NGHIN CU BO CH VIN NN PHNG THCH KO DI

CHA NIFEDIPINE 30 mg
Lm Hu Qun* , Nguyn Thin Hi*

TM TT
Mc tiu: iu ch vin nen phng thch ko di cha hot cht t tan trong nc l nifedipine c gii
phng hot cht t USP XXX hoc tng ng vin i chiu Adalat LA 30 mg.
Phng php: S dng cc polyme cho vin nn phng thch ko di nhHPMC, Eudragit RS PO 100, kt
hp vi phng php bo ch xt ht t ph hp iu ch vin nn phng thch ko di c cu trc matrix v
nh gi gii phng hot cht theo tiu chun USP XXX so snh vi vin i chiu.
Kt qu: Vin nn phng thch ko di cha nifedipine vi thnh phn t dc l HPMC hoc hn hp
polymer HPMC v Eudragit cho ng hc phng thch hot cht bc 0 v gii phng hot cht t tiu chun
USP XXX hoc tng ng vi vin i chiu Adalat LA 30 mg.
Kt lun: Cc kt qu t thc nghim cho thy c th iu ch vin nn phng thch ko di cha nifedipine,
mt dng bo ch mi dng iu tr cao huyt p kh hiu qu hin nay.
T kha: nifedipine, vin nn phng thich keo dai.

ABSTRACT
FORMULATION OF NIFEDIPINE SUSTAINED-RELEASE TABLETS
Lam Hue Quan, Nguyen Thien Hai
* Y Hoc TP. Ho Chi Minh * Vol. 14 - Supplement of No 1 - 2010: 41 46
Objectives: The aim of the present study was to prepare sustained-release tablets of poorly-soluble drug,
nifedipine in which the drug release complied with the specification of USP XXX or reference drug, Adalat LA
30mg.
Methods: Wet granulation method was used to formulate and develop the sustained-release tablet
formulations with HPMC and eudragit RS PO 100. Drug release was tested according to USP XXX.
Results: Drug released from the formulation using HPMC fitted to reference drug, Adalat LA 30 while
using the mixture of HPMC and eudragit RS PO 100 complied with the specification of USP XXX. Both of them
were the best fitted to zero-order kinetics
Conclusions: The present results provided evidence that nifedipine sustained-release tablets can be prepared
and be used for effective treatment of hypertension.
Key words: nifedipine, sustained-release.

T VN
Nifedipine, thuc c ch calci, c ng
dng kh rng ri v hiu qu trong vic iu
tr bnh cao huyt p hin nay. Tuy nhin
tan trong nc ca nifedipine rt thp, do
nh hng n sinh kh dng ca ch phm.
Nhiu nghin cu cho thy tc hp thu ca

nifedipine ph thuc vo cng thc. Nghin

cu bo ch dng phng thch ko di (PTKD)
cho thy c mt s u im nh tc phng
thch thuc hng nh, gim liu dng, ci
thin sinh kh dng. Vit Nam hin nay,
bc u c nhng nghin cu v dng
thuc PTKD vi cc hot cht khc nhau tuy

* B Mn Cng Nghip Dc, Khoa Dc i Hc Y Dc TP.HCM

a ch lin h: TS. Nguyn Thin Hi
T: 0905352679
Email: thienhai2002@yahoo.com

nhin dng bo ch PTKD ca nifedipine liu

30 mg vn cha c nghin cu. Gp phn
nghin cu dng bo ch mi, c bit l i
vi dc cht kh tan trong nc, xut pht t
nhu cu cp thit v dng bo ch mi nng
cao hiu qu tr liu, chng ti thc hin ti:
Nghin cu bo ch vin nn phng thch ko
di cha nifedipine 30 mg.

M C TI U - I TNG - PHNG PHP

NGHIN CU
Mc tiu
iu ch vin nn phng thch ko di
cha hot cht t tan trong nc l nifedipine
c gii phng hot cht t USP XXX hoc
tng ng vin i chiu Adalat LA 30 mg.

i tng
Nguyn vt liu.
Vin i chiu Adalat LA 30 mg (Bayer
Health Care German), nifedipine (tiu chun
USP 29 - India), Eudragit RS PO 100 (Rohm
Pharma - German), HPMC 100000 (Dow
Chemical Co - USA), natri lauryl sulfat (Merck
Co. - German), Avicel PH 101, PH 102 (tiu
chun USP 29 Taiwan) v cc ha cht cn
thit khc.
Trang thit b.
My trn ch Z (Erweka Type LK5 Germany), My dp vin (Sunita Impex TMDGSTD - India) my o ho tan (Pharmatest
PTW S3C - German), my quang ph UV-Vis
(SHIMADZU UV 1061 - Japan) v cc thit b
cn thit khc.

