as seen for cinnarizine, XRPD analyses revealed that the precipitate contained amorphous simvastatin (Fig. 3). Following administration of the super-SNEDDS to beagle dogs the bioavailability of simvastatin increased significantly to 1.8-fold of the bioavailability of dose-equivalent conventional SNEDDS [11]. Importantly, improved bioavailability was observed despite drug precipitation in vitro. It was speculated that the rapid dissolution rate of amorphous simvastatin was able to contribute to the overall bioavailability of the drug. This hypothesis was supported by an increased half-life of elimination calculated for super-SNEDDS compared to conventional SNEDDS (2.3 hours and 1.4 hours, respectively).

In another study an amorphous precipitate was also found for super-SNEDDS containing the antimalarial drug halofantrine [12]. The precipitation during in vitro lipolysis was not reflected in a reduced bioavailability. These results emphasize the need to investigate the solid state properties of precipitates generated during in vitro lipolysis.

Implications of the study

The studies have shown the feasibility of super-SNEDDS containing increased drug loads without compromising bioavailability. Moreover, previous concerns about drug precipitation need to be revised. The use of solid-state techniques has proven complementary to in vitro lipolysis and should be used routinely for the characterization of lipid-based drug delivery systems.


[1] A. Dahan, A. Hoffmann, 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., 67 (2007) 96-105, doi:10.1016/j.ejpb.2007.01.017.

[2] T. Gershanik, S. Benita, Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs, Eur. J. Pharm. Biopharm., 50 (2000) 179-188, doi:10.1016/S0939-6411(00)00089-8.

[3] C.W. Pouton, Lipid formulations for oral administration of drugs: Non-emulsifying, self-emulsifying and 'self-microemulsifying'  drug delivery systems, Eur. J. Pharm. Sci., 11 (2000) S93-S98, doi:10.1016/S0928-0987(00)00167-6

[4] N. Thomas, R. Holm, T. Rades, A. Müllertz, Characterising lipid lipolysis and its implication in lipid-based formulation development, The AAPS Journal, 14 (2012) 860-871, doi:10.1208/s12248-012-9398-6.

[5] D.B. Warren, H. Benameur, C.J.H. Porter, C.W. Pouton, Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility, J. Drug Target., 18 (2011) 704-731, doi:10.3109/1061186X.2010.525652.

[6] C.J.H. Porter, N.L. Trevaskis, W.N. Charman, Lipids and lipid-based formulations: Optimizing the oral delivery of lipophilic drugs, Nat. Rev. Drug Discovery, 6 (2007) 231-248, doi:10.1038/nrd2197.

[7] C.J.H. Porter, W.N. Charman, In vitro assessment of oral lipid based formulations, Adv. Drug Delivery. Rev., 50 (2001) S127-S147, doi:10.1016/S0169-409X(01)00182-X

[8] P.J. Sassene, M.M. Knopp, J.Z. Hesselkilde, V. Koradia, A. Larsen, T. Rades, A. Müllertz, Precipitation of a poorly soluble model drug during in vitro lipolysis: Characterization and dissolution of the precipitate, J. Pharm. Sci., 99 (2010) 4982-4991, doi:10.1002/jps.22226.

[9] N.H. Zangenberg, A. Müllertz, H.G. Kristensen, L. Hovgaard, A dynamic in vitro lipolysis model: I.Controlling the rate of lipolysis by continuous addition of calcium, Eur. J. Pharm. Sci., 14 (2001) 115-122, doi:10.1016/S0928-0987(01)00169-5.

[10] N.H. Zangenberg, A. Müllertz, H.G. Kristensen, L. Hovgaard, A dynamic in vitro lipolysis model: II: Evaluation of the model, Eur. J. Pharm. Sci., 14 (2001) 237-244, doi:10.1016/S0928-0987(01)00182-8

[11] N. Thomas, R. Holm, M. Garmer, J.J. Karlsson, A. Müllertz, T. Rades, Supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS) enhance the bioavailability of the poorly water-soluble drug simvastatin in dogs, The AAPS Journal, 15 (2013) 219-227, doi:10.1208/s12248-012-9433-7.

[12] N. Thomas, R. Holm, A. Müllertz, T. Rades, In vitro and in vivo performance of novel supersaturated self-nanoemulsifying drug delivery systems (super-SNEDDS), J. Controlled Release, 160 (2012) 25-32, doi:10.1016/j.jconrel.2012.02.027.

PSSRC Facilities

The group of Prof Thomas Rades in Copenhagen has extensive experience in solid state characterization of drugs. The group's knowledge has recently been complemented by the expertise of A/Prof Anette Müllertz in the field of biopharmaceutics of lipid-based drug delivery systems. The combination of physical chemistry with the formulation of novel dosage forms underpins the group's translational approach to research. Micro-dissolution testing, in vitro lipolysis, and access to animal facilities complete solid state equipment such as high-throughput stage XRPD.

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