• N g h i e n C L F U - K y t h u a t S u m m a r y
A series of N1-(benzo[d]thiazol-2-yi)-f\i4- hydroxysuccinamide and their derivatives were synthesized by a two-step pathway: i) reaction of succinic anhydride with 6-substituted-2- aminobenzothiazoles; ii) amidation of the resulting carboxylic intermediates with hydroxylamine. Structures of the synthesized compounds were confirmed by MS, IR, 1H-NMR.
Bioassays revealed that only two compounds 3c, 3d inhibited slight HDAC activity (approximated 20%).
Tai lieu t h a m khao
1. Jed L.H., Hua Z., Astrid M.K., Judith C.F., William K.D., Bethany L.H., Richard E.M., Alexander A.S., J. Paul S., Thomas A.M., Amino acid derivatives as histone deacetylase inhibitors, Bioorganic and Medicinal Chemistry Letters, 2008, 18, 34-38.
2. Po CC, Vishal P., William G., Patience G.,
Adegboyega K.O., Synthesis and structure-acitvity relationships of histone deacetylase inhibitors with triazole-linked cap group, Bioorganic and medicinal Chemistry Letters, 2008, 16, 4839-4853.
3. Charles M.M., Thevaki M., Jon D., Stephane S., James M.M., John P. A., Simon P.J., David M.V., Charles R.C, Structure-activity relationships of aryloxyalkanoic acid hydroxamides as potent inhibitors of histone deacetylase, Bioorganic and Medicinal Chemistry Letters, 2007, 17,136-141.
4. Dallavalle S, Cincinelli R, Nannei R, Mertini L, Morini G, Penco S, Pisano C, Vesci L, Barbarino M,- Zuco V, De Cesare M, Zunino F., Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors, Eur. J. Med. Chem., 2009,1-13.
5. Ralph M., Vishal P., Dyann F.W., Jon C, Development of a fluorescence polarization based assay for histone deacetylase ligand discovery, Bioorganic and Medicinal Chemistry Letters, 2008, 18, 2809-2812.
r r B a o c h e v i e n n e n p h o i h o p
a r t e s u n a t - p i p e r a q u i n
Dat vdn de
Artemisinin va cac din xuit la nhdm thuoc co hoat tlnh ching sot ret manh nhit hidn nay.
Nhu-ng den nay ky sinh trung (KST) khang artemisinin dd xuit hidn [ 7l Neu khdng cd bidn phdp kjp thdi va hidu qua, KST khdng thudc se phdt trien vd lan rdng. Bidn phdp de "bao vd"
artemisinin Id han che su dung cdc phdc do den thuoc vd triin khai rdng rdi cdc phdc do phoi hop.
Ndm 2006, To chuc Y te The gidi khuyen cdo si> dyng 4 che phim phoi hgp dirge, bao gom: artemether-lumefantrin, artesunat+mefloquin, artesunat+amodiaquin vd artesunat+sulfadoxin- pyrimethamin | 9'.
Trong so cdc dan xuit cua artemisinin, artesunat cd iru diem ve dd on dinh, sinh kha dyng vd dirge cho Id phu hgp nhit de sir dung trong cdc cdng thirc thudc phdi hgp'51. Trong sd 4 chd phim dirge Td chirc Y td Thd gidi khuydn
Nguyen VSn Han1, Nguyen Thj Huyen2 'Truong dai hoc Duoc Hd Npi, 2Tgp chi Dupe hoc dung, thi cd 3 chd phim Id phdi hgp cua
artesunat.
Piperaquin Id thudc chdng sdt rdt nhdm aminoquinolin dirge dung nap rit tdt vd cd ddc tlnh dugc ddng hpc thich hgp (thdi gian bdn thai ddi) dd phdi hgp vdi artesunat. 0 Vidt Nam, piperaquin ngdy cdng cd vai trd quan trpng trong didu trj sdt rdt tai cdng ddng | 2 , 6 ]. Ndu cdn nhic ddn ca hai ydu td hidu qua vd gid ca, cd le piperaquin Id mdt lira chpn hgp ly dd phdi hgp vdi artesunat.