Phng php nghin cu

nh gi gii phng hot cht (GPHC)
ca ch phm i chiu Adalat LA 30 mg
Th nghim GPHC(6).
Th nghim GPHC c thc hin theo
chuyn lun vin nen nifedipin PTKD liu 30
mg (USP XXX Test 4). Vin th trong 900 ml
mi trng pH 1,2 cha 0,5% natrilauryl sulfat;
dng cnh khuy, tc 100 vng/pht. Mu

thu c em inh lng bng quang ph UV

bc sng 237 nm
Tiu chun v GPHC c trnh by
trong bng 1.
Bng 1. Tiu chun nh gi tc phng thch
nifedipine theo USP XXX Test 4
Thi gian (gi)
1
4
12

(%) hot cht phng thch

12 - 35
44 - 40
> 80

Nghin cu cng thc v phng php bo

ch vin nn PTKD nifedipine 30 mg.
Cng thc tng qut cho vin nn
nifedipine PTKD 30 mg c trnh by trong
bng 2.
Bng 2. Cng thc vin PTKD nifedipine 30 mg
Thnh phn
Nifedipine
PEG 6000
Avicel PH 101
Polyme PTKD(*)
Avicel PH 102
Lactose DC
Aerosil
Magie stearate
Nc ct
(*)

Cng thc (mg/vin)

30
90
90
Kho st
Kho st
Kho st
Va
Va
Va

: Polyme PTKD: HPMC v eudragit RS PO 100

Qui trnh iu ch vin PTKD nifedipin 30 mg

Nifedipin c trn vi PEG va avicel PH
101, xay mn, thm nc va u, trn u, xat
hat, sy, sa hat c cm dc cht. Cm
dc cht c trn vi polymer PTKD kho
st, thm t dc trn bng aerosil v magie
stearat, dp vin v nh gi GPHC theo
USP XXX.
V nifedipine d h bi nh sng, nn cc
thc nghim tin hnh trong iu kin che
sng.
Sn phm sau cng c bao phim chng
sng
X l thng k.
Cc mu thc hin t nht ba ln, kt qua
trnh by di dng trung bnh

KT QU V BN LUN
nh gi gii phng hot cht (GPHC)
ca ch phm i chiu Adalat LA 30
mg.
Kt qua th nghim GPHC cua vin i
chiu theo USP XXX c trinh bay trong
Bng 3 v Hnh 1.
Bng 3. GPHC ca adalat LA 30 mg theo USP
XXX.
Thi gian
(gi)
0
1
2
4
6
8
10
12
16
20
24

% nifedipin phng
thch
(n = 6)
0,00
7,08
9,51
18,61
28,61
41,86
52,72
63,90
82,14
96,90
102,35

RSD
0,00
0,54
0,72
0,28
1,33
0,54
2,50
2,12
2,00
2,09
2,64

USP
XXX
12 - 35
44 - 67

> 80

Trong th nghim ny, ngoi thi im qui

nh trong USP XXX (1, 4 v 12 gi), cc thi
im khc c kho st thm nhm nh gi
ng hc phng thch theo thi gian.

thch. Kho st thm n 24h, 100 % hot cht

phng thch ht. th GPHC theo thi gian
tin hnh n 24 gi gn nh l ng thng.
iu ny ph hp vi thit k ca vin adalat
LA 30 phng thch ko di theo c ch to p
sut thm thu vi ng hc phng thch bc
0. Vin adalat LA 30 c hai lp (mu vng v
mu nu) sau khi r lp bao phim, l phng
thch thuc lun lun nm lp mu vng v
khi kt thc thi gian th nghim vin ch cn
li mt lp mu nu. T kt qu ny, vin
nghin cu thit k phi c ng hc phng
thch hoc l t ng ng adalat LA 30 hoc
l t tiu chun qui nh ca USP XXX.

