Nghien CLFU - Ky thuat
Nghien cii'u mot so yeu to anh hu'ffng toi do hoa tan cua vien nen nifedipin
Dat van de
Do hda tan la mdt tidu chuIn lidn quan din dac tinh giai phdng du-gc chit tii- vidn, do dd cd moi lien he mdt thilt vdi tac dyng cua thuoc.
Oam bao dd hda tan cua thuoc vidn ndn, dac biet vdi cac tru-dng hgp du-gc chit khd tan, la mdt v i n de Idn trong nghidn ciPU va san xuit thudc, ngay ca d cac nu-dc phat triln.
Nifedipin la mdt du'gc chit (DC) thudc nhdm thudc tim mach, thyc t l khdng tan trong nu-dc, vi thd cd rit nhilu nghidn ciPU va u-ng dyng nhim tac ddng den dp hda tan '''•^' V l mat nguyen lieu, nhilu nha san xuit su- dyng nifedipin du-di dang vd djnh hinh, vi tieu phdn hoac sieu vi tieu phan (cd dac tinh cua dang vd djnh hinh). Diing loai nguydn lieu nay de bao c h i thudc vien cd t h i giup tang t i e dd hda tan, nhu-ng cd nhu-gc dilm la cac nguyen lidu dd thu-dng khdng sin cd va gia cao, anh hu-dng den hieu qua san xuit kinh doanh. Cac hu-dng khac bao c h i cac he phan tan rin (HPTR) vdi cac chit mang khac nhau (PEG, PVP, HPMC, cac cyclodextrin...) nhim chuyen nifedipin sang dang vd djnh hinh hoac giam kich thu-dc tieu phan trong chit mang, vi t h i tac ddng din do hda tan cua du-gc chit '^' Cac phu-ang phap nay cho kit qua tit, tuy nhien trdn thyc te then khai cung gap khdng it khd khan nhu-: ty Id chit mang cao, hd hut I m manh. qui trinh phipc tap... Chinh vi t h i vide phat then cac ky thuat cd tinh kha thi d l ipng dyng trong san xuit thuoc vien vdi cac du-gc chit khd tan rit c i n thiet.
Trong nghien ciPU nay. nifedipin du-gc su- dyng nhu- mdt du-gc chit md hinh (model drug).
Cd nhilu phu-ong phap de danh gia dang thii hinh cua du-gc chit trong dang bao chi, nhu- pho nhilu xa tia X, cac phu-ong phap phan tich nhiOt, trong nghidn ciPU su- dyng phu-ong phap phan tich nang lu-gng nhiOt vi sai (differencial scanning colorimetry DSC) de so sanh trang thai cua dygc chit trong cac miu.
Pham Thi Minh Hu?', Nguyen Thanh Hai^
' Trifdng dgi hgc Dugfc Hd Ngi
^ Khoa Y- DuQTc, Dai hpc Quoc gia Hd NQI
Nguyen lieu va phu'O'ng phap nghien
CLFUNguyen lieu
Nifedipin (Dipc) dat tidu chuIn USP, PVP K- 30 (Trung Quoc). cellulose vi tinh the (MCC) (Oai loan), lactose (My), Aerosil (TQ). magnesi stearat (TQ). dicloromethan (TQ), alcol isopropylic (TQ), natri lauryl sulfat (TQ). Cac ta du-gc va dung mdi dat tidu chuan USP/BP hoac tinh khiet hda hpc.
Thilt bj
May dap vien Pye Unicam; may thO dp hda tan Erweka; hd thong HPLC Agilent; may DSC Mettler Toledo; bd ray, can ky thudt va can phan tich, chay coi va cac thilt bj khac.
Phu'o-ng phap nghien ciru Phuong phap bao che vien
Vidn nen nifedipin du-gc bao c h i vdi cac ta du-gc lactose, MCC, PVP, Aerosil, magnesi stearat.
Phwang phdp ddp thing: Cac nguydn lidu du-gc nghien, rdy, trdn theo thu- ty phii hgp, sau dd dem dap vidn vdi bd chay coi cd du-dng kinh 9 mm, lye dap ~ 1 tin.
Phwang phdp tao hat w&t: Nghiln trdn, nhao am, tao hat qua cd ray 0,6 mm. Trdn ta du-gc tron, dap vidn vdi bO chay cdi cd du-dng kinh 9 mm, lye dap ~ 1 tin.
Phieang phap danh gia vien
Dinh lugng DC trong vidn bing phu-ong phap do quang (DDVN IV) '^'
Dd hda tan: Theo phyong phap ghi trong DDVN IV, thilt bj canh khuly, toe dd 50 v/ph;
Mdi tru-dng hda tan: dung dich dem phosphat pH 6,8, them 0,25% natri lauryl sulfat; djnh lugng DC bing phu-ong phap HPLC '^'
Phan tich ndng Iwgng nhiet vi sai: Xac djnh trang thai cua nifedipin cua nguydn liOu, hdn hgp bOt va hat trydc khi dap vidn. Sii- dyng thilt bi DSC vdi chao nhdm chipa mau 40pl, dye
TAP CHI DUQC HQC - 12/2011 (SO 428 NAM 51) 19
Nghien CLPU - Ky thuat
thung n i p , khoi lu-gng m l u khoang tii- 3-7 mg.
