B Y T

TRNG I HC DC H NI

HONG S NG

NGHIN CU BO CH VIN NN GII PHNG KO DI

THEO C CH THM THU CHA FELODIPIN

LUN VN THC S DC HC

2013

LI CM N

Vi lng knh trng v bit n su sc ti xin gi li cm n ti PGS.TS

Nguyn Thanh Hi v PGS.TS Phm Th Minh Hu tn tnh hng dn, gip
ti thc hin v hon thnh lun vn tt nghip ny.
Ti xin gi li cm n ti ban gim hiu nh trng cng cc thy c gio cc
b mn, c bit l cc thy c, anh ch k thut vin b mn Bo ch - Trng i
hc Dc H Ni, Vin Cng ngh dc phm Quc gia tn tnh ging dy cho
ti nhng kin thc qu bu trong nhng nm hc qua cng nh trong qu trnh lm
lun vn tt nghip.
Xin ghi nhn s gip ca ca bn b gn b, chia s gip ti vt qua
nhng kh khn trong sut thi gian hc tp, nghin cu v thc hin kha lun.
V cng bit n s quan tm, khch l, ng vin v to mi iu kin thun
li ca cng ty TNHH MTV Dc Khoa Trng i hc Dc H Ni, gia nh
v ngi thn trong sut thi gian qua.

H Ni, Thng 10 nm 2013

Hc vin

Hong S ng

MC LC
Danh mc cc k hiu v ch vit tt
Danh mc cc bng
Danh mc cc hnh v v th
T VN .......................................................................................................... 1
Chng 1: TNG QUAN ........................................................................................ 2
1.1.Thuc gii phng ko di theo c ch bm thm thu ...................................... 2
1.1.1.Tng quan v h bm thm thu..................................................................... 2
1.1.2.Cc thnh phn c bn ca mt h thm thu................................................. 7
1.1.3.Cc yu t nh hng n kh nng GPDC t bm thm thu ...................... 9
1.1.4.u, nhc im ca h thm thu .................................................................. 13
1.2.Felodipin ............................................................................................................ 15
1.2.1.Cng thc ........................................................................................................ 15
1.2.2.Tnh cht.......................................................................................................... 15
1.2.3.Dc ng hc ................................................................................................ 15
1.2.4.Tc dng v ch nh ....................................................................................... 16
1.2.5.Tc dng khng mong mun v chng ch nh............................................. 16
1.2.6.Liu lng v cch dng................................................................................. 16
1.2.7.Cc sn phm cha felodipin trn th trng.................................................. 17
1.3.Cc nghin cu v felodipin .............................................................................. 17
1.3.1.Cc nghin cu ci thin tan ca felodipin ................................................ 17
1.3.2.Cc nghin cu v cc dng gii phng ko di cha felodipin..................... 21
1.3.3.Gii phng ko di theo c ch bm thm thu.............................................. 21
1.3.4.Gii phng ko di theo c ch khc .............................................................. 22
1.3.5.Cc nghin cu khc ....................................................................................... 24
Chng 2: I TNG V PHNG PHP NGHIN CU ................................27
2.1. Nguyn vt liu v thit b .....................................................................................27
2.1.1. Nguyn vt liu ...................................................................................................27

2.1.2. Thit b ................................................................................................................28

2.2. Phng php nghin cu........................................................................................28
2.2.1. Phng php bo ch vin nhn .........................................................................28
2.2.2. Phng php bao phim .......................................................................................29
2.2.3. Phng php to ming gii phng dc cht....................................................30
2.2.4. Phng php nh gi.........................................................................................30
2.2.4.1. Phng php phn tch nng lng nhit vi sai...............................................30
2.2.4.2. Png php nh gi cng ca vin nhn...................................................30
2.2.4.3. Phng php nh gi mi mn vin nhn.................................................31
2.2.4.4. Phng php nh lng ..................................................................................31
2.2.4.5. Phng php nh gi b mt mng bao .........................................................32
2.2.4.6. Phng php o ng knh ming gii phng dc cht ..............................32
2.2.4.7. Phng php nh gi kh nng gii phng dc cht ...................................32
2.2.4.8. Phng php nh gi ng hc gii phng....................................................34
Chng 3: KT QU NGHIN CU .........................................................................37
3.1. Xy dng ng chun ..........................................................................................37
3.1.1.Phng php o quang ph hp th UV-VIS ......................................................37
3.1.2. Phng php HPLC ............................................................................................38
3.2. Nghin cu ci thin ha tan felodipin .............................................................39
3.2.1. nh hng ca phng php bo ch ti ha tan felodipin ..........................39
3.2.2. nh hng ca t l PVP/felodipin ti ha tan felodipin..............................40
3.2.3. nh hng ca PEO 200.000 n ha tan ca felodipin...............................42
3.3. Nghin cu xy dng cng thc vin thm thu ...................................................43
3.3.1. La chn t dc lp y v lp dc cht........................................................43
3.3.2. Nghin cu xy dng cng thc vin nhn ........................................................46
3

