BM-KT-02-TC03/TMT.KHCN
THUYT MINH TINGHIN CU KHOA HC V PHT TRIN CNG NGH CP THNH PH1 I.
THNG TIN CHUNG V TI. 1 Tn ti: Nghin cu hon thin quy trnh bn tng hp
indirubin-3-oxime v bo ch vin nang cng VINDOXIM h tr iu tr bnh ung
th 3 Thi gian thc hin: 24 thng (T thng 1/2011 n thng 12/2012) 5
Kinh ph: 950 triu ng, trong : Ngun - T Ngn sch s nghip khoa hc: - T
ngun t c ca t chc: - T ngun khc: 6 Lnh vc khoa hc: Ha dc Thuc Chng
trnh (ghi r tn chng trnh, nu c): Y t- Bo h lao ng V sinh an ton lao
ng. M s:01C-08 ti c lp 7 Ch nhim ti H v Tn: Nguyn Mnh Cng Ngy,
thng, nm sinh:11/12/1962 . Hc hm, hc v: PGS.TS Chc danh khoa hc: Ch
tch Hi ng Khoa hc Vin HCTN Chc v: Ph Vin Trng Vin Ha hc cc Hp Cht
thin nhin in thoi: T chc:37913755. Nh
ring:..................................... Mobile: 0904059998 Fax:
043. 3756 4390. E-mail: [email protected] Tn t chc ang cng
tc: Vin Ha hc cc hp cht thin nhin, Vin Khoa hc v Cng ngh Vit Nam a
ch t chc: nh 1H, 18 Hong Quc Vit, Cu Giy, H Ni a ch nh ring: P 702-
Chung c Vn phng Quc Hi, ng 217 La Thnh, qun ng a, H Ni. Nam/N: nam
4 2 M s: 01C-08/11-2011-2 S Quyt nh: 73/2010/Q-UBND ngy 15/12/2010.
Cp qun l Nh B nc TP
C s
Tng s (triu ng) 950
81
Th k ti
Thuyt minh c trnh by v in ra trn kh giy A4
TMT.KHCN - trang 1
H v Tn:Trn Thu Hng Ngy, thng, nm sinh: 18/10/1985. Nam/N: n Hc
hm, hc v: c nhn Chc danh khoa
hc:.....................................................................................................................
Chc v: nghin cu vin in thoi: T chc:37913755. Nh
ring:..................................... Mobile: 0906998327 Fax:
043. 3756 4390. E-mail: [email protected] Tn t chc ang cng tc:
Vin Ha hc cc hp cht thin nhin, Vin Khoa hc v Cng ngh Vit Nam a ch t
chc: nh 1H, 18 Hong Quc Vit, Cu Giy, H Ni a ch nh ring: nh 96, ng
5, Hong Quc Vit, Cu Giy, H Ni. 9 T chc ch tr ti Tn t chc: Vin Ha hc
cc Hp cht thin nhin in thoi: 04 3836 0830. Fax: 04 3756 4390
E-mail: [email protected]. Website:.................. a ch: nh 1H, 18
Hong Quc Vit, Cu Giy, H Ni. H v tn Th trng t chc: PGS.TS. Phm Quc
Long S ti khon: 931.01.016 Ti Kho bcNh nc2: Kho Bc Nh nc Cu Giy, H
Ni. 10 C quan c giao k hoch3 Tn c quan: S Khoa hc v Cng ngh H Ni in
thoi: 034. 3824207 Fax: 034. 3825374 E-mail: www.dost.hanoi.gov.vn
. Website: a ch: S 5 Nguyn Tri, H ng, H Ni
11
Cc t chc phi hp thc hin ti (nu c)
2
Trong trng hp t chc ch tr ti cha c ti khon ti Kho bc Nh nc, thng
tin ny tm thi trng. Khi Thuyt minh ti c ph duyt, n v s tin hnh m ti
khon ti Kho bc Nh nc v khai bo thng tin. 3 Ch khai bo thng tin Mc
10 khi Thuyt minh ti c ph duyt
TMT.KHCN - trang 2
1. T chc 1: Vin Kim nghim thuc Trung ngin thoi: 043. 38252319.
Fax:.........................................................................................
a ch: S 48 Hai B Trng, Hon Kim, H Ni H v tn Th trng t chc: TS. Trnh
Vn Lu
2. T chc 2: Vin Cng Ngh Sinh Hcin thoi: 043. 38361774.
Fax:............... a ch: nh 3B, 18- Hong Quc Vit, Cu Giy, H Ni. H
v tn Th trng t chc: L Quang Hun
3. T chc 3: Cng ty TNHH T vn Y Dc Quc T IMCin thoi: 04.35377274.
Fax: 04.35377273 a ch: tng 3, Trung Tm Thng Mi Interserco, 17 Phm
Hng, M nh, T Lim-H Ni H v tn Th trng t chc: TS. Nguyn Ngc Thnh
4. T chc 4: i hc Dc H NiC quan ch qun: i hc Dc H Ni in thoi:
04.3.. Fax: 04.3 a ch: 13,15 L Thnh Tng, Hon Kim, H Ni. H v tn Th
trng t chc: PGS.TS. Nguyn Vit Hng 12 Cc c nhn thc hin ti(Ghi nhng
ngi d kin ng gp khoa hc v ch tr thc hin nhng ni dung chnh thuc t
chc ch tr v t chc phi hp tham gia thc hin ti, s lng khai bo khng qu
10 ngi k c ch nhim ti)
TT
H v Tn - Hc hm, hc v
T chc cng tc
Ni dung cng vic tham gia Ch nhim ti: ch tr, chu trch nhim v ton
b cc ni dung nghin cu trin khai thc nghim ca ti. Ph trch nghin cu
quy trnh cng ngh sn xut ch phm VINDOXIM.
Thi gian lm vic cho ti(s thng quy i4)
1
PGS. TS. Nguyn Mnh Cng
Vin Ha hc cc hp cht thin nhin
16 thng
2 NCV. Trn Thu Hng Vin Ha hc cc hp cht thin nhin
Th k ti: Phi hp vi S KH&CN, S Y t, S ti chnh v Kho bc nh nc
gii quyt cc th tc v ti chnh ca ti, n c cc t chc, c nhn tham gia phi
hp trong qu trnh trin
16 thng
4
Mt (01) thng quy i l thng gm 22 ngy lm vic, mi ngy lm vic gm 08
gi
TMT.KHCN - trang 3
khai cc ni dung theo s phn cng. Tham gia nghin cu qui trnh sn
xut indirubin-3oxim. 3 ThS. Mai Hng Thanh Tng 4 ThS. H Vit c 5 CN.
Nguyn Th H TS. Nguyn Th Kim Hng TS. Th Tho PGS.TS. Nguyn ng Ha 9
ThS. Nguyn Minh Phc Cng ty IMC Vin Ha hc cc hp cht thin nhin Vin Ha
hc cc hp cht thin nhin Vin Ha hc cc hp cht thin nhin VinKim Nghim
Vin Cng Ngh Sinh hc i hc Dc H Ni Tham gia nghin cu qui trnh sn xut,
tinh ch indirubin-3-oxim. Xy dng tiu chun c s ch phm. Tham gia
nghin cu qui trnh sn xut indirubin-3oxim. Tham gia nghin cu qui
trnh sn xut indirubin-3oxim. Ph trch nghin cu c tnh cp v bn trng
din ca ch phm VINDOXIM. Ph trch xc nh kh nng c ch t bo ung th
invitro Ph trch nghin cu n nh ca ch phm, kim nh tiu chun c s ca ch
phm. Ph trch nghin cu quy trnh bo ch, hon thin h s ng k thc phm chc
nng 8 thng
12 thng
10 thng
6
03 thng 5 thng
7 8
3 thng
4 thng
TMT.KHCN - trang 4
II. MC TIU, NI DUNG KH&CN V PHNG N T CHC THC HIN TI 5 13 Mc
tiu ca ti (bm st v c th ho nh hng mc tiu theo t hng - nu c)
- Hon thin quy trnh cng ngh bn tng hp indirubin-3-oxime quy m
50g/m vphng php tinh ch indirubin-3-oxime.
- nh ga tc dng chng ung th ca indirubin-3-oxime trn ng vt thc
nghimXy dng quy trnh bo ch vin nang cng VINDOXIM. nh gi c tnh cp,
bn trng din v n nh ca ch phm VINDOXIM.
