• Nghien CIFU - Ky thuat
Ket luan
Td cao ehiet la actisfi da phdn lap dygc 3 hgp ehit polyphenol, trong dd cd 2 chit dd xdc djnh cau true id flavonoid (cynarosid vd scoiymosid) vdi khdi iygng vd do tinh khiet cd the sd dijng de thiet lap cde ehat chuin ddi chieu giup eho vige djnh lygng cde flavonoid ndy trong cdc ban thdnh pham (cao chiet) va cde ehd pham do ede flavonoid eo tac dijng hiep ddng vdi cynarin, acid ciorogenie va edn cfi tac dung tren mpt sd benh tim mgch. Ben canh cac flavonoid da dygc cfing bfl, eae hgp ehat polyphenol khac trong cdy actisfi cung se dygc cac tac gia cfing bd trong cdc bai bdo sap tdi.
Tai lieu tham khao 1. D 5 T i t Lgi (2000), NhCing cay thuoc v^ vj thudc vm Nam. NXB Y hpc , tr. 221-222,
2. Vien Dygc lieu (2004), Cay thudc va dong v$t
lam thudc a Viet Nam, NXB Khoa hpc va Ky thult, tgp 1,79-81.
3. Ngfi Van Thu (1998), Sd/sriang Dupc t ^ u , Bai hpc Y Dugc Tp, Hd Chi Minh, tdp 1, tr. 307-311.
4. M. Hausler, M. Ganzera, G. /\bel, M. Pc^p, H Stuppner (2002), "Dertermination of Caffeoylquinic adds and Flavonoids in Cynara scolymus L, by High Peribrmance Liquid Chromatography", Chromatographia, 56, pp, 497-411.
5. Lattanzio V,, Paul A, K., Linsaiata V., Cardinal!
A. (2009), "Globe artichoke; A functional food and source of nutraceuticai ingredients", Joumal of functional food, 1, pp. 131-144.
6. X. F. Zhu, H, X. Zhang (2004), "Flavonoids of Cynara scolymus". Chemistry of Natural Compounds, Voi.40(6), pp. 600-601.
7. Mingfu Wang, James E.Simon, Irma Fabida Aviles, Kan He, Qun-Yi Zheng, and Yaakov Tadmor (2003), "Analysis of /\ntioxidat"ve Phenolic Compounds in Artichoke (Cynara scolymus L.)", Joum^ of Agricultural and F^od Chemistry, 51,601-608.
Xay dirng quy trinh phan tich
•^ r
ddng phan doi quang cua omeprazol
^ r
bang sac liy long hieu nang cao
LS Dinh Chi, Tli^i Nguyin Hung Thu' Trud'ng Dai hoc Ducrc Hd NSi
E-mail: [email protected] Summary
An HPLC method was developed for enantiomeric separation of omeprazole. The main chromatography conditions are as follows: Chiral AGP column (150x4.6 mm; 5 ijm); mobile phase:
aeetonitrile - 10 mM solution of sodium dihydrogenphosphate pH = 5.0; UV detector: 210 nm; flow rate: 0.8 ml/min; injection volume: 20 pi. The method was proven in terms of specificity, linear^, precision and repeatability, all suitable for indentification and assay of esomeprazol. LOD and LOQ of the method were also determined for detecting R-omeprazole as enantiomeric impurity in pharmaceutical preparations containing esomeprazole.
Keywords: HPLC, R-omeprazole, S-omeprazole.
Dat van de
Omeprazol Id mpt hoat chit thuge nhdm dc ehi bom proton HI dyge dung trong ^eu tri ioet da ddy ta trdng. Phan td omeprazol cd mgt nguyen td lyu huynh bit ddi nen hgp chat nay tdn tgi dydi dang hon hgp raeemic cua 2 ddng phdn ddi quang: R-omeprazol vd S-omeprazoi (hay esomeprazol), Theo mfit sd nghien edu da dyge
cfing bd, do ddng phan S-omeprazoi it chju anh hydng cua qud trinh chuyen hda tai njpt non vd gan hon R-omeprazol ndn d cung mfit lieu dung, dgng esomeprazol eho ndng dp trang huyet tyong d pha dn djnh eao hon dgng omeprazol raeemic td 70 - 90% '^"^'. Omeprazol da dyge sd dgng td iau dydi dgng hon hgp raeemic dydi nhieu tdn bidt dyge (Losec, Prilosee,..) vd thudc generic. ^ TAP CHf DirOC HQC - 08/2013 (SO 448 N A M 53)
' Nghien ciru - Ky thuat
Bdn eanh dgng raeemic, ddng phdn S-omeprazol (hay esomeprazol) tinh khilt ci3ng da d y g e s d dgng trong mfit sd bigt d y g c nhy Nexium cOa fi^ra Zeneca.
