jjighjen CLFU - Ky thuat
r
ghien ciru bao che pellet lansoprazol
Dat van de
Loet da ddy - td trdng Id mdt benh e6 the xay ra d mgi quie gia, mgi lua tuoi. Thuic diiu trj loet da ddy - td trdng eo nhieu loai trong do co lansoprazol, mot thuic LPC ehi bam proton, duge su' dung kit hgp vdi ede thuic khde trong nhiiu phdc d i diiu trj mang lai hieu qua diiu trj cao. Cac biet dugc lansoprazol d Viet Nam thudng duge bdo ehi dudi dang nang eung chira pellet bao tan d rudt vd chu yiu duge nhap ngoai. Do vdy, ehung toi thuc hien d i tdi
"Nghien ciru bao chi pellet lansoprazol" vdi muc tieu "Xay dung cdng thue bdo chi pellet lansoprazol d quy m6 phong thi nghiem"
Nguyen lieu va thi§t bj nghien
CLFUNguyen lieu: Lansoprazol, hydroxypropylmethyl cellulose E15 (HPMC El 5), lactose, avieel PH101, mannitol, polyvinyl pyrolidon K30 (PVP), natri laurylsulfat, erospovidon, primellose, natri starch glyeolat, aerosil, magnesi carbonat, gelucire 44/14 (Gelueire), magnesi stearat vd tale dat tieu ehuan Duge dung. Cdc hoa chit khde dat tieu chuin hda ehit phan tich.
Thiit bj nghien cii'u: Mdy dun - tao ciu QZJ - 350, mdy thii' do hod tan ERWEKA DT60, mdy do quang phi UV-VIS VARIAN GARY 100, can phan tfch Mettler AB 204-S, tu say Memmert, tu vi khi hau Climacell, mdy HPLC - Shimadzu.
Phu'O'ng phap nghien
CCFUPhwcfng phap khao sat sw twang hgp cua dwg>c chat va ta dwac
Trpn deu lansoprazol vd moi loai td duge theo ty le duge chat: td dugc Id 1:1,5 (vdi td dugc dgn, ra), hode 1 : 0,25 (vdi ta dugc dfnh, tran, vd polyme tao mang). Cho hin hgp tren vdo tung ing nghiem thuy tinh saeh, kho, nut kin bing b6ng, nilon va bao quan d nhiet dp 55°C trong thdi gian 2 tuin (trir miu chipa acid stearic vd CaHP04 bao quan d 40°C). Sau thdi gian trgn, quan sat khii bpt, so sdnh vdi mau dii chiiu eh! chua lansoprazol trong ciing dieu ki&n,
TAP CHi DUQC HQC - 9/2010 (SO 413 NAM 50)
Nguyen Ngoc Chien, NguySn Thi Hoa, Nguyen Hung Minh Trudng dgi hoe Dugc Hd Ngi
Phwang phap bao che pellet lansoprazol:
theo phuang phdp dun - tao ciu, ii 45 phut, mdt sdng 1 mm, tic dp diin 25 vdng/phut, tic d6 vo 400 vong/phut, thdi gian vo 13 phut, siy d nhiet d6 50°C din do i m dudi 5%. Ray liy pellet dudng kfnh tu 0,8 - 1,25 mm. Mii me 50g pellet. Dung djch td duge dfnh Id HPMC 6%.
Phwang phap dinh Iwofng lansoprazol Phwang phip djnh Iwgng lansoprazol bing HPLC (CT16 din 22):
- Diiu kien sdc ky: Cot: Gemini RP18 (250x4,6 mm; 5pm). Bao ve cot: RP18, 4x3 mm, detector: UV, 285 nm, tic do dong: 1,0 ml/phiit;
thi tfch tiem: 20|i,l, pha dgng: bin hgp acetonitril : nude : triethylamin (600:400:2,5). Diiu ehinh pH 7,0 bang acid phosphoric dam dae.
- Dung dich chuan: chua 0,12mg/ml lansoprazcl ehuin trong pha dpng.
- Dung dich thu: chira khoang 0,12mg/ml lansoprazol thu' trpng pha dpng.
Phwang phip do quang: a bude sdng 284 nm, dung mdi Id methanol (MeOH), so sdnh vdi miu ehuin (nguyen lieu), ning dp khoang 10
|ig/ml (n=2).
Phwang phap danh gia tieu chuan chat Iwofng pellet
Hieu suit bio chi pellet: theo phuang phdp thdng thudng.
Trie nghiem hoi tan: mdy cdnh khuiy, tic dp quay: 75 ± 1 vong/phut Moi trudng thCr: 900 ml mdi trudng dem phosphat pH 6,8 trong 60 phut. Nhiet dp mdi trudng thu': 37 ± 0,5°C. Mii cic chira khii lugng pellet tuang ung vdi 30 mg lansoprazol.