14
Tnh trng ti: (nh du vo cn nh du) Mi K tip hng nghin cu ca chnh
nhm tc gi K tip hng nghin cu ca ngi khc
15
Tng quan tnh hnh nghin cu, lun gii v mc tiu v nhng ni dung nghin
cu ca ti: 15.1. nh gi Tng quan tnh hnh nghin cu thuc lnh vc ca ti
Ngoi nc (Phn tch, nh gi c nhng cng trnh nghin cu c lin quan v nhng
kt qu nghincu mi nht trong lnh vc nghin cu ca ti; nu c nhng bc tin
v trnh KH&CN ca nhng kt qu nghin cu ):
+ Y hc c truyn v ng dng: Nm 1966 khi nghin cu su bi thuc c truyn
Trung Quc Danggui Longhui Wan gm 11 loi cy, cc nh khoa hc Trung Quc
pht hin ra indirubin, mt ancaloit c trong cy Indigofera tinctoria,
l hot cht chnh c tc dng iu tr bnh ung th mu (leukemia) ca bi thuc
ny [Wang, 2010]. Indirubin l thnh phn ph ca bt chm (cha indigo l
chnh) v c sn xut t mt s loi cy nh Isatis indigotica Fort.
(Brassicaceae), Strobilanthes cusia (Acanthaceae), Indigofera
suffrutticosa (Fabaceae), Indigofera tinctoria Linn. (Fabaceae) v t
loi Polygonum tinctorium (Polygonaceae) Nht [Liau, 2007]. Bt chm
(tn ting Anh- Indigo Naturalis, tn Trung quc- Qing dain, tn Vit Nam
- Thanh i) c s dng trong y hc c truyn, c bit Trung quc v Vit Nam.
Trong y hc c truyn bt chm c dng iu tr bnh ung th mu, bnh nm, tiu
si, li tiu, st, th huyt [Ti nguyn cy thuc Vit Nam, 1993). Trung
Quc, cho n nay ngi ta nghin cu v s dng cc ch phm khc nhau cha bt l
cy chm mo Strobilanthes cusia, bt l Indigofera tinctoria, bt chm,
indirubin hoc cc dn xut bn tng hp lm thuc cha nhiu loi bnh, c bit
dng trong cha bnh ung th mu. c nhiu bng sng ch v bi bo nghin cu v
dc tnh lm sng v nghin cu nh tnh, nh lng bt chm. Ngy nay vi cc th
nghim trn ngi bnh ung th mu t nm 1/2005-1/2008 bng thuc Quin Dai vi
thnh phn chnh bt chm t nhin, cho kt qu kh tt khng nh bi thuc l an
ton v hiu qu trong qu trnh iu tr bnh. Kt qu trn c ghi nhn thnh sch
nghin cu t 2/2009 [Yoan, 2009]. Hin nay ti Trung Quc sn xut dng vin
nang cha bnh ung th mu, trong hm lng bt chm chim 28-32% [Yang,
2009] v thuc tim Danquin [Cao, 2009]. + Y hc hin i- sinh hc phn t:
Nm 1999, cc nh khoa hc c nghin cu pht hin indirubin v cc dn xut tng
hp c tc dng c ch mnh mt s enzym kinaza ph thuc cyclin
cyclin-dependent kinases (CDKs) [Hoessel, 1999]. Cc CDKs khng
nhng5
Phn II - Ni dung khoa hc ca ti bt buc trnh by sang trang mi, tch
bit vi phn I - Thng tin chung
TMT.KHCN - trang 5
iu khin chu k phn bo m cn iu khin c qu trnh t cht (apoptosis),
qu trnh phin m v chc nng thn kinh. Ngoi ra, indirubin v cc dn xut
cn c tc dng c ch cc enzym glycogen synthase kinase-3 (GSK-3 ),
glycogen phosphorylase Src kinase (Start-3 signaling), v c-Jun
NH2-terminal kinase (c-JNK). Indirubin-3-oxim, dn xut tan trong nc
tt hn indirubin, c tc dng c ch mnh CDK2/cyclinE vi IC50 mc nanomol.
Indirubin-3-oxim c tc dng lm tng s bit ha, chng tng sinh v t cht ca
t bo ung th mu HL-60 (Kim, 2006). Nghin cu su hn v c ch, Chebel
[Chebel, 2009] pht hin thy indirubin-3-oxim c ch chu trnh t bo v s
t cht (apoptosis) ca t bo lympho malignant B- (IM9, Reh6) and T-
(Jurkat, CEM-T). Indirubin v cc dn xut c ch s pht trin ca t bo
lympho c tnh trong bnh ung th mu [Chebel, 2009]. Gn y, ngi ta pht
hin thy indirubin-3-oxim c tc dng trn in vitro km hm v thc y s t
cht ca t bo ung th thanh qun Hep-2 ngi [Kamerswaran, 2009]. Trn c s
nghin cu trn m hnh ha cu trc 3D ca protein Leishmania (MAPK) ch ra
rng indirubin c kh nng c ch protein HDAC4 v hn th qua phn tch in
vitro khng nh l thuc iu tr bnh ung th trong tng lai. (Mahendra
Awale, 2010) Vi cc nghin cu trn c s sinh hc phn t, gn y cc nh khoa
hc trn th gii pht hin thy indirubin-3-oxim c tc dng sau:
1. 2.3. 4. 5. 6.
Tc dng chng long xng. Krause [Krause, 2010] pht hin thy
indirubin-3-oxim hot ha Wnt signaling, lm tng nguyn bo gc
mesenchymal ngi (hMSCs), l tin sinh ca t bo to xng (osteoblasts).
iu tr bnh Alzheimers, qua th nghim trn chut vi liu dng 20mg/kg, 3
ln/tun (Jundin, 2010). C kh nng c ch con ng -catein trong iu tr ung
th (Eun Jun Park, 2010) C kh nng bo v tim khi s thiu mu cc b (nguy
c nhi mu c tim) v nhim m trong mu (gim chlestorol).(H.L.Yadav,
2010). C kh nng c ch CDK1/cyclin B.(Ying Dong, 2010) C kh nng chng
oxi ha v chng thiu mu cc b (Ana T. Varela, 2010) Chng tng sinh hai
dng ung th bch cu FLT3-WT v FLT3-ITD (Soo Yeong Choi, 2010). iu tr
ung th mu CML qua nghin cu sut 32 nm trn ngi v cho kt qu kh tt khi
i chng vi thuc Imatinib (USA), ang dc dng iu tr ung th mu. (Feng
Chen, 2010)
7.8.
Trong nc (Phn tch, nh gi tnh hnh nghin cu trong nc thuc lnh vc
nghin cu ca ti, c bit phi nu c th c nhng kt qu KH&CN lin quan n
ti m cc cn b tham gia ti thc hin. Nu c cc ti cng bn cht v ang c thc
hin cp khc, ni khc th phi gii trnh r cc ni dung k thut lin quan n
ti ny; Nu pht hin c ti ang tin hnh m ti ny c th phi hp nghin cu c
th cn ghi r tn ti, tn Ch nhim ti v C quan ch tr ti ): Vi hng nghin
cu pht trin cy thuc dn tc, TS. Nguyn Mnh Cng v cs. l nhm nghin cu u
tin v indirubin v indirubin-3-oxim t cy Chm Mo (Strobilanthes
cusia) v c mt s kt qu nghin cu quan trng. Trong qu trnh thc hin cc
ti cp b Vin KHCNVN (2007-2008), v nghin cu c bn (NCCB, 511406) nhm
nghin cu iu ch c indirubin t bt chm [Nguyn Mnh Cng, 2007] v xy dng
phng php nh lng ng thi indigo v indirubin trong bt chm [Bi Hu Ti v
Nguyn Mnh Cng, 2008]. TS. Cng v cs. tng hp v tinh ch hp cht
indirubin-3-oxim trc tip
TMT.KHCN - trang 6
t bt chm ca l cy chm mo Strobilanthes cusia [Nguyn Mnh Cng v Bi
Hu Ti, 2008, Bng c quyn gii php hu ch: Quy trnh sn xut
indirubin-3-oxim, Cc S hu tr tu, s 387, 01/06/2010), v quy trnh tng
hp indirubin-3-oxim s dng pyridine. Mt s dn xut mi ca indirubin c
tng hp v th tc dng sinh hc. Indirubin-3-oxim tng hp t ngun thc vt
trong nc c hot tnh chng tng sinh dng ung th mu LH-60 ngi trn in
vitro vi gi tr GI50 (growth inhibition) l 36,6 M [Nguyn Mnh Cng,
2010b]. Ngoi ra cc tc gi th c tnh cp v c tnh bn trng din ca hot cht
indirubin-3-oxim trn chut v th ti Hc Vin Qun Y. Kt qu th cho thy
hot cht indirubin-3-oxim an ton trn ng vt thc nghim mc liu kho st.