Nghin cu cng thc vin nn PTKD

nifedipine 30 mg.
iu ch vin nn PTKD nifedipine 30 mg
vi polyme HPMC (100000)
HPMC (100000) l t d c to khung
matrix dng ph bin nht hin nay cho vin
PTKD vi c ch trng n trong n c to
thnh lp gel, d c cht PTKD theo c ch
khuch tn qua lp gel ny. Cc cng thc vi
HPMC iu ch vin PTKD nifedipine 30 mg
c trnh by trong Bng 4 trong CT1-CT4
l 4 cng thc c bn. Kt qu v GPHC
ca cc cng c trnh by trong Bng 5.

Kt qu t Bng 3. cho thy GPHC ca

vin adalat LA 30 u khng t c 3 thi
im 1h, 4h v 12h theo qui nh USP XXX.
Sau 12 gi ch c khong 64% hot cht phng
Bng 4. Thnh phn cc cng thc nghin cu vi HPMC 100000
Thnh phn
Cm dc cht
HPMC 100.000
Avicel pH 102
Aerosil
Magnesi stearat
Khi lng vin

Khi lng cho mt vin (mg)

CT 1

CT 2

CT 3

CT 4

CT 5

CT 6

CT 7

210
60
24
3
3
300

210
40
44
3
3
300

210
20
64
3
3
300

210
10
74
3
3
300

210
70
14
3
3
300

210
64
20
3
3
300

210
50
34
3
3
300

Dp vin l 600 vin, chy trn 9 mm,

cng: 50 70 N.
Kt qu t Bng 5 cho thy CT 1 c
GPHC gn vi adalat nht trong khi CT 4 c
GPHC gn t tiu chun USP XXX gi
th 1 v gi th 4. Cc vin nghin cu theo 4
cng thc c bn, phng thch nifedipin theo

c ch khuch tn n mn. Qua thc nghim

quan st lc u vin tr ng phng ln v sau
mt thi gian th vin bt u mn dn. Sau 12
gi th nghim, i vi CT 1 vin cn khong
1/2 v CT 2 vin cn mt t, CT 3 v CT 4 vin
mn ht vo khong 8 gi. Nh vy c hai
h ng nghin cu hoc GPHC t ng

ng ch phm i chiu adalat LA 30 hoc

t tiu chun USP XXX.
Bng 5. GPHC ca cc cng thc nghin cu vi HPMC theo USP XXX
Thi gian
(gi)

CT 1

CT 2

Trung bnh (%) hot cht phng thch (n = 3)

CT 3

CT 4

CT 5

CT 6

CT 7

0
1
2
4
6
8
10
12

0,00
7,69
9,56
17,13
26,10
35,51
43,22
52,13

0,00
7,82
13,79
27,25
42,02
56,25
72,69
88,13

0,00
9,22
15,48
33,83
64,20
92,70
104,74
104,76

0,00
11,02
18,34
43,44
68,43
100,41
100,55
-

0,00
6,79
10,43
18,25
27,00
37,67
46,61
53,94

0,00
6,34
9,23
17,43
27,07
37,76
45,27
54,42

0,00
6,71
10,57
19,59
29,44
43,54
52,65
62,17

Vi kt qu GPHC t Bng 6, dng

phng php phn tch phng sai mt yu t
cho thy gi tr GPHC gia hai loi vin nhn
v vin bao phim khc nhau khng c ngha
(P > 0,05) chng t mng bao v qui trnh bao
khng nh hng n kh nng GPHC ca
vin nn PTKD nifedipine 30 mg. Kt qu t
Hnh 1 cho thy, vin nghin cu sau khi bao
phim c GPHC tng ng vin i chiu
adalat, c ng hc ng hc phng thch bc
0.
Bng 6. GPHC ca vin nng cp cha bao phim,
bao phim (TA1) v adalat theo USP XXX
Thi
gian
(gi)

0
1
2

Trung bnh (%) hot cht

phng thch l nng cp 5000
vin (n = 6)

CT 7
0,00
7,21
11,23

Vin
nhn
0,00
7,69
12,29

Bao phim

Adalat
(n = 6)

