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

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

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

DANH MC CC BNG
Tn bng

Trang

Bng 1.1: Cc ch phm ca glipizid trn th trng

Bng 1.2: Phn loi cc h gii phng ko di

Bng 1.3: Gii hn ho tan ca ba ln th

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

26

dc dnh 5; 10; 15%

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

DANH MC HNH V V S
Tn hnh
Hnh 1.1: th nng dc cht trong mu ca cc dng thuc

Trang
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

24

quang
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

27

t dc dnh khc nhau theo thi gian

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

30

cht
Hnh 3.7: nh hng ca t l HPMC K4M : HPMC K100LV v t l

34

Avicel : lactose ti kh nng gii phng dc cht

Hnh 3.8: nh hng ca t l Avicel : lactose v t l PVP ti kh nng

35

gii phng dc cht

Hnh 3.9: nh hng ca t l HPMC K4M : HPMC K100LV v nng

36

PVP ti kh nng gii phng dc cht

Hnh 3.10: th % gii phng glipizid theo thi gian ca 3 l ti u

39

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.

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)-5methylpyrazin-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].

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].

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

Glucotrol
Glucotrol XL
Glibenese
Glibenese retard
Melizide
Glipid
Dipizide
Minodiab
Glucophage

Pfizer
Merck
Yuong II pharm
Micro labs
Kenfarma
Lipha Sante

Hm lng (mg)

Dng bo ch

5 ; 10
2,5 ; 5 ; 10
5
5 ; 10
5
5
5 ; 10
2,5 ; 5 ; 10
Kt hp: Glipizid
v metformin

Vin nn
Vin GPKD
Vin nn
Vin GPKD
Vin nn
Vin nn
Vin nn
Vin nn
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
C. Dng gii phng c kim sot

B. Thuc nhc li
D. Dng gii phng ko di

Hnh 1.1: th nng dc cht trong mu ca cc dng thuc

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.

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]
T dc

Cu to

H ct

Polyme thn Carbopol, MC, Ct thm

K thut

-H kh t

ho tan

nc ng

HPMC,

nc ho tan

bo ch

gii phng

vai tr ct

alginat, gm

dc cht.

n gin

bc 0

mang dc

xanthan

Polyme

-Gii

trng n

phng ph

to hng ro

thuc nhiu

gel kim sot

yu t mi

gii phng

trng

cht

C ch

Ct b h

u im

Nhc

Tn h

T dc

im

H ct

Dc cht

Sp, alcol bo,

-H kh t

n mn

phi hp

acid bo, ester, men thu

(ct s

vi t dc

du hydrogen

phn hoc n kim, k

bc 0

nc)

l sp, cht

ho, Eudragit

mn trong

thut n

-gii

bo ng

ng tiu

gin

phng ph

r tin, d gii phng

vai tr cht

ho t

thuc nhiu

mang

gii phng

yu t mi

dc cht

trng

H ct

Dc cht

EC, PVC,

khuch

phn tn

tn

Ct thm

-K thut

-Kh t

polyme methyl mi trng

n gin

ng hc

vo mt ct

methacrylat,

s khuch

-Gii

bc 0

tr, xp,

DCP, calci

tn, ho tan

phng t

-Gii

khng tan

carbonat...

dc cht ra

ph thuc phng ph

trong dch

ngoi mi

mi

thuc lc

tiu ho

trng

trng

dp,to ht

H ct

Nha trao

Nha trao i

Thuc s

Thch

-Gii

trao i

i ion

ion

c gii

hp vi

phng

ion

ng vai tr

phng ra

dc cht khng t

ct tr

bng cch

khng

bc 0

mang thuc

trao i vi

bn trong

-Ph thuc

ion trong

dch tiu

pH, nng

dch tiu ho

ho

ion

Bao ngoi

Cellulose

Dc cht

-D t

i hi k

thm

vin mng

acetat, PVC,

y ra ngoi

gii

thut bo

thu

bn thm c

polyurethan

mt cch t

phng

ch cao

ming gii

t nh vo

hng nh

phng dc

chnh lch

-Gii

cht

p sut thm

phng t

thu

ph thuc
mi
trng

Dc cht

CMC,Na

Mng bao

D dng

Tc gii

mng

c bao

CMC, HPMC,

ng vai tr

iu

phng ph

bao ho

bi mt

PVP, gm,

l cc hng

chnh tc

thuc

tan

mng bao

gelatin,

ro lm

gii

nguyn liu

ho tan

Eudragit, sp

chm s gii

phng

bao v

chm hoc

phng dc

bng

phng

cht

cch iu

php bao

n mn

chnh
dy mng

Bao dc

EC, PVC, hn

Mng ht

Gii

Tc gii

mng

cht bng

hp Eudragit,

nc ,

phng t

phng thay

bao

mng bao

PEG, glycerin,

trng n

ph thuc i khng

khuch

polymer

acid stearic,

ho tan dc

yu t

tn

khng tan

PVP, natri

cht. Dc

mi

trong dch

clorid

cht bo ho

trng

trong h ri

nh pH,

tiu ho

hng nh

khuch tn ra tit dch

ngoi

tiu ho

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).

