Nghien CLFU - Ky thuat
Nghien ciru bao che vien nen gliclazid giai phong keo dai
Dat van de
Gliclazid Id mdt trong nhO'ng thudc dugc dung rdng rai didu tri tieu dudng typ 2, nhung thdi gian tdc dung ngin, ndn cdn phai dung nhieu lin trong ngdy dudi dang bao chd quy udc. Khi bdo che dudi dang giai phdng keo ddi (GPKD), gliclazid mang lai nhieu Igi ich. Tuy nhien d Viet Nam thudc GPKD cdn it, vi vay chung tdi thuc hien de tdi: "Nghien ciru bao chd vien nen gliclazid giai phong keo dai" vdi muc tieu xay dyng edng thuc bao che vien nen gliclazid 36 mg GPKD 8 gid.
Nguyen lieu va phu'O'ng phap nghien
CIFUNguyen lieu
Gliclazid, hydroxypropyl methylcellulose El5 (HPMC El 5), hydroxypropyl methylcellulose K4M (HPMC K4M), lactose, avieel pH 101, aerosil, magnesi stearat va talc: dat tidu chuin duge dung. Cae hod chit khae: dat tidu chuan hod chit phan tich.
Thilt bj nghien CIFU
IVIay thu- dp hod tan ERWEKA DT60, mdy do quang phd UV-VIS VARIAN CARY 100, can phan tich Mettler AB 204-S, may dap vien PYE UNICAM, may thii' dp cirng vien Pharma test, may dap vien quay trdn ZP21.
Phu>ang phap nghien cii'u
Phifong phap bao che vien nen gliclazid 30 mg GPKD: Sir dung phuang phap xat hat udt, dung mdi xat hat la edn 96°, sly d nhiet dp 50-60°C, dp I m eua hat 2 - 3%. Ddp vien dudng
Bang 1: dc cdng thirc cd ty le hai polyme khic
Nguyen Ngoc Chien, Ho Thj Tii Truang dgi hoc Duac Hd Noi
kinh 7,06 mm, dp ddy 3,33 mm, chay bing, do cirng 100-1 ION.
Cac phirang phap danh gia tieu chuan chat lipang hat va vien
Op tran chay ciia hat, dp cirng cua vien:
theo cac phuang phdp thdng thudng.
Ojnh lugng gliclazid trong vien theo phuang phdp do quang, ndng dp khoang 10pg/ml, budc sdng 225 nm, dung mdi la dung djch dem phosphat pH 6,8 (dem pH 6,8); sir dung mdt phin methanol de trg giiip hod tan. So sanh vdi miu chuan.
Thir nghiem hod tan: May canh khuly, tdc dp khuly: 100 + 2 vdng/phut. Mdi trudng hod tan:
900 ml dem pH 6,8 (CTI ddn CT6) hoac 900 ml dung dieh HCI 0,1N pH 1,2 trong 1 gid diu va 900 ml ddm pH 6,8 trong eac gid tidp theo (cdc CT cdn lai). Nhiet dp mdi trudng: 37 ± 0,5°C.
Sau cae khoang thdi gian nhlt dinh, hut mau, Ipe, va dp mat dp quang tai budc sdng 225nm (dem pH 6,8) hodc budc sdng 229 nm (dung dieh HCI 0,1N). So sanh vdi miu chuin trong eac mdi trudng tuang u'ng. Cac ket qua nghien ciru duge bieu thj dudi dang gia trj trung binh (n=3). So sdnh hai dd thj giai phdng dugc chit bing chi sd f2.
Ket qua va ban luan
Anh hu'dng ciia polyme kidm soat giai phong
Bang 1 vd 2 trinh bay cac cdng thirc (CT) khao sat anh hudng cua cac polyme kiem sodt giai phdng vd ket qua thir dp hda tan tuang irng.
nhau (mg/vien) Cong thCrc
CTI CT2 CT3 CT4 CT5 CT6
Gliclazid 30 30 30 30 30 30
K4M 40 30 20 10 0 7,5
El 5 0 10 20 30 40 32,5
Avieel 10 10 10 10 10 10
Lactose 79 79 79 79 79 79
Aerosil 0,4 0,4 0,4 0,4 0,4 0,4
MgSt 0,8 0,8 0,8 0,8 0,8 0,6 Ghi chu: MgSt = magnesi stearate; K4M=HPMC K4Mi E15=HPMC El 5
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TAP CHI DUQC HOC - 7/2011 (SO 423 NAM 51)• Ngh
Bang 2:
Thai gian 1 giff 2 gio 3 gia 4 gio 5gi6' 6 gia 7 gia 8 gia
ien 1
CLFU -Ky thuat
: Kit qui thw dd hda tan CTI din CT6 (%)
CT1 10,11 11,74 15,46 17,37 23,71 31,30
cr2
6,32 8,09 17,22 20,42 23,20 27,53
Mgt moi CT3 9,01 13,45 18,70 22,49 28,37 33,65
trwdng pH CT4
9,0 15,87 27,46 37,98 44,28 54,32
6,8 CT5 29,67 45,14 67,09 86,53 93,03 95,44
Diamicron 14,07 19,27 34,70 50,38 60,63 68,41
Halt CT6 17,05 49,57 62,22 68,96 84,64 93,70 98,25 102,70
moi trwang Diamicron
19,17 49,23 65,89 73,62 82,63 88,19 96,75 97,68 Ghi chu: CTI den CT5: thu trong moi truang pH 6,8.
