Carboxymethyl Cellulose‐Coated Tacrolimus Nonspherical Microcrystals for Improved Therapeutic Efficacy of Dry Eye

Abstract

Dry eye (DE) is a highly prevalent ocular surface disease which affects the quality of life and results in low working efficiency. Frequent instillation is required due to low bioavailability of conventional eye drops. The aim of this study is to develop a novel formulation of tacrolimus (TAC), routinely prescribed for DE, by combination of the microcrystal technology and layer‐by‐layer assembly. First, nonspherical tacrolimus microcrystals (TAC MCs) are synthesized by antisolvent‐induced precipitation. These TAC MCs are modified by alternate deposition of poly(allylamine hydrochloride) (PAH) and carboxymethyl cellulose (CMC) subsequently to obtain CMC‐coated TAC MCs (TAC‐(PAH/CMC)3). The resultant formulations are evaluated in vivo in a mouse DE model induced by an intelligently controlled environmental system. Compared with commercially available TAC eye drops and the TAC MCs counterpart, TAC‐(PAH/CMC)3 exhibits superior therapeutic performance with reduced drug instillation frequency, which is attributed to the nonspherical geometry of MCs, the lubricant, mucoadhesive effect of CMC, and the anti‐inflammatory function of TAC. Therefore, TAC‐(PAH/CMC)3 represents a better option for the management of DE.

A comprehensive review of the effects of tacrolimus (FK-506) on dry eye disease (DED): Focus on inflammation and biochemical processes

“…Employing non-spherical TAC microcrystals (TAC MCs) enveloped with carboxymethyl cellulose (CMC) enhances the therapeutic effectiveness of TAC in dry eye treatment through multiple mechanisms [106]. First, the nonspherical geometry of the TAC MCs enhances their mucoadhesive effect, allowing them to adhere better to the ocular surface and prolonging their residence time.…”

“…Second, the CMC coating on the TAC MCs further enhances the mucoadhesive properties, promoting their retention on the ocular surface. CMC is known for its lubricant properties, which can alleviate the discomfort associated with dry eye and improve tear film stability [106]. Lastly, TAC itself has anti-inflammatory properties, which can help reduce the inflammation associated with dry eye.…”

“…Lastly, TAC itself has anti-inflammatory properties, which can help reduce the inflammation associated with dry eye. By combining the anti-inflammatory function of TAC with the mucoadhesive and lubricating effects of CMC-coated TAC MCs, the therapeutic efficacy of the treatment is enhanced [106]. Overall, the use of nonspherical TAC MCs coated with CMC improves the therapeutic efficacy of TAC in the treatment of dry eye by providing sustained release, enhanced mucoadhesive properties, and anti-inflammatory effects.…”

“…Overall, the results highlight the effectiveness of the TAC-(PAH/CMC) 3 BID regimen in improving dry eye symptoms and protecting the cornea. PAH/CMC refers to a combination of polyallylamine hydrochloride (PAH) and CMC [106].…”

Research progress of ophthalmic preparations of immunosuppressants

“…TAC- (PAH/CMC) 3 , followed by TAC MCs, had the higher therapeutic efficiency than the commercial eye drops Talymus®, which includes improvement of preservation of tissue structure, clinical dry eye signs, and suppression of the expression of representative inflammatory mediators. TAC- (PAH/CMC) 3 is notable for its superior therapeutic performance compared with Talymus®, which is attributed to the lubricant, mucoadhesive effect of CMC, the non-spherical geometry of MCs, and the anti-inflammatory function of tacrolimus (Zhang et al., 2020 ).…”