• Nghien CLFU - Ky thugt
2. Trung tim DI&ADR qudc gia (2008), "Tdng hyp vd phdn tich tinh hlnh bdo cdo phdn ung c6 hgi cCia thudc (ADR) tgi tmng tdm ADR phia Bdc td 7/2006 ddn 12/2007".
3. Collabota C. 1. (2002), "A Guide to detecting and reporting Adverse Drug Reactions", Safety of Medicines, Geneva, p. 5>18.
4. Forstor A. J., et al. (2009), "Adverse drug events occurring following hospital discharge", J.
Gen. Intem. Med., Vol 20, p. 317-323.
5. Gregory P. J., Kier K, L. (2001), "Adverse dmg reactions and medication errors". Drug Information-A guide for pharmacists, 2"^ edition, McGraw - Hill, p, 481-518,668-669.
Nghien ctfu bao che vien nen ra nhanh metoclopramid 10 mg
M^dlu
Khi su dyng vign ndn thdng thudng, nhidu bgnh nhdn edm thdy khd khdn khi nudt vien thudc, didu ndy ed nguy ca Idm cho bOnh nhdn khdng tudn thu theo diing chi djnh vd ddn ddn kdt qud tri liOu khOng higu qud. 0d khdc phyc vdn dd ndy, dgng vign nen cd khd ndng ra nhanh trong migng ma khOng cdn nude Id mgi gidi phdp huu higu'. Metoclopramid hydroclorid (MTH) thudng duyc chi djnh de didu tn cdc trigu chung budn ndn vd ndn mda, thudng ggp d nhung bgnh nhdn ung thu sd dyng hda trj liOu hay d phy nu mang thai'*'. Trong tm-dng hyp ndy, khi bgnh nhdn nudt vidn nen chdng ndn thdng thudng, se bj kich thich vd gdy phdn xg ndn ra ngodi, ddn ddn vigc didu trj khdng cd kdt qud.
U Th| Minh Nggc, Hu^nh Vdn Hda Khoa Dufrc, D<fi hgc Y Dugrc Tp. Hd Chi Minh
Dd tdi "Nghign cdu bdo chd vidn ndn rd nhanh trong migng metoclopramid.HCI 10 mg' duyc thyc hign nhdm myc dich bao chd dgng vidn ndn chdng ndn higu qua nhd khd ndng rd nhanh trong migng.
Nguyen li^u va phuxyng phdp Nguygn llOu
Metoclopramid.HCI (An DO) dgt tieu chudn USP 33. Cdc hda chdt vd dung mdi dgt tieu chudn ddnh cho phdn tfch.
Phuwng phdp
Xiy d{mg c6ng thvc tdi tm vi quy trinh bio chi viin nin ra nhanh MTH 10 mg Bdng 1; Cdng thOv ccr bin cOa viin nin MTH 10 mg
Thinh phin Metoclopramid.HCI
C6ng f/idc 1 viin (mg) 10
C6ng tht>c 16 1000 vi6n (g) 10 Td duyc sidu ra (A, B hay C)
Td duyc dOn dgp thing (Tablettose, hole Avivel PH 102, hodc Starlae)
Miiicam Aspartam Magnesi stearat
Aerosill Mannitol vd
1,5 3,0 0,5 0,5 150
1.5 3,0
0,5 ':^
0.5 . : | 150 ' J
Phmyng phdp bdo chd
Vidn nen ra nhanh MTH 10 mg duyc bdo chd bang phuang phap ddp thang. Sd dyng mdy dgp vien xoay trdn 10 chdy, chay 7 mm. Vidn cd khdi luyng 150 mg, dO cdng td 20 - 30 N.
Thidt kd m6 hlnh cdng thijc
Sd dung phdn mdm Design Expert 8.0, md hinh D - Optimal.
Tdi uu h6a cdng thuv
Su dung phdn mdm BC PharSoft. m
T-U *—T'"' n r f i n n r r h m r i T m i ^
• Nghien CIFU - Ky thuat
Dinh gii viin Thai gian phin tin
Mdi vien d u y c dgt trong dng nghigm cd dung tich 10ml, dudng kfnh 1,5em cd chda 2ml n u d c cat. Thdi gian phan tdn (tinh bdng gidy) la thdi gian d u y c tinh t u khi bat ddu eho vien vdo n u d c eho ddn khi vign ra ra tdng mdnh nhd. Lan luyt t h y c hien vdi 6 vien va tinh ket qud trung binh.
