Optimizing Solubilization of Lipid Formulations in the GI Tract




With the advent of improved techniques for drug discovery, there has been a transition towards new chemical entities to be hydrophobic and non-polar, which in turn has made solubilization of these entities difficult. Lipid formulations can provide effective solubilization in the dosage form and in vivo. Pharma IQ interviewed René Holm, PhD, Head of Preformulation, H. Lundbeck A/S to learn more:

Pharma IQ: Can you explain how to suitably screen lipid-based formulations with in vitro dispersion and digestion tests in order to gauge performance in vivo?

R Holm: Initially I would start by conducting simple thermodynamic solubility tests to evaluated if a lipid based formulation system could work for the specific compound. Should those studies demonstrate the formulation type to be a feasible approach with the desired dose I would move into in vitro lipolysis testing.

The in vitro lipolysis models are not fully defined nor validated with respect to in vivo performance, but normally I would suggest to evaluate the solubility of the compound in a digested media of long or medium chain triglycerides to see how the two types of lipid perform for the specific compound. Further, quantification of the compound in the pellet and solid state characterization of the pellets are important parameters to evaluate. Frequently the compounds may precipitate as an amorphours form, i.e. it’s dissolution rate may be sufficient fast in vivo.

Pharma IQ: What are some of the advantages of lipid formulations?

R Holm: Lipid based formulation are really exceptionally good for delivering extremely difficult BCS II compounds as their may lead to high and food independent exposures if formulated correctly. Further, soft or had gelatine capsules are distinct from classical tablets, why they may have a marketing potential – think of "the purple pill"

Pharma IQ: Can you give us your findings on In vitro lipolysis assays and their relevance of data to oral absorption?

R Holm: I’ll have some lipolysis data with at the conference to make a short discussion on how and when to use the model, at least as the current thinking is.
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Pharma IQ: What are the effects of surfactants on solubilization in vivo?

R Holm: The right surfactant may be important for the in vivo performance, i) it may lead to a good dispersion of the formulation in the gastro intestinal tract, ii) the solubilising power of the formed micelles upon potential digestion of a lipid based formulation is very dependent upon the used surfactant and iii) different surfactants have different cyrstallisation inhibitory effects in case an oversaturated system is formed as a function of the digestion of the formulations.

Pharma IQ: What have been your findings on the use of long chain glyceride formulations and pro?drugs to promote lymphatic absorption?

R Holm: It normally takes a long chain based lipid formulation to promote lymphatic transport. There is a limited number of methods to evaluate lymphatic transport and there is no knowledge on how these correlate to the human situation. This means that I would not claim to target my formulations for the lymph but rather look at the obtained total espouse and potentially evaluate the lymphatic fraction in rats with the focus of a mechanistic understanding of my formulations performance.

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Join us in Philadelphia March 26 to 28, 2012 for the 6th annual IQPC Improving Solubility conference, and hear more on these and other important trends in the industry. For more information or to register, visit www.improvingsolubility.com