Hign tgi, trang Dygc d i l n Vi$t Nam IV v i n chya cfi chuyen ludn rieng eho S-omeprazol eung nhy phyong phdp ehinh thdng d l phdn t i d i ddng phdn ddi quang eua omefxazol. Tgi Vi^ Nam, g i n day da cd quy trinh d y g c cfing bd s d dyng k j thudt HPLC trdn cpt hogt quang gan c l - a d d glyeopratein (AGP) d l tdch cac ddng phdn ddi quang eua amlodipin^"^. Trong nghien cdu ndy, ehCing toi s d dgng ky thugt ndy de thidt ldp quy trinh phdn tich ddng phdn ddi quang cua omeprazd.
<J
/
Hinh 1 : Cong thuv cau t^o eua R-omeprazol (A) va S-omeprazol (B)
N g u y e n l i e u v a p h u x y n g p h a p C h i t d d i c h i l u , t r a n g thiet b j , d u n g m d i v d hoa chat
C/iitdid/c/iieu
- Chuan lam vigc omeprazol eua Vign Kiem nghigm thude TW (hdm l y g n g : 99,89%; dp I m : 0,16 %).
- Chuan esomeprazol natri eua Cipla (An Dp) (SKS: ESFP 11001; hdm l y g n g : 98,6%).
Tiang thiet bi
- May sac ky long hieu ndng eao Shimadzu trang bj detector PDA.
- c o t Chiral AGP (150 >« 4,6 mm, 5 pm) eua Chiral Technologies Inc.
Dung moi va hoa chit
- Dung mfii loai dCing cho HPLC: acetonitril, methanol, isopropanoi.
- Hfia ehat logi tinh khilt phdn tieh' acid phosphoric, natri hydroxyd, natri dihydraphophat, nydc d t .
D d i t i r g n g n g h i d n c d t i
M l u thudc tiem Esomeprazol 40 mg, Pharbaeo, SKS: 132011.
TAP CHf DirqC HQC - 08/2013 (S6 448 NAM S3)
P h u v n g phap nghien c u u Didu kiin sac ky
Qud trinh taeh hai ddng phdn R-omeprazoi vd esomeprazol d y g c thyc hien bang ky thudt sde ky long hidu nang eao tren ept s i c ky hoat quang Chiral AGP (pha tTnh id a l - acid glycoprotein) vdi cde dieu kien khdi diem eua hd thdng sac ky nhy sau: detector PDA ddt tai b y d c song 210 nm; the tfch tiem m l u 20 pi; tde dfi dfing 0,8 ml/phut; pha dgng Id hdn hgp acetonitril - dung djch natri di hydrophosphat 10 mM. Khao sdt tdi y u hda pH dung dich ddm vd thdnh phan pha dfing Id hai y l u td quan trgng n h i t anh h y d n g tdi khd ndng tdeh hai ddng phan ddi quang cua omeprazol. Quy trinh phan tich sau khi tdi y u hda se d y g e tham djnh va dp dung djnh l y g n g cdc ddng phdn ddi quang cua omeprazol trong c h l pham thude.
Chuan bi miu
- Dung djch chuin S-omeprazol: c h u i n bj dung djeh ehuan esomeprazol trong methanol cfi ndng dp esomeprazol ehinh xde khoang 150 iag/mi. Pha loang ehinh xde dung djch ndy trong pha dfing d l thu d y g c dung djch chuan esomeprazol eo ndng dp khodng 15 ng/ml. Lgc qua mdng Igc 0,45 jim t r y d c khi tiem s i e ky.
- Dung djch chain omeprazol raeemic. c h u i n bj dung djch chuin omeprazol raeemic trong methanol cd ndng dp omeprazol raeemic chinh xdc khodng 300ng/ml. Pha loang ehinh xde dung djch nay trong pha dpng de thu dyge dung djeh chuan omeprazol cd ndng dp khodng 30|ig/mL Lpc qua mdng Ipe 0,45 pm tryde khi tiem sac ky.