Indirubin-3-oxim v dn xut cn c tc dng gy tng sinh v gy bit ha dng t
bo tin to xng MC3T3-E1 (Nguyn Mnh Cng, 2010c). y l c s khoa hc cho
vic pht trin tip hot cht indirubin-3-oxime thnh ch phm, lu hnh trn
th trng, p ng nhu cu phng v cha tr bnh ung th. Indirubin-3-oxime:
bt ; mp. 225-2350C. IR (KBr) max (cm1 ): 3279, 2879, 1656, 1608,
1569, 1461, 1333, 1235, 1149, 1007, 742, 606. 1HNMR (DMSO, 500
MHz), (ppm): 13.46 (1H, s, OH), 11.73 (1H, s, H-1), 10.70 (1H, s,
H-1), 8.65 (1H, d, J = 7.5 Hz, H-4), 8.24 (1H, d, J = 8.0 Hz, H-4),
7.39 (1H, m, H-6), 7.39 (1H, m, H-7), 7.13 (1H, dt, J = 1.0; 7.5
Hz, H-6), 7.03 (1H, m, H-5), 6.95 (1H, dt, J = 1.0; 7.5 Hz, H-5),
6.90 (1H, d, J = 8.0 Hz, H-7); 13 C-NMR (DMSO), (ppm): 170.91
(C-2), 151.28 (C-3), 145.22 (C-2), 144.82 (C-7a), 138.29 (C-7a),
131.97 (C-6), 127.92 (C-4), 125.86 (C-6), 122.94 (C-4), 122.63
(C-3a), 121.39 (C-5), 120.31 (C-5), 116.48 (C-3a), 111.45 (C-7),
108.78 (C-7), 98.88 (C3). ESI-MS m/z: 278 [M+H]+, 250, 132 v m/z:
276 [M-H]-. Hnh 1. Indirubin-3-oximeHO N
5 4 3' 2' 3a 3 2O
4' 5' 6' 7' 3'a
6 7 7a 1NH
7'a
N 1' H
Danh php:
3-[1,3-Dihydro-3(hydroxyimino)-2H-indol-2-ylidene]-1,3-dihydro2H-indol-2-one.
S ng k CAS: [160807-49-8] CTPT: C16H11N3O2 KLPT: 227,28 g/mol. Cm
quan: Bt mu .
15.2. Lun gii v vic t ra mc tiu v nhng ni dung cn nghin cu ca
ti(Trn c s nh gi tnh hnh nghin cu trong nc v ngoi nc, phn tch nhng
cng trnh nghin cu c lin quan, nhng kt qu mi nht trong lnh vc nghin
cu ti, nh gi nhng khc bit v trnh KH&CN trong nc v th gii, nhng
vn c gii quyt, cn nu r nhng vn cn tn ti, ch ra nhng hn ch c th, t
nu c nhng hng gii quyt mi - lun gii v c th ho mc tiu t ra ca ti v
nhng ni dung cn thc hin trong ti t c mc tiu):
T khi cc indirubin c pht hin c tc dng trn CDKs [Hoessel, 1999] v
cc ch phn t khc, cho n nay c hng trm cng trnh, pht minh lin quan n
indirubin v dn xut. Cc nhm nghin cu mnh trn th gii v indirubin tp
trung Php, c, Trung Quc, v Hn Quc. Tnh trong 13 thng gn y, t 1-2009
n 3-2010, c trn 50 cng trnh nghin cu lin quan n indirubin (trong 24
l cc patent, 9 t Trung quc) v trn 20 bi bo v indirubin-3-oxime
(ChemFinder CAPLUS and MEDLINE). Indirubin, indirubin-3-oxime v cc
dn xut ang c nh gi nh l mt lp cht mi y ha hn trong vic phng chng
nhiu loi bnh vi c ch tc dng mi, c hiu. Cc nghin cu tp TMT.KHCN -
trang 7
trung vo vic lm sng t bn cht, c ch ca indirubin-3-oxime v dn xut
trn c s tc dng ch sinh hc phn t, nghin cu ng dng cc hot cht, dch
chit, thm ch bt l cha indirubin trong bi thuc, v thuc, v tiu chun
ha cc bi thuc, v thuc dn tc hoc kt hp vi s dng indirubin,
indirubin-3-oxime vi cc dc cht ang c s dng nhm lm tng tc dng cha
bnh. Trn th gii, indirubin-3-oxime ang c nh hng trong cha bnh ung
th mu v long xng. Indirubin, indirubin-3-oxime cn c c tc dng vi
nhiu ung th khc nh rut gi, d dy, phi Hin ti, indirubin v
indirubin-3-oxim c cc hng ha cht cho bn vi gi tng i cao. V d, hng
Betu-bio (betu-bio.com) cho gi 5mg - 361 , 1mg 91 ; Hng
Sigmaaldrich cho gi 1mg 218.34 SGD, 5mg - 792.37 SGD. Gi cao l do
trn th gii cc indirubin c sn xut bng con ng tng hp ton phn, c dng
pyridine trong phn ng nn c hi. Vic nghin cu sn xut indirubin-3-oxim
dng lm thc phm chc nng hoc h tr iu tr t nguyn liu thc vt trong nc l
hon ton kh thi. Cy Chm Mo l cy ph bin cc tnh min ni pha Bc. Ngi dn
tc Mo thng dng nhum vi. TS. Nguyn Mnh Cng v cs. nghin cu a ra quy
trnh iu ch indirubin-3-oxim trc tip t bt chm. Tuy nhin quy trnh mi
mc phng th nghim v s dng dung mi pyridin nn khng hiu qu vi sn xut
lng ln. Chng ti tip tc nghin cu v bc u tng hp indirubin-3- oxim t
bt chm bng phng php mi, khng dng pyridin. Qui trnh mi ny hiu qu hn,
khng c hi cho mi trng, d trin khai, sn xut lng ln v chuyn giao cng
ngh. Vic tip tc nghin cu ci tin quy trnh v tng hp indirubin-3-oxim
quy m ln hn, tinh ch sch v th nghim tc dng chng ung th trn ng vt
thc nghim, c tnh cp v bn trng din, n nh ca ch phm l cc iu kin tin
quyt pht trin hp indirubin-3-oxim thnh ch phm thc phm chc nng dng h
tr iu tr bnh ung th. Cc ni dung thc hin bao gm: - Hon thin quy trnh
cng ngh bn tng hp indirubin-3-oxime quy m 50g/m v phng php tinh ch
indirubin -3-oxime, nhm pht trin tip kt qu v khc phc nhc im ca ti
trc nh phng php bn tng hp cn nhi yu im: quy m phng th nghim, dung
mi c hai vi mi trng, thi gian phn ng di, cng on tinh ch cn nhiu cng
on phc tp. - nh gi tc dng dc l ca indirubin-3-oxime trn c vt thc
nghim, theo cc ti liu thu c hot cht indirubin-3-oxime c hot tnh in
vitro vi nhiu dng ung th, vic nghin cu in vivo trn ng vt thc nghim
l iu cn thit a ra bo ch hot cht c tc dng h tr iu tr bnh ung th. Xy
dng quy trnh bo ch vin nang cng VINDOXIM, nhm a hot cht
indirubin3-oxime thnh dng ch phm, m bo khng lm nh hng n tc dng ca
hot cht v d s dng trong qu trnh h tr iu tr bnh ung th. - nh gi c
tnh cp, bn trng din v n nh ca ch phm VINDOXIM, nhm kim tra c tnh ca
ch phm bo ch c nh hng ti c th, xc nh hn dng cho thuc, m bo tnh an
ton khi s dng, p ng y iu kin, tiu chun ca B Y T. 16 Lit k danh mc
cc cng trnh nghin cu, ti liu c lin quan n ti trch dn khi nh gi tng
quan:(Tn cng trnh, tc gi, ni v nm cng b, ch nu nhng danh mc c trch
dn lun gii cho s cn thit nghin cu ti)
1.
