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B Y T
TRNG I HC DC H NI ============
TRN VN C
NGHIN CU VIN NN GLIPIZID
GII PHNG KO DI S DNG CT
THN NC HPMC
KHA LUN TT NGHIP DC S
H NI - 2013
-
B Y T
TRNG I HC DC H NI ============
TRN VN C
NGHIN CU VIN NN GLIPIZID
GII PHNG KO DI
S DNG CT THN NC HPMC
KHA LUN TT NGHIP DC S
Ngi hng dn:
ThS. Nguyn Duy Th
DS.Trn Ngc Bo
Ni thc hin:
B mn Cng nghip dc
Vin Cng ngh dc phm quc gia
H NI - 2013
-
LI CM N
Ti xin by t lng cm n chn thnh su sc ti:
Ths. Nguyn Duy Th
DS. Trn Ngc Bo
Nhng ngi thy tn tnh hng dn v gip ti hon thnh kho lun
ny trong sut thi gian qua.
Ti chn thnh cm n :
TS. Nguyn Ngc Chin
ThS. Nguyn Hnh Thu
lun bn cnh hng dn, gip tn tnh v ng vin tinh thn ti trn
con ng hc tp v nghin cu khoa hc.
Ti cng xin t lng cm lng cm n ton th cc thy c, anh ch k thut
vin ti B mn Cng Nghip Dc, cc thy c, anh ch ti Phng th nghim
trung tm - Trng i hc Dc H Ni lun gip to iu kin thun li
cho ti trong qu trnh hc tp, thc nghim v nghin cu hon thnh kho lun
ny.
Cui cng, ti xin by t lng bit n su sc ti gia nh, cc thy c trong
trng v tt c bn b lun ng vin gip ti trong sut qu trnh hc tp.
H Ni, ngy 19 thng 5 nm 2013
Sinh vin
Trn Vn c
-
MC LC
T VN ........................................................................................................ 1
CHNG I: TNG QUAN .................................................................................. 2
1.1. Glipizid ...................................................................................................... 2
1.1.1. Cng thc cu to ..............................................................................................2
1.1.2. Tnh cht l ha ..................................................................................................2
1.1.3. Dc ng hc ...................................................................................................2
1.1.4. Ch nh, cch dng v liu dng ..................................................................3
1.1.5. Qu liu v x tr ...............................................................................................3
1.1.6. Phng php nh lng ..................................................................................3
1.1.7. Mt s ch phm glipizid trn th trng ....................................................4
1.2. Thuc tc dng ko di ............................................................................... 4
1.2.1. Khi nim: ...........................................................................................................4
1.2.2. Phn loi thuc tc dng ko di ...................................................................5
1.2.3. u nhc im ca thuc gii phng ko di ...........................................5
1.2.4. Cc h gii phng ko di ...............................................................................6
1.2.5. nh gi cht lng thuc tc dng ko di ..............................................9
1.3. Ti u ho ................................................................................................ 10
1.3.1. Khi nim: .........................................................................................................10
1.3.2. Bin u vo v bin u ra: .........................................................................11
1.3.3. Thit k th nghim .........................................................................................11
1.3.4. Trnh t tin hnh thit k th nghim v ti u ho ..............................11
1.4. Mt s nghin cu v glipizid .................................................................. 12
CHNG 2: I TNG V PHNG PHP NGHIN CU .................. 14
2.1. Nguyn liu, thit b ................................................................................. 14
2.1.1. Nguyn liu........................................................................................................14
2.1.2. Thit b ................................................................................................................14
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2.2. Ni dung nghin cu ................................................................................ 15
2.3. Phng php nghin cu .......................................................................... 15
2.3.1. Thm nh phng php nh lng p dng cho th ho tan vin ...15
2.3.2. Phng php bo ch vin nn glipizid 10mg gii phng ko di ct
thn nc. ......................................................................................................................17
2.3.3. Phng php nh gi mt s tiu chun vin nn glipizid .................18
CHNG 3: KT QU NGHIN CU ........................................................... 22
3.1. Thm nh phng php nh lng ......................................................... 22
3.1.1. Tnh c hiu .....................................................................................................22
3.1.2. chnh xc ......................................................................................................22
3.1.3. ng ..............................................................................................................23
3.1.4. tuyn tnh .....................................................................................................23
3.2. Kho st cng thc vin ........................................................................... 24
3.2.1. Kho st kh nng gii phng dc cht glipizid t vin chun
Glipizide XL trong mi trng m phosphat ....................................................24
3.2.2. Kho st nh hng ca t dc dnh ti kh nng gii phng dc
cht ..................................................................................................................................25
3.2.3.Kho st nh hng ca t dc n ti kh nng gii phng dc
cht .......................................................................................................... 27
3.2.4. Kho st nh hng ca t dc trn ti kh nng gii phng dc
cht ..................................................................................................................................29
3.3. Thit k nghin cu v ti u ho cng thc vin nn glipizid gii phng
ko di ............................................................................................................ 30
3.3.1. La chn bin cng thc v thit k th nghim .....................................30
3.3.2. Phn tch bng tnh quy lut ca th nghim.............................................32
3.3.3. La chn cng thc ti u ...........................................................................36
3.3.4. nh gi cng thc ti u .............................................................................36
3.3.5. xut tiu chun vin.39
KT LUN V XUT ................................................................................. 40
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DANH MC CC K HIU, CC CH VIT TT
CMC Carboxymethyl cellulose
CT Cng thc
DCP Dicalci phosphat
EC Ethyl cellulose
EtOH Ethanol
GPKD Gii phng ko di
HPMC Hydroxypropyl methyl cellulose
MC Methyl cellulose
Na CMC Natri carboxymethyl cellulose
PEG Polyethylen glycol
PVP Polyvinylpyrolidon
SKD Sinh kh dng
PVC Polyvinyl clorid
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DANH MC CC BNG
Tn bng Trang
Bng 1.1: Cc ch phm ca glipizid trn th trng 4
Bng 1.2: Phn loi cc h gii phng ko di 6
Bng 1.3: Gii hn ho tan ca ba ln th 9
Bng 2.1: Nguyn liu, t dc dng trong bo ch vin nn glipizid GPKD 14
Bng 3.1: chnh xc ca phng php nh lng glipizid 22
Bng 3.2: ng ca phng php nh lng 23
Bng 3.3: % gii phng dc cht t vin Glipizide XL 24
Bng 3.4: Cng thc vin nn glipizid GPKD c t l t dc dnh 26
Bng 3.5: % gii phng dc cht t vin nn glipizid GPKD c t l t
dc dnh 5; 10; 15%
26
Bng 3.6: Thnh phn cng thc c loi, t l t dc n khc nhau 28
Bng 3.7: Thnh phn cng thc khi thay i t l t dc trn 29
Bng 3.8: Bin c lp v cc khong bin thin 31
Bng 3.9: Thit k th nghim v kt qu bin ph thuc 32
Bng 3.10: Gi tr R2 32
Bng 3.11: Cng thc ti u 36
Bng 3.12: Thnh phn cng thc ti u 36
Bng 3.13: Hm m cc l ti u 37
Bng 3.14: ng u khi lng vin 38
Bng 3.15: % gii phng glipizid t cc l v vin i chiu theo thi gian 38
Bng 3.16: xut tiu chun ht v vin nn glipizid GPKD 39
Bng 3.17: xut tiu chun ho tan dc cht theo thi gian vin nn glipizid GPKD
39
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DANH MC HNH V V S
Tn hnh Trang
Hnh 1.1: th nng dc cht trong mu ca cc dng thuc 4
Hnh 2.1: Cc giai on bo ch vin nn glipizid 10mg GPKD 18
Hnh 3.1: nh hp th cc i ca glipizid trong m phosphat pH 6,8 22
Hnh 3.2: Mi tng quan gia nng dung dch glipizid v mt
quang
24
Hnh 3.3: th % gii phng dc cht t Glipizide XL 25
Hnh 3.4: th gii phng dc cht t vin nn glipizid GPKD vi t l
t dc dnh khc nhau theo thi gian
27
Hnh 3.5: nh hng ca t dc n ti kh nng gii phng dc cht 28
Hnh 3.6: th nh hng ca t dc trn ti kh nng gii phng dc
cht
30
Hnh 3.7: nh hng ca t l HPMC K4M : HPMC K100LV v t l
Avicel : lactose ti kh nng gii phng dc cht
34
Hnh 3.8: nh hng ca t l Avicel : lactose v t l PVP ti kh nng
gii phng dc cht
35
Hnh 3.9: nh hng ca t l HPMC K4M : HPMC K100LV v nng
PVP ti kh nng gii phng dc cht
36
Hnh 3.10: th % gii phng glipizid theo thi gian ca 3 l ti u 39
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1
T VN
Nm 1985, i tho ng c T chc Y t th gii nh ngha nh l mt
tnh trng tng ng huyt mn tnh, i khi km theo cc triu chng kht nhiu,
i nhiu, st cn v n, c th dn ti hn m v t vong nu khng c iu
tr. i tho ng gy ra nhng bin chng cc k nguy him nh nhi mu c
tim, c thu tinh th, hoi th, suy thn, nhim toan mu, hn m. [5], [7], [10].