- Dung dich thir. Can mpt l y g n g ehe p h i m t y o n g dng vdi khodng 15,0 mg esomeprazol (vdi c h l p h i m chda esomeprazol) ho^c 30,0 mg omeprazol raeemic (vdi c h l p h i m chda omeprazol raeemic) vdo binh i^nh mde 100 ml, hfia tan va them v d a du bang methanol, Ipe qua g i l y Ipc. Hut chfnh xde 2,0 ml djeh Ige pha lodng bang pha dpng thdnh 20 ml, Ipc qua mdng igc 0,45 pm tryde khi tiem sde ky,
K e t q u a v a b a n l u $ n Khao sat chgn dieu kign sac ky L u a chgn pH dung dfch NaH2P0i 10 mM Do quy ^ n h s d dung cfit Chiral AGP cht cho phep pH pha dpng dao dpng trong khodng t d 4 den 7 nen ehung tfii da Wiay ddi pH dung djch natn dihydrophosphat 10 mM t d 5,0 d i n 6,5 vd gid nguyen ty Id pha dfing acetonitril : dung d j d i natri dihydrophosphat 10 mM (10:90). K i t qud thye nghigm eho thiy, mde pH = 5,0 (hinh 2d) Id hgp ly
i Nghien CIFU - Ky thuat
hon ca, eho phdp tdeh tdt hai ddng phan ddi quang eCia omeprazol vdi dydng nen phang, it nhieu, trong khi cac mde pH cao hon (Hinh 2a, 2b
va 2c) deu khdng cai thien nhilu dygc dg phan gidi vd sde kjf dd thu dygc eho thay tgi cdc mde pH ndy khd ndng phdn tich khfing dn ^nh.
1
c) . « - « . ^ - d) Hinh 2: Anh hwang cOa pH dung djch NaH2P04 10 mM tdi kha nang tach eac ddng phin ddi quang
cua omeprazol: a) pH = 6,5; b) pH = 6,0; c) pH = 6,5; d) pH = 5,0 LiPa chgn ty /g thinh phdn pha dgng
Sd dyng hon hgp acetonitril idung djch NaH2p04 10 mM pH = 5,0 Idm pha dfing, Chiing tdi da khdo sdt anh hydng cua vide thay ddi ty Id 2 thdnh phin trong h5n hgp trdn tdi kha ndng tach hai ddng phdn ddi quang cOa omeprazol.
Kit qua thyc nghigm cho thay ty le dung djch natri dihydrophosphat trong pha dfing tdng se
lam tang khd nang tach hai dong phdn, nhyng eung Idm tang thdi gian lyu cua ea hai ddng phdn do do kdo ddi thdi gian phan tieh (hinh 3).
De thda man hai ydu cau: dfi phdn gidi tdt vd thdi gian phdn tieh hgp ly, ty id pha ddng acetonitril: dung djch NaH2P04 pH = 5,0 (10:90) Id thieh hgp hon ed (hinh 3e).
.rviViL
Hinh Z: Anh huxmg cOa t^ li thanh phan hdn hcfp pha dgng acetonitri: NaH2P04 10mf\4pH=5,0t(n khi nang tieh eac ddng phan ddi quang cua omeprazol: a) 25:75; b) 12,5:87,5; c) 10:90 Nhy vdy, dilu kign sde ky cudi cung dyge
Chung tfii thiet lgp cho quy trinh phdn tieh ddng phan ddi quang cCia omeprazol nhy sau:
Cgt Chiral AGP (150 x 4,6 mm, 5 pm).
Detector UV: 210 nm,
Pha dgng: aeetonitril;NaH2P04 10 mM pH=5,0 (10:90),
32
Tde dp ddng: 0,8 ml/phut.
The tieh tiem mau: 20 \x\.
Tham djnh quy trinh
Quy trinh phdn tieh ddng phdn ddi quang eiia omeprazol dygc xdy dyng nham mge dfch cho ede dng dyng sau:
T ^ CHf DITQC HQC - 08/2013 (SO 448 NAM 53)
Nghien CIFU - Ky thuat
- Djnh tinh phdn bi^t omeprazol raeemic vd esomeprazol trong chl phim thudc.
- Ojnh lygng esomeprazol trong che phim thudc.
- Phat hign tgp R-omeprazol trong chl phim ehda esomeprazol.