Trdn ca sd dd, chiing tdi tidn hdnh bdo chd vd ddnh gid hoat tlnh chdng sdt rdt cua thudc phdi hap artesunat-piperaquin, vdi muc dich dua ra duac mdt phdi hap mdi cd lieu cd djnh, hiru hidu vd an todn, phii hgp vdi cdc tidu chi md Td chirc Y td Thd gidi dd khuydn cdo. Bdi bdo ndy gidi thidu kdt qua nghidn ciru vd bdo chd. Kdt qud ddnh gid ddc tinh vd hoat tlnh chdng sdt rdt se dugc trinh bdy trong sd bdo sau.
TAP C H I D U O C H Q C - 4/2011 (so 420 N A M 51) 51
• N g h i e n c u » u - K y t h u a t N g u y e n lieu, t h i e t b j v a p h u - c n g p h a p n g h i e n ci>u
Nguyen lieu
Artesunat (Viet Nam), piperaquin phosphat tetrahydrat (Trung Quoc); p-cyclodextrin, acid stearic, talc, tinh bot mi dat tidu chuan dugc didn Vidt Nam 3; hda chat va dung mdi khdc loai tinh khiet phdn tich hodc dung cho HPLC.
Thidt bj
Mdy ddp vidn tdm sai KP2 (Due), may ddp vien thu cdng Unicam (Thdi Lan), mdy phun say Buchi B-191, tu vi khi hau Gallenkamp (Nhdt Ban), mdy sdc ki Idng hidu ndng cao Shimadzu (Nhdt Ban).
Gian dd nhidt vi sai: xdc dinh gian dd nhidt vi sai trdn mdy DSC-TGA 131 trong cdc didu kidn:
mdi trudng khdng khi, tdc dd gia nhidt 10°C/phut, thdi gian 30-35 phut. Thi nghidm dugc tidn hdnh tai phdng thi nghidm Hod Vdt lidu - Khoa Hda hpc - Trudng Dai hpc Qudc gia Hd Ndi.
Phuang phdp nghien cuu
Djnh Iwong artesunat trong vien nen Phuang phdp sdc ky Idng m.
Djnh Iwong piperaquin phosphat trong vien nen
Phuang phdp sdc ky Idng 1 4 1 Thw do hoa tan
Diiu kiin hoa tan: Theo chuydn ludn "vidn ndn artesunat" cua Dugc dien Vidt Nam 3
Xdc dinh lugng artesunat hod tan: phuang phdp sdc ky Idng.
Dung dich thu: sau thdi gian qui dinh, hut dich thu trong cdc cdc thu, Ipc qua mdng Ipc 0,45 pm.
Dung dich chuan: can chinh xdc khoang 35 mg artesunat chuan hod tan trong vua du 25 mL acetonitril. Hut chinh xdc 1 mL dung dich ndy vdo binh dinh muc 25 mL, bd sung nude den vach, ldc deu. Loc qua mdng 0,45 pm.
Dieu kidn sdc ky: nhu trinh bdy d phuang phdp dinh lugng, nhung the tich tidm Id 100 pi.
Xdc djnh lugng piperaquin phosphat hod tan:
phuang phdp do quang.
Dung dich thu: sau thdi gian qui djnh, hut dich thu trong cdc cdc thu, Ipc qua giay Ipc, bd djch Ipc dau. Hut chinh xdc 1 mL djch Ipc vdo binh dinh muc 25 mL, pha lodng bdng dung dich acid hydrocloric 0,1 M den vach, ldc ddu.
Dung dich chudn: cdn chinh xdc mdt lugng piperaquin phosphat chuan tuang ung khoang 35 mg piperaquin phosphat khan vdo binh dinh muc 100 mL. Hod tan trong dung djch acid hydrocloric 0,1M vd pha loang den vach vdi cung dung mdi, ldc ddu. Hut chinh xdc 1 mL dung djch ndy vdo binh djnh muc 25 mL, pha lodng ddn vach bdng dung dich acid hydrocloric 0,1 M.
Tien hdnh: do d$ hap thu cua dung dich chuan vd cdc dung dich thu d budc sdng 347 nm. Tlnh lugng piperaquin phosphat da hod tan dua vdo dd hap thu cua dung dich chuan, dung dich thu vd lugng chdt chuan da cdn.
