알츠하이머 치료를 위한 PLA 서방형 미립구 제형 개발

설은영; 윤권혁; 이희용; 조성준; 박종일; 황성주; 조정원; Eunyoung Seol; Kwonhyeok Yoon; Heeyong Lee; Seong-Jun Jo; Jong II Park; Sung-Joo Hwang; Cheong-Weon Cho

Polymer(Korea), Vol.46, No.2, 238-245, March, 2022

DOI10.7317/pk.2022.46.2.238 Export Citation

알츠하이머 치료를 위한 PLA 서방형 미립구 제형 개발

Donepezil-loaded Poly(D,L-lactic acid) Microspheres for Potent and Sustained Drug Release in the Treatment of Alzheimer’s Disease

설은영^{1, 2}, 윤권혁¹, 이희용¹, 조성준³, 박종일^{4, †}, 황성주^{5, †}, 조정원^{2, †}

¹㈜지투지바이오
²충남대학교 약학과
³가톨릭대학교 약학과
⁴한국폴리텍대학 바이오나노소재과
⁵연세대학교 약학과

Eunyoung Seol^{1, 2}, Kwonhyeok Yoon^{1, 3}, Heeyong Lee^{1, 3}, Seong-Jun Jo⁴, Jong II Park^{5, †}, Sung-Joo Hwang^{6, †}, and Cheong-Weon Cho^{2, †}

¹G2GBIO, Inc., 1646 Yuseong-daero, Science Park #302, Yuseong-gu, Daejeon 34054, Korea
²College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-Gu, Daejeon 34134, Korea
³, Korea
⁴College of Pharmacy and Integrated Research Institute of Pharmaceutical Sciences,, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon 14662, Korea
⁵Department of Bio Nanomaterials, Bio Campus of Korea Polytechnics, #48, Dongan-ro 112, Ganggeong-up, Nonsan, Chungnam 32943, Korea
⁶Yonsei Institute of Pharmaceutical Sciences & College of Pharmacy, Yonsei University, 85 Songdogwahak-ro, Yeonsu-Gu, Incheon 21983, Korea

E-mail:, ,

초록

알츠하이머병은 기억력 결핍 및 인지 저하가 수반되는 진행성 신경 퇴행성 질환이다. 본 연구에서는 도네페 질(donepezil)이 함유된 균일한 입자크기를 갖는 신규한 미립구 제형에 대하여 연구하였다. 도네페질이 함유된 미립 구는 막유화 기술을 이용하여 제조하였으며, 평균 직경은 58-83 μm, 스팬값은 0.71 미만으로 입도가 균일하였고, 전 자현미경 관찰결과 입자가 구형으로 제조되었음을 확인하였다. Poly(D,L-lactic acid)(PLA) 미립구에서 도네페질의 봉입 효율이 61.8±3.7%(w/w)이었고, 가속 방출 시험 및 쥐의 단일 용량 피하 약동학 시험에서 poly(lactic-coglycolic acid)(PLGA)으로 제조된 미립구보다 더 오랫동안 방출이 지속되는 것을 확인할 수 있었다. 비모수 중첩법 을 사용하여 분석한 농도-시간 프로파일은 PLA를 이용하여 제조된 미립구인 DM-L3가 1개월 동안 체내에서 약물이 지속적으로 방출될 수 있음을 확인하였다.

Alzheimer’s disease is a progressive neurodegenerative disease associated with memory deficit and cognitive decline. Herein, a new formulation of donepezil-loaded microspheres of uniform particle size was investigated. Donepezil-loaded microspheres were successfully prepared using a cross-flow membrane emulsification technology. The size analysis showed that the average diameter of the microspheres was 58-83 μm, indicating a narrow size distribution with a span value of less than 0.71. Scanning electron microscopy showed that the microspheres had a spherical shape. The loading efficiency of donepezil in the poly(D,L-lactic acid) (PLA) microspheres was 61.8±3.7% (w/w). Donepezil-loaded microspheres prepared using PLA (DM-L3) presented a more sustained release efficacy than poly(lactic-co-glycolic acid) (PLGA) microspheres in an in vitro accelerated release test and single-dose subcutaneous pharmacokinetic test in rats. The concentration-time profile analyzed using the non-parametric superposition method showed that the DM-L3 microspheres could achieve a sustained release of the drug for 1 month.

Keywords:donepezil;Alzheimer's disease;microsphere;poly(D,L-lactic acid)

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[2] Citron M, Nat. Rev. Drug Discov., 9, 387 (2010)

[3] Khan MM, Ahsan F, Ahmad U, Akhtar J, Badruddeen, Mujahid M, World J. Pharm. Pharm. Sci., 5, 649 (2016)

[4] Folch J, Petrov D, Ettcheto M, Abad S, Sánchez-López E, García ML, Olloquequi J, Beas-Zarate C, Auladell C, Camins A, Neural Plast., 2016, 8501693 (2016)

[5] Scott KR, Barrett AM, Expert Rev. Neurother., 7, 407 (2007)

[6] Cummings J, Lee G, Ritter A, Sabbagh M, Zhong K, Alzheimers Dement., 5, 272 (2019)

[7] Yiannopoulou KG, Papageorgiou SG, Ther. Adv. Neurol. Disord., 6, 19 (2013)

[8] Priano L, Gasco MR, Mauro A, Drugs Aging, 23, 357 (2006)

[9] Möller HJ, Hampel H, Hegerl U, Schmitt W, Walter K, Pharmacopsychiatry, 32, 99 (1999)

[10] Levy A, Brandeis R, Treves TA, Meshulam Y, Mawassi F, Feiler D, Wengier A, Glikfeld P, Grunwald J, Dachir S, Alzheimer Dis. Assoc. Disord., 8, 15 (1994)

[11] Lu L, Peter SJ, Lyman MD, Lai H, Leite SM, Tamada JA, Uyama S, Vacanti JP, Langer R, Mikos AG, Biomaterials, 21, 1837 (2000)

[12] Lu L, Garcia CA, Mikos AG, J. Biomed. Mater. Res., 46, 236 (1999)

[13] Park TG, Biomaterials, 16, 1123 (1995)

[14] Blasi P, J. Pharma. Investig., 49, 337 (2019)

[15] Piacentini E, Drioli E, Giorno L, J. Membr. Sci., 468, 410 (2014)

[16] Stillwell MT, Holdich RG, Kosvintsev SR, Gasparini G, Cumming IW, Ind. Eng. Chem. Res., 46, 965 (2007)

[17] Parmar A, Mishra A, Pathak A, Int. J. Adv. Pharm., 4, 72 (2015)

[18] Brown A, Zaky S, Ray H Jr, Sfeir C, Acta Biomater., 11, 543 (2015)

[19] Ramot Y, Haim-Zada M, Domb AJ, Nyska A, Adv. Drug Deliv. Rev., 107, 153 (2016)

[20] Mohammadi-Samani S, Taghipour B, Pharm. Dev. Technol., 20, 385 (2015)

[21] Makadia HK, Siegel SJ, Polymer, 3, 1377 (2011)

[22] Guo W, Quan P, Fang L, Cun D, Yang M, Asian J. Pharm. Sci., 10, 405 (2015)

[23] Siggle SJ, Kahn JB, Metzger K, Winey KI, Werner K, Dan N, Eur. J. Pharm. Biopharm., 64, 287 (2006)