Ngi mc bnh i tho ng phi dng thuc c i v tun th nghim
ngt phc iu tr. Cc bin php iu tr l dng thuc tim insulin, dng cc
thuc dng ung c c ch kim sot ng huyt v phi hp vi iu chnh li
sng, sinh hot hp l c bit l ch n ung v vn ng [2], [5], [7].
Glipizid l sulfonylure dng ng ung, c tc dng lm gim glucose
huyt ti mc bnh thng ngi i tho ng khng ph thuc insulin thng
qua c ch l kch thch tit insulin t t bo beta ca tuyn tu, thuc lm tng tc
dng ca insulin t bo ch ngoi bin [5].
Tnh theo trng lng glipizid l mt trong cc thuc c tc dng mnh nht
ca nhm sufonylure, c na i ngn hn so vi cc sufonylure khc nn gim
nguy c gy h ng huyt trm trng. Hin nay, glipizid ang c s dng rng
ri trn th gii cng nh ti Vit Nam di nhiu dng bo ch. Trong dng bo
ch gii phng ko di c nhiu u im l tng kh nng kim sot ng huyt,
gim tc dng khng mong mun, thun tin trong s dng Tip tc nghin cu
ca DS. Phm Th Giang chng ti thc hin ti: Nghin cu vin nn glipizid
gii phng ko di s dng ct thn nc hydroxypropyl methyl cellulose vi
cc mc tiu sau:
1. Xy dng cng thc bo ch ti u vin nn glipizid gii phng ko di 24
gi s dng ct thn nc HPMC.
2. xut tiu chun c s cho vin nn bo ch c.
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2
CHNG I: TNG QUAN
1.1. Glipizid
1.1.1. Cng thc cu to
+ Cng thc phn t: C21H27N5O4S
+ Phn t lng: 445,536 g/mol
+ Tn khoa hc: N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-5-
methylpyrazin-2 carboxamid [11], [25].
1.1.2. Tnh cht l ha
+ L tnh: Bt kt tinh mu trng hoc gn trng, nng chy 208- 209 C ,
thc t gn nh khng tan trong nc (37,2 mg/l), rt t tan trong ethanol. Tan t
trong methylclorid, aceton, methanol, ha tan tt trong dung dch kim v
dimethylformanid [11], [25].
+ Ha tnh: pKa = 5,9; c tnh acid yu; ch s logP = 2,5 [11], [25].
1.1.3. Dc ng hc
Glipizid hp thu nhanh v hu nh hon ton qua ng tiu ha, sinh kh
dng cao gn 100% khi ung. Nng nh ca thuc trong huyt tng t sau
khi ung khong 1-3 gi, thi gian bn thi 2-4 gi c ng ung v ng tim
tnh mch, thc n lm chm qu trnh hp thu khong 40 pht nhng khng phn
hy thuc. Thuc gn mnh vi protein huyt tng (98-99%), nhng khng tch
ly khi dng liu nhc li, th tch phn b Vd=11lt (tim tnh mch). Thuc c
chuyn ha mnh ch yu gan thnh nhng sn phm khng cn hot tnh. Cc
cht chuyn ho ca glipizid thi tr hon ton qua nc tiu. Khong < 10% thuc
thi tr qua nc tiu di dng khng i [2], [5].
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3
1.1.4. Ch nh, cch dng v liu dng
1.1.4.1. Ch nh:
iu tr i tho ng typ II (khng ph thuc vo insulin), m khng kim
sot c bng iu chnh ch n n c [5], [18].
1.1.4.2 Cch dng, liu dng
Cch dng: Ung mt ln vo bui sng khong 30 pht trc ba n; 15 -
20 mg/ngy. Liu dng ti a mi ngy 1 ln c khuyn co l 15mg. Liu hng
ngy cao hn 30mg, chia lm 2 ln dng trong thi gian di c s dng an
ton.
Liu khi u ngi bnh cha c iu tr: Liu khi u ngi ln l
5 mg mi ngy; ngi cao tui hoc ngi c bnh gan l 2,5 mg mi ngy.
Liu duy tr: Mt s trng hp c th c iu tr c kt qu vi ch
ung thuc 1 ln mi ngy, trong khi mt s khc li p ng tt hn vi ch
iu tr chia lm nhiu ln. Tng liu hng ngy trn 15 mg thng phi chia lm
nhiu ln [5].
1.1.5. Qu liu v x tr
Triu chng: ng huyt thp, au nhi mi v li, bun nn, ngp, l
ln, kch ng, nhp tim nhanh, ra m hi, co git, sng s, hn m.
iu tr tt nht l dng glucose (ung cho trng hp h ng huyt nh,
tim nu nng hn) [5].
1.1.6. Phng php nh lng
- Dc in M 32 s dng sc k lng hiu nng cao (HPLC).
Pha ng: Dung dch m phosphat pH 6,8 methanol = 55 : 45, mu chun
v mu th c pha trong methanol. Da vo pic p ng ca mu chun v mu
th tnh ton ra hm lng glipizid trong mu th t suy ra hm lng glipizid
trong vin [25].
-Dc in Anh s dng phng php o quang ti bc sng = 274 nm
trong mi trng methanol [11].
-
4
1.1.7. Mt s ch phm glipizid trn th trng
Bng 1.1: Cc ch phm ca Glipizid trn th trng
Tn bit dc Nh sn xut Hm lng (mg) Dng bo ch
Glucotrol
Pfizer
5 ; 10 Vin nn
Glucotrol XL 2,5 ; 5 ; 10 Vin GPKD
Glibenese 5 Vin nn
Glibenese retard 5 ; 10 Vin GPKD
Melizide Merck 5 Vin nn
Glipid Yuong II pharm 5 Vin nn
Dipizide Micro labs 5 ; 10 Vin nn
Minodiab Kenfarma 2,5 ; 5 ; 10 Vin nn
Glucophage Lipha Sante Kt hp: Glipizid v metformin
Vin nn
1.2. Thuc tc dng ko di
1.2.1. Khi nim:
- Thuc tc dng ko di (TDKD) l nhng ch phm c kh nng ko di qu
trnh gii phng v hp thu dc cht t dng thuc nhm duy tr nng dc cht
trong mu trong vng iu tr mt thi gian di vi mc ch ko di thi gan iu
tr, gim s ln a thuc cho ngi bnh, gim tc dng khng mong mun, nng
cao hiu qu iu tr ca thuc [1].
A. Thuc quy c B. Thuc nhc li
C. Dng gii phng c kim sot D. Dng gii phng ko di
Hnh 1.1: th nng dc cht trong mu ca cc dng thuc
-
5
Theo dc in M, thuc TDKD t nht phi gim c mt na s ln
dng thuc cho ngi bnh [1].
1.2.2. Phn loi thuc tc dng ko di
Hin nay, cha c cch phn loi thng nht v r rng.
Theo dc in M, thuc TDKD gm 2 loi: loi ko di v loi tc dng
chm [1].
Tuy nhin hin nay trong cc ti liu chuyn mn c rt nhiu thut ng
ch thuc TDKD: Thuc gii phng ko di, thuc gii phng c kim sot, thuc
gii phng theo chng trnh, thuc gii phng nhc li, thuc gii phng ti
ch[1].
1.2.3. u nhc im ca thuc gii phng ko di
1.2.3.1. u im
- Duy tr nng dc cht trong mu trong vng iu tr, gim c dao
ng nng mu ca thuc (trnh c hin tng y - nh), do gim tc
dng khng mong mun ca thuc [1].
- Gim s ln dng thuc cho ngi bnh, trnh hin tng qun thuc, b
thuc, thc dy na m ung thuc T m bo s tun th iu tr ca bnh
nhn, nng cao hiu qu iu tr ca thuc [1].
- Nng cao sinh kh dng ca thuc do thuc c hp thu u n, trit
hn. Trong nhiu trng hp c th tp trung c nng thuc cao ti c quan
ch, nng cao hiu qu iu tr [1], [26].
- Gim lng thuc dng cho c t iu tr, do gim gi thnh cho c liu
trnh iu tr [1].
1.2.3.2. Nhc im
- Trong trng hp ng c, gp tc dng khng mong mun hay khng chu
thuc th khng thi tr ngay thuc ra khi c th.
