Formulation and in vitro characterization of long-acting PLGA injectable microspheres encapsulating a peptide analog of LHRH

doi:10.1016/j.jmst.2020.04.020

Abstract

Abstract:

The present study aimed to formulate triptorelin acetate (TA) into poly (D, L-lactic-co-glycolic) acid (PLGA) based injectable sustained-release microspheres (TA-PLGA-MS) by usingdouble emulsion solvent extraction/evaporation (DESE) technique and investigate the effects of various material attributes and process parameters on the quality attributes such as size, shape, surface morphology, encapsulation efficiency (EE) and in vitro release behavior of these microspheres. Variable compositions of the outer water phase, type of the organic solvents, volume ratios of inner water phase to oil phase, PLGA concentrations, and the powers for emulsification in the preparation of the microspheres showed an influence on their quality attributes. An optimal formulation (F-2) obtained from this univariate approach possess an excellent EE value of 63.5% ± 3.4% and an average volumetric particle size of 35.3 ± 1.8 μm. This formulation was further accomplished with different solidification rates assisted by variable incubation temperatures, which exhibited an impact on the shape/surface and inner morphology of the microspheres. The resultant microspheres also displayed different in vitro release patterns. The matrices processed with a high incubation temperature conferred the fastest and the most complete drug release profile over the period of 63 days. Thus, the solidification rate could be identified as one of the critical process parameters that affected the quality of the PLGA based injectable microspheres specifically designed for the prolonged delivery of TA.

Key words: Triptorelin acetate, Peptide delivery, Poly (D,L-lactic-co-glycolic) acid, Microspheres, Long-acting injectable

Chengqian Zhang, Lan Wu, Anjin Tao, Hriday Bera, Xing Tang, Dongmei Cun, Mingshi Yang. Formulation and in vitro characterization of long-acting PLGA injectable microspheres encapsulating a peptide analog of LHRH[J]. J. Mater. Sci. Technol., 2021, 63: 133-144.

