Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs

Abstract

The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by 1 H NMR with a degree of substitution of Cur of 4.52-10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size ($200 nm). In situ single-pass perfusion studies in rats showed that both CsA + CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher K a and P eff than CsA suspension in the duodenum and jejunum segments (p5 0.01), which was comparable to verapamil coperfusion effect. Similarly, CsA + CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.

A Hybrid System for Magnetic Hyperthermia and Drug Delivery: SPION Functionalized by Curcumin Conjugate

“…Due to its hydrophobic character and low solubility in aqueous media, curcumin has been incorporated in various delivery systems to increase its bioavailability [19,20,21]. Polymeric conjugates have also been reported to effectively deliver curcumin [22,23]. Recently, a targeted anti-cancer was proposed, in which magnetic heating generated by gadolinium-doped nickel ferrite nanoparticles was used to trigger the release of curcumin from the thermosensitive polymeric matrix composed of amine-terminated poly-N-isopropylacrylamide and chitosan [24].…”

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

“…These include micelles, liposomes, emulsions, SMEDDS, SNEDDS, SLNs, NLCs, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. These drug delivery systems can combine the P-gp inhibitory effects of their components and the ability to bypass P-gp efflux by themselves [ 43 , 44 ]. Two major approaches are frequently used for the incorporation of P-gp inhibitors: (i) co-administration of a small drug molecule as a specific P-gp inhibitor or a natural constituent and (ii) co-encapsulation of both P-gp substrates and P-gp inhibitors in a drug delivery system [ 30 ].…”

“…Two major approaches are frequently used for the incorporation of P-gp inhibitors: (i) co-administration of a small drug molecule as a specific P-gp inhibitor or a natural constituent and (ii) co-encapsulation of both P-gp substrates and P-gp inhibitors in a drug delivery system [ 30 ]. In the latter case, the P-gp inhibitor can be a small drug molecule, natural constituent, pharmaceutical excipient, or combinations of these [ 44 , 133 , 134 ].…”

“…These include micelles, emulsions, liposomes, microspheres, solid lipid nanoparticles, polymeric nanoparticles, dendrimers, and solid dispersions [ 41 , 42 ]. In addition to the P-gp inhibitory effect of the excipients, the formulations themselves can improve drug solubility and affinity to the intestinal membrane, promote paracellular passage and endocytic uptake, and enable the lymph transport pathway, resulting in improved oral bioavailability [ 43 , 44 ]. P-gp substrates with poor and inconsistent oral bioavailability due to poor permeability may have a marked benefit from combining with P-gp inhibitors.…”

“…Secondly, we summarize various formulation approaches with P-gp inhibitory activity, including emulsion, self-micro, and nano emulsifying drug delivery systems (SMEDDS, SNEDDS), liposomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), micelles, polymeric nanoparticles, microspheres, dendrimers, and solid dispersions. They can combine the P-gp inhibitory effects of their components and the ability to bypass P-gp efflux by different mechanisms attributed to the characteristic of each formulation [ 43 , 44 ]. Considering that many drugs are limited by P-gp-mediated efflux, this review could be helpful for designing the formulations of P-gp substrates.…”