K i t q u a n g h i e n c u u
Khao sat SIP tuang hgp giira artesunat vd piperaquin phosphat
De cd the phdi hgp trong cung mdt vidn ndn, artesunat vd piperaquin phosphat phai khdng cd nhung tuong tdc ly hda anh hudng ddn dd dn djnh khi tiep xiic vdi nhau. Su tuang hgp cua 2 dugc chat ndy dugc khao sdt bdng 2 phuang phdp: phdn tich nhidt vd Ido hda cap tdc.
Khao sdf sy twong hop giira artesunat va piperaquin phosphat bang phwong phip phan tich nhiet
Tien hdnh qudt nhidt vi sai cdc mdu artesunat, piperaquin phosphat vd miu hdn hgp artesunat+piperaquin phosphat ti Id (5:32) (tuang ung vdi tl Id hai dugc chit trong cdng thirc vidn ndn da kien bdo che). Kdt qua dugc thd hidn trong hinh 1.
50 150 250 350 450°C Hinh 1: Giin dd nhi$t vi sai cua artesunat, piperaquin phosphat va h6n hop artesunat+piperaquin phosphat
Nhdn xdt:
Gian dd nhidt cua miu artesunat cd mdt pic thu nhidt d khoang 163°C, lidn quan ddn qud trinh ndng chdy cua artesunat. Ngay sau dd Id pic tda nhidt d 171,9°C, tuang irng vdi sa phdn huy nhidt. Gian dd nhidt cua piperaquin phosphat cd hai pic thu nhidt. Pic thir nhit d
52 TAP CHI DUQC HQC - 4/2011 (S6 420 NAM 51)
N g n i e n C I F U - K y t h u a t 149,5°C tuang irng vdi qua trinh mit nude ket tinh. Pic thu hai d 256,2°C tuang ung vdi qua trinh ndng chay.
Gian do nhidt cua miu hdn hgp cho thiy trong khoang nhidt dd dudi 200°C, cd du cdc pic ddc trung cua ca artesunat vd piperaquin phosphat vd khdng thiy xuit hidn pic mdi, chung td khdng cd su tuang tdc ly hod giua hai dugc chit trong khoang nhidt dd ndyI 8 ].
Khio sit sir twang hgp giwa artesunat vi
piperaquin phosphat bing phwong phip tao hda cap toe
Cho cdc miu artesunat, piperaquin phosphat vd miu hdn hap artesunat+piperaquin phosphat vdo dng nghidm thuy tinh (khdng nut) vd bao quan trong tu vi khi hdu, nhidt dd 60 ± 2°C, dd i m 85 ± 5%. Sau 7, 14, 21 ngdy, liy mdu xdc djnh hdm lugng artesunat vd piperaquin phosphat bing phuang phdp sdc ky Idng. Kit qua thd hidn trong bang 1.
Bang 1: Mire giim him Iwpng (%) cic mau sau th&i gian bio quin (n=6)
Th&i gian MCrc giam ham Mwc giam ham Hon hop artesunat-piperaquin Th&i gian iwong (%)
artesunat Iwong (%)
piperaquin Artesunat Piperaquin 7 ngay 1,28 ±0,09 0,72 ± 0,07 2,20 ±0,12 0,95 ± 0,08 14-ngay 2,97 ±0,13 1,42 ±0,11 2,83 ±0,14 1.14 ± 0,13 21 ngdy 3,54 ±0,15 2,13±0,16 4,21 ±0,17 1,92 ± 0,09
Gia tri p p3,i= 0,270 P3.2= 0,642
Nhin xit:
- Muc giam hdm lugng artesunat sau 21 ngdy bao quan trong miu M3 so vdi miu khdc nhau khdng cd y nghTa ( p3 1 = 0,270 >
0,05). Nhu vdy su cd mdt cua piperaquin phosphat khdng anh hudng ddn dd dn dinh cua artesunat trong dieu kidn khao sdt.