- Tc dng lm sng ca thuc ph thuc nhiu vo k thut bo ch, nhng
thay i sinh hc trong c th ngi bnh.
-
6
- Ch c mt s t dc cht bo ch c di dng TDKD, c bit vi
nhng dc cht m liu tc dng gn vi liu c th khng nn bo ch di dng
TDKD [1], [18].
1.2.4. Cc h gii phng ko di
1.2.4.1 Phn loi
Bng 1.2: Phn loi cc h gii phng ko di [1]
Tn h Cu to T dc C ch u im Nhc
im
H ct
ho tan
Polyme thn
nc ng
vai tr ct
mang dc
cht
Carbopol, MC,
HPMC,
alginat, gm
xanthan
Ct thm
nc ho tan
dc cht.
Polyme
trng n
to hng ro
gel kim sot
gii phng
K thut
bo ch
n gin
-H kh t
gii phng
bc 0
-Gii
phng ph
thuc nhiu
yu t mi
trng
H ct
n mn
(ct s
nc)
Dc cht
phi hp
vi t dc
l sp, cht
bo ng
vai tr cht
mang
Sp, alcol bo,
acid bo, ester,
du hydrogen
ho, Eudragit
Ct b h
men thu
phn hoc n
mn trong
ng tiu
ho t
gii phng
dc cht
T dc
r tin, d
kim, k
thut n
gin
-H kh t
gii phng
bc 0
-gii
phng ph
thuc nhiu
yu t mi
trng
H ct
khuch
tn
Dc cht
phn tn
vo mt ct
tr, xp,
EC, PVC,
polyme methyl
methacrylat,
DCP, calci
Ct thm
mi trng
s khuch
tn, ho tan
-K thut
n gin
-Gii
phng t
-Kh t
ng hc
bc 0
-Gii
-
7
khng tan
trong dch
tiu ho
carbonat... dc cht ra
ngoi mi
trng
ph thuc
mi
trng
phng ph
thuc lc
dp,to ht
H ct
trao i
ion
Nha trao
i ion
ng vai tr
ct tr
mang thuc
Nha trao i
ion
Thuc s
c gii
phng ra
bng cch
trao i vi
ion trong
dch tiu ho
Thch
hp vi
dc cht
khng
bn trong
dch tiu
ho
-Gii
phng
khng t
bc 0
-Ph thuc
pH, nng
ion
H
thm
thu
Bao ngoi
vin mng
bn thm c
ming gii
phng dc
cht
Cellulose
acetat, PVC,
polyurethan
Dc cht
y ra ngoi
mt cch t
t nh vo
chnh lch
p sut thm
thu
-D t
gii
phng
hng nh
-Gii
phng t
ph thuc
mi
trng
i hi k
thut bo
ch cao
H
mng
bao ho
tan
Dc cht
c bao
bi mt
mng bao
ho tan
chm hoc
n mn
CMC,Na
CMC, HPMC,
PVP, gm,
gelatin,
Eudragit, sp
Mng bao
ng vai tr
l cc hng
ro lm
chm s gii
phng dc
cht
D dng
iu
chnh tc
gii
phng
bng
cch iu
chnh
dy mng
Tc gii
phng ph
thuc
nguyn liu
bao v
phng
php bao
-
8
H
mng
bao
khuch
tn
Bao dc
cht bng
mng bao
polymer
khng tan
trong dch
tiu ho
EC, PVC, hn
hp Eudragit,
PEG, glycerin,
acid stearic,
PVP, natri
clorid
Mng ht
nc ,
trng n
ho tan dc
cht. Dc
cht bo ho
trong h ri
khuch tn ra
ngoi
Gii
phng t
ph thuc
yu t
mi
trng
nh pH,
tit dch
tiu ho
Tc gii
phng thay
i khng
hng nh
1.2.4.2 T dc hydroxypropyl methyl cellulose
Hydroxypropyl methyl cellulose (HPMC) l nhng polyme tan trong nc, c
ngun gc t cellulose. HPMC c s dng rng ri trong ngnh dc phm cng
nh nhiu ngnh cng ngh khc. N l thnh phn quan trng trong nhiu cng
thc thuc. Vic s dng HPMC lm h ct kim sot gii phng dc cht, lm
mng bao ang rt c a chung hin nay v: thuc thng bo ch dng ng
ung nn d dng s dng, m hnh gii phng tng i n gin, k thut bo ch
khng i hi cao, chi ph thp v c chng minh an ton [16], [20].
C ch kim sot gii phng dc cht ca HPMC l nhanh chng thm t b
mt to thnh lp gel ngn cn bn ngoi khng cho dc cht ho tan ra ngoi mi
trng v bo v cu trc ca vin khng b r [16], [20].
C rt nhiu loi HPMC, mi loi c 1 tn thng mi khc nhau vi nhng k
hiu l nhng ch ci vit hoa c trng cho tnh cht ca tng loi HPMC:
E, F, K dng ch nhng loi HPMC c cu trc ho hc khc nhau.
Ch C biu th nht mc 100, ch M biu th nht mc 1000 (
nht o nng 2%, nhit 20 C).
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9
Hu t P dng ch loi HPMC cao cp, LV ch loi c nht thp,
CR ch lp kim sot gii phng, LH ch loi HPMC c hm lng
hydroxypropyl thp [16].
1.2.5. nh gi cht lng thuc tc dng ko di
1.2.5.1. nh gi tnh an ton v hiu qu
Yu cu nh gi tnh an ton v hiu qu tu thuc vo loi thuc TDKD
- Vi thuc TDKD cha dc cht c dng qui c c php lu hnh
trn th trng th phi nh gi SKD (sinh kh dng) ca thuc TDKD so vi dng
qui c: nng dc cht trong mu hoc dc cht bi tit trong nc tiu
trng thi cn bng phi tng ng vi ch nhiu liu ca dng qui c.
- Vi thuc TDKD cha dc cht c dng TDKD c php sn xut lu
hnh trn th trng th phi nh gi SKD tng i ca thuc nghin cu so vi
dng TDKD c: ch phm nghin cu phi tng ng sinh hc vi ch phm
i chiu.
i vi cc thuc mun khng nh ch nh iu tr mi hoc khng nh u
th vt tri ca ch phm phi tin hnh th lm sng [1].
1.2.5.2 nh gi tnh cht ko di
1.2.5.2.1. V gii phng dc cht in vitro
Tin hnh th ho tan nh vi cc dng thuc rn. Php th ho tan cho
thuc TDKD phi c thit k m bo tnh lp li gia cc ln th, nhy
pht hin c nhng thay i v cng thc v iu kin sn xut gia cc l m.
iu kin th ho tan cn c la chn theo hng thit lp c mi tng quan
gia ho tan vi hp thu [1].
Bng 1.3: Gii hn ho tan ca ba ln th
Ln th S mu th Gii hn ho tan
1 6 Khng c mu no nm ngoi gii hn qui nh v
khng c mu no thp hn t l qui nh ln th cui.
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10
2 6
Trung bnh ca 12 mu nm trong gii hn v khng c
mu no > 10% gii hn; khng c mu no thp hn
gii hn ln th cui cng.
3 12
Trung bnh ca 24 mu nm trong gii hn v khng c
qu 2 mu > 10% gii hn; c khng qu 2 mu thp
hn gii hn ln th cui cng v khng c mu no
cao hn hoc thp hn 20% gii hn qui nh.
Vi thuc TDKD dng ung, ngi ta thng qui nh ba mc gii hn
ho tan theo thi gian: ln 1 (trong vng 1 2 gi) th trong mi trng dch v, hai
ln sau th trong mi trng dch rut nhn to.
m bo s ng nht gia cc l m sn xut, Dc in M qui nh
gii hn ho tan ca ba ln th nh trn bng 1.2 [1], [25].
1.2.5.2.2. V sinh kh dng in vivo
- Khi nghin cu SKD phn trm dc cht c hp thu t liu TDKD
c th thc hin theo ch liu n.
- Khi tm hiu nh hng ca thc n ti SKD ca thuc TDKD dng liu
n v b tr th nghim theo phng php chia 3 nhm, th cho so snh dng qui
c vi dng ko di ung khi nhn i v ung sau khi n.
- Khi nh gi tng ng sinh hc so snh dng ko di vi dng qui c
hoc vi dng TDKD qui c khc c lu hnh th vic nh gi SKD c
tin hnh trng thi cn bng theo ch nhiu liu [1].
1.3. Ti u ho
1.3.1. Khi nim:
- Ti u ho mt cng thc hay quy trnh bo ch l vic tm cng thc,
thng s (hay iu kin tin hnh) ca quy trnh sn phm lm ra t kt qu tt
nht trong gii hn mong mun ca ngi lm th nghim [9].