Bang 1 va 2 cho t h i y ty le HPMC K4M:HPMC E l 5 tdng t u CT5 ddn CT2 thi tdc dp giai phdng duac c h i t cdng giam vd ngugc lai.
HPMC K4M cd dp nhdt cao, truang nd tao thanh hdng rdo khudch tan duge c h i t HPMC E l 5 cd dp nhdt t h i p , dd tan trong nudc, do vdy khi lugng HPMC E l 5 tang, thi tdc dp giai phdng tang. CT6 eho dd thj hda tan g i n vdi vien ddi chidu n h l t (f2 = 71,85).
Ket qua thir hda tan cua vien Diamicron MR Bang 3: Cac cdng thirc khao sdf inh hwdng cua
CT6 thCr trong 2 moi truang.
30mg (hang Servier, Phdp, sd Id 021522539, han dung 04/2012) cho t h i y gliclazid de tan han trong mdi trudng pH 1,2 so vdi mdi trudng p H . 6,8 (Bang 2). Ket qua ndy ggi y cho vide lua chpn mdi trudng thCr thich hgp dd thu dugc mdi tuang quan in vitro in vivo.
Anh hu'dng ciia Ccic ta du'O'c khcic
Anh hudng td duge ddn, td dugc tran dugc thidt kd theo cac CT d bang 3, ket qua dd hda tan d hinh 2 vd hinh 3.
cie ti dwac ddn, tran (mg/vidn) Cong thirc
CT7 CT8 CT9 CT10 CT11 CT12 CTI 3 CT14
Gliclazid 30 30 30 30 30 30 30 30
K4M 7,5 7,5 7,5 7,5 7,5 7,5 7,5 7,5
E15 32,5 32,5 32,5 32,5 32,5 32,5 32,5 32,5
Avieel 0 10 40 50 30 30 30 30
Lactose 89 79 49 39 59 57 56 57
Aerosil 0,4 0,4 0,4 0,4 0,4 2,0 3,0 0,4
MgSt 0,8 0,8 0,8 0,8 0,8 0,8 0,8 3,0
TlKyiglan(gi(>) -Diamicron - • — C H - X - C T 8 - * - C T 9 -
Hinh 2: Anh hwdng cua ty le aviceI/lactose din dd hda tan cua vien gliclazid GPKD
Thd'i gian (gid')
- • — D i a m i c r o n - 0 - C T 1 1 — • — C T 1 2 — * - C T 1 3 - W — C T 1 4
Hinh 3: Anh hwdng cua ti dirac tran din dd hda tan cua vi§n gliclazid GPKD
TAP C H i DUQC HQC - 7/2011 (SO 423 NAM 51) 27
Nghien CLFU - Ky thuat
Hinh 2 cho t h i y anh hudng cua ty Id avieel va lactose len s u giai phdng gliclazid tir eac vien nghien ciru. Cdng thue chira 50 mg avieel (CT10) lam giam tdc dp giai phdng d u g c c h i t trong khi dd vien nen khdng chira avieel (CT7) thi ngugc lai. Khi ham lugng avieel thay ddi t u 10 mg - 40 mg (CT 8, 9 va 11) thi dd thi giai phdng dugc c h i t khdng khac nhau ed y nghTa (Hinh 2).
Hinh 3 bidu dien anh hudng eua ta d u g c tran len dp hda tan eua gliclazid tir eac CT11-
14. Trong 2 gid dau tdc dp giai phdng eiia CT11 (0,4 mg aerosil), 12 (2mg aerosil), 13 (3mg aerosil) nhu nhau, nhung d ede gid tidp theo, vien CT12, va C T I 3 bj va Idm ddi, va tdc dp giai phdng dugc c h i t tang. Ngugc lai, khi ham lugng magnesi stearat thay ddi tCr 0,8 mg (0,5%, CT11) ddn 3,0 mg (1,875%, CT14) thi tdc dp giai phdng dugc c h i t khdng thay ddi.