Nguyn Mnh Cng v Bi Hu Ti, Quy trnh sn xut indirubin-3-oxim t bt
TMT.KHCN - trang 8
chm, Bng c quyn Gii php hu ch (s 837) do Cc S hu tr tu cp ngy
1/6/2010 theo quyt nh s 10375/Q-SHTT. 2. Nguyen Manh Cuong, Bui Huu
Tai, Dang Hoang Hoan, Study on the acetylation and NMR reassignment
of indirubin derivatives, Natural Product Research, 2010a, 24(2),
99105. 3. Nguyen Manh Cuong, Bui Huu Tai, Dang Hoang Hoan, Tran Thu
Huong, Young Ho Kim, Jae-Hee Hyun, Hee-Kyoung Kang, Inhibitory
Effects of Indirubin Derivatives on the Growth of HL-60 Leukemia
Cells, Natural Product Communications, 2010b, 5(1), 103106. 4.
Nguyen Manh Cuong, Bui Huu Tai, Dang Hoang Hoan, Pham Quoc Long,
Eun-Mi Choi, Young Ho Kim, Synthesis and anti osteoporosis
potential of two new indirubin-3oxime derivative, J. Korean Soc.
Appl. Biol. Chem., 2010c, 53(1), 22-26. 5. Bi Hu Ti, Nguyn Mnh Cng,
Improvement of the method for simultaneous determination of
indirubin and indigo by UV-visible spectrophotometry, Tp ch Dc liu,
2008, 13(4), 152-156. 6. Bi Hu Ti, Trn Thu Hng, ng Hong Hoan, Nguyn
Mnh Cng, Nghin cu iu kin phn ng tng hp dn xut axetyl ca
indirubin-3-oxim, Tp ch Ha hc, 2008, 46(5A), 367-371. 7. Cao S.H.
et al., Determination of components in Dangqin injection with
RP-HPLC. Yiyao Daobao Zazhishe, 28 (6), 786-787. 8. Chebel A. et
al., Indirubin derivatives inhibit malignant lymphoid cell
proliferation. Leukemia & Lymphoma, 2009, 50(12), 2049-2060. 9.
Chen X.B., Cao X.G., Zhang J.H., Dong W.J., Luo S.X.. Effects of
indirubin-3'monoxime on expression of STAT3 and Bcl-2/bax in HT-29
cells. Shiyong Zhongliu Zazhi, 2009a, 24(5), 458-461. 10. Chen
X.B., Zhang J.H., Dong W.J., Cao X.G., Luo S.X., Suo Z.H.. Effect
of indirubin3'-monoxime on proliferation and apoptosis of human
HT-29 cells. Zhongguo Aizheng Zazhi, 2009b, 19(7), 503-507. 11.
Hosessel R. et al., Indirubin, the active constituent of a Chinese
antileukemia medicine, inhibits cyclin-dependent kinases. Natural
Cell Biology, 1999, 1, 60-67. 12. Institute of Haematology, Chin.
J. Int. Med., 1979. 13. Kameswaran T.R., Ramanibai R.,
Indirubin-3-monooxime induced cell cycle arrest and apoptosis in
Hep-2 human laryngeal carcinoma cells Biomedicine &
Pharmacotherapy, 2009, 63(2), 146-154. 14. Liau B.C., Jong T.T.,
Lee M.R., Chen S.S. LC-APCI-MS method for detection and analysis of
tryptanthrin, indigo, and indirubin in Daqingye and Banlangen.
Journal of Pharmaceutical and Biomedical Analysis, 2007, 43(1),
246-351. 15. Nguyn Mnh Cng, Th Thanh Thy, Nguyn Vit H, Bi Hu Ti,
Phn lp indirubin t l cy Chm Mo Strobilanthes cusia, Tp Ch Khoa hc v
Cng ngh, 2007, 45(3A), 195-199. 16. Pharmacopoeia of the Peoples
Republic of China, English, Edition 2000, Vol. 1, p. 126). 17. Yang
Y.J. et al., Chinese medicinal capsule for treating chronic
myelocytic leukemia. Patent CN2009-10043353. 18. Yoan G. et al.,
Qing Dai, a traditional Chinese medicine for the treatment of
chronic hemorrhagic radiation proctitis, Chinese-German journal of
Clinical Oncology, 2009, 8(2), 114-116. 19. Yun Ding, Aimin Qiao,
Guo-Huang Fan, Indirubin-3-monoxime rescues spatial memory deficits
and attenuates -amyloid-associated neuropathology in a mouse model
of Alzheimer's disease, Neurobiology of Disease 39 (2010) 156168.
TMT.KHCN - trang 9
20.
Eun-Jung Park, Soo Jeong Choi, Yong-Chul Kim, Sang Hyung Lee,
Seoung Woo Park, Sang Kook Lee. Novel small molecule activators of
b-catenin-mediated signaling pathway: structureactivity
relationships of indirubins. Bioorganic & Medicinal Chemistry
Letters 19 (2009) 22822284. 21. Ying Dong, Bingren Xiang, Teng
Wang, Hao Liu, Lingbo Qu, Rough set-based SAR analysis: An
inductive method. Expert Systems with Applications 37 (2010)
50325039. 22. Ana T. Varela, Anabela M. Simes, Joo S. Teodoro,
Filipe V. Duarte, Ana P. Gomes, Carlos M. Palmeira,
Indirubin-30-oxime prevents hepatic I/R damage by inhibiting GSK3b
and mitochondrial permeability transition, Mitochondrion 10 (2010)
456463. 23. Soo Jeong Choi, Myoung Ju Moon, So Deok Lee, Sang-Un
Choi, Sun-Young Han, Yong-Chul Kim, Indirubin derivatives as potent
FLT3 inhibitors with anti-proliferative activity of acute myeloid
leukemic cells. Bioorganic & Medicinal Chemistry Letters 20
(2010) 20332037. 24. Feng Chen, Lizhen Li, Daoxin Ma, Shuxin Yan,
Jianzhi Sun, Maohong Zhang, Chunyan Ji, Imatinib achieved complete
cytogenetic response in a CML patient received 32-year indirubin
and its derivative treatment, Leukemia Research 34 (2010) e75e77.
17 Ni dung nghin cu khoa hc - trin khai thc nghim ca ti v phng n
thc hin:(Lit k v m t chi tit nhng ni dung nghin cu khoa hc v trin
khai thc nghim ph hp cn thc hin gii quyt vn t ra km theo cc nhu cu
v nhn lc, ti chnh v nguyn vt liu trong ch r nhng ni dung mi, nhng
ni dung k tha kt qu nghin cu ca cc ti trc ; nhng hot ng chuyn giao
kt qu nghin cu n ngi s dng, d kin nhng ni dung c tnh ri ro v gii
php khc phc-nu c)
1. Ni dung 1:Tng quan nghin cu bn tng hp indirubin-3-oxime
2. Ni dung 2: Nghin cu to mu bt chmNghin cu, xy dng quy trnh to
mu bt chm 20-30% indirubin, quy m 30kg nguyn liu/m. Nghin cu p dng
v hon thin quy trnh, to 5 kg bt chm Nghin cu, xy dng quy trnh to bt
chm 60% indirubin t mu bt chm 20-30% indirubin, quy m 30 g/m p dng
v hon thin quy trnh xy dng, iu ch 1.5 kg bt chm 60% indirubin Nghin
cu, xy dng quy trnh bn tng hp indirubin-3-oxime, quy m 50g/m
3. Ni dung 3: Nghin cu hon thin quy trnh bn tng hp
indirubin-3-oximep dng v hon thin quy trnh bn tng hp
indirubin-3-oxime, iu ch 0.8 kg indirubin-3-oxime th Nghin cu, xy
dng quy trnh tinh ch indirubin-3-oxime, sch 97%, t
indirubin-3-oxime th, quy m 30 g/m. Nghin cu p dng v hon thin quy
trnh tinh ch indirubin-3-oxime, to 0.5 kg indirubin-3-oxime vi sch
97%.