Thdi gian ndy phdi thdp han 30 gidy'^'.
Th&i gian thim u d t
Dat 05 Idp giay Igc d u d n g kinh 10cm vdo dTa petri cd dudng kinh 10cm. Cho vdo dTa 10ml dung djch xanh methylen. Vien d u y c dgt cdn thgn tren be mat eua t d giay. Thdi gian u d t (tinh bdng giay) Id thdi gian n u d c tham hdt len bd mgt ciia vign. Lan luyt thyc hign vdi 6 vien va tinh kdt qua trung blnh. Thdi gian ndy phai thdp han 60 gidy'^l
Do hoa tan
S u dyng thiet bj do do hda tan kieu canh khuay vdi mdi trudng la 900 ml HCI 0,1 N, tde dg 50 vong/phiit. g i u nhiet do d 37 °C ± 0,5. Sau 15 phiit t h u nghiem, idy djch hda tan dem lgc qua giay Igc 0,45 pm, d u y c dung djch thu. Do dd hap thu cLia dung djch thd trong ede do ddy 1 cm, d b u d e sdng 310 nm, s d dung dung djch HCI 0,1N ldm mdu trang.
T h a m d j n h q u y t r i n h d j n h l u y n g MTH t r o n g che p h a m
Dinh iwgng
Tidn hdnh bdng phuang phdp sdc ky Idng higu nang eao.
Pha dgng
10 thd tfch dung djch A va 90 thd tich methanol.
Dung djch A
Hoa tan 2,25 g natri octansulphonat vd 0,3 g natri acetat trong n u d c vda dii 1000 ml, chinh pH ve 3,8 bang acid acetic dgm dac ndu can.
Dung djch thir
Can 20 vign, tfnh khdi l u y n g trung binh eCia vien va nghidn thanh bdt mjn. Can chinh xdc mgt l u y n g bOt mjn t u y n g dng vdi khoang 20 mg MHT cho vdo blnh djnh muc 100 ml, hda
tan vdi 80 ml methanol bang may sieu am trong 10 phdt. Tidp tyc lac c a hgc trong 20 phiit. Them methanol den vua du 200 ml. Lgc qua igc 0,45 ym.
Dung djch ddi chiiu
Hod tan MHT chudn vdi methanol de d u y c dung djch ed ndng dO 0,01% (ki/tt).
Quy trinh djnh luyng d u y c thdm djnh vd CQ tuydn tfnh, dg chinh xdc va dO diing.
Xay d y n g tieu chuan c a s d theo DDVN IV, USP32 vd Hudng ddn ve vign ra nhanh trong migng cOa F D A ' ^ ' ^ 1
Ndng cdp c d Id len 10.000 vien t d edng thdc tdi u u , tidp tue tham do thdi gian trgn tdi u u . Kiem nghigm vien theo tieu chudn da xdy dyng,
T h d nghigm do d n d j n h
Chd phdm d u y c theo doi do dn djnh trong dieu kien gid hda cap tde (nhigt do 40 °C, RH 75%) va trong didu kign binh thudng theo quy Jinh cua A S E A N " ^ ' .
K ^ t q u a n g h i i n CLPU
Xay d y n g c o n g t h u v tdi i r u vd quy t r i n h bdo c h d
Ket qua thdi gian phdn tan vd thdi gian thdm u d t ciia ede cdng thdc tham dd d u y c neu d bang 2. T d kdt qua cCia C T I , CT2, va CT3, B va C d u y c chgn lam td d u y c sieu ra eho cac t h d nghlgm kd tidp. T u ket qua eiia CT4, CT5, CT6 chgn avicel PH 102 idm td d u y c ddn ddp thang cho vien nen ra nhanh MTH.
