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 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

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

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.

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].

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).

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.

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].

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

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.

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

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

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.

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 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:

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

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%.

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

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.

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