- Muc giam hdm luang piperaquin phosphat sau 21 ngdy bao quan trong miu M3 so vdi mdu M2 khdc nhau khdng cd y nghTa (p3 2= 0,642 >
0,05). Sg cd mdt cua artesunat khdng anh hudng den dd dn djnh cua piperaquin phosphat trong diiu kidn khao sdt. Nhu vdy cd thd phdi hap true tiip hai dugc chit ndy trong ciing mdt vidn.
Che tao he phan tdn rdn artesunat - p- cyclodextrin
Hda tan 4g artesunat trong 100mL ethanol 96%. Hda tan 16g p-cyclodextrin trong 100mL nude d 80°C, dd ngudi ddn 40°C. Phdi hap 2 dung djch rdi phun siy vdi cdc thdng sd nhu tdi lieu, thu dugc hd phdn tdn rin artesunat-p- cyclodextrin (1:4) [ 3l
Xay dung cdng thirc vien nen
Artesunat Id dugc chit nhay cam vdi nhidt vd im. Piperaquin phosphat nhay cam vdi dnh sdng. Qua khao sdt thiy ring piperaquin phosphat vd hd phdn tdn rdn artesunat - p- cyclodextrin deu dd tron chay vd chju ndn tdt.
Do dd, phuong phdp ddp thing dugc su dung di bdo chd vidn ndn phdi hgp.
B i dam bdo dd dn djnh cua artesunat, cdc td dugc phai khdng dugc cd tlnh kiem, it hut i m
vd chira hdm lugng thip cdc ion kim loai. Cho ndn khi xdy dgng cdng thuc vidn, chung tdi chon talc vd acid stearic Idm td dugc tron vd tinh bdt Idm td duac rd.
Mdy Unicam Id mdy ddp vidn thu cdng cd the xdc djnh vd didu chinh duac luc ndn. Qua cdc thi nghidm so bd nhdn thdy hdn hgp bdt chi gdm 2 dugc chit (piperaquin phosphat, hd phdn tdn rdn artesunat) vd td dugc tron (talc, acid stearic) Id cd thd ddp thing dugc thdnh vidn chic bdn. Lugng bdt talc 15 mg/vidn vd acid stearic 15 mg/vidn Id phu hgp, vidn dugc diy ra khdi cdi dd ddng vd khdng cd hidn tugng dfnh chdy cdi. Vdi Igc ndn 0,5 tdn, vidn ndn tao thdnh khd chdc (luc gdy vd vidn khoang 150 N) nhung dd rd chua dat ydu ciu (> 40 phut), cin thdm tinh bdt mi Idm td dugc rd. Vdi ydu ciu dd rd khdng qud 10 phut, dd mdi mdn khdng qud 0,8%, luc gdy vd vidn > 30N, chung tdi dd khao sdt vd xdc djnh dugc lugng tinh bdt 60 mg/vidn vd Igc ndn 1 tin Id phu hgp. Vidn ndn cd cdng thuc bdo chi nhu sau:
HPTR artesunat/p-cyclodextrin (1:4): 230 mg (tuong duang 50 mg artesunat)
Piperaquin phosphat tetrahydrat: 350 mg tuong duong 320 mg piperaquin phosphat khan).
Talc: 15 mg Acid stearic: 15 mg Tinh bdt ml: 60 mg
Khdi lugng 1 vidn: 670 mg
TAP CHI DUQC HQC - 4/2011 (SO 420 NAM 51) 53
• N g h i e n c u o i - K y t h u a t Bao che viin nen phoi hop so dung may dip vien tam sai
Tien hanh bao che 3 me, m6i me 300 vien vol c6ng thuc nhu- tren. Qua trinh dap vien duyc tien hanh tren may ddp vien tam sai. Dieu chinh may de vidn cd khoi luang trung binh
Die tinh vit ly vi dd ddng diu phin liiu
Bang 2: Mdt sd chi tiiu chit Iwong vien dip trin miy tim sai
khoang 670 mg va lyc gdy vd vidn trong khoang 60 - 80 N (tuang Cpng vdi lyc ndn 1 tan trdn mdy Unicam). Cdc miu vidn duyc ddnh gid mdt s i chi tidu chit luyng: tlnh chat co hoc, dO ding deu phdn lieu vd kha ndng giai phdng duyc chit.