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
Khng c mu no nm ngoi gii hn qui nh v
khng c mu no thp hn t l qui nh ln th cui.

10

Trung bnh ca 12 mu nm trong gii hn v khng c

2

mu no > 10% gii hn; khng c mu no thp hn

gii hn ln th cui cng.
Trung bnh ca 24 mu nm trong gii hn v khng c

12

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].

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].

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

Glipizid

USP

HPMC K4M

TCNSX

HPMC K100LV

TCNSX

Avicel PH 102

TCNSX

Dicalci phosphat

Trung Quc

TCNSX

Lactose monohydrat

TCNSX

PVP K30

Trung Quc

TCNSX

Ethanol 96%

Vit Nam

TCCS

Methanol

Trung Quc

TCNSX

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.

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:

18

Nguyn liu, t dc n, t
dc kim sot gii phng

PVP/EtOH 96%

Magnesi stearat,
Aerosil, Talc

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

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

Dn
(g/ml)
Dch

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.

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

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 l
% tm
D l
% tm
D l
% tm
D thc
D thc
D thc
thuyt li
thuyt li
thuyt li
Ln 1 0,629 0,628 100,16 0,738 0,732 100,77 0,851 0,852 99,86
Ln 2
Ln 3
Ln 4
Ln 5
TB
SD
RSD

0,611
0,612
0,647
0,603

0,622 98,26
0,609 100,43
0,630 102,62
0,617 97,76
99,85
1,94
1,94

0,718
0,708
0,762
0,718

0,725 99,01
0,711 99,62
0,735 103,63
0,719 99,81
100,57
1,82
1,81

0,820
0,804
0,852
0,815

0,844
0,827
0,856
0,837

97,18
97,23
99,58
97,37
98,24
1,35
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

10

12

16

20

24

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:

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

Aerosil

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

12

CT 1

11,26

17,99

27,93

60,64

83,81

100,78 112,54 119,19

CT 2

11,19

17,11

27,41

49,64

79,11

93,89

111,04 117,75

CT 3

10,32

16,87

23,91

40,07

65,46

77,14

91,28

gian

16

20

24

92,68

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

Aerosil

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

Glipizid

10mg

HPMC K4M

50mg

HPMC K100LV

50mg

Lactose

60mg

PVP 10%

Va

Magnesi stearat

1,15%

Talc

0,5%

Kt qu nh trong th sau:

1%

CT 10

CT 11

1,5%

2,0%

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%.

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

T l Avicel : lactose

X2

0,5

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

T l

K4M:K100LV Avicel:lactose

Nng
PVP

Y1

Y2

Y3

Y4

Y5

N1

9,81

23,96

58,67

86,24

101,23

N2

15

10,69

22,61

50,46

85,32

102,96

N3

0,5

21,99

30,42

71,21

92,21

120,51

N4

0,5

15

20,67

30,65

57,77

91,85

112,08

N5

0,5

14,14

22,09

38,31

68,29

102,81

N6

0,5

15

7,06

16,98

52,78

73,41

106,18

N7

0,5

0,5

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

0,8

4,65

13,91

35,29

69,93

103,51

N10

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

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

10

13,77

23,64

51,53

84,48

112,25

N 16

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

R2

2 gi

4 gi

8 gi

16 gi

24 gi

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

T l

Nng

K4M : K100LV

Avicel : lactose

PVP

1,38

0,5

14,8

Cng thc ti u

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

Aerosil

PVP/EtOH 96%
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.

14,8%

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

Khi lng trung bnh (mg)

SD

L 1

L 2

L 3

175,32

171,17

176,25

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

4,39

3,66

3,83

4,5

8,14

7,73

7,25

4,66

18,31

20,84

16,69

15,03

29,06

31,51

28,66

30,53

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

3,52 4,25 %

< 5%

Bn thnh phm
Hm m
Thnh phm
Hnh thc

cng (N)
ng u khi lng (mg)

Vin trng bng, chc,

khng v vin, bong mt.