Figures/Tables 11

References 39

[1]	K. Park, G.Y. Jung, M.-K. Kim, M.S. Park, Y.K. Shin, J.-K. Hwang, S.H. Yuk, Macromol. Res. 20 (2012) 847-851. DOI URL
[2]	F. Wan, M. Yang, Int. J. Pharm. 498 (2016) 82-95. DOI URL PMID
[3]	P.W. Lee, J.K. Pokorski, WIREs. Nanomed. Nanobiotechnol. (2018) e1516.
[4]	C. Zhu, Y. Huang, X. Zhang, L. Mei, X. Pan, G. Li, C. Wu, Coll. Surf. B Biointerf. 132 (2015) 103-110. DOI URL
[5]	Y. Yang, Q. Chen, J. Lin, Z. Cai, G. Liao, K. Wang, L. Bai, P. Zhao, Y.Z. Yu, Curr. Med. Chem. 26 (2019) 2285-2296. DOI URL PMID
[6]	W. Chen, A. Palazzo, W.E. Hennink, R.J. Kok, Mol. Pharm. 14 (2017) 459-467. DOI URL PMID
[7]	E.D. Crawford, J.M. Phillips, Cancer Manag Res. 3 (2011) 201-209. DOI URL PMID
[8]	C. Busatto, J. Pesoa, I. Helbling, J. Luna, D. Estenoz, Int. J. Pharm. 536 (2018) 360-369. DOI URL PMID
[9]	F. Ramazani, W. Chen, C.F. van Nostrum, G. Storm, F. Kiessling, T. Lammers, W.E. Hennink, R.J. Kok, Int. J. Pharm. 499 (2016) 358-367. DOI URL PMID
[10]	C. Martin-Sabroso, A.I. Fraguas-Sanchez, J. Aparicio-Blanco, M.F. Cano-Abad, A.I. Torres-Suarez, Int. J. Pharm. 480 (2015) 27-36. DOI URL PMID
[11]	F. Qi, J. Wu, D. Hao, T. Yang, Y. Ren, G. Ma, Z. Su, Pharm. Res. 31 (2014) 1566-1574. DOI URL PMID
[12]	R.B. Shah, S.P. Schwendeman, J. Control. Release. 196 (2014) 60-70. DOI URL PMID
[13]	S.E. Reinhold, S.P. Schwendeman, Macromol. Biosci. 13 (2013) 1700-1710. DOI URL PMID
[14]	F. Wan, M.J. Maltesen, S.K. Andersen, S. Bjerregaard, S.G. Baldursdottir, C. Foged, J. Rantanen, M. Yang, Pharm. Res. 31 (2014) 2940-2951. DOI URL PMID
[15]	M. Ye, S. Kim, K. Park, J. Control. Release. 146 (2010) 241-260. DOI URL PMID
[16]	S.A. Malik, W.H. Ng, J. Bowen, J. Tang, A. Gomez, A.J. Kenyon, R.M. Day, J. Colloid. Interf. Sci. 467 (2016) 220-229. DOI URL
[17]	E. Jafarifar, M. Hajialyani, M. Akbari, M. Rahimi, Y. Shokoohinia, A. Fattahi, Pharm. Dev. Technol. 22 (2017) 836-843. DOI URL PMID
[18]	G. Della Porta, R. Campardelli, V. Cricchio, F. Oliva, N. Maffulli, E. Reverchon, J. Pharm. Sci. 105 (2016) 2164-2172. DOI URL PMID
[19]	P. Tomar, N. Giri, V.S. Karwasara, R.S. Pandey, V.K. Dixit, Pharm. Dev. Technol. 17 (2011) 421-428. DOI URL PMID
[20]	A. Mahboubian, S.K. Hashemein, S. Moghadam, F. Atyabia, R. Dinarvand, Iran. J. Pharm. Res. 9 (2010) 369-378. URL PMID
[21]	F. Cui, D. Cun, A. Tao, M. Yang, K. Shi, M. Zhao, Y. Guan, J. Control. Release. 107 (2005) 310-319. URL PMID
[22]	X. Li, S. Chang, G. Du, Y. Li, J. Gong, M. Yang, Z. Wei, Int. J. Pharm. 433 (2012) 79-88. DOI URL PMID
[23]	I. Tomic, A. Vidis-Millward, M. Mueller-Zsigmondy, J.M. Cardot, Int. J. Pharm. 505 (2016) 42-51. DOI URL PMID
[24]	S. Hao, Y. Wang, B. Wang, J. Deng, L. Zhu, Y. Cao, Mater. Sci. Eng. C.Mater. Biol. Appl. 39 (2014) 113-119.
[25]	B. Amoyav, O. Benny, Polymers 11 (2019) 1-14. DOI URL
[26]	S. Nicoli, P. Santi, P. Couvreur, G. Couarraze, P. Colombo, E. Fattal, Int. J. Pharm. 214 (2001) 31-35. DOI URL PMID
[27]	R. Liu, S.S. Huang, Y.H. Wan, G.H. Ma, Z.G. Su, Coll. Surf. B Biointerf. 51 (2006) 30-38. DOI URL
[28]	S. Marquette, C. Peerboom, A. Yates, L. Denis, J. Goole, K. Amighi, Eur. J. Pharm. Biopharm. 86 (2014) 393-403. DOI URL PMID
[29]	Y. Wei, Y. Wang, L. Wang, D. Hao, G. Ma, Coll. Surf. B Biointerf. 87 (2011) 399-408. DOI URL
[30]	G. Ruan, S.-S. Feng, Q.-T. Li, J. Control. Release. 84 (2002) 151-160. DOI URL PMID
[31]	F. Ito, H. Fujimori, K. Makino, Coll. Surf. B Biointerf. 54 (2007) 173-178. DOI URL
[32]	S. Mao, J. Xu, C. Cai, O. Germershaus, A. Schaper, T. Kissel, Int. J. Pharm. 334 (2007) 137-148. DOI URL PMID
[33]	A. Gaignaux, J. Reeff, F. Siepmann, J. Siepmann, C. De Vriese, J. Goole, K. Amighi, Int. J. Pharm. 437 (2012) 20-28. DOI URL PMID
[34]	Y.-Y. Yang, T.-S. Chung, X.-L. Bai, W.-K. Chan, Chem. Eng. Sci. 55 (2000) 2223-2236. DOI URL
[35]	G. Gasparini, S.R. Kosvintsev, M.T. Stillwell, R.G. Holdich, Coll. Surf. B Biointerf. 61 (2008) 199-207. DOI URL
[36]	J. Wu, T. Kong, K.W. Yeung, H.C. Shum, K.M. Cheung, L. Wang, M.K. To, Acta. Biomater. 9 (2013) 7410-7419. DOI URL PMID
[37]	Y.-Y. Yang, Hui-Hui Chia, T.-S. Chung, J. Control. Release. 69 (2000) 81-96. DOI URL PMID
[38]	H. Zhang, C. Pu, Q. Wang, X. Tan, J. Gou, H. He, Y. Zhang, T. Yin, Y. Wang, X. Tang, Pharm. Res. 36 (2018) 9. DOI URL PMID
[39]	S. Fredenberg, M. Wahlgren, M. Reslow, A. Axelsson, Int. J. Pharm. 415 (2011) 34-52. DOI URL PMID