Sau cdc khoang thdi gian nhit djnh, hut miu, Igc, do mat do quang d bude song 284 nm, so sdnh vdi miu ehuin (n =3).
K i t qua va ban luan
Cdc td dugc biiu hien su khdng tuang hgp
vdi lansoprazol Id CaHP04 (khii bgt mdu nau
sdm), PVP (khii bgt bj von cue, mdu vdng sam),
acid stearic (khii bpt bj ehay Idng, mdu den),
eudragit L100 (khii bgt mdu vdng nhat), DEP
39• N g h i e n CLFU - K y t h u a t
(khii bpt bi chay long, mau den), vd cetyl aleol (khii bpt bj ehay Idng, mau den). Cdc td dugc
Bang 1: Cac cdng thirc bio chi pellet ban diu
duge su dung trong ede CT d bang 1 vd 2 khdng co biiu hien tuang ky vdi lansoprazol.
Thanh phan (%) Lansoprazol
MgCOa Na2HP04 Avieel PH 101
I\/lannitol Dung moi pha TDD
CT1 10
0 0 50 40 Nude
CT2 10
5 0 50 35 Nude
CT3 10
0 5 50 35 Nude
CT4 10
0 5 50 35 pH6,8
CT5 10
0 5 40 45 pH6,8
ere
10 0 5 30 55 pH6,8
0 7 7 10
0 5 20 65 pH6,8 Ghi chu: pH 6,8 = dem phosphat pH 6,8; TDD = ta duoc dinh
Khi kh6ng c6 td duge k i i m (CT1) k h i i bgt da ehuyen mau vdng ngay giai doan trdn, va ehuyen sang mau tia d giai doan u. D i i u ndy Id do lansoprazol r i t khdng b i n dudi tae dgng eua i m , nhiet dp '^', dae biet bj phan buy r i t nhanh trong mdi trudng acid '^'^l Khi eo mat td duge k i i m (CT2, CT3, CT4) pellet thu duge khong bj thay doi mdu. Hdm lugng lansoprazol trong cdc mdu CT2, CT3 vd CT4 theo thir t u la 93,7%, 99,7% vd 100,3%.
K i t qua anh hudng avieel (bang 2) eho t h i y khi ty le avieel giam t u 50% (CT4) xuing 40%
(CT5) va 30% (CT6), kha nang tao c i u v i n t i t , tuy nhien khi giam xuing ty le 20% (CT7) kha nang tao c i u giam. Dp hod tan lansoprazol tu
cdc CT nay r i t t h i p , nguyen nhdn Id do dp tan cua lanzoprazol t h i p '^' ^'.
Bang 2: Anh hwang cua ty le avieel din mpt sd dac tinh cua pellet lansoprazol
Cong thii'c Hinh thipc
Hieu s u i t (%) Bo hoa tan
(%)
CT4 ++++
90,7
12,1
0 7 5 ++++
88,5
15,9
076 +++
83,2
18,4
CT7 + 74,1
22,5 Ki hieu "+" thee su tang dan ciia dp cdu deu vd dp nhin b i mat
De tang dp hod tan ciia lansoprazol, td dugc sieu ra (TDSR) va natri laurylsulfat dugc sip dung, vd k i t qua thu dugc d bang 3.
Bang 3: Cac cdng Thanh phan* (%)
Primellose Crospovidon
SSG Natri laurylsulfat
Mannitol Dp hoa tan (%)
thirc chira TDSR, natri CT8
5 0 0 0 50 46,2
0 7 9 0 5 0 0 50 38,6
laurylsulfat va ket CT10
0 0 5 0 50 54,5
CT11 0 0 3 0 52 49,4
qui
do
hoi tanCT12 0 0 7 0 48 56,7
CT13 0 0 5 1 49 57,1
CT14 0 0 5 3 47 59,0
07^5 0 0 5 5 45 59,6 Chu y: Thanh phan khac giong nhu CT6.
T i t ea cdc edng thirc tren d i u ra ngay sau it phut thip hda tan vd d6 hoa tan lansoprazol tu cdc cong thirc nay cQng tang len ro ret so vdi ede CT d bang 2. Lugng SSG tang thi dp hod tan lanzoprazol tang, nhung b i mat pellet s i n siii han.
Natri laurylsulfat Idm tang dp hod tan eua lansoprazol (so sanh CT13, CT14, CT15 vdi
CT10), nhung khdng nhiiu, do vay Tween 80 va gelueire duge SLP dung. Do ehua t i i n hanh thir tuang ky giQ'a lansoprazol vd nhQ'ng td dugc nay, nen t i i n hdnh trpn d i u lansoprazol vdi Na2HP04, trude khi cho Tween 80 hoac gelucire vdo h i n hgp lansoprazol, sau dd thuc hien cac bude khde. K i t qua thu dugc d bang 4.