10 12 kp

8 14 kp

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 (%)

7,71

4 10

18,6

15 20

36,64

30 45

16

97,04

85 105

24

109,26

105 120

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.
5. B y t (2002), Dc th quc gia Vit Nam, NXB Y hc, tr 506- 508.
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.
7. Phm Song - Nguyn Hu Qunh(2008), Bch khoa th bnh hc, NXB Gio
dc, tr 146.
8. Phm Th Giang (2011), Nghin cu bo ch vin nn glipizid gii phng ko
di , kha lun tt nghip dc s, Trng i hc Dc H Ni.
9. Nguyn Trn Linh (2005), Mt s phng php thit k th nghim v ti u ho
ng dng trong bo ch, i hc Dc H Ni, tr 1 5.
10. Trng i hc Y H Ni cc b mn ni(1998), Bi ging bnh hc ni khoa
tp I, NXB Y hc, tr 274 286.
Ti liu ting Anh.
11 The British Pharmacopoeia (2009), pp.2771- 2777.
12 Bhosale Ashok V. ,Hardikar Sharwaree R. (2009), Formualation of Beta
Cyclodextrin complexed controlled release matrix tablet of glipizide and its invitro evaluation, International Journal of PharmTech Research, Vol.1, No.3,
pp 773-778.
13 E.M. Ghoneim, M.A. El-Attar (2006), Stripping voltammetric quantification
of the anti-diabetic drug glipizide in bulk form and pharmaceutical
formulation, Journal of Pharmaceutical and Biomedical Analysi, (43), 1465 -

1469.
14 E.M. Ghoneim, M.A. El-Attar, E. Hammam, P.Y. Khashaba (2006), Stripping
voltammetric quantification of the anti-diabetic drug glipizide in bulk form and
pharmaceutical formulation, Journal of Pharmaceutical and Biomedical
Analysis,( 43) pp 14651469.
15 Elisabeth Wahlin-Boll, Arne Melander (1979), High-performance liquid
chromatographic determination of glipizide and some other sulfonylurea drugs
in serum, Journal of Chromatography, (164), pp 541 546.
16 J.Siemann (1999), HPMC Matrices for controlled drug delivery: A new
model combining diffusion, swelling, and dissolution mechanisms and
predicting the release kinetics, Pharmaceutical Research, Vol. 16, pp 1748
1756.
17 Lakshmana murthy G (2011), Drug release and swelling kinetic studies of
glipizide sustained release matrix tablet wet granulation method, Int. J.
Pharm & Ind. Res, Vol 1, pp 43-51.
18 Martindale 36th , The Complete Drug Reference (2009), p. 441.
19 P.R. Radhika, T.K. Pal, T. Sivakumar (2009), Formulation and Evaluation of
Sustained Release Matrix Tablets of Glipizide, Iranian Journal of
Pharmaceutical Sciences, 5(4), pp.205-214.
20 Paolo Colombo (1999), Observation of swelling process and diffusion fornt
position during swelling in hydroxypropyl methyl cellulose (HPMC) matrices
containing a soluble drug, Journal of Controlled Release, (61), pp 83 91.
21 Parasuran Rajam Radhika, Tapan Kumar Pal, Thangavel Sivakumar ( 2009 ),
Optimization of Glipizide sustained release matrix tablet formulation by
central composite design- response surface methodology, Journal of
Pharmacy Research, Vol.2, pp 94 102.
22 Pavithra .T.K, Harshitha .R ( 2010 ), Formulation and Evaluation of Hydrogel
Based Oral Controlled Drug Delivery System for Antihypertensive Drug,

Journal of Pharmaceutical Science and Technology, Vol. 2 (8), pp 276 283.

23 Sri Devi S, Kishore Yadav S (2011), Design of glipizide controlled release
tablets evaluation of ethylene vinyl acetate and ethyl cellulose as rate
controlling polymers, Journal of Advances in Drug Research, pp 31 36.
24 T. Ramanji reddy, Dr. D. Dhachinamoorthi, Dr. K.B. Chandrasekhar (2010),
Independent release behavior of Glipizide matrix release tablets containing
chitosan and xanthan gum, International Journal on Pharmaceutical and
Biomedical Research, Vol. 1(2), pp 64-70.
25 The United States pharmacopoeia 32.
26 Yang (1996), Characterization of compressibility and compacitibility of
polyethylene oxide polymers for modified release application by compaction
simulator, J Pharm. Sci, 85, pp.1085- 1090.
27 Zhongping

John

Lin,

Daksha

Desai-Krieger,

Linyee

Shum

(2002),

Simultaneous determination of glipizide and rosiglitazone unbound drug

concentrations in plasma by equilibrium dialysis and liquid chromatography
tandem mass spectrometry, Journal of Chromatography B, 801, pp 265272.