Td xuit phat diem dd, ehung tfii da thim djnh quy trinh ve:
- Dg dge higu khi djnh tfnh phan bidt gida omeprjzol raeemic vd esomeprazol.
- t n phu hgp hg thdng, khoang tuyln tfnh, dd ldp ldi, dfi chfnh xdc trung gian, dp dung khi djnh iLong esomeprazol.
- Gidi han dinh lygng, gidl hgn phdt hidn khi xdc dinh tap R-omeprazol.
Dg die hiiu
Tien hdnh phdn tich chuan omeprazol raeemic, chuin esomeprazol va chl pham thudc tidm Esofirst chda esomeprazol, ket qud thgc nghigm cho thiy: sac ky do eua chuin esomeprazol vd ehe pham Esofirst chi cho 1 pic dygc tdch rieng bigt eua esomeprazol tgi thdi gian iyu khodng 8,8 phCit (hinh 4b vd 4c); trong khi dfi sdc ky dd ehuin omeprazol raeemic cho 2 pie dygc tach rieng bigt tyong dng vdi 2 ddng phan ddi quang, trong dd pic rda rdi ra sau Id esomeprazol, pie xuit hidn sdm hon (cfi thdi gian lyu khoang 5,3 phut) Id R-omeprazol (hinh 4a). Nhy vdy, quy trinh ddp dng dygc ydu clu ve dfi dae higu khi phdn tich ehe phim chda omeprazol raeemic hoge esomeprazol.
K A iL_
JL
c;
Hinh 4: Sic ky dd cua chuan omeprazol raeemic (a), cOa ehuin esomeprazol (b), vi cOa thude tiem Esofirst (c)
vd 3 Iln phdn tfch ddc lgp khae ngdy. Gid trj RSD thu dyoc Id 1,8%.
Do dung
Dygc kilm tra bdng them chuin esomeprazol vdo nln mau d 3 mde ndng dp khdc nhau, mdi ndng dg tien hdnh 3 lan, d mil mde, lygng chuin esomeprazol dygc thdm vdo nln mlu da cd mdt lygng che pham tyong dng vdi khoang 10 mg esomeprazol de cd tdng lygng esomeprazol khodng 12 mg, 15 mg vd 18 mg (tyong dng Iln lygt vdi 80%, 100% vd 120% ndng dO mlu thd sd dgng d l djnh lygng), sau do xdc djnh ty 1^ tim Igi dygc so vdi lugng thdm vdo miu. Kit qud nhy sau:
- A^tic 1: Lygng esomeprazol ehuin thdm vdo nln mlu Id 2,06 mg, ty lg tim lgi ndm trong khoang: 99,1 -101,6%.
Do phu hgp h$ thdng
Dygc kiem tra tren kit qud sau 6 lan tiem lgp Igi dung djch chuin esomeprazol. RSD cQa thdi gian lyu Id 0,09% vd eua dign tieh pie Id 0,5%.
Khoing tuydn tinh
Trong khoang ndng dfi khao sdt 5,66 - 35,37 ^g/ml, phyong trinh hdi quy thu dyge Id S
= 135710.C-3372a vdi r= 0,9992, Dd lip Ifti
Dygc kiem tra tren hdm lygng esomeprazol thu dygc sau 6 Iln phdn tfch dpe lgp mau chl pham. Gid trj RSD thu dygc Id 1,4%.
D^ chinh xic trung gian
Dygc kilm tra trdn hdm lygng esomeprazol thu dygc sau 6 Iln phdn tfch ddnh gid dO i$p Igi
TAP CHi DlTQC HQC - 08/2013 (S6 448 NAM 53) 33
• Nghien CIFU - Ky thuat
- fi/ICfc 2: Lygng esomeprazol chuin eho thdm vdo nen mau Id 5,14 mg, ty lg tim Igi ndm trong khoang: 98,2 -101,5%.
- Mde 3: Lygng esomeprazol chuin cho them vdo nen mau Id 8,22 mg, ty Id tim lai nam trong khodng: 98,3 -101,8%.