Me Lwc gay vo* vien
Od
mai mdn Do ra (phut, n=6)
Dong deu khoi Iwong
Dong deu ham Iwong (n=10, mg/vien) (N, n=10) (%, n=3)
Do ra
(phut, n=6) (n=20, mg) Artesunat Piperaquin 1 64 ±6 0,6 ±0,1 7 ±2 691,5 ±15,9 51,7 ±3,1 324,9 ± 13,5 2 68 ±4 0,5 ±0,2 8 ±2 702,9 ± 14,5 52,6 ± 3,9 330,8 ± 18,4 3 65 ±4 0,5 ±0,1 7± 1 690,5 ±18,0 51,3 ±3,3 322,1 ± 12,8
* Bp lech max 4,2% 11,4% 7,3%
Ghi chu: * dp lech max la gia tri do lich (%) cua vien cd khoi Iwong (hoac ham Iwong) lich nhat so vdi khii Iwong (hoac ham Iwong) trung binh.
Nhdn xdt: Cdc miu vidn ndn dap tren mdy tdm sai cd dd mdi mdn vd dp rd dat yeu ciu vd khdng khdc nhiiu so vdi vidn ddp tren mdy Unicam. Od dong deu khoi luong vd ham luong cua cdc mdu vidn deu dat qui djnh theo DOVN 3.
Dd hoi tan
Bang 3: Phin trim dwoc chit hoi tan sau 30phut(n=6)
Dwov chat Me 1 Me 2 Me 3 Artesunat 92,4 ±2,2 92,6 ± 2,4 91,2 ±4,2 Piperaquin 85,7 ±2,9 86,8 ± 4,4 83,6 ± 2,6 Nhin xit: Sau 30 phut, tf Id duyc chat hod tan cao vd khd dong deu giua cdc me.
Tdm lai, cdc miu vidn bdo che vdi mdy ddp vidn tdm sai dat cdc chi tidu chat luyng chung cua vidn ndn vd cd d0 hda tan khd cao.
Xay dirng tieu chuan vien nin artesunat- piperaquin
Cdn cu vdo ket qua nghidn cuu vd dya theo chuydn ludn "vien ndn artesunat" cua DDVN 3 vd chuydn ludn "vidn ndn piperaquin" cua Duyc dien Trung Quoc 2005, dy thao tidu chuin vidn ndn phoi hyp duyc de xuit nhu bang 4. Trong dd chi tidu dd hda tan cua artesunat duyc diiu chinh tdng tu 60% ldn 70% vd bd sung chi tidu dd hda tan cua piperaquin phosphat.
Bang 4: Dw thio tiiu chuin cua vien nin artesunat-piperaquin Chi tieu
chat Iwong Yeu cau Phwong phip thw
Hinh thuc Vien nen khong bao mau vang,
thanh va canh vien lanh ldn Cam quan Bp dong deu
kh6i lupng Op lpch khong qua 5% so vdi
khoi lupng trung binh vien Theo DDVN 3
Djnh tinh Artesunat
Piperaquin phosphat Artesunat: sac ky long
Piperaquin phosphat: sac ky Idp mong.
Dp hod tan Khong dudi 70% lupng artesunat va 70% lupng piperaquin phosphat dupe
hoa tan sau 30 phut
Xac dinh lupng artesunat hoa tan bing sic ky long yd luyng piperaquin phosphat
hod tan bdng phuong phap do quang Tap chat
lien quan Phai dat qui djnh Phuong phdp sac ky Idp mong Ham lupng Phai chua 90-110% artesunat va
93-107% piperaquin phosphat so vdi lupng ghi tren nhan
Djnh lupng artesunat: phuang phap sac ky Idng Djnh lupng piperaquin phosphat: phuang phdp
do quang ho$c sic ky Idng
54 TAP CHI DUQC HQC - 4/2011 (SO 420 NAM 51)
Ket luan
Thu- nghiem lao h6a cap toe va phan tich nhidt vi sai dd chung minh artesunat va piperaquin phosphat khdng c6 tuang tac anh huang den do on djnh khi tiep xuc true tiep.
