Solid dispersion-based pellet for colon delivery of tacrolimus through time- and pH-dependent layer coating: preparation, in vitro and in vivo studies

The intent of the present investigation is to develop and evaluate colon-specific coated tacrolimus solid dispersion pellet (SDP) that retards drug release in the stomach and small intestine but progressively releases in the colon. Tacrolimus-SDP was prepared by extrusion-spheronization technology and optimized by the micromeritic properties including flowability, friability, yields and dissolution rate. Subsequently, the pH-dependent layer (Eudragit L30D55) and time-dependent layer (Eudragit NE30D and L30D55) were coated on the SDP to form tacrolimus colon-specific pellets (CSP) using a fluidized bed coater. Under in vitro gradient pH environment, tacrolimus only released from CSP after changing pH to 6.8 and then quickly released in the phosphate buffer solution of pH 7.2. The Cmax of CSP was 195.68 ± 3.14 ng/mL at Tmax 4.5 ± 0.24 h where as in case of SDP, the Cmax was 646.16 ± 8.15 ng/mL at Tmax 0.5 ± 0.03 h, indicating the ability of CSP targeted to colon. The highest area under the curve was achieved 2479.58 ± 183.33 ng·h/mL for SDP, which was 2.27-fold higher than tacrolimus suspension. However, the best biodistribution performance was achieved from CSP. In conclusion, SDP combining of pH- and time-dependent approaches was suitable for targeted delivery of tacrolimus to colon.

Síndrome de dor óssea induzida por tacrolimo pós-transplante renal: relato de caso e revisão da literatura / Tacrolimus induced bone pain syndrome after kidney transplantation: case report and review of the literature

Objetivo: Relatar um caso de síndrome de dor óssea induzida por inibidores da calcineurina. Relato de caso: Paciente masculino de 54 anos, branco, foi que submetido a transplante renal haploidêntico e, ao fim do terceiro mês pós-transplante, apresentou dor espontânea, de forte intensidade, em joelhos, tornozelos e pés, de maneira simétrica, com incapacidade funcional, induzida por inibidores da calcineurina. O diagnóstico foi comprovado por ressonância magnética e cintilografia óssea. Evolução: Houve remissão espontânea e completa dos sintomas no fim do sexto mês após o transplante. Conclusão: A síndrome de dor osteoarticular induzida por inibidores da calcineurina é uma condição clínica incomum, mas que pode comprometer a qualidade de vida e a boa evolução do paciente transplantado. Seu diagnóstico correto deve ser feito prontamente por meio de estudos de ressonância magnética e de cintilografia óssea.

Objective: To present a case of calcineurin inhibitor-induced bone pain syndrome. Case report: A 54-year-old Caucasian male patient underwent a haploidentical kidney transplant and, at the end of the third postoperative month, developed severe, spontaneous, symmetrical pain in his knees, ankles, and feet, associated with functional impairment, induced by calcineurin inhibitors. The diagnosis was confirmed by MRI and bone scan. Evolution: The patient presented spontaneous remission of symptoms at the end of the sixth postoperative month. Conclusion: Calcineurin inhibitorinduced bone pain syndrome is an uncommon clinical condition, but it can impair the quality of life and good evolution of transplant recipients. Correct and prompt diagnosis with MRI and bone scan is recommended.