NhiOt dO qudt til- 25-190°C, toe dO gia nhiOt:
10°/phut. Trong qua trinh thu-, thoi nito vdi lu-u lu-gng 20 ml/phiit.
K§tqua va banluan
Vidn bao e h i du-gc dat cac tidu e h u i n ve hinh thu-c, d$e tinh eo ly va ham lygng du-gc c h i t (100 ±3,45%).
Danh gia dnh h i f d n g cua phxjpang phdp bao c h i t d i do hda tan cua vien nifedipin
Vidn nifedipin du-gc bao c h i vdi ty 10 PVP Bang 1: Lwgng nifedipin hda tan (%) tw vidn bdo
nifedipin la 1:1 theo 3 each: dap t h i n g ( N l ) , tao hgt y d t vdi dung djch PVP trong hdn hgp dung mdi dicloromethan- isopropanol (N2), tao hat y d t vdi dung djch nifedipin va PVP trong hdn hgp dung mdi dicloromethan isopropanol (N3).
c a c m i u nifedipin nguydn liOu, hdn hgp bdt ho0e hgt trdn hoan chinh tru-dc khi dOp vidn du-gc phan tich nhiOt vi sai de xac djnh trang thai k i t tinh cua nifedipin. Vidn d y g c thu- hda tan theo phu-ong phap cua DDVN IV. K i t qua du-gc trinh bay d b i n g 1 va hinh 1:
chi theo cdc phwang phdp khdc nhau
Mau Lwtyng DC hda tan theo thirl gian (%±SD)
ISphut 30 phut 45 phut 60 phut
N1 30,24 ±5,34 42,78 ±4,21 50,32 ± 3,67 60,53 ± 3,70
N2 51,40 ±4,27 58,62 ± 3,76 60,42 ± 2,45 65,13 + 4,29
N3 76,63 ±3,14 89,47 ±3,75 95,72 ±2,95 102,68 ±4,29
Nhdn xdt: Ciing mdt cdng thiPc, du-gc bao c h i theo pbu-ong phap khac nhau cho t h i y t i c dd giai phdng DC tip cac m i u vidn khac nhau rd ret. Vide SLP dyng dung mdi hda tan PVP lam ta du-gc dinh Idng lam tang toe dd giai phdng DC tip vidn, nhat Id khi hda tan dong thdi DC va c h i t
mang tru-dc khi nhao I m , Qua trinh nay thay t h i cho bu-dc chd tao HPTR b i n g phu-ong phap dung mdi. Gian do DSC cung cho t h i y pic thu nhidt giam ( d diem chay ~ 173-174°C). chipng to DC c h u y i n tip trang thai k i t tinh sang vd djnh hinh, do vOy dO tan cua DC tang (hinh 1).
to
1
s^*fc »ut'o».ti. smcamif
. ^ t c l - •!!'» -n. •_ ». •"•)
C 115 u o
•rai-n^livd -107 U Jq*-!
O i l * 172 79 "C Au I 173 90 'C
W-TJ^I -* -^ 111 -.. -r i ( - . ! -1 ^ I T "
Vi 13 0 U 5 KQ !•
U'^W
uo
A
(
l i i --
Hinh 1: Gidn dd DSC cua: A - nifedipin; B - Nl; C - N2: D - N3 Nghien c i r u anh h i f d n g cua ty le PVP t d i
dp hoa tan ciia nifedipin tie vien
o l danh gia anh hu-dng cua PVP tdi t i c dO hda tan nifedipin tu- vidn, thay doi ty 10 PVP so vdi nifedipin trong cdng thu-c tij- 0 (N4); 0,5:1 (N5); 1,5:1 (N6). Thay doi lygng lactose sao cho khoi lu-gng vien khdng doi. Vidn du-gc bao c h i b i n g phu-ong
phap tao hat u-dt vdi dung djch nifedipin va PVP ho^c nifedipin (N4) trong hdn hgp dung mdi dicloromethan- isopropanol. Hat trdn hoan chfnh topdc khi dap viOn d y g c phan tich nhiOt vi sai de xac dinh trang thai cua nifedipin (hinh 2). ViOn dygc thu- hda tan theo phyo-ng phap cua DOVN IV, kit qua dygc trinh bay d bang 2.