Vien ndn phoi hap artesunat 50 mg - piperaquin phosphat 320 mg da dugc bdo che theo phuong phdp ddp thing, su dung tinh bdt mi Idm td duoc rd, talc vd acid stearic Idm td duac tron. Vidn ndn dat cdc chi tieu chat luang dd rd, dd dong ddu khoi luang, hdm luang theo DDVN 3 vd cd dd hda tan khd cao (trdn 90% doi vdi artesunat vd trdn 80% doi vdi piperaquin).
S u m m a r y
Regarding the fact that multidrug resistance has rendered malarial monotherapy useless in most parts of the world, new antimalarial regimens are urgently needed, and artemisinin-based combination therapies (ACTs) have taken the prominence with available artemisinin derivative artesunate which have the most favourable pharmacological profile; while piperaquine as an aminoquinoline antimalarial of favourable tolerability, efficacy, pharmacokinetic profile and low cost is a promising partner drug for use on this purpose, the present study was aimed to develop a new co-formulated antimalarial combination of artesunate and piperaquine. Previously, a solid dispersion of artesunate was prepared with j8- cyclodextrin by spray drying for improving the its water-solubility and enhancing its stability. Co- formulated artesunate 50mg and piperaquine
phosphate 320mg tablets were prepared by direct compression, using talc and stearic acid as lubricants, com starch as disintegrant. The combination tablets met all the general quality requirements, including disintegration, weight variation, uniformity of dosage units and dissolution.
Tai lieu t h a m k h a o
1. Bp Y te, Dupe dien Viet Nam 3, Nha xuat ban Y hoc, Ha Npi, (2002).
2. Bp Y te, Du an Quoc gia Phong chong sot rdt, Huong dan chin dodn va dieu tri b$nh sot ret, Ha Npi, (2007).
3. Nguyen Van Hdn, Do Hu-u Nghj, Trin Vdn Nam, Che tao hp phan tan ran artesunat vdi B- cyclodextrin bing phuong phap phun siy, Tap chi duvc hoc, (2008), 388, tr. 14-17.
4. Do HO-u Nghj, Nguyen Vdn Han, Djnh lupng piperaquin trong vien ndn bdng phuong phdp sic ky long hipu nang cao, Tap chi kiem nghi$m thudc, (2007), 18(5), tr. 11-13.
5. Davis T. M. E. et al., Artemisinin-based combination therapies for uncomplicated malaria, Med. J. Aust, 2005, 182, pp. 181-185.
6. Davis T. M. E. et al., Piperaquine: A Resurgent Antimalarial Drug, Drugs, (2005), 65, pp. 75-87.
7. Noedl H. et al., Evidence of artemisinin- resistant malaria in western Cambodia, N. Engl. J.
Med, (2008), 359(24), pp. 2619-2620.
8. Swarbrick J., Boylan J. C, Encyclopedia of Pharmaceutical Technology, Vol. I, Marcel Dekker Inc., New York, (2002).
9. World Health Organisation, Guidelines for the Treatment of Malaria, WHO Press, Geneva, (2006).
h o a t < J 6 n g . . . (Tiip theo trang 07) N g h i e n cu>u
substances. Morever, antibiotics have specific characteristics as: drug resistance, necessaries and spread, violent competitiveness, prescriptive feature and clear segments feature.
It's very important for all business to plan suitable marketing strategies for each antibiotical product based on specific characteristics. These marketing strategies which adapt to market's changes will help products to stand firmly on the market and help business to develope more and more PA1.
Keywords: marketing, antibiotics
Tai lieu t h a m k h a o
1. B0 mon Quan ly vd Kinh te dupe- Bai hpc Dupe Ha N$i, Djch td Dupe hpc, nha xuit ban Y hoc (2007)
2. Cue Quin ly duyc V/#f Nam, Bao cdo t6ng kdt cong tac Dupe ndm 2010, Ha Npi (2010)
3. Mickey C.S, Pharmaceutical Marketing, Strategy and Cases, Trie Haworth Press, New York, USA, (2000).
4. Mickey C.S, E.M "Mick" Kolassa, Grey Perkins, Bruce Siecke (2002), Pharmaceutical Marketing, principles, environment and practice, The Haworth Press, New York, USA (2002).