-
11
1.3.2. Bin u vo v bin u ra:
- Bin u ra: cn gi l bin ph thuc hay p ng, l cc kt qu ca th
nghim m ngi lm th nghim thy cn phi o c v nh gi. V d: r,
ho tan, ng u khi lng [9].
- Bin u vo: cn gi l bin c lp hay yu t, l nhng bin m ngi
lm th nghim c th thay i gi tr ca n khi tin hnh th nghim v s thay i
ny s ko theo s thay i gi tr ca bin u ra. V d: lc dp, t dc, nhit
sy [9].
1.3.3. Thit k th nghim
Thit k th nghim l phng php lp k hoch v tin hnh thc nghim
thu nhn c thng tin ti a t tp hp cc d liu th nghim trong s c mt
ca nhiu yu t c th lm bin i kt qu th nghim vi s th nghim ti thiu
[9].
1.3.4. Trnh t tin hnh thit k th nghim v ti u ho
- Xc nh bin u ra (bin ph thuc) cn ti u ho v yu cu ca chng.
- Xc nh cc bin u vo c kh nng nh hng n bin u ra.
- Sng lc: Thit k v tin hnh cc th nghim s b nhm phn tch nh
hng ca cc bin u vo ln cc bin u ra loi b cc bin u vo khng
hoc t nh hng
- Thit k v tin hnh th nghim phn tch nh hng ca cc bin u
vo cn li ln cc bin u ra. T cc kt qu th nghim, xy dng mi quan h
gia cc bin u ra v cc bin u vo.
- Ti u ho cc bin u ra da trn cc mi quan h xy dng tm
cc gi tr ti u ca cc bin u vo.
- Lm th nghim theo cc gi tr ti u ca cc bin u vo va tm c
kim tra v iu chnh nu cn.
- Trin khai sn xut trn quy m bn cng nghip v cng nghip [9].
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12
1.4. Mt s nghin cu v glipizid
Sri Devi S. v cc cng s nghin cu pht trin v nh gi kh nng
kim sot gii phng glipizid ca ethyl cellulose (EC) v ethylene vinyl acetat
copolyme (EVA). Tc gi tin hnh bo ch vin bng phng php xt ht t
vi cc thnh phn: t dc polyme kim sot gii phng l s thay i t l EC v
EVA, t dc n lactose, xt ht vi t dc dnh chloroform, t dc trn
magnesi stearat (2%), Talc (2%). Tin hnh th ho tan vin vi cc iu kin: tc
khuy 50 1 vng/ pht, 900 ml m phosphat pH 6,8, nhit 37 1 C, vin
i chiu Glynase XL. S dng phng trnh ng hc bc 0, ng hc bc 1;
Higuchi v phng trnh Peppas phn tch d liu. Kt qu cho thy cng thc
c t l EVA 5% theo khi lng vin c kh nng kim sot gii phng gn ging
vi vin i chiu nht [23].
Parasuran Rajam Radhika v cc cng s nghin cu ti u ho cng thc
vin nn glipizid GPKD. La chn bin u vo l khi lng polyme HPMC K100
t 50 n 70 mg, khi lng polyme Eudragit L 100 t 50 n 70 mg. La chn
bin u ra l % gii phng dc cht ti cc thi im 2 gi, 8 gi v 12 gi. Cc
thnh phn cn li trong cng thc vin: glipizid 10 mg, t dc n lactose, t
dc dnh isopropyl alcohol, t dc trn l Aerosil v magnesi stearat. Vin c
bo ch theo phng php xt ht t v c tin hnh th ho tan vi cc iu
kin: tc quay 50 vng/pht, 900 ml dung dch m phosphat pH 6,8 hoc HCl
0,1 N, nhit 37 0,5 C. o quang ti bc sng 276 nm. Sau khi tin hnh th
ho tan, s dng m hnh ng hc Higuchi, phng trnh Kovesmeger v cc cng
c thng k phn tch s liu. Kt qu thu c l phn trm dc cht gii
phng ti thi im 8 gi l 52,24 78,46%, ti thi im 12 gi l 82,24
98,43%. Tm ra cng thc ti u cho vin c thnh phn 70 mg HPMC K100 v 60
mg Eudragit L 100 [21].
Do c tnh kh tan trong nc nn vn ci thin tan ca glipizid cng
l mt mc tiu nghin cu. Tc gi Bhosale Ashok V. cng cc cng s phi
hp glipizid vi beta-cyclodextrin nhm ci thin tan ca glipizid. Kt qu l
-
13
phc hp vi t l beta-cyclodextrin : glipizid bng 1 : 1 cho thy tan c ci
thin nhiu nht v th ho tan tuyn tnh nht. Phc hp sau c em i to
vin GPKD vi poly ethylen oxit tip tc th in vitro [12].
H nh Triu nghin cu bo ch vin nn glipizid gii phng ko di theo
c ch bm thm thu. Tc gi dng mui Na3PO4 vi mc ch va to p sut
thm thu va to vi mi trng kim mnh trong vin nhm ci thin tan ca
glipizid. Kt qu l xy dng c cng thc bo ch vin nn glipizid theo c ch
bm thm thu vi thnh phn vin nhn gm c glipizid (10 mg), PVP K30 (12
mg), Manitol (237 mg), Na3PO4 (15 mg) [6].
Phm Th Giang s dng cc loi HPMC c nht khc nhau bo ch
vin nn glipizid gii phng ko di dng ct thn nc. Vi cc loi HPMC c
nht khc nhau th kh nng kim sot gii phng khc nhau do nh hng ti cu
trc ca h. Khi s dng HPMC c nht thp nh HPMC K100LV th to gel
lng nn lp gel b n mn nhanh gi th 8 gii phng 87,56%. Khi dng HPMC
c nht cao nh HPMC K100M to thnh lp gel c nht qu cao cn tr gii
phng dc cht, gi th 10 ch gii phng 5%. Khi phi hp s dng 2 loi
polyme HPMC K4M v HPMC K100LV vi t l HPMC K4M : HPMC K100LV
bng 50:50 th thu c cng thc c kh nng kim sot gii phng gn vi vin
i chiu. Da trn nhng kt qu nghin cu ca tc gi Phm Th Giang chng ti
tip tc nghin cu vi mc tiu ti u ho cng thc bo ch vin nn glipizid gii
phng ko di dng ct thn nc s dng 2 loi polyme l HPMC K4M v HPMC
K100LV [8].
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14
CHNG 2: I TNG V PHNG PHP NGHIN CU
2.1. Nguyn liu, thit b
2.1.1. Nguyn liu
Bng 2.1: Nguyn liu, t dc dng trong bo ch vin nn glipizid GPKD
STT Nguyn liu v ha cht Ngun gc Tiu chun
1 Glipizid n USP
2 HPMC K4M M TCNSX
3 HPMC K100LV M TCNSX
4 Avicel PH 102 M TCNSX
5 Dicalci phosphat Trung Quc TCNSX
6 Lactose monohydrat M TCNSX
7 PVP K30 Trung Quc TCNSX
8 Ethanol 96% Vit Nam TCCS
9 Methanol Trung Quc TCNSX
9 Magnesi stearat Trung Quc TCNSX
10 Aerosil Trung Quc TCNSX
11 Talc Trung Quc TCNSX
12 Natri hydroxyd Trung Quc TCNSX
13 Kali dihydro phosphat Trung Quc TCNSX
2.1.2. Thit b
My dp vin quay trn ZPW21A (Trung Quc).
My dp vin Pye Unicam.
Cn k thut Sartorius Te 3102S (c).
Cn hm m Precisa XM 60 (Thy in).
My o cng PTB-511E (c).
My o quang Hitachi U-1900 (Nht Bn).
-
15
My th ha tan PHARMA TEST (c).
My o pH Sartorius TE 412 (c).
Chu siu m Ultrasonic LC 60H.
My ly tm Hettich (c)
T sy Memmert (c).
My o trn chy ERWEKA GWF (c).
Bnh nh mc, ry, pipet.
2.2. Ni dung nghin cu
Xy dng v thm nh quy trnh nh lng glipizid p dng cho th ho
tan vin nn glipzid 10mg GPKD.
Kho st nh hng ca cc loi t dc n s gii phng glipizid t vin
nn GPKD.
La chn cng thc ti u cho vin nn glipizid 10mg GPKD 24 gi da vo
tiu chun vin i chiu Glipizide XL.
xut mt s tiu chun c s vin nn glipizid gii phng ko di
2.3. Phng php nghin cu
2.3.1. Thm nh phng php nh lng p dng cho th ho tan vin
2.3.1.1 c hiu
- Dung dch chun: Pha dung dch chun glipizid 10 g/ml trong mi trng
m phosphat pH 6,8. Cn chnh xc khong 100 mg glipizid ho tan hon ton vo
100 ml methanol. Ht 1 ml dung dch va pha cho vo bnh nh mc 100 ml thm
dung dch m phosphat pH 6,8 n vch.