4. Ni dung 4: nh gi tc dng chng ung th ca indirubin-3-oxime trn
ng vt thc-
nghim nh gi tc dng ca hot cht indirubin-3-oxime c ch di cn trn
dng LLC gy u
thc nghim cc liu lng khc nhau. ng thi, sau khi chut xut hin u do
b tim t TMT.KHCN - trang10
bo ung th LLC, chut c s dng ch phm nh cht cha tr cc liu lng khc
nhau. L s 9 c s dng nh l i chng ca th nghim. Theo di chut hng ngy,
cn khi lng v o kch thc khi u s cp hng tun trn chut th nghim theo
phng php ca Abrham(1978) v ca Iigo et al (1991) xc nh kh nng c ch
khi u ca Hot cht indirubin-3-oxime. Th tch khi u c tnh theo cng thc
ca Iigo (1991). Kim tra v nh gi cc ch s huyt hc; mt s ch tiu enzyme
c bn ca gan gm SGPT, SGOT; nh gi chc nng thn thng qua ch s
creatine; ng thi kim tra s di cn ca cc khi u bng trc quan.
5. Ni dung 5: Nghin cu quy trnh bo ch vin nang cng VINDOXIM, xy
dngTCCS ,kim nghim TCCS v xy dng h s thc phm chc nng. Nghin cu quy
trnh bo ch vin nang cng VINDOXIM + Nghin cu xy dng thnh phn ca vin
nang VINDOXIM + Nghin cu xy dng quy trnh bo ch v ng gi. + Bo ch th
nghim 5.000 vin nang cng Xy dng tiu chun c s + xy dng thng s ha l,
ha hc, xc nh ca hp cht. + xc nh phng php nh lng bng HPLC + xc nh hm
lng tm cht lin quan + gim hm lng do lm kh, tro sunfat, hm lng kim
loi nng, iu kin bo qun. Kim nghim tiu chun c s. + Kim nghim thuc
theo tiu chun c s xy dng v mt ha l, ha hc, phng php nh lng HPLC,
lng tp cht, gim lng do lm kh, hm lng tp cht, tro sunfat, hm lng kim
loi nng, iu kin bo qun.
- Xy dng h s thc phm chc nng+ Tp hp y cc giy t cn thit ng k ch
phm VINDOXIM lm thc phm chc nng vi B Y t Quy nh.
6. Ni dung 6: Nghin cu c tnh cp, bn trng din v n nh ca ch
phmVINDOXIM - Nghin cu c tnh cp ca ch phm VINDOXIM Xc nh liu gy c
LD50 (mg cht/kg trng lng c th) - Nghin cu c tnh bn trng din ca ch
phm VINDOXIM + Cc kt qu nghin cu th nghim trn ng vt c th v: + Trng
lng c th khi bt u, kt thc/ thay i. + Tiu th thc n, nc ung. + nh gi
v tnh trng sc khe, mc hot ng. + Nhng du hiu ng c quan st c. + Kt qu
quan st i th.
TMT.KHCN - trang11
+ Kt qu theo di v x l thng k v thng s huyt hc, sinh ha.
+ Kt qu quan st vi th, du hiu bnh l trn cc t chc (nu c).- Nghin
cu n nh ca ch phm VINDOXIM + Xc nh cht lng sn phm iu kin lo ha cp
tc. 18 Cch tip cn, phng php nghin cu, k thut s dng:(Lun c r cch tip
cn vn nghin cu, thit k nghin cu, phng php nghin cu, k thut s s dng
gn vi tng ni dung chnh ca ti; so snh vi cc phng php gii quyt tng t
khc v phn tch lm r c tnh mi, tnh c o, tnh sng to ca ti)
Cch tip cn: Cy chm mo c tn khoa hc l Strobilanthes cusia (Nees)
O. Kunze (h r Acanthaceae). Cy chm mo kh ph bin n , Trung Quc, Lo v
Vit Nam. Vit Nam theo iu tra thc t cy Chm c trng ch yu : Lai Chu,
Sn La, H Giang, Lo Cai, Yn Bi, Cao Bng, Bc Cn v ngi HMng s dng nhum
vi mu chm nn c tn l Chm Mo. Cy chm c dng sn xut bt chm nhum vi. Bt
chm c v ng, c tc dng thanh nhit, tn ut, lng huyt, gi c, tr nhit c,
sng l. Chm mo c kt hp vi cc cy thuc khc cha mt s bnh nh: vim li rng
chy mu chn rng, cha vim hnh nhn, vim hng, cha cam tu m, cha rong
kinh [1]. Mt s cht tm c trong cy chm mo: indigotin (mu xanh),
indigo (mu xanh), isoindigo (mu nu), indirubin (mu ), isoindigo (mu
), indican [3]. Cng ng ngi HMng dng cy ti ch ly l, b cnh, hi v cho
ngay vo thng g. nc vo ln men trong vng 2-3 ngy. Sau lc gn cnh l, ly
nc. vi cc vo kim ha dung dch lc. Sau bt chm c vt ra p ht nc, ct
thnh tng lp mng, phi ch mt cho n kh. Bt chm thu c c mu xanh lam, cn
c gi l bt thanh i. Bt chm ny c thnh phn ch yu l indigo v dng ch yu
nhum vi. Hm lng indirubin kh thp khong 0.5 1,5% khi lng bt chm.
Phng php nghin cu, k thut s dng:
* Tng hp ha hc:Dng phng php thc nghim cc phn ng ha hc hu c la
chn phn ng ph hp; dng phng php kho st thc nghim la chn cc iu kin
thch hp cho hiu sut cao trong phn ng. Phn ng din ra theo s 3. *
Tinh ch sn phm v kim tra tinh khit: Tinh ch sn phm s c tin hnh bng
cc phng php chy ct sc k vi cc cht hp ph nh Sephadex LH-20, Dianion
HP-20, silica gel, kt hp vi kt tinh t cc dung mi/h dung mi thch hp.
tinh khit c s b kim tra bng sc k lp mng. Kim tra nh lng bng HPLC (i
vi sn phm cui cng, nh trong phn kim nghim).
* Xc nh cu trc: Cc phng php ph nh IR, MS, NMR (1H v 13C) s c s
dng khng nh cu trc indirubin-3-oxime. * Phng php tc dng chng ung th
trn ng vt thc nghim ng vt th nghim gm 45 chut BALB/c kho mnh (chia
lm 9 l vi 5 chut/l), c nui ti khu nui ng vt ca Vin Cng ngh sinh hc
v c gy u thc nghim TMT.KHCN - trang12
bng dng t bo LLC theo tng l th nghim nh sau:
- L 1: ung ch phm X liu X1 mg/kgP/ngy trc 4 tun sau tim t bo LLC
gy u v vn tip tc cho ung ch phm thm 6 tun na.
- L 2: ung ch phm X liu X2 mg/kgP/ngy trc 4 tun sau tim t bo LLC
gy u v vn tip tc cho ung ch phm thm 6 tun na.
- L 3: tim t bo LLC gy u, ng thi ung ch phm liu X1 mg/kgP/ngy
lintc trong 6 tun na.
- L 4: tim t bo LLC gy u, ng thi ung ch phm liu X2 mg/kgP/ngy
lintc trong 6 tun na.
- L 5: tim t bo LLC gy u, sau khi c u s cp th cho ung ch phm liu
X1mg/kgP/ngy lin tc trong 6 tun na.
- L 6: tim t bo LLC gy u ng thi cho ung ch phm liu X2
mg/kgP/ngylin tc trong 6 tun na.
- L 7: tim t bo LLC gy u ng thi cho ung ch phm liu X3
mg/kgP/ngylin tc trong 6 tun na.
- L 8: tim t bo LLC gy u ng thi cho ung ch phm liu X4
mg/kgP/ngylin tc trong 6 tun na.
- L 9 (i chng): ch tim t bo LLC v cho ung PBS l dung mi c s dng
pha ch phm trong sut thi gian thc hin th nghim. Nh vy, vi b tr th
nghim nh trn, chng ti s kim tra c kh nng bo v c th ca hot cht trc
khi gy u bng t bo ung th LLC cc liu lng khc nhau. ng thi, sau khi
chut xut hin u do b tim t bo ung th LLC, chut c s dng ch phm nh cht
cha tr cc liu lng khc nhau. L s 9 c s dng nh l i chng ca th nghim.
