Establishing a Fundamental Understanding of the Fate of Mixed Micellar Formulations after Intravenous Administration

Prof. Dr. H. Heerklotz1) and L. Naßwetter1), University of Freiburg/Germany

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1.

Prof. Dr. Heiko Heerklotz and Leonie NaßwetterDepartment of Pharmaceutical Technology and Biopharmacy, University of Freiburg, Hermann-Herder-Straße 9, D-79104 Freiburg i. Br./Germany

People involved

Leonie Naßwetter (PhD fellow sponsored by the PRC) - University of Freiburg, Germany (leonie.nasswetter@pharmazie.uni-freiburg.de)

Abstract

Mixed micellar drug delivery systems (MM-DDS) solubilize poorly soluble drugs. They are applicable for oral and parenteral administration, well tolerated, stable upon storage, and easy to produce. MM-DDS have been marketed for decades but despite all the advantages, the number of products has remained quite limited. A reflection paper issued by the EMA1) names several issues that impede a more widespread application. The sensitivity of MM-DDS to transformations after administration is named a key problem. The classic MM-DDS consists of a bile salt and lecithin in an equimolar mixture. Diluting bile salt/lecithin MM causes a release of bile salts into solution and, below a critical micellar concentration (CMC) of the MM, the conversion of the increasingly lipid-rich MM to liposomes. After intravenous injection, the MM-DDS get diluted and exposed to plasma proteins and blood cells. Depending on MM composition and conditions, micelles can persist, transform to liposomes, or vanish all together. Particularly the latter poses the risk of precipitation if the active pharmaceutical ingredient (API) cannot dissolve or bind to plasma proteins quickly enough. MM consisting of surfactants with a very low CMC can persist dilution but may still be affected by plasma proteins or release the API despite their persistence.

The aim of the proposed work is to establish a better, mechanistic and quantitative, physicochemical understanding of MM-DDS before and after administration. This should permit insights into the parameters governing the fate of MM-DDS in vivo. It shall benefit the field of lipid-based drug delivery systems by aiding a more rational, faster formulation development.

Benefit for the community

There is a gap between fundamental, physicochemical theories predicting the behavior of rather simple, well-defined systems and drug delivery research and development, which often has no alternative but to follow very simple, empirical trial-and-error approaches. As mentioned also by the EMA reflection paper on MM-DDS, one reason is the complex, multi-component and heterogeneous nature of most pharmaceutical product candidates. Our general aim is to render this gap smaller or bridge it by developing a better, basic science understanding of systems of increasing complexity. Rational design based on basic science may not replace high-throughput screening, but it may narrow it down and speed up the subsequent development.

Specifically, we think that the classic, lecithin-based MM-DDS may remain superior to alternative micellar formulations. Fully physiological lipids that slow down micelle dissolution or provide a metastable “lifeboat” for the API to safely transfer to plasma proteins may, in fact, outperform polymeric and other long-term stable MM formulations. However, we need to understand much better what is going on.

While not a primary objective here, this understanding shall also benefit the development of MM-DDS for oral delivery.

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References:
1.
European Medicines Agency (2012)
Reflection paper on the pharmaceutical development of intravenous medicinal products containing active substances solubilised in micellar systems
EMA, 44, 1–12
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