Nshien cuu. Phdt trien va ting duns Cons nshe Vdt lieu (KC.02/06-10)- Hd N6i 27/11/2009 TRUNG HOP MO VONG DIEU CHE POLY (LACTIT - CO-GLYCOLIT) (PLGA)
PHAN A. CAC YEU TO A N H HUONG T O ! QUA T R I N H TRUNG HOP Pham The Trinh1, Do Quang Khang 2, Phung Ha 3, Mai Van Tien1
] ) Vien hoa hoc cong nghiep Viet Nam. Email: [email protected].
2 ) Vien hoa hoc - Vien khoa hoc va Cong nghe Viet Nam.
3 ) Cue hoa chit - Bo Cong Thuomg.
Tom tit. Poly (lactit -co-glycolit)(PLGA) dupe dieu che bang phuong phdp ddng trung hop md vong, su dung octanoal - thiec lam chdt xuc tdc. Ty le ham luong lactit/ glycolit dupe lua chon cho nghien cuu nay ldn lupt la 95/5; 90/10; 85/15; 80/20; 75/25 va 70/30. Ham luong xuc tdc dupe thay ddi tu 0,01% den 0,06%. Nhiet dp phan ung dupe thay ddi tic 160 "C den 210 °C, thoi gian thay ddi tic 1 den 6 gid. Dd nghien cuu anh hudng ciia ty le ham luong lactic/glycolit, ciia ham luong chdt xiic tdc, ciia nhiet dp vd thdi gian den hieu sudt trung hop va chi sd dp nhdt ciia sdn pham. Ket qua dd lua chon dupe dieu kien tdi uu ciia qua trinh trung hop dieu che PLGA. \
I. GIOlTfflEU
Poly (lactit-co-glycolit) (PLGA) la san pham cua phan img dong trung hop md vong lactit (LA) va glycolit (GA), sir dung octanoat - thile lam xuc tac [1,2,3]. PLGA cd nhieu uu dilm vugt troi ve tfnh nang ca ly va kha nang phan huy sinh hoc so vdi cac polyme rieng re (PLA hoac PGA) [4,5]. N l u nhu polylactic axit (PLA) tu phan huy trong vong 18 din 24 thang, trong khi polyglycolit axit (PGA) lai phan huy qua nhanh (tir 2 din 4 thang); thi san phim ddng trung hop PLGA (ty le LA/GA = 85/15) co thai gian tu phan huy hop ly hon khi ung dung (tir 5 den 6 thang) [6,7]. Do nhung tinh chat uu viet, noi troi, PLGA dugc su dung lam nguyen lieu de che tao chi khau tu tieu, ung dung trong y t i [8]. Bao cao nay trinh bay anh hudng ciia cac dieu kien phan ung den hieu suat chuyen hda va chi sd dd nhdt ciia PLGA tao thanh. Ket qua dac trung tinh chat ciia PLGA dugc trinh bay trong bai bao tiep theo: phin B[9].
II.THU'C NGHIEM 2.1. Nguyen lieu, hoa chat
- Lactit mach vong (khdi lugng rieng 1,12 g/cm3, do tinh khilt 98%, tinh thi hinh kim mau trang) dugc tong hop va tinh che tai Vien hda hoc cong nghiep Viet nam.
- Glycolit mach vong (khdi lugng rieng 1.15 g/cm3, dd tinh khilt 99%, tinh the mau vang sang) dugc tong hop va tinh che tai Vien hda hoc cong nghiep Viet nam.
- Octanoat - thiec, ham lugng > 95% (Sigma-Aldrich).
- Laurylancol: 99% (Merck).
- Va mot sd hda chat phan tich khac ...
2.2. Phuong phdp nghien cuu a) Nghien cuu cdc yeu to dnh hudng.
Dl nghien cuu anh hudng ciia cac dilu kien phan ung (ty le cac thanh phin, ham lugng chit
xuc tic, nhiet dd, thai gian ...) din hieu suat va chi sd do nhdt ciia san phim, cac thi nghiem dugc thuc hien theo mot quy trinh chung v i trung hop md vong dilu che PLGA da duac rnieu ta trong [10]. 0 day chi thay ddi cac thong sd khi can khao sat tdi uu:
- Khao sat anh hudng ciia ty le cac thanh phan: giu c l dinh cac dilu kien thi nghiem- ty le ham lugng lactit/glycolit thay ddi tir 95/5; 90/10; 85/15; 80/20; 75/25 va 70/30 (tuans duan?