Formulation	Outer water phase	Organic solvent	Volume ratio of inner water phase to oil phase	PLGA concentration	Ultrasonic power	Homogenization rate
F-1	1% (w/v) PVA	DCM	1:2	15% (w/v)	195 W	8000 rpm
F-2	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	195 W	8000 rpm
F-3	1% (w/v) PVA-SC	DCM	1:2	15% (w/v)	195 W	8000 rpm
F-4	1% (w/v) PVA-SA	EA	1:2	15% (w/v)	195 W	8000 rpm
F-5	1% (w/v) PVA-SA	EA: DCM (v/v, 1:1)	1:2	15% (w/v)	195 W	8000 rpm
F-6	1% (w/v) PVA-SA	DCM	1:5	15% (w/v)	195 W	8000 rpm
F-7	1% (w/v) PVA-SA	DCM	1:8	15% (w/v)	195 W	8000 rpm
F-8	1% (w/v) PVA-SA	DCM	1:2	10% (w/v)	195 W	8000 rpm
F-9	1% (w/v) PVA-SA	DCM	1:2	5% (w/v)	195 W	8000 rpm
F-10	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	260 W	8000 rpm
F-11	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	130 W	8000 rpm
F-12	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	195W	14500 rpm
F-13	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	195 W	0 rpm

Formulation	Outer water phase	Organic solvent	Volume ratio of inner water phase to oil phase	PLGA concentration	Ultrasonic power	Homogenization rate
F-1	1% (w/v) PVA	DCM	1:2	15% (w/v)	195 W	8000 rpm
F-2	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	195 W	8000 rpm
F-3	1% (w/v) PVA-SC	DCM	1:2	15% (w/v)	195 W	8000 rpm
F-4	1% (w/v) PVA-SA	EA	1:2	15% (w/v)	195 W	8000 rpm
F-5	1% (w/v) PVA-SA	EA: DCM (v/v, 1:1)	1:2	15% (w/v)	195 W	8000 rpm
F-6	1% (w/v) PVA-SA	DCM	1:5	15% (w/v)	195 W	8000 rpm
F-7	1% (w/v) PVA-SA	DCM	1:8	15% (w/v)	195 W	8000 rpm
F-8	1% (w/v) PVA-SA	DCM	1:2	10% (w/v)	195 W	8000 rpm
F-9	1% (w/v) PVA-SA	DCM	1:2	5% (w/v)	195 W	8000 rpm
F-10	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	260 W	8000 rpm
F-11	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	130 W	8000 rpm
F-12	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	195W	14500 rpm
F-13	1% (w/v) PVA-SA	DCM	1:2	15% (w/v)	195 W	0 rpm

