Transport mechanisms across the intestinal barrier of novel self-assembling polymeric micelles loading poorly soluble drugs
(2007)
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- Purpose: To investigate mechanisms involved in the permeation through the intestinal barrier of mmPEG750P(CL-co-TMC) [monomethylether poly(ethylene glycol)750 poly(caprolactone-co-trimethylene carbonate)], a self-assembling polymeric surfactant entrapping poorly soluble drugs, upon oral delivery [1]. Methods: Transport of radiolabelled [14C]-mmPEG750P(CL-co-TMC) was investigated in vitro (PAMPA, Caco-2 and Follicle-associated epithelium FAE) and in vivo (rats). Results: After oral delivery, the polymer is absorbed with a bioavailability of 40 % [2]. Passive diffusion of the polymer across lipid bilayers (PAMPA) was demonstrated [3]. A weak rigidification effect by the polymer on lipid membrane was established [3]. The polymer permeated through cell monolayers (Caco-2 & FAE) with Papp of 2.3 x 10-5 and 2.5 x 10 6 cm.sec-1 below and above CMC, respectively [4]. The paracellular route was not involved. Investigation of the endocytic pathways revealed that azithromycin, a fluid-phase endocytosis inhibitor, slowed down the polymeric micelle transport without affecting the unimer transport. Similar results were obtained by depleting ATP cell content. These data demonstrate that unimers passively diffuse while micelles are internalized via fluid-phase endocytosis [4]. The intrinsic permeability of poorly soluble drugs (according to the BCS) was not affected by their entrapment inside polymeric micelles. Polymer and drug seem therefore to cross the intestinal barrier independently of each other. Moreover, it has been assessed that mmPEG750P(CL-co-TMC) does not inhibit the P-gp efflux pump, conversely to some other polymeric micelles [4]. Conclusions: Self-assembling mmPEG750P(CL-co-TMC) micelles containing poorly soluble drugs use both passive diffusion and fluid-phase endocytosis in order to cross the intestinal barrier; free unimers diffusing while micelles follow the endocytic route. [1] L. Ould-Ouali et al., Biodegradable Self-Assembling PEG-Copolymer as Vehicle for Poorly Water-Soluble Drugs, Pharm. Res. 21(9) (2004) 1581-1590. [2] F. Mathot et al., Intestinal uptake and biodistribution of novel self-assembling polymeric micelles after oral administration, J. Control. Release 111 (2006) 47-55. [3] F. Mathot, et al., Passive diffusion of polymeric surfactants across lipid bilayers, J. Control. Release 120 (2007) 79-87. [4] F. Mathot et al., Transport mechanisms of polymeric micelles across the intestinal barrier, J. Control. Release, doi: 10.1016/j.jconrel.2007.09.001, in press.
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Mathot, F. (2007). Transport mechanisms across the intestinal barrier of novel self-assembling polymeric micelles loading poorly soluble drugs. https://hdl.handle.net/2078.5/112073