Bang 2: Lwgng nifedipin hda tan (%) tw vidn bdo chd vdi cdc ty Id PVP khdc nhau Mau (PVP-.Nife)
15 phut
Lwgng DC hda tan theo thdi gian (%±SD)
30 phut 45 phut 60 phiit
N4(0:1) 52,58 ±2,72 78,32 ± 2,54 80.43 ± 2,83 85,39 ±4,32 N5 (0,5:1) 75,53 ±4,64 90,35 ± 4,21 96,17 ±2.57
N3(1:1) 76,63 ±3,14 89,47 ± 3,75 95,72 ± 2,95
98,84 ±2,19 102,68 ±4,29 N6 (1,5:1) 70,34 ± 3,67 85,32 ± 2,48 85,41 ±3,31 90,32 ± 2,83
20 TAP CHI DUQC HQC - 12/2011 (SO 428 NAIVl 51)
Nghien CLFU - Ky thuat
Sdmofc: WIFE rn-t, 7,5700 mg
? lnjs^'al -i9 06 mj io' nidbcd -3 S* J g^-1 Q'BA 171.71 'C
Hinh 2: G/dn c?d DSC cua:
Nhdn xet: Khdng SLP dung PVP trong cdng thiPC, lu-gng nifedipin k i t tinh v i n eon, do dd dp hda tan vien m i u N4 t h i p hon so vdi cac m i u cd PVP Ty Id PVP cang tang, lu-gng nifedipin k i t tinh cang giam, cac cdng thiPC N3, N6 hau nhu- nifedipin da chuyen sang dang vd djnh hinh. Ta du-gc PVP du-a vao vien cd y nghTa r i t quan trpng, vipa tang dp k i t dinh dam bao dd c h i c cho vien, vii-a cd the tang dp tan. Tuy nhien PVP cung cd thd anh hu-dng nhieu den qua trinh bao c h i va dp on djnh vien do hut am manh. K i t qua nghien ciPu cho t h i y ehi can SLP dung ty Id PVP so vdi nifedipin Id 0,5:1 da du de lam tang dp tan va t i e dp tan tu- vien nen. Ty Id PVP' DC la 1:1 cho dp hda tan cao nhit, tang them PVP (1,5:1) dd hda tan lai cd xu hu-dng giam di, cd the do tang dd nhdt, tang lien k i t hydro giu-a DC vd PVP, lam giam toe dp hda tan cua DC " '
K§t luan
Phu-ong phap bao chd anh hu-dng nhieu tdi tdc dp giai phdng du-gc c h i t tii- vidn. Qua danh gia b i n g phu-ong phap DSC, cd s y tu-ong quan v l trang thai nifedipin khi su- dung ky thuat bao c h i va ty Id ta du-gc dinh khac nhau vdi dp hda tan DC tip vien. K i t qua cho t h i y chi c i n thay doi phu-ong phdp bao e h i cung cd the tang dp tan cho DC. Cae k i t qua cung ggi y cho cho cac nghien ciPU ipng dung khi mudn du-a HPTR vdo cac dang thudc r I n vdi DC it tan.
N4; F - A/5; D - N3; G - N6
Summary
The effects of the processing method and PVP percentage in formulation on the dissolution of nifedipine tablets were investigated. The DSC curves depicted the crystallinity for pure nifedipine (a sharp melting endotherm at 173.9°C), but revealed the amorphism for it in its granules prepared by wet granulating (with a dicloromethan- isopropanol solution of nifedipine in combination with PVP). These changes in tableting improved the drug release from tabletsmm, a special wet granulation technique could be applicable to preparing solid dispersions of poor solubility drugs in solid dosage forms.
Tai lieu tham khao
1. DDVN IV, chuyen luan vien nen nifedipin.
2. E. Karavas et al. Investigation of thee release mechanism of a sparingly water- soluble drug from solid dispersion in hydrophilic carriers based on physical state of drug, particle size distribution and drug polymer interactions, Eur J. Phann, (2007), Vol 66 (3), 334-347.
3. Ping Gao, Amorphous pharmaceutical solids:
characterization, stabilization and development of marketable formulation of poor soluble drug with improved oral absorption. Molecular phanmaceutics, (2008), Vol 5(6), 903-904.
4. Tamaki M. et al. Crystallization rate of amorphous nifedipine analogues unrelated to the glass transition temperature. Int. J. Phann. (2007), 336,191-195.
5. Vibha Puri et al. Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug, Eur. J. Pham). (2010), 40, 84-93.
S LF d U n g . . . (Tlip theo trang 18)
3. Charles Warlow et al.. Stroke Practical Management 3th. Blackwell Publishing; (2007) p.
635-90.
4. David M. G. et al. , Acute Ischemic Stroke - An Evidence-based Approach. John Wiley & Sons, /nc;(2007) p.97-122, 137-62.
5. Ken Usino et al.. Acute Stroke Care - A Manual from the University of Texas-Houston Stroke Team.
Cambridge University Press; (2007) p. 13-33.
6. Michael Brainin et al.. Textbook of Stroke Medicine. Cambridge University Press; (2010) p.77- 88, 230-282
TAP CHI DUQC H Q C - 12/2011 (SO 428 NAIM 51) 21