19/1; 18/2; 17/3; 16/4; 15/5 va 14/6 g LA/g GA) &
- Khao sat anh hudng ciia ham lugng xiic tac: giu nguyen cac dilu kien thi nghiem ham
Nghien cim. Phdt triin vd Uhe dune Cons nehi Vdt lieu (KC.02/06-10)- Ha Noi 27/11/2009 - Khao sat anh huong ciia nhiet do phan ung: giu cd djnh cac dieu kien thi nghiem khac, chi thay ddi nhiet dd trong viing tir 160 °C den 210 °C.
- Khao sat anh hudng ciia thdi gian phan ung: giu nguyen cac dieu kien thi nghiem khac, chi thay ddi thdi gian tir 1,2,3,4,5 va 6 gid.
b)Xdc dinh chi so do nh&t Staudinger [7]]:
Chi sd dd nhdt [r|] dugc xac dinh tir phep ngoai suy do thi tir phuang trinh HUGGINS
^-w+tir-c, ,khica^o
CB
Tir nhung gia tri tim dugc ciia [r|], ta cd thi tinh ra khdi lugng phan tir trung binh tuong ung cho tfirng mau theo phuong trinh KUHN-MARK - HOUWINK.
in. KET QUA VA THAO LUAN
3.1 Anh hu&ng cua ty le ham luong cdc thanh phin din hieu suat vd tinh chat cud PLGA.
Be nghien cuu anh hudng ty le ham lugng giua lactit va glycolit den hieu suat phan ung va tinh chit ciia san phim PLGA, mot day thi nghiem ung vdi cac mau tir LG-1 den LG-6 da dugc tiln hanh, trong dd ty le LA/GA da dugc chon la 95/05, 90/10, 85/15, 80/20, 75/25 va 70/30. Cac dieu kien khac dugc giu cd dinh khong doi nhu ham lugng chit xuc tac la 0.03%, ham lugng chit dieu chinh mach lauryl ancol la 0.01%, nhiet dd phan irng la 200°C va thdi gian tien hanh phan ung la 3h (xem them 2.2). K i t qua chi ra trong bang 1: K i t qua bang 1 cho thiy khi thay ddi ty le khdi lugng ciia lactit/glycolit hieu suit chuyen hoa tang tir 85.6% irng vdi ty le LA/GA = 95/05 len 95.1% ung vdi ty le LA/GA = 80/20. Khi tang dip lugng GA len, hieu unit chuyen hda cd xu hudng giam nhe, trong khi dd chi sd dp nhdt ciia PLGA giam tir 1.01 [dl/g] xudng 0.76 [dl/g]. Bieu nay chung to ring khi tang ham lugng ciia GA trong hdn hgp phan ung da din tdi su suy giam khdi luong phan tir ciia PLGA tao thanh. Tir kit qua tren, ty le LA/GA = 80/20 (mau LG-4) dupe lira chon cho cac nghien cuu tiep theo.
Bdng 1. Anh hudng ty le monome tdi hieu suat chuyen hod, vd tinh chdt ciia san pham (Nhiet do 20O°C, xiic tdc 0.03%, lauryl 0.01%, thdi gian 3h)
Mdu Ty le lactit/glycolit
(w/w) Hieu suit [H%] San pham
(Dang be ngoai)
Chi so dp nh&t ftJlfdUg]
LG-1 95/05 85.6 Bdt mau nau 1.01
LG-2 90/10 88.3 Bdt mau kem nhat 0.98
LG-3 85/15 90.7 Mau kem 0.86
LG-4 80/20 95.1 Mdu kem 0.85
LG-5 75/25 94.4 Mau trang 0.80
LG-6 70/30 92.8 Mau trang 0.76
3.2. Anh hudng ty le ham luong chat xuc tac den tinh chat cua san pham
Xiic tac ddng vai trd quan trong va anh hudng true tiep tdi qua tjinh phan img, nd quyet dinh hieu suat va tinh chit ciia polyme tao thanh. Be nghien cuu anh hudng ciia ham luong chit xiic tie octanoat -thiec tdi hieu suat va chi sd dp nhdt ciia san pham, mot day cac thi nghiem da dupe thuc hien, trong do ham luong chat xiic tic dugc chon tir 0.01% den 0.06% (xem them 2.2). Kit qua nghien cuu anh hudng ciia ty le ham lugng chit xiic tic den hieu suat va dp nhdt ciia san phim dupe trinh bay trong hinhl.