	Size		EE (%)	DL (%)
	D₅₀ (μm)	Span	EE (%)
F-1	39.9 ± 2.2	1.4 ± 0.1	16.7 ± 1.2**	0.8 ± 0.1**
F-2	35.3 ± 1.8	1.4 ± 0.0	63.5 ± 3.4	3.2 ± 0.2
F-3	21.0 ± 0.7**	1.7 ± 0.0**	8.4 ± 0.5**	0.4 ± 0.0**
F-4	80.0 ± 7.7**	1.3 ± 0.1	38.9 ± 0.4**	1.9 ± 0.0**
F-5	35.4 ± 2.9	1.4 ± 0.1	65.1 ± 2.7	3.3 ± 0.1
F-6	30.3 ± 2.6**	1.4 ± 0.1	36.9 ± 4.2**	1.8 ± 0.2**
F-7	25.4 ± 0.8**	1.5 ± 0.0*	33.8 ± 6.4**	1.7 ± 0.3**
F-8	27.8 ± 3.3**	1.6 ± 0.0**	41.9 ± 1.1**	2.1 ± 0.1**
F-9	21.7 ± 1.0**	1.6 ± 0.0**	35.4 ± 3.5**	1.8 ± 0.2**
F-10	42.3 ± 0.1**	1.3 ± 0.0	52.2 ± 4.2*	2.6 ± 0.2*
F-11	42.0 ± 2.0**	1.4 ± 0.0	53.8 ± 3.6*	2.7 ± 0.2*
F-12	23.9 ± 1.4**	1.6 ± 0.1*	58.1 ± 2.7	2.9 ± 0.1
F-13	77.5 ± 5.7**	1.2 ± 0.1*	57.7 ± 2.2	2.9 ± 0.1

	Size		EE (%)	DL (%)
	D₅₀ (μm)	Span	EE (%)
F-1	39.9 ± 2.2	1.4 ± 0.1	16.7 ± 1.2**	0.8 ± 0.1**
F-2	35.3 ± 1.8	1.4 ± 0.0	63.5 ± 3.4	3.2 ± 0.2
F-3	21.0 ± 0.7**	1.7 ± 0.0**	8.4 ± 0.5**	0.4 ± 0.0**
F-4	80.0 ± 7.7**	1.3 ± 0.1	38.9 ± 0.4**	1.9 ± 0.0**
F-5	35.4 ± 2.9	1.4 ± 0.1	65.1 ± 2.7	3.3 ± 0.1
F-6	30.3 ± 2.6**	1.4 ± 0.1	36.9 ± 4.2**	1.8 ± 0.2**
F-7	25.4 ± 0.8**	1.5 ± 0.0*	33.8 ± 6.4**	1.7 ± 0.3**
F-8	27.8 ± 3.3**	1.6 ± 0.0**	41.9 ± 1.1**	2.1 ± 0.1**
F-9	21.7 ± 1.0**	1.6 ± 0.0**	35.4 ± 3.5**	1.8 ± 0.2**
F-10	42.3 ± 0.1**	1.3 ± 0.0	52.2 ± 4.2*	2.6 ± 0.2*
F-11	42.0 ± 2.0**	1.4 ± 0.0	53.8 ± 3.6*	2.7 ± 0.2*
F-12	23.9 ± 1.4**	1.6 ± 0.1*	58.1 ± 2.7	2.9 ± 0.1
F-13	77.5 ± 5.7**	1.2 ± 0.1*	57.7 ± 2.2	2.9 ± 0.1

	Size		EE (%)	DL (%)
	D₅₀ (μm)	Span	EE (%)
4 ℃	32.8 ± 2.2	1.5 ± 0.1	64.2 ± 1.9	3.2 ± 0.1
26 ℃	35.3 ± 1.8	1.4 ± 0.0	63.5 ± 3.4	3.2 ± 0.2
39 ℃	36.6 ± 1.0	1.4 ± 0.0	60.8 ± 5.9	3.0 ± 0.3