Thiet ke mo hinh cong (hdc Bien doe lip
x^•. Logi td d u y c sieu ra (B hay C) X2. Luyng ta d u y c sieu ra X3: L u y n g avicel PH 102 Bien phy thuoc
y i : Thdi gian phdn tdn (giay) Yz- Thdi gian Idm u d t (gidy)
Muv khio sit X, B C X2 5 g 6 g 7 g X3 80 g 100 g 120 g
TAP r H ^ n i W ^ j P n r ^ n f i / ^ m r r i r s q i i i V A M ^7^
• N g h i e n C I F U - Ky tiiuat
Bdng 2: Kit qui thdi gian phin tin vi th&i Thinh phin (mg)
Metoclopramid Td duyc sidu rS A Td duyc sidu rd B Td duyc sIdu rd 0
Tablettose Avicel PH 102
Starlae Mui cam Aspartam Magnesi stearat
Aerosill Mannitol vd Thd'i gian phdn tdn (gidy) Thyi gian thdm uOt (gidy)
CT1 10 6
100 1,5 3.0 0.5 0.5 160
>60"
>60-
gian thdm wdi cita CT2
10 6
100 1.5 3.0 0.5 0.5 150 12"76 42"03
CT3 10
-
6•
100
•
1.5 3.0 0.5 0.5 160 6"36 32'76
Cic cdng thirc thim dd CT4 CT5
10 10
6 6 100
100 1.5 1,5 3,0 3,0 0.5 0,5 0,5 0,5 150 150
>60- 6-28
>120- 32'18 CT6
10
6
- -
100 1.5 3.0 0.5 0.5 150 22-21
>120'
Md hinh thyc nghigm gdm 14 c6ng thdc
duyc thidt kd bdi phdn mdm Design - Expert 8.0, md hinh D - Optimal vd du ligu thyc nghigm duyc ngu trong bdng 3.
Bang 3: / nghiim
STT 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Xf C C C C C C C B B B B B B B
Wa hinh
Xi 5 6 6 6 7 7 7 5 5 5 6 6 7 7
1 cong thirc vi du' liiu thux:
X3 100 80 100 120 80 100 120 80 100 120 80 120 100 120
yi 6,16 6,91' 7,4 7,41 7,66 9,96 8,48 10,18 10,12 10,58 9,35 8,13 8,93 8.92
yi 33.47 34.06 36,36 34,48 41,43 43,35 41,44 37,43 34,32 41,75 37,45 44,69 49,23 45,13
"; DO" Hiu sd dyng nhu nhdm thu nhim dinh gii
chat luang m6 hinh dy doAnDieu kifn tdi wu
yi £ 30 gidy, yz £ 60 gidy. Cde thong sd tdi uu va tinh chdt dy dodn eho bdi phdn mdm BCPharSoft duyc trinh bdy trong bang 4.
Bdng 4: Cic thdng sd tdi uv vi tinh chit dt/
doin cOa viin nin ra nhanh
Thinh phin c6ng thircGid trj ' tlm difQ'c xi C X2 5
Tinh chM sin pham yi
y i ys
Gid tii di/dodn
6.173 33.563 X3 84,18
Cdng thdc tdi uu duyc dy dodn cho vien nen rd nhanh MTH 10 mg duyc trinh bdy trong t)ang 5.
Bdng 5: Thinh phin edng thuv tdi uv cho viin nin ra nhanh
Thinh phin cdng thirc Metoclopramid HCI 7i diFO'c siSu ra C
Avicel pH 102 Aspartam
Mill cam Magnesi stearat
Aerosil Mannitol vu'a du
Cho 1 viin (mg)
10,0 5,0 84,0
3,0 1,5 0,6 0,5 150,0
Cho 116 1000 viin (g)
10,0 5,0 84,0 3,0 1,5 0,5 0,5 150,0 Kiim chung thyv nghiem
Vign ndn ra nhanh MTH duyc bao chd theo eong thdc tdi uu thanh 3 16 vdi cung didu kign va quytrinh.
Sdn phdm duyc kidm tra thdi gian phdn tdn vd thdi gian Idm udt. Kdt qud duyc trinh bdy trong bang 6.