- Mu trng t dc: Cn chnh xc mt lng t dc tng ng vi t l t
dc c trong vin, pha trong dung dch m phosphat pH 6,8 n t l pha long
nh mu em i nh lng.
- Mu trng: dung dch m phosphat pH 6,8.
- Qut ph mu chun v mu trng t dc trn my o quang ph hp th
UV VIS trong khong bc sng 200 450 nm. Xc nh bc sng ti xut
-
16
hin nh hp th cc i. So snh ph ca mu chun v mu trng t dc (khng
c dc cht) xc nh nh hng ca t dc n kh nng hp th quang ca
dc cht.
2.3.1.2 tuyn tnh
Pha dy dung dch chun c nng 4 ; 6; 8; 10; 12; 16 g/ml trong mu
trng t dc: Cn chnh xc khong 50 mg glipizid ho tan hon ton trong 50 ml
methanol. Ht chnh xc 10 ml dung dch va pha cho vo bnh nh mc 100 ml,
thm mu trng t dc ti vch. Ht chnh xc ln lt 4; 6; 8; 10; 12; 16 ml dung
dch thu c, pha long trong bnh nh mc 100 ml vi mu trng t dc.
o mt quang D ca cc dung dch trn bc sng 223 nm.
Xy dng phng trnh hi quy thc nghim, v th tng quan gia mt
quang v nng dc cht.
2.3.1.3 chnh xc
Dung dch nn c nng 4 g/ml trong mu trng t dc.
Dung dch chun gc 100 g/ml trong dung dch m phosphat pH 6,8: Cn
chnh xc khong 100 mg glipizid ho tan hon ton vo 100 ml methanol. Ht 10
ml dung dch va pha cho vo bnh nh mc 100 ml ri thm dung dch m
phosphat pH 6,8 ti vch. Ht ln lt 2 ml; 2,5 ml v 3 ml dung dch chun gc
cho vo bnh nh mc 25 ml, b sung bng dung dch nn cho th tch. Cc
dung dch sau khi pha long c nng hiu chnh tnh theo cng thc:
Trong Vi l th tch dung dch chun gc ht ra khi pha long.
Mi nng c tin hnh o 5 ln.
2.3.1.4 ng
Tin hnh kho st vi 5 mu khc nhau mi mu 3 nng 8; 10; 12 g/ml.
Cch pha: tin hnh nh chnh xc.
o quang v so snh nng thc vi nng l thuyt.
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17
2.3.2. Phng php bo ch vin nn glipizid 10mg gii phng ko di ct thn
nc.
- Phng php bo ch: to ht t gm 2 giai on:
Giai on kho st cng thc: dp 100 vin/1 CT bng my dp vin Pye
Unicam.
Giai on ti u ho cng thc: dp 1000 vin/1 CT bng my dp vin quay
trn ZPW21A.
Cc bc tin hnh:
Nghin mn glipizid nguyn liu, t dc, ry qua ry 0,25 mm.
Trn bt kp theo phng php ng lng.
To ht: Nho m bt kp vi lng va t dc dnh, sau xt ht qua
ry 1,0 mm, ht c sy 50 60 C n khi m cn di 5%.
Sa ht qua ry 1,0 mm. Sau em ht trn vi t dc trn ry qua ry
0,125 mm.
Dp vin: dp vin bng chy ci c ng knh 7 mm.
M hnh bo ch vin nn glipizid 10 mg nh hnh di y:
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18
Hnh 2.1: Cc giai on bo ch vin nn glipizid 10mg GPKD
2.3.3. Phng php nh gi mt s tiu chun vin nn glipizid
2.3.3.1 nh gi tnh cht ht
m: Dng cn xc nh m nhanh. Cn khong 1 g cm, cho vo a
cn, t nhit 1050C, theo di v c kt qu.
2.3.3.2 nh gi tnh cht vin
nh lng: S dng phng php o quang ti bc sng 223 nm, so snh
mt quang ca mu th v mu chun tnh hm lng glipizid trong vin.
Mu th: Cn 20 vin, tnh khi lng trung bnh vin, nghin thnh bt.
Cn chnh xc mt lng bt tng ng khong 25 mg glipizid cho vo bnh nh
mc 25 ml, thm khong 20 ml methanol v em siu m khong 15 pht. B sung
methanol n vch v lc qua giy lc. B 2 ml dch lc u, sau ht 1 ml dch
lc cho vo bnh nh mc 100 ml, thm m phosphat pH 6,8 n vch, lc u.
Mu chun: Cn chnh xc khong 100 mg glipizid chun, cho vo bnh nh
Nguyn liu, t dc n, t
dc kim sot gii phng
PVP/EtOH 96%
Magnesi stearat,
Aerosil, Talc
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19
mc 100 ml, thm khong 80 ml methanol, siu m 15 pht, b sung methanol n
vch, lc u. Ly 1 ml cho vo bnh nh mc 100 ml, thm dung dch m
phosphat pH 6,8 n vch, lc u.
Hm lng % glipizid trong vin c tnh theo cng thc:
Hm lng glipizid so vi hm lng ghi trn nhn:
G = %G mtb
10
G: Hm lng % glipizid trong vin.
G: Hm lng % glipizid trong vin so vi hm lng ghi trn nhn.
mth, mch: Ln lt l khi lng mu th v mu chun.
Dth, Dch: ln lt l hp th ca mu th v mu chun.
Th nghim ha tan:
Tin hnh trn my th ha tan PHARMA TEST, mi cng thc vin tin
hnh th 6 vin (n=6).
iu kin th:
Thit b cnh khuy
Tc khuy: 100 2 vng/pht
Mi trng: 900ml dung dch c cha glipizid nng 4g/ml trong
mi trng m phosphat pH 6,8.
Nhit : 37 0,50C.
Thi im ly mu: Cch 1 gi ly mu mt ln trong 24 gi, th tch ly
mu 5 ml. Mi trng ha tan ban u v cc mu th ti cc thi im c em
i o quang ti bc sng 223 nm.
Mu trng l dung dch m phosphat pH 6,8.
Mu chun: Dung dch glipizid 10 g/ml trong m phosphat pH 6,8
Cch tnh kt qu:
Nng glipizid trong mu th n:
-
20
Cn = Cch DnDch
(g/ml)
Nng glipizid hiu chnh (tr i nng nn) l:
Cn = Cn 4 (g/ml)
Lng dc cht gii phng sau 1 gi (mu th 1):
M1 = C1 900 (g)
Lng dc cht gii phng sau 2 gi (mu th 2):
M2 = C1 5 + C2 895 (g)
Lng dc cht gii phng sau n gi (mg):
% glipizid gii phng:
Trong :
- Cn, Cn, Dn, Mn, Hn ln lt l nng glipizid trong mu th, nng
glipizid hiu chnh, hp th Dn223, lng glipizid gii phng, % glipizid
gii phng ca dung dch rt ti thi im n.
- Cch, Dch: nng glipizid, hp th Dch223 ca dung dch chun.
- mv, mtb ln lt l khi lng vin v khi lng trung bnh vin.
So snh hai th gii phng dc cht in vitro bng ch s f2. Ch s f2 th
hin s ging nhau gia 2 th gii phng dc cht v c tnh theo cng thc
sau:
Trong : n: S im ly mu th; Ri, Ti: % dc cht gii phng ti thi
im t ca mu i chiu, mu th.
-
21
Gi tr f2 = 50 n 100 th 2 th c coi l ging nhau.
Gi tr f2 = 100 hai th c coi l ging nhau hon ton.
Gi tr f2 = 50 th 2 th c s sai khc trung bnh ti mi thi im
l 10% [18].
nh gi lc gy v vin: o lc gy v vin trn my o cng
PHARMATEST, tin hnh th 10 vin/1 CT.
nh gi ng u khi lng vin (p dng vi cc cng thc ti
u): Cn 20 vin, tnh khi lng trung bnh. Cn tng vin, so snh vi khi lng
trung bnh. Tiu chun: khng qu 2 vin c khi lng lch qu 7,5% khi lng
trung bnh v khng c vin no lch qu 15% khi lng trung bnh.
2.3.4 La chn cng thc ti u ho vin nn glipizid 10 mg GPKD
Da vo nhng kho st trc v kt qu kho st vin i chiu la chn
cc bin u vo v cc bin u ra.
S dng phn mm Modde 8.0 thit k th nghim la chn cng thc ti u.
Bo ch vin nn theo cc cng thc thit k v tin hnh th ho tan thu
c kt qu l cc bin u ra.
