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

Document Type : Research article

Authors

1 Department of Pharmacy, Fuzong Clinical Medical College of Fujian Medical University (Fuzhou General Hospital), Fuzhou 350025, PR China.

2 Department of Inorganic Chemistry, College of Pharmacy, Fujian Medical University, Fuzhou 350108, PR China.

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

Main Subjects


References
(2007) 2: 25-32.
Rahman MA, Hussain A, Hussain MS, Mirza MA and
Iqbal Z. Role of excipients in successful development
of self-emulsifying/microemulsifying drug delivery
system (SEDDS/SMEDDS). Drug Dev. Ind. Pharm.
(2013) 39: 1-19.
Cho W, Kim MS, Kim JS, Park J, Park HJ, Cha KH,
Park JS and Hwang SJ. Optimized formulation of solid
self-microemulsifying sirolimus delivery systems. Int.
J. Nanomedicine (2013) 8: 1673-82.
Hu X, Lin C, Chen D, Zhang J, Liu Z, Wu W
and Song H. Sirolimus solid self-microemulsifying
pellets: formulation development, characterization and
bioavailability evaluation. Int. J. Pharm. (2012) 438:
123-33.
Tao C, Chen J, Huang A, Zhang J, Lin B, Liu Z,
Zhang M, Chen X, Zeng L, Zhang L and Song
H. Development of solidified self-microemulsifying
delivery systems with enhanced stability of sirolimus
and extended release. Int. J. Pharm. (2016) 513: 255-61.
Kim MS, Kim JS, Park HJ, Cho WK, Cha KH and
Hwang SJ. Enhanced bioavailability of sirolimus via
preparation of solid dispersion nanoparticles using a
supercritical antisolvent process. Int. J. Nanomedicine
(2011) 6: 2997-3009.
Krupa A, Szlek J, Jany BR and Jachowicz R.
Preformulation studies on solid self-emulsifying
systems in powder form containing magnesium
aluminometasilicate as porous carrier. AAPS
PharmSciTech. (2015) 16: 623-35.
Banerjee A, Qi J, Gogoi R, Wong J and Mitragotri S.
Role of nanoparticle size, shape and surface chemistry
in oral drug delivery. J. Control. Release (2016) 238:
176-85.
Yin X, Li H, Guo Z, Wu L, Chen F, de Matas M, Shao
Q, Xiao T, York P, He Y and Zhang J. Quantification
of swelling and erosion in the controlled release
of a poorly water-soluble drug using synchrotron
X-ray computed microtomography. AAPS J. (2013)
15: 1025-34.
Colombo P, Bettini R, Santi P and Peppas NA.
Swellable matrices for controlled drug delivery: gellayer behaviour, mechanisms and optimal performance.
Pharm. Sci. Technol. Today (2000) 3: 198-204.
Khanvilkar KH, Huang Y and Moore AD. Influence
of hydroxypropyl methylcellulose mixture, apparent
viscosity, and tablet hardness on drug release using
a 2(3) full factorial design. Drug Dev. Ind. Pharm.
(2002) 28: 601-8.
Tanabe H, Otsuka K and Otsuka M. Theoretical analysis
of tablet hardness prediction using chemoinformetric
near-infrared spectroscopy. Anal. Sci. (2007) 23: 857-62.
Liu M, Zhang S, Cui S, Chen F, Jia L, Wang S, Gai
X, Li P, Yang F, Pan W and Yang X. Preparation
and evaluation of Vinpocetine self-emulsifying pH
gradient release pellets. Drug Deliv. (2017) 24: 1598-
604.
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
(17)
(18)
Zhao DQ, Li SW and Sun QQ. Sirolimus-based
immunosuppressive regimens in renal transplantation:
a systemic review. Transplant. Proc. (2016) 48: 3-9.
Stenton SB, Partovi N and Ensom MH. Sirolimus:
the evidence for clinical pharmacokinetic monitoring.
Clin. Pharmacokinet. (2005) 44: 769-86.
Thibodeau JT, Mishkin JD, Patel PC, Kaiser PA, Ayers
CR, Mammen PP, Markham DW, Ring WS, Peltz M
and Drazner MH. Tolerability of sirolimus: a decade of
experience at a single cardiac transplant center. Clin.
Transplant. (2013) 27: 945-52.
Ventura-Aguiar P, Campistol JM and Diekmann
F. Safety of mTOR inhibitors in adult solid organ
transplantation. Expert Opin. Drug Saf. (2016) 15:
303-19.
Dokania S and Joshi AK. Self-microemulsifying drug
delivery system (SMEDDS)-challenges and road
ahead. Drug Deliv. (2015) 22: 675-90.
Shen LJ and Wu FL. Nanomedicines in renal transplant
rejection-focus on sirolimus. Int. J. Nanomedicine