USP
XXX

0,00
7,34
13,69

0,00
7,08
9,51

12-35

4
6
8
10
12
16
20
24

20,12
30,24
43,16
52,51
63,02
84,51
98,10
101,80

22,24
32,02
44,77
54,18
66,99
86,87
99,58
100,77

0,00
7,08
9,51
18,61
28,61
41,86
52,72
63,90

12 - 35
44 - 67

> 80
23,57
33,26
44,15
54,33
65,72
85,88
99,36
101,52

Adalat
( n = 6)

18,61
28,61
41,86
52,72
63,90
82,14
96,90
102,35

44-67

> 80

120
100
% GPHC

GPHC tng ng adalat. Vi CT 1 cn

iu chnh t l gia HPMC v avicel sao cho
t CT c GPHC gn vi adalat nht v
cng thc CT 5, CT 6 v CT 7 c kho st.
Kt qu t Bng 5 cng cho thy CT 7 c
GPHC tng ng adalat 30 mg, nn c
chn kho st nng cp c l 5000 vin (L
TA1), tin hnh bao phim che sng vi thnh
phn cng thc dch bao HPMC (3,5%), PEG
6000 (1%), oxid st nu (0,1%), oxid st
(0,5%), titan dioixid (0,4%), talc (2,5%) cn 500
(92%). Kt qu GPHC ca vin nng cp cha
bao phim v bao phim c trnh by trong
Bng 6 v Hnh 1.

USP XXX

80
L TA1
Adalat

60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Thi gian (gi)

Hnh 1. th GPHC theo thi gian ca vin PTKD

nifedipine 30 mg (L TA1) v vin adalat LA 30

GPHC t USP XXX.

Vi CT 4 c GPHC thp hn v gn t
tiu chun USP XXX gi th 1 v gi th 4.
Vin mn dn v tan ht sau gn 8 gi vi 100%
dc cht phng thch. Nghin cu ci tin CT 4
bng cch thay i t l HPMC v thay th mt
phn HPMC c nht cao bng cc t dc c
nht thp v kh nng trng n nhanh,
thm nhanh nhm gip hot cht phng thch ra
nhanh hn, vin bn hn. Cng thc ci tin CT
8, 9, 10 c trnh by trong Bng 7.
iu ch vin nn PTKD nifedipine 30mg vi
polyme HPMC phi hp eudrgit RS PO 100.

Khi lng cho mt vin (mg)

Thnh phn

CT 4

CT 8

CT 9

CT 10

Cm dc cht

210

210

210

210

HPMC 100.000
Eudragit RS PO 100

10
0

30
25

30
15

30
20

Na CMC
Avicel pH 102
Lactose DC
Aerosil
Magnesi stearat
Khi lng vin

0
74
0
3
3

27
67
43
4
4

27
77
43
4
4

27
72
43
4
4

300

410

410

410

Dp vin l 600 vin, chy trn 11 mm,

cng: 50-70 N.
Eudragit RS PO 100 l polyme lm t dc
PTKD do c tnh trng n v to s thm.
Chng c cu trc cng chc. Din tch tip
xc ca thuc vi mi trng ha tan b gim
khi tng lng eudragit ny (1,2,5). Trong cc
cng thc kho st trn, vic tng ng knh
vin nhm tng din tch tip xc gip cho kh
nng GPHC nhanh hn, bn cnh Na CMC
gip cho vin bn hn trong mi trng th
ho tan , nh tnh dnh v trng n.
Lactose thm vo nhm ci thin nn. Mt
s nghin cu cho thy vic phi hp HPMC
vi eudragit cho vin nn PTKD felodipine 5
mg t ng hc phng thch bc 0 (3,4). Kt
qu GPHC ca cc cng thc c trnh by
trong Bng 8.
Bng 8. GPHC ca cc cng thc nghin cu
vi hn hp HPMC va eudragit theo USP XXX
Thi gian
(gi)

TB (%) hot cht phng thch (n = 3)