D liu thc nghim v ho tan cc cng thc c x l bng phn
mm Form Rules v2 nhm tm ra quy lut nh hng ca cc bin u vo ti cc
bin u ra.
La chn thnh phn cng thc ti u bng phn mm Inform v3.1.
Bo ch cc l cng thc ti u v tin hnh nh gi cng thc ti u.
xut mt s tiu chun vin nn glipizid GPKD.
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22
CHNG 3: THC NGHIM V KT QU NGHIN CU
3.1. Thm nh phng php nh lng
3.1.1. Tnh c hiu
Tin hnh pha dung dch glipizid nng 10 g/ml v qut ph nh m t
mc 2.1, thu c ph hp th ca glipizid nh hnh 3.1.
Hnh 3.1: nh hp th cc i ca glipizid trong m phosphat pH 6,8
Nhn xt: Ph UV cho thy glipizid hp th cc i ti 223 nm v 275,5 nm
trong mi trng m pH 6,8. Trong khi , khi qut ph ca mu trng t dc,
khng thy xut hin nh hp th ti bc sng 223 nm. Nh vy, ti bc sng
223 nm hp th quang ca glipizid khng b nh hng bi cc t dc s dng.
3.1.2. chnh xc
Tin hnh pha dung dch glipizid theo mc 2.3.1 v o quang ti bc sng 223 nm.
Bng 3.1: chnh xc ca phng php nh lng glipizid
Nng khi pha(g/ml) 8,096 10,120 12,144
Nng thm nn(g/ml) 11,776 13,800 15,824
Ln 1 0,623 0,738 0,851
Ln 2 0,631 0,747 0,854
Ln 3 0,632 0,731 0,849
Ln 4 0,615 0,727 0,862
Ln 5 0,639 0,719 0,845
Trung bnh 0,628 0,732 0,852
SD 0,009 0,011 0,006
RSD (%) 1,47 1,46 0,75
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23
chnh xc ca phng php nh lng c tin hnh lp li 5 ln vi
cc mu c pha nh m t trong mc 2.3.1.
Kt qu thu c th hin trong bng 3.1 cho thy ti cc nng khc nhau,
hp th quang c s lp li tt vi gi tr RSD thu c u nh hn 2%.
Kt lun: phng php ny t v lp li.
3.1.3. ng
ng ca phng php nh lng c tin hnh 3 nng 80; 100 v
120% nng nh lng vi cch pha mu nh m t trong mc 2.1 v kt qu
c trnh by trong bng 3.2.
Bng 3.2: ng ca phng php nh lng
TT 80% nng C0 100% nng C0 120% nng C0
D thc D l
thuyt
% tm
li D thc
D l
thuyt
% tm
li D thc
D l
thuyt
% tm
li
Ln 1 0,629 0,628 100,16 0,738 0,732 100,77 0,851 0,852 99,86
Ln 2 0,611 0,622 98,26 0,718 0,725 99,01 0,820 0,844 97,18
Ln 3 0,612 0,609 100,43 0,708 0,711 99,62 0,804 0,827 97,23
Ln 4 0,647 0,630 102,62 0,762 0,735 103,63 0,852 0,856 99,58
Ln 5 0,603 0,617 97,76 0,718 0,719 99,81 0,815 0,837 97,37
TB 99,85 100,57 98,24
SD 1,94 1,82 1,35
RSD 1,94 1,81 1,38
Kt qu trong bng 3.2 t l tm li ti mi nng u t 98-101%, RSD < 2%.
Kt lun: Phng php c ng tt.
3.1.4. tuyn tnh
Tin hnh o mt quang ca 5 dung dch glipizid c nng ln lt
khong: 4 g/ml, 6 g/ml, 8 g/ml, 10 g/ml, 12 g/ml v 16 g/ml trong mu
trng t dc ti bc sng 223 nm. Kt qu c trnh by trong hnh 3.2.
Nhn xt: Kt qu trn cho thy mt quang c mi quan h tuyn tnh vi
nng dung dch glipizid trong mu trng t dc khong nng t 4 g/ml
-
24
n 16 g/ml vi R2 l 0,999. Nh vy, phng php o quang cho tuyn tnh
tt trong khong nng xc nh.
Vy c th s dng phng php o quang UV-VIS ti bc sng 223 nm
xc nh hm lng dc cht c trong cc mu nghin cu.
Hnh 3.2: Mi tng quan gia nng dung dch glipizid v mt quang
3.2. Kho st cng thc vin
3.2.1. Kho st kh nng gii phng dc cht glipizid t vin chun Glipizide
XL trong mi trng m phosphat
Vin i chiu l vin Glipizide XL.
Hng sn xut: GreenStone.
Tin hnh th ho tan nh mc 2.1.
Kt qu thu c bng 3.3 sau:
Bng 3.3: % gii phng dc cht t vin Glipizide XL
Thi gian 0 1 2 4 6 8 10 12 16 20 24
% 0 4,5 4,66 15,03 30,53 44,32 61,87 77,85 94,81 102,01 114,59
-
25
Hnh 3.3: th % gii phng dc cht t Glipizide XL
Nhn xt: Vin nn Glipizide XL c dc cht l glipizid c bo ch di
dng GPKD theo c ch bm thm thu. Khi tin hnh th ho tan vi iu kin
nh mc 2.1, trong 2 gi u dc cht gii phng t l do vin cn thi gian
nc thm qua mng bao vo bn trong v ho tan dc cht. Nhng gi tip theo
do chnh lch p sut thm thu gia bn trong v bn ngoi vin s y dung dch
dc cht ra ngoi mi trng. T khong 2 gi n 6 gi, lng dc cht gii
phng trung bnh khong 4 - 6%/1 gi. T khong 16 n 24 gi, lng dc cht
gii phng trung bnh khong 2 3%/1 gi. iu ny c gii thch l do cng v
sau s chnh lch p sut thm thu gia bn trong v bn ngoi vin cng gim
lm tc gii phng dc cht gim.
3.2.2. Kho st nh hng ca t dc dnh ti kh nng gii phng dc cht
Da trn nhng nghin cu ca Phm Th Giang, tip tc tin hnh kho st
qu trnh gii phng dc cht t vin nn khi thay i t l t dc dnh 5%, 10%,
15% theo khi lng vin ng vi cc cng thc (CT) c thnh phn nh trong
bng sau:
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26
Bng 3.4: Cng thc vin nn glipizid GPKD c t l t dc dnh khc nhau
Cng thc/thnh phn(mg) CT1 CT2 CT3
Glipizid 10 10 10
HPMC K4M 50 50 50
HPMC K100LV 50 50 50
Lactose 60 60 60
Mg Stearat 2 2 2
Aerosil 1 1 1
PVP/ethanol 96% 5% 10% 15%
Bo ch vin theo mc 2.3.2.
Tin hnh th ho tan vi cc iu kin theo mc 2.3.3.
Kt qu c trnh by trong bng 3.5.
Bng 3.5: % gii phng dc cht t vin nn glipizid GPKD c t l t dc dnh
5; 10; 15%
Thi
gian 0 1 2 4 8 12 16 20 24
CT 1 0 11,26 17,99 27,93 60,64 83,81 100,78 112,54 119,19
CT 2 0 11,19 17,11 27,41 49,64 79,11 93,89 111,04 117,75
CT 3 0 10,32 16,87 23,91 40,07 65,46 77,14 91,28 92,68
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27
Hnh 3.4: th gii phng dc cht t vin nn glipizid GPKD vi t l t dc
dnh khc nhau theo thi gian
Nhn xt: T kt qu kho st ta thy t l t dc dnh nh hng ti kh
nng gii phng dc cht. Khi t l t dc dnh tng ln ti 15% lm tng kh
nng lin kt gia cc tiu phn dc cht dn ti lm gim kh nng ho tan, gii
phng dc cht. So snh th ca cc cng thc vi vin chun da vo ch s f2
thu c kt qu:
So snh CT 1 vi vin chun: f2 = 49,27.
So snh CT 2 vi vin chun: f2 = 52,99.
So snh CT 3 vi vin chun: f2 = 41,22.
Kt lun: Vi kt qu trn cho thy cng thc vi t l PVP 10% theo khi
lng vin c tc gii phng gn ging vin i chiu nht f2 = 52,99 (>50).
