EMA Publish Guidance on IV Products in Micellar Systems.

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This paper describes a basic package of information which could be relevant to confirm the sound pharmaceutical development and full characterisation of products of this type.
In particular, this text applies in the following contexts cumulatively:
• medicinal products for intravenous injection or infusion which contain active substances, which have a low aqueous solubility and which are therefore solubilised in an aqueous micellar system1, where the main objective of the development is to solubilise the drug, and not to create a system where special size- or surface-dependent properties of the disperse phase are critical factors in the kinetics and disposition of the drug.
• it is particularly relevant to ‘traditional’ or ‘established’ ‘small molecule, non-polymeric’ surfactants which are sensitive to dilution effects during slow intravenous administration, which are quickly metabolised and which therefore do not have a long halflife in plasma, e.g. polysorbate 80.
Additional considerations may apply to certain polymeric surfactant systems developed to create a ‘delivery system’ in addition to a solubilising system and which have special properties affecting kinetics and distribution in vivo, e.g. very low critical micelle concentration (cmc) or prolonged half-life2 (e.g. innovative block co-polymer surfactants) or those oncology products designed to utilise the EPR effect3 (Enhanced Permeability and Retention). Such systems may indeed be characterised in partby the following tests, but it is likely that additional studies could be needed to fully characterise thesproducts in a relevant way.
In micellar solutions, there exists, in rapid dynamic equilibrium, different species of the drug substance (as aqueous solute or drug substance solubilised in the micelle) and surfactant (as monomer or in micelle form). In this way, the drug substance is maintained in solubilsed form and precipitation is avoided. These drug products are normally presented as stable sterile concentrates (e.g. powder and solvent for concentrate solution for infusion, sterile concentrate and solvent for solution for infusion, concentrate for solution for infusion).
The micellar solution is normally prepared for intravenous infusion by dilution with a large volume of aqueous 0.9% sodium chloride or 5% dextrose injection.
On slow intravenous infusion of the products described by the bullet points above, the micellar solution is deaggregated such that the drug substance is presented to the blood compartment in a ‘free’ rather than ‘solubilised’ form. Nevertheless, it should be acknowledged that these are generalisations and that the specific qualities and attributes of the both the drug substance and micellar and formulation excipients need to be specifically considered on a case by case basis.
Given the complexity of micelle systems, a comprehensive pharmaceutical development is necessary, needing an understanding of what happens to the product after administration. It is acknowledged that this development may involve some tests which are not currently well-reported, and applicants are encouraged to develop and validate such techniques for themselves, particularly those which give information on the likely state of these systems in vivo. Therefore, applicants are advised to discuss the pharmaceutical development with the regulatory authorities and/or to seek Scientific Advice from the CHMP.

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