CT 8

CT 9

CT 10

0,00

0,00

0,00

14,76

19,38

15,26

24,53

32,29

25,42

49,47

61,19

49,15

6
8
10

73,69
99,79
105,79

82,15
102,27
102,98

73,90
99,34
104,28

12

USP
XXX
12 35
44 67

> 80

Kt qu t Bng 8 cho thy vin c 3 CT

8, 9, 10 u b mn ht vo khong 8 gi. C 3
CT 8, 9, 10 u c GPHC t tiu chun
USP XXX. Tuy nhin CT 9 c GPHC gi
th 4 gn vi cn trn ca tiu chun v CT 10

c GPHC gn nh tng ng vi CT 8
nhng li hi cao hn gi th 1, v vy CT 10
c chn tip tc kho st nng cp c l
4000 vin (L TU). Tin hnh bao phim che
sng vi thnh phn cng thc dch bao nh
cp trn. Kt qu GPHC ca vin nng
cp cha bao phim v bao phim c trnh
by trong Bng 9 v Hnh 2.
Bng 9. GPHC ca vin nng cp cha bao phim,
bao phim (TU) theo USP XXX
Trung bnh (%) hot cht phng
thch l nng cp vin (n = 6)

Thi
gian
(gi)

CT 10

Vin nhn

Bao phim

0,00

0,00

0,00

15,26

14,77

14,64

25,42

25,74

26,44

49,15

50,43

51,99

6
8
10

73,90
99,34
104,28

75,62
100,09
101,12

76,80
99,22
101,19

12

USP
XXX

12 35
44 67

> 80

120
100
%GPHC

Bng 7. Thnh phn cac cng thc cai tin t CT 4

bng phi hp HPMC vi eudragit RS PO 100.

80
60
Vi n nhn
Vi n bao phi m

40
20
0
0

10

12

Thi gi an (gi )

Hnh 2. th GPHC theo thi gian ca vin nng

cp cha bao him, bao phim (TU) theo USP XXX
Vi kt qu GPHC t Bng 9, dng
phng php phn tch phng sai mt yu t
cho thy gi tr GPHC gia hai loi vin nhn
v vin bao phim khc nhau khng c ngha
(P > 0,05) chng t mng bao v qui trnh bao
khng nh hng n kh nng GPHC ca
vin nn PTKD nifedipine 30 mg. Kt qu t
Hnh 2 cho thy, vin nghin cu sau khi bao
phim c GPHC t tiu chun USP XXX, c
ng hc ng hc phng thch bc 0.

KT LUN
Vin nn PTKD cha nifedipine 30 mg
c bo ch thnh cng vi cc t dc
phng thch ko di HPMC 100000 hoc hn
hp HPMC vi Eudragit RS PO 100. Vi
HPMC, ch phm nghin cu cho thy c

GPHC tng ng vi vin i chiu adalat

LA 30 trong 24 gi trong khi s dng hn hp
eudragit RS PO 100 v HPMC cho thy vin
nn PTKD cha nifedipine 30 mg c GPHC
t yu cu chuyn lun USP XXX. Kt qu
ny cho thy c th bo ch vin nn PTKD
cha nifedipine 30 mg, mt dng bo ch mi,
dng phng v iu tr hiu qu cc bnh
cao huyt p.

TI LIU THAM KHO

1.

2.

3.

4.

5.

6.

Heun, G., Lambov, N. and Groning, R., (1998),

Experimental and molecular modeling studies on
interactions between drugs and Eudragit(R) RL/RS resins in
aqueous environment, Pharmaceutica Acta Helvetiae 73,
57-62.
Carla Sanchez-Lafuente, M., Teresa Faucci, Mercedes
Fernandez-Arevalo, Josefa Alvarez-Fuentes, Antonio M.
Rabasco, Paola Mura (2002), Development of sustained
release matrix tablets of didanosine containing
methacrylic and ethylcellulose polymers, Int. J. Pharm.,
234, 213-221.
Ali, N., Shabnam Norouzi-Sani, Mohmmad-Reza SiahiShadbad, Farzaneh Lotfipoor, Majid Saeedi, (2002), The
effect of various surfactants on the release rate of
propranolol
hydrochloride
from
hydroxypropyl
methylcellulose (HPMC)-Eudragit matrices. Eur. J. Pharm.
Biopharm., 54, 349-356.
Nguyn Thin Hi, Sang-Cheol Chi (2009), Nghin cu
bo ch vin nn phng thch ko di cha felodipin 5mg,
Tp ch Y hc TP.HCM, Ph bn s 1, tp 13, trang 29-33.
Azarmi, S., Farid, J., Nokhodchi, A., Bahari-Saravi, S. M.,
Valizade, H., (2002), Thermal treating as a tool for
sustained release of indomethacin from Eudragit RS and
RL matrices. Int. J.Pharm., 246, 171-177.
USP XXX (2007), CD Rom