3.2.3. Kho st nh hng ca t dc n ti kh nng gii phng dc cht
Tin hnh kho st nh gi kh nng gii phng dc cht t vin nn
glipizid GPKD khi thay i loi, t l t dc n vi cc thnh phn theo bng 3.6
sau
-
28
Bng 3.6: Thnh phn cng thc c loi, t l t dc n khc nhau
Thnh phn (mg) CT2 CT4 CT5 CT6 CT7
Glipizid 10 10 10 10 10
HPMC K4M 50 50 50 50 50
HPMC K100LV 50 50 50 50 50
Avicel PH 102 - 60 - 30 40
DCP - - 60 - -
Lactose 60 - - 30 20
Magnesi stearat 2 2 2 2 2
Aerosil 1 1 1 1 1
PVP 10%/EtOH 96% Va
Kt qu th ho tan cc cng thc c trnh by trong hnh 3.4 sau:
Hnh 3.5: nh hng ca t dc n ti kh nng gii phng dc cht
Nhn xt: Khi s dng cc loi t dc n khc nhau th kh nng gii
phng dc cht ca vin nn c s thay i. Trong khong 8 gi u s khc bit
-
29
l cha nhiu. Tuy nhin nhng gi sau s khc bit l ng k. CT2 s dng
lactose c s gii phng nhanh hn l s dng Avicel, DCP (s nc). Khi tin
hnh phi hp 2 loi t dc Avicel v lactose vi t l 30:30 v 40:20 th cho thy
kh nng kim sot gii phng tt hn. So snh th ca cc cng thc vi vin
chun thu c kt qu nh sau:
F2 (CT2/vin chun) = 52,99
F2 (CT4/vin chun) = 51,79
F2 (CT5/vin chun) = 52,51
F2 (CT6/vin chun) = 56,11
F2 (CT7/vin chun) = 53,69
Kt qu: Vin nn c thnh phn t dc n vi t l Avicel : lactose bng
30:30 cho kt qu gii phng dc cht gn ging vi vin chun nht.
3.2.4. Kho st nh hng ca t dc trn ti kh nng gii phng dc cht
Trn c s cng thc kho st tin hnh kho st cc cng thc tip theo
vi s thay i t l t dc trn Talc t 0,5 n 2 %. Thnh phn cc cng thc
nh trong bng di y:
Bng 3.7: Thnh phn cng thc khi thay i t l t dc trn
Thnh phn CT 8 CT 9 CT 10 CT 11
Glipizid 10mg
HPMC K4M 50mg
HPMC K100LV 50mg
Lactose 60mg
PVP 10% Va
Magnesi stearat 1,15%
Talc 0,5% 1% 1,5% 2,0%
Kt qu nh trong th sau:
-
30
Hnh 3.6: th nh hng ca t dc trn ti kh nng gii phng dc cht
Nhn xt: T kt qu kho st trn ta thy khng c s khc bit r rng v
kh nng gii phng dc cht khi thay i t l t dc trn Talc t 0,5% n 2%.
Tin hnh so snh cc th thu c kt qu f2 u ln hn 80.
Kt lun: T dc trn khng nh hng ti kh nng gii phng dc cht.
3.3. Thit k nghin cu v ti u ho cng thc vin nn glipizid gii phng
ko di
3.3.1. La chn bin cng thc v thit k th nghim
Da vo nghin cu ca Phm Th Giang v nhng kt qu kho st trn, la
chn cc bin u vo thit k th nghim ti u ho vin nn glipizid gii phng
ko di dng ct thn nc nh sau:
Cc bin u vo gm: 3 bin nh lng
T l 2 loi polyme HPMC K4M : HPMC K100LV (gi nguyn tng khi
lng polyme 100mg/ vin): t t l 1:2 (0,5) n t l 2:1 (2).
T l t dc dnh theo khi lng vin: 5 15%.
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31
T l 2 loi t dc n Avicel : lactose (gi nguyn tng khi lng t dc
n 60mg/ vin): t t l 1:2 (0,5) n t l 2:1 (2)
Bng 3.8: Bin c lp v cc khong bin thin
Bin c lp K hiu Mc thp Mc cao
T l HPMC K4M : HPMC K100LV X1 0,5 2
T l Avicel : lactose X2 0,5 2
PVP/ EtOH 96% X3 5% 15%
Cc thnh phn cn li: glipizid 10mg, magnesi stearat 2mg, Aerosil 1mg gi
nguyn trong cc cng thc ti u.
Da trn kt qu th ho tan vin i chiu, la chn bin ph thuc (bin
u ra): % gii phng dc cht ti cc thi im 2 gi (Y1), 4 gi (Y2), 8 gi
(Y3), 16 gi (Y4), 24 gi (Y5).
Thit k th nghim bng phn mm Modde 8.0 theo m hnh D-optimal gm
16 th nghim .
Bo ch vin nn theo mc 2.3.2.
Tin hnh th ho tan theo mc 2.3.3.
Thit k th nghim v kt qu % gii phng dc cht ti cc thi im 2
gi, 4 gi, 8 gi, 16 gi, 24 gi c trnh by trong bng di y:
-
32
Bng 3.9: Thit k th nghim v kt qu bin ph thuc
CT T l
K4M:K100LV
T l
Avicel:lactose
Nng
PVP Y1 Y2 Y3 Y4 Y5
N1 2 2 5 9,81 23,96 58,67 86,24 101,23
N2 2 2 15 10,69 22,61 50,46 85,32 102,96
N3 0,5 2 5 21,99 30,42 71,21 92,21 120,51
N4 0,5 2 15 20,67 30,65 57,77 91,85 112,08
N5 2 0,5 5 14,14 22,09 38,31 68,29 102,81
N6 2 0,5 15 7,06 16,98 52,78 73,41 106,18
N7 0,5 0,5 5 11,84 29,71 66,13 102,08 109,81
N8 0,5 0,5 15 12,21 26,72 61,33 102,67 104,91
N9 2 0,8 5 4,65 13,91 35,29 69,93 103,51
N10 2 0,8 10 5,51 15,32 35,58 67,39 100,44
N11 0,5 0,8 10 10,48 25,48 53,76 106,71 115,12
N12 1 0,8 10 9,92 31,68 45,69 93,11 120,45
N13 0,8 0,8 10 13,03 37,17 57,28 99,91 118,41
N14 0,8 0,8 10 14,49 27,81 55,12 90,57 117,99
N15 1 1 10 13,77 23,64 51,53 84,48 112,25
N 16 1 2 10 14,69 26,16 51,71 85,62 115,55
3.3.2 Phn tch tnh quy lut ca th nghim
D liu thc nghim v ho tan ca 16 cng thc vin nn glipizid 10 mg
GPKD c x l bng phn mm Form Rules v2 nhm tm ra quy lut ca cc
bin u vo i vi cc bin u ra v phn mm Inform v3.1 ti u ho thnh
phn cc cng thc.
3.3.2.1 . Phn tch bng ANOVA
D liu c nh gi cho kt qu gi tr R2 nh trong bng di y:
Bng 3.10: Gi tr R2
2 gi 4 gi 8 gi 16 gi 24 gi
R2 95,41 84,81 85,92 89,71 70,02
-
33
Nhn xt: Ta thy cc R2 > 70 ti tt c cc thi im, ti thi im 2 gi
R2 > 90. Nh vy phng trnh hi qui thu c c th m t mi tng quan ca
cc bin u vo v cc bin u ra.
3.3.2.2. Phn tch quy lut tc ng
Theo kt qu t phn mm Form Rules v2 cho thy: tr thi im 4 gi, hu
ht cc thi im cn li ca qu trnh th ho tan u chu nh hng ca 3 bin
u vo theo cng 1 quy lut.
3.3.2.3. Phn tch mt p
La chn thi im 8 gi (l thi im vin i chiu gii phng c 45
50% dc cht phn tch nh hng ca cc bin u vo) cho thy:
nh hng ca t l HPMC K4M : HPMC K100LV ti kh nng gii phng
dc cht.
Hnh 3.7: nh hng ca t l HPMC K4M : HPMC K100LV v t l Avicel :
lactose ti kh nng gii phng dc cht khi %PVP = 14,81%.
-
34
Nhn xt: Phn tch mt p ti thi im 8 gi vi gi tr PVP/EtOH 96%
l 14,81 % theo khi lng ta thy rng t l HPMC K4M : HPMC K100LV (X1)
nh hng ln ti kh nng gii phng dc cht. Khi X1 tng th kh nng gii
phng dc cht gim nhiu. Khi X1 = 0,5 th % gii phng dc cht dao ng t
53,46 n 71,21 %, khi X1 = 2 th % gii phng dc cht dao ng t 35,29 n
57,77 %. iu ny c gii thch l do s thay i cu trc ca h ct. X1 tng
lm tng t l HPMC c nht cao dn ti gim kh nng gii phng dc cht.
T l Avicel : lactose (X2) cng nh hng ti % gii phng dc cht. Tuy nhin
nh hng ca X2 kh phc tp. Khi X2 tng t 0,5 n 2 th % gii phng dc
cht gim dn ti cc tr khong t l l 1,5 sau li c xu hng tng ln. Nh
vy cng t l t dc kim sot th t l 2 t dc n Avicel : lactose l 1,4
1,6 cho ho tan thu c ti 8 gi thp hn so vi cc t l khc.
nh hng ca t l Avicel : lactose v t l PVP ti kh nng gii phng
dc cht.