Nghien cuu. Plidt then vd Ung duns Cons nshe Vdt lieu (KC.02/06-10)- Ha Noi 27/11/2009 Ket qua hinh 1 cho thay su phu thuoc ciia hieu suat va chi so do nhdt ciia san pham vao ham lugng chat xuc tac. Duong do thj ve hieu suat chuyen hda trong hinh 1 chi ra rang: khi cd mat chat xiic tac phan ung xay ra nhanh, hieu suat dat 82% ung vdi ham luong chat xiic tac la 0.01% va tang len 94.1% ung vdi ham lugng xiic tac bang 0.03% va dat 95,6% ung vdi ham lugng chat xiic tac la 0.06%. Chi sd dd nhdt ciia san pham tang dan ung vdi ham lugng xuc tac tang tir 0,01 den 0,03 % va dat gia tri cao nhat irng vdi ndng dd chat xuc tac la 0,03%. Khi tiep tuc tang ndng do chat xuc tac len, do nhdt ciia san pham cd xu hudng giam di. Nguyen nhan la do sd tam xiic tac hoat ddng tang len din den san pham tao thanh cd khdi lugng phan tir trung binh giam din, dugc bieu thj qua dudng do thi di xudng ciia chi sd dd nhdt.
Chi sd dd nhdt [TI] [dl/g]
~e — Hieu suat
—•— Chi sd dd nhdt
0.01 0.02 0.03 0.04 0.05
Ham luong xuc tac [%]
0.06
Hinh 1. Anh huong ham luong xiic tdc tdi hieu sudt va dd nh&t cua PLGA (Lauryl ancol 0,01%; nhiet dd 200°C; thdi gian phan img 3h; ty le LA/GA= 80/20) 3.3. Anh hudng ciia nhiet dp din dp chuyin hda va tinh chdt ciia PLGA.
Cac thi nghiem dugc thuc hien tai cac nhiet dp 160, 170, 180, 190, 200 va 210 °C.
Cac dieu kien khac giu khong ddi (xem 2.2). K i t qua dugc trinh bay chi t i l t d hinh 2
Hieu suat
Chi sd dp nhdt
n [TU[di/g]
„ „ ° Hieu suat
• Chi sd dd nhdt
Nhiet dp [°C]
" " • " • 1 /111
Ham 2. Anh Incdng ciia nhiet do polyme hda tdi hieu sudt vd chi sd dd nhdt cua PLGA (Xuc tdc 0,03%; Lauryl ancol 0,01%; thdi gian phan irng 3h; ty le LA/GA = 80/20) Kit qua hinh 2 cho thay hieu suit polyme hda it bi anh hudng trong khoang nhiet dp tir 160 ± 210°C. Khi tang nhiet dp, hieu suat ciia phan ung cd xu hudng giam nhe tir 95% tai 160°C xudng 82% tai nhiet dp 210°C. Tuy nhien, chi sd dp nhdt ciia PLGA dat gia tri cao nhat [Til =
Nghien cim. Phdt triin vd ting duns Cons nshe Vdt lieu (KC.02/06-10)- Ha Noi 27/11/2009 len tir 170 -f 210°C, nguyen nhan co thi la do xay ra phan irng cat mach tai nhung nhiet do cao lam giam khdi lugng phan tu trung binh ciia PLGA. Nhu vay, tai nhiet dd 170°C phan irng cho dd chuyen hda cao va KLPT trung binh thu dugc la ldn nhat.
