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. 2019 Fall;18(4):1648-1658.
doi: 10.22037/ijpr.2019.1100847.

Solid Sirolimus Self-microemulsifying Drug Delivery System: Development and Evaluation of Tablets with Sustained Release Property

Chun Tao  1 , Xu Wen  1   2 , Qian Zhang  2 , Hongtao Song  1
Affiliations

Solid Sirolimus Self-microemulsifying Drug Delivery System: Development and Evaluation of Tablets with Sustained Release Property

Chun Tao et al. Iran J Pharm Res. 2019 Fall.

Abstract

The clinical application of sirolimus (SRL) as an immunosuppressive agent is largely hampered by its narrow therapeutic range. This study focused on developing SRL tablets with a sustained release profile for better safety. SRL was highly water insoluble and its solubility has been efficiently enhanced by preparing self-microemulsifying drug delivery system (SMEDDS). The SRL-SMEDDS was physically adsorbed by microcrystalline cellulose (MCC). The sustained release of SRL was achieved by addition of hydroxypropyl methylcellulose (HPMC) to prepare tablets. The formulation of the tablets was optimized by single factor test and orthogonal design. The optimal formulation was composed of 10% of HPMC 100lv and 5% of HPMC K4M. The in-vitro release profiles of the optimal tablets were further investigated for the influence of hardness, shape, preparing method, release method, stirring speed, and medium. The release kinetic of SRL from the tablets was demonstrated to be erosion of HPMC. Pharmacokinetic study on beagle dogs showed that the SRL-SMEDDS tablets were bio-equivalent to the commercial tablets but lower Cmax and larger Tmax were achieved. In conclusion, the SMEDDS tablets were presented as promising delivery system for sustained release of SRL.

Keywords: Bio-equivalent; Self-microemulsifying drug delivery system; Sirolimus; Sustained release; Tablet.

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Figures

Figure 1
Figure 1
The (A) size distribution and (B) in-vitro dissolution of the SRL-SMEDDS in various media
Figure 2
Figure 2
In-vitro release of SRL from SMEDDS-tablets. (A) tablets using HPMC of 100lv, K4M, K15M and K100M, respectively. (B) tablets using 0, 10%, 15%, 20% and 25% of HPMC 100lv. (C) tablets using 0, 10%, 15%, 20% and 25% of HPMC K4M. (D) tablets using HPMC 100lv and K4M with ratios of 4:1, 1:1 and 1:4
Figure 3
Figure 3
The (A) morphology and (B) in-vitro release of the optimal SRL-SMEDDS tablets
Figure 4
Figure 4
In-vitro release of SRL from SMEDDS-tablets. (A) tablets with hardness of 60, 80 and 100 N. (B) tablets prepared using direct powder compression and wet granulation. (C) round-shaped and irregular-shaped tablets. (D) three batches of the optimal tablets
Figure 5
Figure 5
In-vitro release of SRL from SMEDDS-tablets. (A) release test using paddle apparatus and basket apparatus. (B) release test using stirring speed of 50, 75 and 100 rpm. (C) release test using media of water, 0.4% SDS, pH 1.2 hydrochloric acid solution, and pH 6.8 phosphate buffer solution
Figure 6
Figure 6
Blood concentration-time profiles of SRL after oral administration of the SRL-SMEDDS tablets and the commercial tablets (n = 5)
See this image and copyright information in PMC

References

    1. Zhao DQ, Li SW, Sun QQ. Sirolimus-based immunosuppressive regimens in renal transplantation: a systemic review. Transplant. Proc. 2016;48:3–9. - PubMed
    1. Stenton SB, Partovi N, Ensom MH. Sirolimus: the evidence for clinical pharmacokinetic monitoring. Clin. Pharmacokinet. 2005;44:769–86. - PubMed
    1. Thibodeau JT, Mishkin JD, Patel PC, Kaiser PA, Ayers CR, Mammen PP, Markham DW, Ring WS, Peltz M, Drazner MH. Tolerability of sirolimus: a decade of experience at a single cardiac transplant center. Clin. Transplant. 2013;27:945–52. - PubMed
    1. Ventura-Aguiar P, Campistol JM, Diekmann F. Safety of mTOR inhibitors in adult solid organ transplantation. Expert Opin. Drug Saf. 2016;15:303–19. - PubMed
    1. Dokania S, Joshi AK. Self-microemulsifying drug delivery system (SMEDDS)-challenges and road ahead. Drug Deliv. 2015;22:675–90. - PubMed

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