Tacrolimus-loaded methoxy poly(ethylene glycol)-block-poly(D,L)-lactic-co-glycolic acid micelles self-assembled in aqueous solution for treating cornea immune rejection after allogenic penetrating keratoplasty in rats.

This study aimed to develop a stable and biodegradable tacrolimus loaded nanocarrier that enhanced tacrolimus corneal penetration and delivered in a sustained manner, thus to create a promising treatment to prevent immune rejection after corneal allografts. Spherical tacrolimus loaded methoxy poly (ethylene glycol)-block-poly (D,L)-lactic-co-glycolic acid (mPEG-b-PLGA) micelles with a mean diameter of 81.3 ±â€¯1.3 nm were prepared by the solvent-evaporation-induced self-assembly. The physicochemical properties of tacrolimus loaded mPEG-b-PLGA micelles were evaluated, and the in vitro release behavior, degradation, cytotoxicity and bio-safety were all assessed. The ex vivo permeation of tacrolimus using rabbit corneas was also performed, and the cumulative permeation amount of tacrolimus from mPEG-b-PLGA micelles was significantly higher than 0.05% tacrolimus eye drops (p < 0.05). These results indicated that the formulations were feasible for intraocular drug delivery. Compared with 0.05% tacrolimus eye drops, the in vivo immunofluorescence analysis indicated the tacrolimus loaded mPEG-b-PLGA micelles remarkably inhibit the immune rejection after corneal allograft, with the lower expression levels of nuclear factor of activated T cells (NFAT), cluster of differentiation 4 (CD4) and cluster of differentiation 8 (CD8). In conclusion, we provided evidences that tacrolimus loaded mPEG-b-PLGA micelles would be a promising treatment for immune rejection after corneal transplantation.

A novel FK506 loaded nanomicelles consisting of amino-terminated poly(ethylene glycol)-block-poly(D,L)-lactic acid and hydroxypropyl methylcellulose for ocular drug delivery.

FK506 (tacrolimus) is an effective immunosuppressant, but its poor water solubility and low bioavailability impose barriers to ocular drug delivery. The nanomicelles (NMs) formulations comprised of amino-terminated poly(ethylene glycol-block-poly(D,L)-lactic acid) (NH2-PEG-b-PLA) and hydroxypropyl methylcellulose (HPMC) were developed to increase the penetration of hydrophobic drugs in the eye and enhance the drug bioavailability for ocular disorder therapy. Spherical FK506/NH2-PEG-b-PLA/HPMC NMs with mean diameter of 101.4 ±â€¯1.3 nm were prepared by solvent-evaporation-induced self-assembly in aqueous solution. The NMs that sufficiently solubilized FK506 were evaluated in terms of stability, drug loading, encapsulation efficiency, surface tension, cellular cytotoxicity and in vitro release, and the results revealed the NMs were suitable for intraocular drug delivery. Compared with the 0.05% FK506 suspension drops, the in vitro permeation amount of FK506 from NMs exhibited significant increase. Besides, the higher concentration and longer retention of FK506 in ocular tissue were also confirmed in vivo. Furthermore, the FK506/NH2-PEG-b-PLA/HPMC NMs obviously inhibited the allograft rejection after corneal transplantation in rats. In conclusion, FK506/NH2-PEG-b-PLA/HPMC NMs formulations as a promising ocular drug delivery system would be able to improve the bioavailability and efficacy of FK506 in anti-allograft rejection.

Preparation and In Vitro and In Vivo Evaluation of Sirolimus Ophthalmic Micelles / 中国药学杂志

OBJECTIVE: To prepare sirolimus micelles for the purpose of improving the solubility and applicability in the eye. METHODS: Sirolimus micelles were prepared by thin-film dispersion with Tween-80 and polyoxyethylene stearate (P40S) as carriers. Size distribution, X-ray diffraction spectra, IR spectra and encapsulation efficiency were used to evaluated the character of micelles. The in vitro release and scleral permeability were investigated, and the pharmacokinetics of micelles formulation in rabbit aqueous humor was preliminarily studied. RESULTS: The average particle size was (12.36±0.21) nm, the mean potential was (-6.08±0.98) mV, and the entrapment efficiency was (99.6±0.20)%. Both X-ray diffraction and IR spectra showed that there was almost no free drug. The in vitro release and scleral permeation profiles were in accordance with Higuchi equation. The pharmacokinetic RESULTS: of aqueous humor showed that sirolimus micelles could reach and maintain the therapeutic concentration in the eye for a long time. CONCLUSION: The prepared sirolimus ophthalmic micelles is suitable for ocular administration and is expected to become a promising formulation in the treatment of immune rejection for corneal transplantation.