Gfdv h^n dinh luvng (LOQ), gidi han phit hien (LOD) vai R-omeprazol
Vdi cdc chl phim chda esomeprazol, R- omeprazol la tgp ddi quang can kiem sodt. LOD, LOQ vdi R-omeprazol dyge xdc i^nh bdng cdch pha loang chfnh xdc dung djch chuan omeprazol raeemic (ehda 49,47% R-omeprazol) d nhilu mde dfi khdc nhau, so sdnh ddp dng pic cOa R- omeprazol vdi dao dpng cua dydng nen. Vdi ndng dO R-omeprazoi d ede mde 1,08 ng/ml vd 3,56 pg/ml, ddp dng pic thu dygc tren sac ky dd cCia R-omeprazol cao hon Iln lygt gap 3 iln (hinh 5a) vd 10 Iln so vdi dao dpng dydng nln (hinh 5b). Nhy vdy LOD Id 1,08 pg/ml va LOQ Id 3,56 pg/ml tfnh trdn ndng dp R-omeprazol trong dung djch tidm vdo hg thdng sic ky.
_JL.
Hinh 5: Sic ky dd chuan omeprazol raeemic d ndng dp giai han phit hi^n (a) vi gi&i h?n djnh lu^ng (b) eua R-omeprazol vi sie k^ dd mdu Esofirst (c)
Chuydn lugn esomeprazol magnesium cua Dygc (Sdn An DO 2010 '^', gidi hgn R-omeprazol
dygc quy djnh khong qud 0,2%. De phdt higr dygc tgp R-omeprazol d mde ndy, chung tfii chuan bj dung djch thd (thudc tidm Esofirst) cfi ndng do esomeprazol khodng 2 mg/ml. Khi dfi, neu tap R-omeprazol cd trong mHu d mde 0,2%
(4 pg/ml) hay cao hon, chung toi se phdt hi$n dygc vdi eac dilu kign sac ky da xay dg'ng, do trong trydng hgp dd ndng dfi tgp R-omeprazol trong mlu da Idn hon LOQ eua quy trinh vdi R- omeprazol.
Cdc ehf tidu dd duQfc thim djnh d trdn, chdng td quy trinh chung tdi xay dgng efi khoang tuyln ti'nh phu hgp, dfi dung, dg lap lgi vd dg chfnh xac trung gian tdt khi dp dgng djnh lygng omeprazol raeemic hay S-omeprazol trong chl phim thudc.
Lfng dung quy trinh
Quy trinh sau khi thim djnh da dygc dng dgng de kiem tra djnh tinh, djnh lygng esomeprazol va xdc ^nh tgp R-omeprazol trong ehe phim thudc tidm Esofirst. Kit qud thyc nghidm cho thay:
Vg djnh tinh: ehe pham Esofirst ehda esomeprazol, dung nhy thdnh phan tren nhan (hinh 4c).
- Vd dinh Iwong: ham lygng esomeprazol trong chl pham Esofirst xac djnh dygc Id 39,1 mg/ip bfit ddng khfi. Ham iygng ndy dgt 97,8%
so vdi hdm lygng ghi trdn nhan.
- Tnen dung dich thu' dCing de xde d\nh tgp R-omeprazol, khfing phdt hi$n thay pic R-omeprazol (hinh 4c vd 5e).
Ket lu|n
Quy trinh phdn tfch cdc ddng phdn ddi quang cua omeprazol bdng HPLC sd dgng cOt sac ky chda pha tTnh hoat quang a1-add glyeoprotan ChCing tfii xdy dgng dygc da dygc thim djnh v l dp dge higu, khoang tuyen tinh, dg dung, dp lgp Igi khi djnh tinh, ^nh lygng esomeprazol eung nhy xae djnh gidi han phat hi^n, gidi han djnh lygng khi kilm tra tgp ddi quang R-omeprazd. Kit qud thu^ nghigm eho thiy quy trinh thiet lgp dygc phO hgp eho dng dyng flnh tinh, (^nh lygng esomeprazol vd kilm tra tgp ddi quang R-omeprazol trang ehe phim ehda esomeprazol.
Tai li$u t h a m k h a o 1. T. Lind. L. Rydberg, A Kyleback, et al (2000).
"Esomeprazole provides improved acid control vs.
omeprazole in patients with symptoms of gastro- T ^ CHf DlTQC HQC - 08/2013 (S6 448 NAM 53)
• Nghidn CIFU - Ky thuat
oesophageal reflux disease". Alimentary Phannacohgy & Therapeutics.U. 861- 867.