CT11 ed dudng cong dp hda tan g i n vdi vien ddi chidu nhlt.
Nghien ciru do dn djnh
Ket qua nghien cuu CT11 Id 2500 vidn (may dap vien quay trdn ZP21) cho t h i y CT11 Id 2500 vien va Id 50 vien ed dd thj hda tan gidng nhau vd tuang tu nhu dd th| vien ddi chidu (f2=73,12, vd 81,70 khi so sanh CT11 Id 2500 va 50 vien vdi vien ddi ehieu tuang irng). Sau 3 thdng nghien eiru d didu kien thudng CT11 Id 2500 vien, ham lugng duge ehIt (giam 1,3%) va dp hda tan (f2=76,05 so vdi vien ddi chidu) thay ddi khdng cd y nghTa. Nhung d didu kien lao hda c l p tdc ham lugng giam 7%, va p h i n tram giai phdng duge c h i t t u 1-6 gid tang len t u 2,5% ddn 8% (f2 giam xudng edn 53,87), ddng thdi dp eung vien giam t u 100N xudng edn 70N (10 vien).
Ban luan
Vien nen gliclazid GPKD da d u g c mpf sd tae gia trong va ngoai nude nghien cuu. Cae tdc gia da sir dung HPMC 4000 cps va HPMC 100 cps '^' hoac HPMC K15M va alginat'^' cho nghien CU'U dang vien nen gliclazid GPKD. Trong nude, Vd Thuy C i m Vy vd edng su'^' da nghien ciru vd tdi uu hod thdnh edng vidn nen gliclazid GPKD sir dung mpt sd polyme than nude, nhung tae gia khdng edng bd ban c h i t cae polyme. Dua vdo nhO'ng nghien cu'u tren, trong nghien cuu nay da phdi hgp sir dung HPMC K4M vdi HPMC E l 5 . Hat tir cae edng thuc nghien cuu cd
dp chay tdt (thdi gian chay eua 100 g hat >20 giay), ty Id bdt mjn cd kich t h u d c d u d i 125 pm thap (~ 10%). Tuy nhien, vien nen nghien cuu chira hai loai HPMC, cd kha nang hut I m . Do vdy, khi dd d didu kien lao hda cdp tdc lam giam dp cirng, ddn ddn giam ham lugng d u g c chit, ldm vien de ra va tang dp iroa tan SP vdi didu kien thudng.
Ket luan
Ty Id HPMC K4M:HPMC E15 anh hudng manh ddn s u giai phdng gliclazid tir cdc vien nghien eiru. Ty le avicel/lactose anh hudng it han, trong khoang khao sat 0,5% ddn 1,88%, magnesi stearat khdng anh hudng ddn s u giai phdng duge chit. Cdng thu'c ed dd thj giai phdng gidng vdi vien ddi chidu chira: 30 mg gliclazid; 7,5 mg HPMC K4M; 32,5 mg HPMC E l 5 ; 30 mg avieel pH 101; 59 mg lactose; 0,4 mg aerpsil; 0,8 mg magnesi stearat; dp cirng vien 100-11 ON. Vien CT tren dn djnh ba thang trong didu kien thudng.
S u m m a r y
Glipizide sustained-release tablets containing hydroxypropyl methylcellulose E15 (HPMC El5) and hydroxypropyl methylcellulose K4M (HPMC K4M) were prepared by wet granulation method. HPMC K4M, HPMC E15 Influenced glipizide release significantly.
Whereas, little was the effect of avieel and lactose on drug release. Magnesium stearate in a range of 0.5-1.88%, did not affect glipizide release. The dissolution profile of the tablets of 7.06 mm in diameter containing 30 mg gliclazlde with 7.5 mg HPMC K4M; 32.5 mg HPMC E15 and other ingredients, compressed at compression pressure of 1.5 tons was similar to that of Diamicron MR 30 mg. The obtained tablets were stable for 3 months In the room condition.
Tai lieu tham khao
1. Cifter et al., Extended release Gliclazlde formulations, US patents. No. 20090017116A1, (2009).
2 Jin, X. et al., Optimization of extended zero- order release Gliclazlde tablets using D-optimal mixture design, The Phanvaceutical Society of Japan;
(2008): 128(10), p.1475-1483.
3. Vo Thuy Cam Vy va cong su, Toi uu hoa thanh phin cdng thirc vien nen gliclazid phdng thich keo dai. Tap chi Dwgc hgc; (2006); s6 361, tr. 21-23.
28 TAP CHI DUQC HQC - 7/2011 (SO 423 NAM 51)