Theo di chut hng ngy, cn khi lng v o kch thc khi u s cp hng tun trn
chut th nghim theo phng php ca Abrham(1978) v ca Iigo et al (1991)
xc nh kh nng c ch khi u ca ch phm X. Th tch khi u c tnh theo cng
thc ca Iigo (1991). V = a b2/2 Trong : V : th tch khi u a : chiu di
khi u b : ng knh khi u
TMT.KHCN - trang13
Sau khi kt thc th nghim, ton b chut c git m, thu mu kim tra cc
ch s huyt hc; mt s ch tiu enzyme c bn ca gan gm SGPT, SGOT; nh gi
chc nng thn thng qua ch s creatine; ng thi kim tra s di cn ca cc
khi u bng trc quan. Nu thy c hin tng bt thng bt k c quan ni quan no
th s thu mu c quan ni quan , c nh trong formol v chuyn vo B mn Gii
phu bnh ca Vin qun y 103 lm tiu bn t bo v phn tch bnh hc.
* c tnh cpNguyn l ca phng php: Th c tnh cp l xc nh cc mc liu gy
c (cht) ng vt th nghim sau khi cho dng mt ln hoc vi ln mu th trong
ngy. Trong trng hp cc mu th t c hoc khng c, c th xc nh mc liu dung
np ti a (liu cao nht ng vt th nghim c th chu ng c m khng b cht). Mu
th c th l thuc, nguyn liu lm thuc ang nghin cu hoc thuc mi a ra th
trng cn th c tnh cp Phng php: - ng vt th nghim: Chut nht trng, c
trng lng khong 18-22 g, tng ng vi 4-5 tun tui. - Mc liu: trong
nghin cu c tnh cp, chn cc mc liu th sao cho c th pht hin c kh nng
gy c (nu c) ca mu th, liu gy cht ti thiu, liu gy cht 50%, hoc liu
dung np ti a. - ng dng ca mu th: Mu th c a vo c th ng vt th nghim
theo ng dng d kin dng cho ngi trn lm sng hoc ng dng ang nghin cu:
ng ung, ng tim. - Theo di ng vt th nghim: theo di cc hot ng, cc biu
hin ng c/cht (nu c) ca ng vt th nghim. Ghi chp nhng biu hin, nhng
thay i so vi trc khi th hoc so vi nhm chng (nhm ng vt c dng nc ct
theo ng dng ging nh nhm th nghim). Thi gian theo di trung bnh t
48-72 gi, c th ko di n 7 hoc 10 ngy ty thuc vo thi gian bn thi v mc
c ca mu th. Kt qu: Ty vo cc d liu thu c ca th nghim c th a ra cc kt
qu: - Cc biu hin c cc mc liu th nghim - Liu dung np ti a - Liu gy
cht 50% - LD50 * c tnh bn trng din Nguyn l ca phng php: Th c tnh di
ngy ca thuc nhm xc nh kh nng dung np ca ng vt th nghim khi dng mu
th nhiu ln. Th c tnh di ngy ch c tin hnh sau khi c thng tin v c tnh
cp trn ng vt v mu th c d nh s dng hoc tip xc di ngy trn ngi. Thng
tin cn xc nh c nhng biu hin c tnh sau khi dng di ngy bao gm: - Mc
liu khng hoc c gy thay i ng k ti chc nng, c quan hoc mt s biu hin
sng c th quan st c trn ng vt th nghim. - Nhng c tnh c th quan st c
trn ng vt v kh nng hi phc nu c. Phng php: - ng vt th nghim: - Th
trng thun chng, cn nng t 2 2,5 kg. - S lng: t 8 10 con/ 1 nhm x 2 3
nhm/ mu th.
TMT.KHCN - trang14
- Thi gian th nghim: Thi gian th nghim: 28 ngy. Mc liu: Mc liu
th phi c la chn sao cho c ngha trong vic nh gi v kh nng an ton hay
mc gy c ca mu th khi dng nhiu ngy trn ng vt. Mc liu th thng c tnh t
cc thng tin thu c t th c tnh cp v c qui i tng ng theo liu gia cc
loi. Php th cn c tin hnh song song vi 1 nhm chng trong cng iu kin
vi cng s lng ng vt dng trong nhm th. Hin nay phn ln cc nghin cu c
th chp nhn vi 1 nhm chng v 2 nhm th (dng liu lm sng v liu cao hn
liu lm sng t 3-5 ln). Cho ng vt dng thuc hng ngy, 7 ngy/ tun, tr
khi c ch liu c bit. - Theo di VTN: + Quan st trn tt c cc ng vt th
nghim dng th, ghi chp cc thng s quan st c ca tng VTN khi xem xt. -
Ch tiu quan st: Theo di hng ngy v tnh trng sc khe, kh nng tiu th
thc n, nc ung, tnh trng phn, nc tiu ca ng vt th nghim. + Trng lng:
xc nh trng lng khi bt u, hng tun v khi kt thc th nghim. + Xt nghim
cc ch s huyt hc v sinh ha trc th nghim v sau th nghim so snh (c th
xt nghim gia th nghim nu cn thit): - Huyt hc: s lng hng cu, bch cu,
tiu cu, hematocrit, hemoglobin. - Sinh ha: GOT, GPT, creatinin,
bilirubin, protein ton phn, urea. - Quan st v m t cc biu hin bt
thng ca VTN, c bit lin quan ti cc chc nng h hp, tun hon, tiu ha
(nhp th, nhp tim, tnh trng nn ma, a chy, si bt mp), trn thn kinh,
vn ng nh hnh vi, c ng, i li, co git, phn x ca gic quan nh mt, mi ca
con vt. Cn c nhng quan st, nh gi phn bit cc triu chng ng c vi nhng
biu hin do tc dng dc l ca thuc (an thn, gy ng, h huyt p...). - Phn
tch m bnh hc: M nhng ng vt cht trong qu trnh nghin cu v nhng con cn
sng khi kt thc th nghim quan st i th cc t chc, u tin cc t chc gan,
thn. Quan st, nh gi cc biu hin v mu sc, hnh dng ca cc t chc. Nu thy
c biu hin khc thng so vi nhm chng, cn quan st trn vi th kim tra cc
bin i trn m hc. nh gi nhng bin i trn m hc phi c thc hin cc phng th
nghim chuyn ngnh c kinh nghim. - Khi cn theo di kh nng hi phc, phi
b sung s VTN mun gi li theo di (sau khi ht thi gian dng thuc). Vi c
quan thy b tn thng nhm th, cn xt nghim m bnh hc trn c quan nhm ph
nh gi kh nng hi phc c r hn. Kt qu: - Vi cc gi tr xc nh c biu th bng
s, lp bng tm tt cc kt qu ca c nhm v tnh thng k gi tr trung bnh
(test t student), - Vi cc ch tiu khng biu th bng s c nhn xt nh gi
lin quan - Cc kt qu c th v: + Trng lng c th khi bt u, kt thc/ thay
i. + Tiu th thc n, nc ung. + nh gi v tnh trng sc khe, mc hot ng. +
Nhng du hiu ng c quan st c. + Kt qu quan st i th. + Kt qu theo di v
x l thng k v thng s huyt hc, sinh ha. + Kt qu quan st vi th, du hiu
bnh l trn cc t chc (nu c). *Th n nh ca sn phm indirubin-3-oxime tng
hp c:
TMT.KHCN - trang15
n nh c nghin cu theo hng dn ca ICH Harmonised Tripartite
Guideline International Conference on Harmanisation of Technical
Requirements for the Registration of Pharmaceuticals for Human use.
C th s nghin cu mt iu kin lo ha cp tc nh sau: Nghin cu n nh iu kin
l ha: nhit 40C v m 75 % v/hoc nhit 60 C v m 75 % trong thi gian t
1-3 thng.