Hnh 3.8: nh hng ca t l Avicel : lactose v t l PVP ti kh nng gii phng
dc cht khi X1 = 1,38
-
35
Nhn xt: T l Avicel : lactose vn nh hng ti % gii phng dc theo
quy lut trn. Khi nng PVP (X3) l 15%, X2 dao ng t 0,5 n 2 th % gii
phng gim t 57,06 n 54,12%. S nh hng ca X3 ti % gii phng dc cht
tun theo quy lut khi X3 tng th % gii phng dc cht gim. Khi X2 = 2, X3
tng t 5 n 15% th % gii phng dc cht gim t 64,94 n 54,12%. Quy lut
ny c gii thch ti mc 3.2.2.
nh hng ca t l HPMC K4M : HPMC K100LV v nng PVP ti kh
nng gii phng dc cht
Hnh 3.9: nh hng ca t l HPMC K4M : HPMC K100LV v nng PVP ti
kh nng gii phng dc cht khi X2 = 0,5
Nhn xt: Qua phn tch mt p hnh 3.9 cho thy bt k t l PVP no th
vic tng lng HPMC K4M so vi lng HPMC K100LV u lm chm s gii
phng dc cht ti 5 thi im bin u ra., trong chm nht l t l HPMC
K4M : HPMC K100LV (X2) = 2 v s dng 5% PVP. nh hng ca PVP ch thay
i nhiu khi X1 mc cao vi xu hng ho tan khi tng PVP. mc X1 thp
(0,5) t l % glipizid ho tan gn nh khng thay i khi PVP thay i.
Kt lun: Nh vy, c th thy trong 3 bin u vo, nh hng ca t l
HPMC l r rt nht. T l t dc n lm gim ha tan khi duy tr khong t
l thch hp. nh hng ca PVP ch th hin khi s dng t l HPMC K4M ln.
-
36
3.3.3. La chn cng thc ti u
Da trn kt qu thc nghim v kt qu kho st vin i chiu Glipizide
XL, iu kin ti u ca vin c t ra cho cc bin ph thuc nh sau:
0% Y1 10% 10% Y2 22%
37% Y3 50% 87% Y4 100%
105% Y5 115%
Kt qu chy phn mm Inform cho cng thc ti u:
Bng 3.11: Cng thc ti u
Thnh phn T l
K4M : K100LV
T l
Avicel : lactose
Nng
PVP
Cng thc ti u 1,38 0,5 14,8
Thnh phn cng thc ti u c trnh by trong bng di y:
Bng 3.12: Thnh phn cng thc ti u
Thnh phn Khi lng (mg/vin)
Glipizid 10
HPMC K4M 58
HPMC K100LV 42
Avicel 20
Lactose 40
Magnesi stearat 2
Aerosil 1
PVP/EtOH 96% 14,8%
3.3.4. nh gi cng thc ti u
Tin hnh bo ch 3 l, 1000 vin/l.
Cch bo ch theo mc 2.3.2.
3.3.4.1 . nh gi hm m ht.
-
37
Dng cn xc nh m nhanh. Cn khong 1g cm, cho vo a cn, t
nhit 1050C, theo di v c kt qu:
Bng 3.13: Hm m cc l ti u
L L 1 L 2 L3
Hm m (%) 3,52 3,68 4,25
3.3.4.2 . nh gi lc gy v vin
o lc gy v vin trn my o cng PHARMATEST, tin hnh th 10
vin/ 1 CT.
Kt qu: Lc gy v vin nm trong khong 10 12 kp.
3.3.4.3 . nh gi ng u khi lng
Vi mi l tin hnh nh gi ng u khi lng nh mc 2.3.3.
Kt qu cho thy cc vin u nm trong khong quy nh.
Bng 3.14: ng u khi lng vin
L 1 L 2 L 3
Khi lng trung bnh (mg) 175,32 171,17 176,25
SD 2,77 3,34 4,36
Nhn xt: Khi lng cc vin u t tiu chun.
3.3.4.4 . nh gi kh nng gii phng dc cht
Tin hnh th ho tan cc l nh mc 2.3.3 v so snh th gii phng cc
l vi th vin i chiu da trn gi tr f2. Kt qu c trnh by trong bng
di y:
-
38
Bng 3.15: % glipizid gii phng t cc l v vin i chiu theo thi gian
Thi gian (gi) L 1 L 2 L 3 Glipizide XL
1 4,39 3,66 3,83 4,5
2 8,14 7,73 7,25 4,66
4 18,31 20,84 16,69 15,03
6 29,06 31,51 28,66 30,53
8 32,73 38,92 38,26 44,32
12 62,44 70,67 62,77 77,85
16 95,74 100,71 94,68 94,81
20 103,07 105,51 101,77 102,01
24 109,99 108,77 109,01 114,59
F2 58,04 65,52 61,31
Hnh 3.10: th % gii phng glipizid theo thi gian ca 3 l ti u
-
39
Nhn xt: Tc gii phng dc cht theo thi gian t cc l bo ch theo
cng thc ti u so vi vin i chiu Glipizide XL u c f2 > 50. Nh vy th
gii phng glipizid t cc l ti u v vin i chiu ging nhau.
3.3.5 xut tiu chun vin
T kt qu kho st cc l ca vin ti u ho trn chng ti a ra xut
tiu chun vin nn glipizid GPKD s dng ct thn nc nh trong bng 3.16 di
y:
Bng 3.16: xut tiu chun ht v vin nn glipizid GPKD
Tn ch tiu Kt qu thc nghim xut
Bn thnh phm
Hm m 3,52 4,25 % < 5%
Thnh phm
Hnh thc t Vin trng bng, chc,
khng v vin, bong mt.
cng (N) 10 12 kp 8 14 kp
ng u khi lng (mg) 175 3,6 (mg) 7,5%
xut ho tan: da vo kt qu kho st trung bnh cc l ti u v vin
i chiu a ra xut tiu chun v ho tan cho vin nn glipizid GPKD trong
bng 3.17 di y.
Bng 3.17: xut tiu chun ho tan dc cht theo thi gian vin nn glipizid
Thi gian (gi) % glipizid thc nghim (%) % glipizid xut (%)
2 7,71 4 10
4 18,6 15 20
8 36,64 30 45
16 97,04 85 105
24 109,26 105 120
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40
KT LUN V XUT
Kt lun:
Qua nghin cu chng ti t c mt s kt qu sau:
1. Kho st nh hng ca cc t dc ti kh nng gii phng dc cht.
Kt qu:
T dc dnh nh hng ti kh nng gii phng dc cht. Khi t l
t dc dnh tng th kh nng gii phng dc cht gim.
T dc n nh hng ti kh nng gii phng dc cht. Khi kt
hp 2 loi t dc n Avicel, lactose vi t l 30:30 cho kt qu th ho tan gn
ging vin i chiu nht.
T dc trn khng nh hng ti kh nng gii phng dc cht.
2. Thit k th nghim v ti u ho cng thc.La chn cng thc bo ch
vin nn glipizid GPKD:
Glipizid: 10 mg Lactose: 40 mg
HPMC K4M: 58 mg Magnesi stearat: 2 mg
HPMC K100LV: 42 mg Aerosil: 1 mg
Avicel: 20 mg PVP/EtOH 96%: 14,81 % theo khi
lng vin
3. Bc u xut mt s tiu chun c s cho vin nn bo ch c: tiu
chun bn thnh phm (hm m) v tiu chun thnh phm (hnh thc, cng,
ng u khi lng, ho tan theo thi gian).
xut:
Nghin cu quy m pilot th thch cng thc ti u. Nu t th tip tc
th n nh ca vin.
Nghin cu quy m sn xut ln, thm nh quy trnh sn xut.
Nghin cu th nghim nh gi in vivo ca vin.
-
TI LIU THAM KHO
Ti liu ting Vit
1. B mn bo ch (2005), Mt s chuyn bo ch hin i, NXB Y hc, tr.
132- 157.
2. B mn dc l (2006), Dc l hc tp 2, NXB Y hc, tr. 301.
3. B mn ha dc (2006), Ha dc tp 2, NXB Y hc, tr. 72-73.
4. B y t (2002), Dc in Vit Nam IV, NXB Y hc, ph lc 11.1.
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6. H nh Triu (2011), Nghin cu bo ch vin nn glipizid gii phng ko di
theo c ch bm thm thu, kho lun tt nghip dc s, Trng i hc Dc
H Ni.
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20 Paolo Colombo (1999), Observation of swelling process and diffusion fornt
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-
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25 The United States pharmacopoeia 32.
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