Bang 4: Anh hwang cua Tween 80 hoac gelucire din do hoa tan cua lansoprazol ' '' Cong thu'c* CT16 CT17 CT18 CT19 CT20 CT21
Ta duoc Tween Tween Tween Tween Ge Ge
' . • ' • . •
0722 Ge
Tyle (%) 0,5 1,0 2,0 3,0 2,5 3,5 5,0
Ham luong (%) 104,2 101,9 101,3 104,2 99,0 99,5 102,5
Do hoa tan (% 66,5 67,0 69,0 69,5 79,2 81,9 77,8
Chiiy: cac thanh phan khac giing CT10, ta duoc bii thay d6i theo la mannitol. Tween = Tween 80, Ge = Gelucire
40 TAP CHI DLTQC HQC - 9/2010 (SO 413 NAM 50)
Nghien
CLFU- Ky thuat
Ham luang lansoprazol trong m i u pellet su dung cac ta dugc tren d i u dat yeu c i u USP 31, s i c ky d i thu dugc khdng phdt hien cd tap chit.
Cdc m i u SLP dung Tween 80 ty le 0,5 d i n 3% eo dp hda tan lansoprazol t u 66,5 d i n 69,5%.
Cac m i u SLP dung gelucire (CT20, CT21, CT22) CO d6 hoa tan lansoprazol cao ban ro ret, CT21 (3,5% gelueire) eo dp boa tan lansoprazol tren 80%, dat yeu edu Duac d i i n My ''*'.
Ty le Na2HP04 3-7% duac khao sdt K i t qua ham lugng vd do hod tan duge ghi d bang 5.
Bang 5: Anh hwang cua ty le Na2HP04 din do hoa tan ciia lansoprazol
Cong thirc*
CT23 CT24
Ty le Na2HP04 (%)
3 7
Ham Iwang Bo hoa tan (%)' ' (%) 99,8 79,5 100,6 83,1 Chil y: cac thanh phan khac giong CT21, ta duoc bii thay doi theo la mannitol
Dp hod tan cua CT24>CT21 vd CT23 (bang 4 va 5). CT24 co dp hod tan cao n h i t (83,1%), De tang dp c i u , 1 % talc duge them vdo CT 24, gpi Id CT25. T i i n hdnh bdo e h i hai m i u CT25, m i i me 100 g, bao quan d i i u kien thudng 1 thdng va lao hod c i p t i c (45°C, dp i m tuang d i i 75%) trong 3 t u i n . K i t qua d hinh 1.
Ml-thui-ng • M2-thu'd'ng •
-M1-cApt6c -M2-cApt4c;
ThW gian (phiit)
Hinh 1 : Do hoa tan CT25 sau tho'i gian nghien ciru do dn djnh
Hinh 1 cho thay phin tram giai phdng lansoprazol d tung thdi diem eua hai m i u trong hai diiu kien nghien ciPU khac nhau khdng ed y nghTa. Hinh thue pellet vd hdm luang duge chit cua CT25 (diu tren 99% ca hai mdu, trudc vd sau bao quan) kh6ng doi so vdi thdi diem ban d i u .
K§t luan
Da bdo e h i dugc pellet lansoprazol on djnh trong met thdng d d i i u kien thudng va ba t u i n d d i i u kien lao hod c i p t i e vdi dp hod tan tren 80% theo phuang phap dun-tao c i u , su" dung ehit i n djnh la Na2HP04 7%, ta duge trg tan gelucire 44/14 3,5%, td duge ra SSG 5% vd dung moi pha td duge dfnh Id dem phosphat pH 6,8. Day Id cdng thue ea sd de t i i p tue nghien euu bao c h i pellet lansoprazol bao tan d rupt
S u m m a r y
With regard to its practical water-insolubility, unstabilty in highly acidic media, at high temperature and high humidity, Lansoprazol was formulated into pellets with Na2HP04 (7.0%,), gelucire 44/14 (3.5%o) and sodium glycolate starch (5.0%o) by extrusion and spheronizatlon using a phosphate buffer (pH 6.8) as the solvent for the binder The obtained pellets were stable for one month at room temperature and 3 weeks at 4^C with relative humidity of 75%o.
Tai lieu t h a m k h a o
1. DellaGreca, M. (2006) et al.. Degradation of Lansoprazol and omeprazole in the aquatic environment, Chemosphere, 63, p. 1087-1093.
2. Mamatha, T ; et al. (2008), Studies to enhance dissolution of Lansoprazol, The Indian Pharmacists /SS/V0972-7914,7, p. 65-70.
3. Pasic, IVl. (2008); Study to design stable Lansoprazol pellets; Ph.D. Thesis, University of Basel, Sarajevo, Bosnia and Herzegovina.
4. The United States Pharmacopoeia 31 (2008), p.
2502 - 2504
T h u d c d u n g t r o n g . . . (Hip theo trang 10)
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Med. 360, 563-572 (2009).
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Nature Rev Dmg Discov 8,447-448 (2009).
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TA! CHI DUQC HQC - 9/2010 (SO 413 NAM 50) 41