19
Phng n phi hp vi cc t chc nghin cu v c s sn xut trong nc(Trnh by
r phng n phi hp: tn cc t chc phi hp chnh tham gia thc hin ti v ni
dung cng vic tham gia trong ti k c cc c s sn xut hoc nhng ngi s dng
kt qu nghin cu; kh nng ng gp v nhn lc, ti chnh, c s h tng - nu
c)
+ Vin Cng ngh sinh hc - Xc nh tc dng chng ung th trn ng vt thc
nghim + B mn bo ch - i Hc Dc H ni
Nghin cu n nh ca sn phm VINDOXIM Kim nh tiu chun c s ch phm. +
Cng ty IMC
Nghin cu bo ch sn phm VINDOXIM t indirubin-3-oxime Sn xut th
nghim 5.000 vin nang cng. nng vi B Y T + Vin kim nghim thuc Trung
ng Xc nh c tnh cp v bn trng din ca ch phm. 20 Phng n hp tc quc t
(nu c)(Trnh by r phng n phi hp: tn i tc nc ngoi; ni dng hp tc - i
vi i tc c hp tc t trc; ni dung cn hp tc trong khun kh ti; hnh thc
thc hin. Phn tch r l do cn hp tc v d kin kt qu hp tc, tc ng ca hp
tc i vi kt qu ca ti)
Xy dng tiu chun c s sn phm VINDOXIM v ng k h s thc phm chc
Khng
Tin thc hin Cc ni dung, cng vic ch yu cn c thc hin; TT cc mc nh
gi ch yu 1 Ni dung 1 Tng quan v bn tng hp indirubin-3-oxime
21
Kt qu phi t
Thi gian(bt u Kt thc)
C nhn, t chc thc hin6 NM Cng, Vin HCTN
D kin kinh ph
6-8 trang tng quan v bn tng hp
1/20113/2011
5
6
Ch ghi nhng c nhn c tn Mc 12
TMT.KHCN - trang16
indirubin-3oxime 2 Ni dung 2 Quy trnh t sn phm bt chm 2030%
indirubin, quy m 30 kg nguyn liu/m 5 kg sn phm bt chm 2030%
indirubin Quy trnh vi quy m 30g/m. 1.5 kg sn phm bt chm 60%
indirubin Quy trnh quy m 50g/m 0.8 kg sn phm indirubin-3oxime th
Quy trnh vi quy m 30g/m 0.5 kg sn phm indirubin-3oxime 97% a ra tiu
chun ha l v ha hc nh CTPT, MS, HPLC, IR., iu kin bo 1/20115/2011 NM
Cng, Vin HCTN 20
Nghin cu, xy dng quy trnh to bt chm 20-30% indirubin.
Nghin cu p dng quy trnh xy dng, to 5 kg bt chm 20-30% indirubin
Nghin cu, xy dng quy trnh tinh ch to bt chm 50-60% indirubin t bt
chm 20-30% indirubin Nghin cu p dng quy trnh xy dng, to 1.5 kg bt
chm 50-60% indirubin 3 Ni dung 3 Nghin cu hon thin quy trnh bn tng
hp indirubin3-oxime, quy m 50g/m Nghin cu p dng quy trnh bn tng hp,
to 0.8 kg indirubin-3-oxime th Nghin cu, xy dng quy trnh tinh ch to
indirubin3-oxime sch 97% t indirubin-3-oxime th Nghin cu p dng quy
trnh xy dng, to 0.5 kg bt indirubin-3-oxime 97% Xy dng tiu chun c s
ca indirubin-3-oxime
3/20117/2011
NM Cng, Vin HCTN
80
5/20118/2011
NM Cng, Vin HCTN
18
6/20119/2011
NM Cng, Vin HCTN
60
7/201110/2011 8/201011/2011
NM Cng, Vin HCTN NM Cng, Vin HCTN
20
50
9/201012/2011
NM Cng, Vin HCTN
18
10/201012/2011
NM Cng, Vin HCTN
60
1-2/2012
NM Cng, Vin HCTN
16
TMT.KHCN - trang17
qun 4 Ni dung 4 B kt qu v ch s huyt hc, mt s ch tiu enzyme, ch s
creatine, s di cn khi u bng trc quan Quy trnh y s liu v thnh phn
vin nang, 5.000 vin nang cng kt qu cho bit liu gy c LD50 kt qa cho
bit cht lng ch phm iu kin lo ha cp tc giy xc nhn kim ra TCCS ch phm
01 hi tho 3/2012 10/2011 12/2010 8/2012 10/2012 NM Cng v cs., Vin
HCTN 24 1-3/2012 T Tho, Vin CNSH 30
Nghin cu tc dng chng ung th ca indirubin-3oxime trn ng vt thc
nghim
5
Ni dung 5 1-5/2012 Xy dng quy trnh bo ch vin nang cng VINDOXIM,
to 5.000 vin nang cng. Lm h s ng k thc phm chc nng NV Phc, Cng ty
IMC 25
6
Ni dung 6 Nghin cu c tnh cp v bn trng din ca ch phm VINDOXIM
5-9/2012 NK Hng, Vin KN NV Hng, i Hc Dc H Ni 50
5-9/2012
20
Nghin cu n nh v kim nghim TCCS ca ch phm VINDOXIM
7
Ni dung cng vic khc Hi tho khoa hc Kim tra tin 2011 Tng kt giai
on 1 Kim tra tin 2012 Nghim thu cp c s v Thnh ph.
III. SN PHM KH&CN CA TI TMT.KHCN - trang18
22
Sn phm chnh ca ti v yu cu cht lng cn t (lit k theo dng sn phm):
Dng I: Mu (model, maket); Sn phm (l hng ho, c th c tiu th trn th
trng); Vt liu, Thit b, my mc; Dy chuyn cng ngh; Ging cy trng; Ging
vt nui v cc sn phm khc) Mc cht lng
Tn sn phm c th v ch TT tiu cht lng ch yu ca sn phm 1
n v o
Cn t
Mu tng t (theo cc tiu chun mi nht) Trong nc Th gii c tinh khit
97% theo HPLC CTPT C16H11 O2
D kin khi lng, quy m sn phm to ra
Khi lng 5 g tinh 97%. khit Cha c
Indirubin-3oxime dng tinh g khit
Ha l: bt mu Ha hc: CTPT C16H11O2, c d kin ph
Khi lng 5 g vi tinh khit l 97 %.
2
Ch phm VINDOXIM Vin
5.000 vin nang cng, c thnh phn ng vi cng thc bo ch ng k trn nhn
sn phm chc nng VINDOXIM Hm lng 25-40 mg indirubin-3oxime /vin
Cha c
Cha c
5.000 vin nang cng
22.1. Mc cht lng cc sn phm thuc Dng I so vi cc sn phm tng t
trong nc v nc ngoi (Lm r c s khoa hc v thc tin xc nh cc ch tiu v
cht lng cn tca cc sn phm ca ti)
Sn phm indirubin-3-oxime tinh khit c nh gi qua ch tiu cm quan,
ha l v ha hc, c d kin ph ng theo cht chun c s CAS: [160807-49-8].
Sn phm indirubin-3-oxime c nghin cu bo ch, sn xut to ch phm v ng k
h s thc phm chc nng. Sn phm cn t trong ti l c B Y T chp nhn thc phm
chc nng VINDOXIM. Dng II: Nguyn l ng dng; Phng php; Tiu chun; Quy
phm; Phn mm my tnh; Bn v thit k; Quy trnh cng ngh; S , bn ; S liu,
c s d liu; Bo co phn tch; Ti liu d bo (phng php, quy trnh, m
hnh,...); n, quy hoch; Lun chng kinh t - k thut, bo co nghin cu kh
thi v cc sn phm khc Tn sn phm Yu cu khoa hc cn t Ghi ch TT qui trnh
to bt chm, quy m 30 kg nguyn liu/m, 01 1 Quy trnh to bt TMT.KHCN -
trang19
2
3
4
5
6
chm vi quy m 30 kg nguyn liu/m Quy trnh bn tng hp
indirubin-3-oxim vi quy m 50g/m Quy trnh bo ch vin nang cng
VINDOXIM Bo co nh gi nghin cu tc dng chng ung th ca
indirubin3-oxime Bo co phn tch nh ga tnh an ton v n nh ca ch phm
VINDOXIM B h s thc phm chc nng vi B Y T B bo co chuyn K yu hi tho
Bo co tng kt Bo co tm tt Ph lc a CD
bt chm cha 20-30% indirubin 01 qui trnh bn tng hp
indirubin-3-oxime, quy m 50g/m. qui trnh bo ch dng vin nang cng vi
s lng 5000 vin B bo co phn tch s liu nghin cu tc dng chng ung th
trn dng LLC, xc nh liu, cc ch s huyt hc v mt s ch tiu ha sinh c bn
01 B bo co phn tch biu hin c ti liu kho st, liu dung np ti a, liu
gy cht 50% (LD50) B bo phn tch kt qu v thng s huyt hc, sinh hc co s
liu y Tng quan c tnh hnh nghin cu, xy dng c quy trnh bn tng hp
indirubin-3-oxime, kt qu th kh nng chng ung th, an ton ch phm, bo
ch v bo ch ch phm VINDOXIM y co bo co tham lun ti hi ngh y kt qu ti
y kt qu ti Cc kt qu ti Cc kt qu ti D kin ni cng b(Tp ch, Nh xut
bn)
01 01
01 01
7 8 9 10 11 12
01 01 01 01 01
Dng III: Bi bo; sch chuyn kho v cc sn phm khcTT
Tn sn phm Kt qu nghin cu dc l ca indirubin-3oxime hoc ch phm
Yu cu khoa hc cn t
Ghi ch
1
c bin tp trn c s kt qu nghin cu ca ti
- Tp ch Dc hc, Tp ch KH&CN -Tp ch Ha hc
1
22.2. Trnh khoa hc ca cc sn phm thuc Dng II v Dng III so vi cc
sn phm tng t hin c (Lm r c s khoa hc v thc tin xc nh cc yu cu khoa
hc cn tca cc sn phm ca ti)
Cc sn phm dng II c lit k v m t nh trn m bo p ng yu cu ca S
KH&CN, S Y t i vi mt ti nghin cu khoa hc cp thnh ph. Cc bi bo m
bo yu cu chun xc v mt ni dung khoa hc v p ng yu cu ca ban bin tp,
nh xut bn. TMT.KHCN - trang20
Cc quy trnh bo co y tnh s liu khoa hc theo yu cu t ra ca nhim v
ti.