3.4. Anh hudng cua thai gian phan img tai hieu suat vd chi so dp nh&t ciia PLGA.
Cac thi nghiem dugc tiln hanh trong ciing mot dieu kien nhu nhau:
- Xiic tac 0,03 % (6mg - theo tong nhua) - Lauryl ancol 0,01 % (2mg - theo tong nhua) - Nhiet dd phan img 170°C
- Ty le LA/ GA dugc chon la 80/20 (Tong nhua L A + GA = 20 g) - Phan img dugc tiln hanh d ap suat thudng
- Khi N2 dugc sue vao trong sudt qua trinh phan ung vdi tdc do 1.98. lO^l/s.
- Tai day, chi thay ddi thai gian phan ung. Thdi gian phan ung dugc chon la 1, 2, 3, 4, 5 va 6h (xem them 2.2). Ket qua dugc trinh bay trong bang 2.
Bang 2. Anh huong cua thdi gian phan irng den hieu sudt va chi sd dp nhat cua san pham PLGA.
Thdi gian [h] 1 2 3 4 5 6
Hieu suat [%] 65.4 71.5 95 94.8 93.3 90.1
7
Chi sd dd nhdt [TI] di/g
0.32 0.58 1.01 0.96 0.94 0.90
Ket qua bang 2 cho thay phan ung polyme hda xay ra nhanh, hieu suat dat 65.4% sau 1 gid phan ung, sau dd tang len cung vdi thai gian tien hanh phan ung, phan ung dat hieu suat 95% sau 3 gid. Keo dai thdi gian phan ung den 4,5,6 gid chi sd dd nhdt cd xu hudng giam nhe. Chi sd do nhdt ciia san phim tang tir 0.32 dl/g ung vdi thdi gian sau lgid phan ung, len 1.01 dl/g sau 3h phan ung. Chi sd dd nhdt ciia san pham PLGA dat gia tri cao nhat ung vdi khoang thdi gian la 3 gid ([q] = 1,01 dl/g).
3.5. Lua chon cdc dieu kien tdi uu de tong hop PLGA Tir cac kit qua tren, cd thi tdng hgp dieu kien tdi uu nhu sau:
Bdng 3. Cdc dieu ki$n tdi uu duac lua chon de tdng hap PLGA
STT • * *
Dieu kien tdng hop Don vi Gid tri
1 Ty le LA/GA 80/20
2 Ham lugng chat xiic tac Sn(Oct)2 % 0.03
3 Ham lugng chat dieu chinh mach lauryl ancol % 0.01
4 Nhiet do phan irng °C 170°C
5 Thdi gian tien hanh phan ung Gid 3
IV. KET LUAN
*) Da tien hanh phan ung ddng trung hgp md vong dilu chi PLGA sir dung octanoat - thilc lam chat xiic tac va da xac dinh cac dieu kien tdi uu ciia qua trinh trung hop.
- Ty le ham lugng lactit/glycolit da dugc lira chon la 80/20; ham lugng xiic tac la 0,03% (so vdi tdng nhua); nhiet dd phan ung tai 170 °C, thoi gian phan ung la 3 gid.
*) Da xac dinh hieu suit chuyin hda tao thanh PLGA. K i t qua cho thiy: hieu suit chuyln hda dat gia tri cao nhat 95%.
*) Tir kit qua xac dinh chi si dd nhdt da tinh toan khdi lugng phan tir trung binh khdi lugng {MYI ) ciia PLGA nam trong khoang 3.1xl04 din 9.4xl04 g/mol.
Nghien ciru. Phdt trien va L"ng dung Cons nghe Vdt lieu (KC.02/06-10)- Ha Noi 27/11/2009 Loi cam on
Cong trinh nay dugc thuc hien vdi su hd trg \k kinh phi ciia Bd Khoa hoc Cong nghe va ban chii nhiem chuong trinh KC-02, la mot phan ket qua thuc hien de tai cap nha nude KC02- 03/06-10.
Chiing tdi xin chan thanh cam on.
Tai lieu tham khao
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