TJ^^
• Ngiiien CLKU - Ky tiiuat
Bang 6: Kdt qua thuc nghiim vi gia tri dy doin
L61 Th^l gian phan lin (giay) 6.47 Thoi gian tham \rtr\ (giay) 33.63
Gii tri thijK nghidm L6 2 Ld3 6.62 6.56 33.15 32,87
TB 6,55 33,22
6,173 33,563 Tfnh chat giua cdc Id san phdm khong khdc
nhau cd y nghTa (P = 0,999 > 0,05), gia trj thyc nghigm trung binh ciia cac 16 vd gia trj d y dodn bdi phdn mdm khdng khdc nhau ed y nghTa (P = 0,973 > 0,05).
Tham dmh q u y trinh djnh l u y n g MTH trong che pham
Quy trinh djnh luyng d u y c tham ^ n h va dgt cac yeu cdu vd ve do dgc higu, tinh tuydn tinh (eho thdy ed s y tuang quan tuydn tinh giua ndng dg (x) va dO hap thu (y) eiia metodopramid, bidu dien bang
phuang trinh hdi quy tuydn tinh:
y = 0,0444x + 0,0012 vdi R^ = 0,9998), dO ehfnh xde (CV% la 1,05%) va dO diing (tj- Id hdi phuc Id 99,72%)
Xdy di^ng tieu chuan c c s d Cdng f/idc bao chi 1 vien Metoclopramid.HCI: 10 mg T S d u y c vd: 150 mg
Kdt qua kidm nghigm vidn nen thdnh phdm theo tieu chudn ea s d d u y c neu d bdng 7 Bdng 7: Kit qui kiem nghiem vien nen thanh pham theo tiiu chuin ca s d
Chi tieu Tinh chat Djnh tinh DO adng ddu khoi luyng
Thdi gian phan tdn Dp hoa tan
Djnh luyng 90,0% - Vien
MOv chat lugng nen tr6n , mau trang, cd mCii tho'm,
Metoclopramid
±7,5% KLTB vign Khdng qua 20 gidy Khong it hen 80%, sau 5 phut
Vl nggt
• 110% metoclopramid HCI, so voi ham luang ghi tren nhan Ket qua
Dgt Diing Dgt Dat (7,21 giay)
Dat (98,11%) Dat (99,04%) Ndng cap c d Id len quy m d 10.000 vien
Da tham dd thdi gian trgn bdt hoan tat vdi thdi gian la 7 phut. Dieu ehd 16 tdi u u d quy md 10.000 vien, tinh chdt vien eho thdy khdng khac nhau ed y nghTa so vdi vien dieu ehd d quy mo 1.000 vien (p = 0,263 > 0,05)
T h d nghigm d o dn d j n h
Khdo sat do dn djnh trong didu kien binh t h u d n g cho thay vien dgt yeu cau vd cam quan, dd hda tan, thdi gian phan tan vd ham luyng trong 4 thdng t h u nghigm.
Kdt qua nghign c d u do dn djnh trong dieu kien gia hda cdp tdc cho thay vidn dgt cdc chi tidu vd cam quan, thdi gian phdn tan, do hda tan, rieng ham luyng hogt chat sau 4 thang theo ddi gidm qua quy djnh (90%) nen ngung khdo sat. Tudi thg cua vien se tfnh d y a theo ket qua khao sdt thdi gian thgt.
Ket luan
Vign nen ra nhanh trong mieng metoclopramid.HCI 10 mg da d u y c bao chd thdnh edng va dat cdc tieu chudn ea s d . TAP CHNMr'0feWH(Oe«Wil«2Ol^«6 434 N A M 52)
S u m m a r y
Regarding that (1) orally disintegrating tablets (ODTs) are claimed to be better soluble than conventional solid oral dosage fonns, as the latter create problems for pediatric, geriatric, bedridden, nauseous or non-compliant patients, (2) the ODTs would be preferred by the patients in emetic conditions due to its administration without aid of water, and (3) conveniently consumed during traveling, this study undertook formulating ODTs of metoclopramide HCI (as an anU-emetie) of intermediate disintegration in the oral cavity without water within a matter of seconds, and furthermore improving the dissolution rate and drug bioavailability and onset of pharmacological action; thus, metoclopramid 10 mg tablets were prepared by direct compression. The formulation experimental plan was designed by Design Expert 8.0 software and optimized by the BC PharSoft software.
Metoclopramid tablets prepared from the optimal formula showed the disintegration time less than 20 seconds and met in-house specifications. The
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