22.3. Kt qu tham gia o to trn i hc S Cp o to l Chuyn ngnh o to
TT ng
Ghi ch
22.4. Sn phm d kin ng k bo h quyn s hu tr tu, quyn i vi ging cy
trng khng
23
Kh nng ng dng v phng thc chuyn giao kt qu nghin cu 23.1. Kh nng
v th trng (Nhu cu th trng trong v ngoi nc, nu tn v nhu cu ca
khchhng c th nu c; iu kin cn thit c th a sn phm ra th trng)
Hin nay trn th trng Vit Nam c nhu cu iu tr bnh ung th rt cao. Hu
ht thuc ang phi nhp khu m cha c sn xut trong nc. Gi thnh thuc nhp
khu cao. Nh vy, nu trin khai sn xut trong nc c th gi thnh s gim ng
k, tit kim c chi ph cho bnh nhn. Tuy nhin, nu sn xut m phi nhp khu
nguyn liu th gi thnh vn cao. Chnh v vy, ti ny thnh cng s l c s cho
vic tn dng c nguyn liu bt chm sn c cho nhu cu h tr iu tr ca bnh nhn
ung th ti H Ni cng nh nhu cu chung ca c nc hin ang ngy cng tng.
23.2. Kh nng v ng dng cc kt qu nghin cu vo sn xut kinh doanh (kh
nngcnh tranh v gi thnh v cht lng sn phm)
Vi quy trnh v dy chuyn cng ngh tng hp indirubin-3-oxime c th ng
dng trin khai tng hp to ngun nguyn liu ha dc phc v cho nhu cu sn
xut ch phm iu tr ung th trn a bn thnh ph H Ni cng nh ton quc. Qua
tham kho quy m sn xut mt s cng ty ca Trung Quc, chng ti thy hu ht
cng ch sn xut bng quy trnh quy m nh (kg), gi tng i cao, v vy v gi
thnh indirubin-3-oxime tng hp trong nc hon ton c kh nng cnh tranh v
gi (v li th v gi nguyn liu, hn na chi ph nhn cng Vit Nam cng thp hn
cc nc khc). 23.3. Kh nng lin doanh lin kt vi cc doanh nghip trong
qu trnh nghin cu Cng ty IMC s phi hp cht ch thc hin ti. Hin Cng ty
IMC c nhiu sn phm thc phm chc nng v thuc trn th trng. Cc kt qu (quy
trnh, sn phm VINDOXIM) s c chuyn giao vo sn xut ti TMT.KHCN -
trang21
nh my ca cng ty IMC. 23.4. M t phng thc chuyn giao (chuyn giao
cng ngh trn gi, chuyn giao cng ngh co to, chuyn giao theo hnh thc
tr dn theo t l % ca doanh thu, lin kt vi doanh nghip sn xut hoc gp
vn - vi n v phi hp nghin cu hoc vi c s s p dng kt qu nghin cu -
theo t l tho thun cng trin khai sn xut, t thnh lp doanh nghip trn c
s kt qu nghin cu to ra,...)
Lin kt vi Vin thc phm chc nng sn xut theo phng thc chuyn giao
cht u to sn phm VINDOXIM sn xut vin nang cng thc phm chc nng dng
cho ng k sn xut trong nc. 24 Phm vi v a ch (d kin) ng dng cc kt qu
ca ti Cng ty IMC l n v phi hp sn xut thc phm chc nng cha hot cht
indirubin-3oxime phc v nhu cu phng v h tr iu tr cho bnh nhn ti TP H
Ni cng nh trn ton quc. 25 Cc li ch mng li v cc tc ng ca kt qu nghin
cu 25.1. i vi lnh vc KH&CN c lin quan(Nu nhng d kin ng gp vo cc
lnh vc KH&CN trong nc v quc t)
a ra mt quy trnh mi cho sn xut indirubin-3-oxime t ngun nguyn
liu thc vt sn xut nguyn liu thuc trong nc. Gip pht trin kinh t vng
ng bo t ngi, c th em v ngoi t cho ngn sch thnh ph qua xut khu thuc.
25.2. i vi t chc ch tr v cc c s ng dng kt qu nghin cu Kt qu ca ti c
ng dng vo sn xut s em li nhng li ch to ln cho t chc ch tr v cc c s
ng dng. i ng cn b nghin cu tham gia vo ti c iu kin hc hi v thu c
nhiu kinh nghim cho thc hin cc ti tip theo. ti cng ng gp quan trng
trong nhim v o to ca c quan ch tr ti. 25.3. i vi kinh t - x hi v mi
trng(Nu nhng tc ng d kin ca kt qu nghin cu i vi s pht trin kinh t -
x hi v mi trng)
...Kt qu ca ti cung cp c ch phm thuc h tr cho cc bnh ung, mt
thuc ang c nhu cu tng cao ti Vit Nam. D kin kt qu ca ti s c ng dng
trin khai vo thc t, to cng n vic lm cho nhiu ngi lao ng thnh ph H
Ni v ng bo dn tc t ngi, tit kim ngoi t t vic khng phi nhp khu thuc,
gim gi thnh thuc, gim gnh nng chi ph cho ngi bnh ti TP H Ni cng nh
c nc.
TMT.KHCN - trang22
IV. KINH PH THC HIN TI V NGUN KINH PH7 (Gii trnh chi tit xem ph
lc km theo) n v: Triu ng 25TT
Tng hp kinh ph thc hin ti theo cc Khon chiKhon chi Ngun kinh ph
Tng s Trong : Ngn sch SNKH Nm th nht Nm th hai Nm th ba Vn t c ca t
chc Nm th nht Nm th hai Vn khc Nm th nht Nm th hai Tng sCng lao ng%
Kinh ph t ch Kinh ph khng t
Trong :Nguyn, vt liu, nng lngKinh ph t ch Kinh ph khng t %
Thit b, my mcKinh ph khng t
%
Xy dng sa cha nhKinh ph khng t
Chi khc% Kinh ph t ch Kinh ph khng t %
950
434 434 194 240
45.69 45.69 29.84 80.00
419 419 412 7
44.10 44.10 43.3 7 1.76
97 97 44 53
10.21 10.21 4.63 5.58
1 a b c 2 a b 3 a b
650 300
................., ngy ........ thng ........ nm ..........CH
NHIM TI T CHC CH TR THC HIN TI C QUAN C GIAO K HOCH8 S KHOA HC V
CNG NGH H NI9
Nguyn Mnh Cng7 8
Phm Quc Long
Phn V - Kinh ph thc hin bt buc trnh by sang trang mi, tch bit vi
Phn III - Sn phm ca ti Ch ghi h tn, k v ng du khi ti c ph duyt. 9
Ch ghi h tn, k v ng du khi ti c ph duyt
TMT.KHCN - trang 23
