Development and characteriza

Tacrolimus is a potent immunosuppressant; however, it suffers from several problems such as poor water solubility (4–12 μg/mL), low and variable oral bioavailability in patients, and narrow therapeutic window that could not be solved by the currently available i.v. formulation (Prograf®). Moreover, Prograf® contains HCO-60 (PEGylated castor oil) as a surfactant, which is reported to cause several side effects including hypersensitivity reactions. Therefore, the aim of the present study was to investigate the potential of PEO-b-PCL polymeric micelles as alternative vehicles for the solubilization and delivery of tacrolimus. Four PEO-b-PCL block copolymers, with different molecular weights of PCL, were synthesized by ring opening polymerization of ε-caprolactone using methoxy polyethylene oxide (5,000 g mol−1) as initiator and stannous octoate as catalyst. Synthesized copolymers were characterized for their average molecular weights and polydispersity index by 1H NMR and gel permeation chromatography (GPC), respectively. Drug-free micelles of PEO-b-PCL were prepared through a co-solvent evaporation method using acetone as the organic co-solvent. Tacrolimus-loaded micelles were prepared using the same method with different initial amounts of drug. Prepared micelles were characterized for their mean diameter size and polydispersity of the micellar population by dynamic light scattering, and an HPLC assay was used to determine the encapsulation efficiency of tacrolimus. The average molecular weights of the synthesized copolymers were in the range of 8,400–28,000 with narrow distributions (PDI = 1.06–1.11). The copolymers were designated according to the degree of polymerization of ε-caprolactone, namely PEO114-b-PCL30, PEO114-b-PCL60, PEO114-b-PCL120, and PEO114-b-PCL200. All the prepared micelles were having diameters sizes less than 100 nm with narrow distributions. The highest drug solubilization was achieved with PEO114-b-PCL120, where the aqueous solubility of tacrolimus exceeded 300 μg/mL. Our results show a potential for PEO-b-PCL micelles as solubilizing vehicles for the delivery of tacrolimus

Development and Characterization of PEGylated Fatty Acid-Block-Poly(ε-caprolactone) Novel Block Copolymers and Their Self-Assembled Nanostructures for Ocular Delivery of Cyclosporine A

Low aqueous solubility and membrane permeability of some drugs are considered major limitations for their use in clinical practice. Polymeric micelles are one of the potential nano-drug delivery systems that were found to ameliorate the low aqueous solubility of hydrophobic drugs. The main objective of this study was to develop and characterize a novel copolymer based on poly (ethylene glycol) stearate (Myrj™)-block-poly(ε-caprolactone) (Myrj-b-PCL) and evaluate its potential as a nanosystem for ocular delivery of cyclosporine A (CyA). Myrj-b-PCL copolymer with various PCL/Myrj ratios were synthesized via ring-opening bulk polymerization of ε-caprolactone using Myrj (Myrj S40 or Myrj S100), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. The co-solvent evaporation method was used to prepare CyA-loaded Myrj-b-PCL micelles. The prepared micelles were characterized for their size, polydispersity, and CMC using the dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Transmission electron microscopy (TEM) images of the prepared micelles showed spherical shapes with diameters in the nano range (<200 nm). Ex vivo corneal permeation study showed sustained release of CyA from the developed Myrj S100-b-PCL micelles. In vivo ocular irritation study (Draize test) showed that CyA-loaded Myrj S100-b-PCL88 was well tolerated in the rabbit eye. Our results point to a great potential of Myrj S100-b-PCL as an ocular drug delivery system