2. T. Anderson, K. Rohss, E. Bredberg, M.Hassan-/yin (2001), "Pharmacokinetics and phannacodynamics of esomeprazole, the S-isomer of omeprazole". Alimentary Pharmacology &
Therapeutics. 15,1563-1569.
3. T. Andersson, M. Hassan-Alin, G. Hasselgren G. et al (2001), "Pharmacokinetic studies with
esomeprazole, the (S)-isomffl" of omeprazole", Clinical Pharmacokinetics, 40, 411- 426.
4. Phan Thi £>do Hanh, Thdi Nguyen Hiing Thu, D 6 Thu Trang, Le Thj Hydng Hoa, Le Dinh Chi (2011), "Xdy dyng phyong phap sac ky lfing hi#u nang cao de phan tich ddng phan ddi quang cOa amlodipin". Tap chi Kiem nghiem thudc, 3, 10 - 15.
5. Indian Pharmacopoeia 2010, Esomeprazole magnesium monograph, electronic edition.
Nghien cvu dieu che kojic dipalmitat Phan 1: Sang loc chung Aspergillus oryzae va nghien cihi dieu Men len men thu nhan acid kojic
Tnrffng Phirong*, Tran Cat Dong, Nguyin Tri Th^nh Dai hoc YDuirc TP. Ho Chi Minh E-mail: phuongnq@,hcm.fpt.vn Summary
Through screening Ho Chi Minh City's environment, Aspergillus oryzae 4F was isolated. The obtained strain was of ability to produce kojic acid in high yield. The fenrtentation pn^cess was optimized by MODDE 5.0 software. Pradieally, the optimised process showed simple, econcmical and suitable for Vietnam's conditions. The purity and strur^ure of the product were detennined by TLC and UV, IR, MS spectroscopy.
Key words: Part 1, kojic dipalmitate, creening, A. oryzae, kojic acid.
D$t van de
Ngdy nay, cCing vdi sy phdt triln kinh t e - x a hOi, eon ngydi quan tdm nhilu hon din vide Idm dgp. Cdc logi my phim Idm trang da cung xuit hi^n ngdy cdng nhieu vd dygc tieu thg rflng rai, Cdc sdn phim nay cfi thdnh phan rat da dgng, bao gdm nhdng ehit ehiet xuit td thidn nhien (arbutin) eung nhy tdng hgp (hydroquinon, cdc acid alpha hydroxy...). Trong sd dd, aeid kojic da dyge ehdng minh cd tac dyng Idm trdng da (de chl enzym tyrosinase, mi5t enzym quan trgng trong con dydng sinh tdng hgp melanin),'^' ft dpe, it gdy tac dung phg.'^' Ben egnh dfi, din xuit ester cua acid kojic - kojic dipalmitat - cung dygc sd dyng d l tdng dd bin, dp hfia tan trong chl pham. Hien nay d nydc ta cdc nguydn li^u ndy vin phdi nh|lp khiu hodn todn vdi gid cao.
Aeid kojic Id sdn phim ehuyin hfia thd cap cua nhieu lodi nim nhy Aspergillus fJavus. A.
TAP CHi DlTOC HQC - 08/2013 (S6 448 NAM 53)
oryzae, A. parasiticus, Penicillium daleae...^' Trong dd, A oryzae khfing cd kha ndng sinh aflatoxin va dyge xem Id an todn '*'. A. oryzae id lodi nam mde rat phd biln trong tg nhidn, thydng phat trien tren mfii trydng cfi ngudn gdc tinh bfit nhy bdnh mi, com... Hon nda qua nhyng nghidn cdu so bp, ehung tdi nhgn thay nhdng vi nam cfi ngudn gdc Viet Nam thydng ed sde sdng mgnh hon cdc chung nhap ngogi va do dd cd the eho kha nang tgo cde san phim hda dyge cao, thdm chi hon ed nhdng ehung nhdp ngoai.
Vi ly do dfi, cung vdi mgc tidu tao ngudn nguyen lieu trong nydc cho sdn xuat dyge phim, chung tfii thgc hien de tdi "Sdng Ipc ehung Aspergillus oryzae vd nghidn cdu ^ l u kien len men thu nhdn acid kojic". Oe tai hodn thdnh se eho 2 sdn phim: Sang Igc dygc chung A. oryzae d Viet Nam cd kha ndng sinh acid kojic cao vd sdn phim acid kojic cho cfing nghigp dygc.
35