Enhanced Oral Absorption of Hydrophobic and Hydrophilic Drugs Using Quaternary Ammonium Palmitoyl Glycol Chitosan Nanoparticles

Abstract

As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.

Exploring uptake mechanisms of oral nanomedicines using multimodal nonlinear optical microscopy

“…There are many potential routes of administration for nanoparticle drug delivery, including but not limited to: intravenous, transcutaneous, inhalation, ocular and oral [7,10]. Each of these routes presents a unique set of obstacles that the formulation must overcome before reaching the target site in the body, therefore understanding the underlying uptake and transport mechanisms at the cellular level is of crucial importance to improving the efficacy of nanomedicines.…”

“…One recently developed polymeric nanoparticle that has attracted much interest for enhancing drug uptake by up to an order of magnitude is Quaternary Ammonium Palmitoyl Glycol Chitosan (GCPQ) [7,10,33]. GCPQ can self-assemble into micelles which can encapsulate drugs and is known to facilitate the oral absorption of hydrophobic and hydrophilic drugs; promoting hydrophobic drug transport by a combination of increased dissolution, mucoadhesion to prolong drug residence time and drug transcellular transport [10].…”

“…GCPQ can self-assemble into micelles which can encapsulate drugs and is known to facilitate the oral absorption of hydrophobic and hydrophilic drugs; promoting hydrophobic drug transport by a combination of increased dissolution, mucoadhesion to prolong drug residence time and drug transcellular transport [10]. While low level (2-3% of the dose) liver uptake of GCPQ nanoparticles has been shown on oral administration (Lalatsa et.…”

“…To facilitate palmitoylation, a coupling agent was employed (4-Methylmorpholine, 4-[4,6-Dimethoxy-1,3,5-triazin-2-yl]-4-methylmorpholine chloride !96.0%, Sigma). Purified deuterated palmitoyl chitosan was then quaternised following Domard's method [34] with some minor modifications [7,10]. Deuterated Quaternary Ammonium Palmitoyl Glycol Chitosan (dGCPQ) dGCPQ was characterized as previously described [10] and two molecular weights of were produced for this experiment, dGCPQ50 (Mw ¼ 75.4 kDa, Mw/Mn ¼ 1.32) and dGCPQ6 (Mw ¼ 9.11 kDa, Mw/Mn ¼ 1.06), in order to facilitate investigation into the effect of molecular weight on nanoparticle uptake and distribution.…”

“…For dosing, nanoparticle formulations were reconstituted with water until a concentration of 75 mg mL À1 was achieved. The dGCPQ particles were imaged by transmission electron microscopy (TEM) and analyses by photon correlation spectroscopy (PCS) was also attempted using previously described methods [10]. Orally dosed dispersions of dGCPQ50 presented as more viscous than dGCPQ6 because of their higher molecular weight.…”