Carbohydrate-Based Micelle Clusters Which Enhance Hydrophobic Drug Bioavailability by Up to 1 Order of Magnitude

Abstract

Amphiphilic chitosan-based polymers (Mw < 20 kDa) self-assemble in aqueous media at low micromolar concentrations to give previously unknown micellar clusters of 100-300 nm in size. Micellar clusters comprise smaller 10-30 nm aggregates, and the nanopolarity/drug incorporation efficiency of their hydrophobic domains can be tailored by varying the degree of lipidic derivatization and molecular weight of the carbohydrate. The extent of drug incorporation by these novel micellar clusters is 1 order of magnitude higher than is seen with triblock copolymers, with molar polymer/drug ratios of 1:48 to 1:67. On intravenous injection, the pharmacodynamic activity of a carbohydrate propofol formulation is increased by 1 order of magnitude when compared to a commercial emulsion formulation, and on topical ocular application of a carbohydrate prednisolone formulation, initial drug aqueous humor levels are similar to those found with a 10-fold dose of prednisolone suspension.

Exploring uptake mechanisms of oral nanomedicines using multimodal nonlinear optical microscopy

“…tion's bioavailability and biocompatibility [1][2][3] resulting in targeted drug delivery [4] with improved drug release [5], solubility [6] and bioactivity [7] while reducing toxicity [8]. These developments may address the major problem faced by pharmaceutical development whereby 95% of all new potential pharmaceuticals have poor biocompatibility or bioavailability [5].…”

“…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].…”

“…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.…”

Mucoadhesive Polymers for Oral Transmucosal Drug Delivery: A Review

“…trimethyl chitosan, glycol chitosan, carboxymethylchitosan and half-acetylated chitosan) from chitosan; however, only in few cases their mucoadhesive properties for transmucosal drug delivery have been reviewed [52,[75][76][77][78].…”