3.3.2.1. Nghin cu t l PEO 200.000 v PEO 5.000.000 trong vin nhn................46

3.3.2.2. Nghin cu nh hng ca t l natri clorid n tc GPDC ......................48
3.3.3. Nghin cu nh hng ca dy mng bao n tc GPDC .......................50
3.3.4. Nghin cu nh hng ca kch thc ming gii phng n tc GPDC.....52
3.4. Nghin cu nh hng ca cc yu t mi trng ha tan n kh nng GPDC .54
3.4.1. nh hng ca pH mi trng ha tan ..............................................................54
3.4.2. nh hng ca tc cnh khuy......................................................................55
3.4.3. nh hng ca p sut thm thu mi trng ha tan .......................................55
3.5. nh gi cc c tnh ca vin v xut tiu chun............................................56
3.5.1. nh gi cc c tnh ca vin bo ch c .....................................................56
3.5.2. xut tiu chun vin thm thu felodipin 5mg ..............................................61
Chng 4: BN LUN ................................................................................................62
4.1. V phng php bo ch........................................................................................62
4.1.1. Phng php ci thin ha tan ca dc cht................................................62
4.1.2. Phng php dp vin.........................................................................................62
4.1.3 Phng php bao mng bn thm ........................................................................63
4.1.4. Phng php khoan ming gii phng dc cht...............................................63
4.2. V xy dng cng thc vin thm thu .................................................................64
4.2.1. Xy dng cng thc vin nhn ...........................................................................64
4.2.2. La chn dy mng bao .................................................................................66
4.2.3. La chn kch thc ming gii phng dc cht..............................................66
4.3. V nh gi mu vin bo ch c ......................................................................67
4.3.1. Cc phng php nh gi..................................................................................67
4.3.2. nh gi nh hng ca cc yu t mi trng ha tan n kh nng GPDC ..68
4.3.3. Kt qu nh gi mu vin c la chn..........................................................68
4

KT LUN V KIN NGH.......................................................................................70

TI LIU THAM KHO
PH LC

DANH MC CC K HIU V CH VIT TT

ASTT

: p sut thm thu

CA

: Cellulose acetat

BP

: Dc in Anh

DVN

: Dc in Vit Nam

DSC

: Phn tch nhit vi sai

GPDC

: Gii phng dc cht

HPTR

: H phn tn rn

HPLC

: Sc k lng hiu nng cao

HPMC

: Hydroxy propyl methyl cellulose

PEG

: Polyethylen glycol

MCC

: Cellulose vi tinh th

NSX

: Nh sn xut

PVP

: Polyvinyl pyrolydon

PLX

: Poloxamer

PEO

: Polyethylen oxyd

SEM

: Knh hin vi in t qut

TEM

: Knh hin vi in t truyn qua

USP

: Dc in M

DANH MC CC BNG
STT

Tn bng

Trang

Bng 1.1: Mt s cht hay dng to p sut thm thu

Bng 1.2: p sut thm thu to ra bi cc dung dch bo ha

12

Bng 1.3: Mt s sn phm vin gii phng ko di theo c

15

ch bm thm thu ko y hin nay

Bng 1.4: Cc sn phm cha felodipin trn th trng

17

Bng 2.1: Nguyn vt liu

27

Bng 2.2: Yu cu v ha tan theo Test 1 USP 35

34

Bng 2.3: Gii thch c ch gii phng thuc theo h s n

36

Bng 3.1: S ph thuc mt quang (D) vo nng felodipin

37

(C) trong mi trng m phosphat 0,1M pH 6,5 c 1%

natrilauryl sulfat bc sng 238nm

10

11

12
13

Bng 3.2: S ph thuc din tch pic v nng felodipin trong

phng php HPLC
Bng 3.3: T l dc cht gii phng(%SD) t cc mu N1,

40

N2 (n=3)
Bng 3.4 : Thnh phn cng thc lp dc cht mu N3, N4,

41

N5
Bng 3.5: T l dc cht gii phng (%SD) t cc mu N3,

41

N4, N5(n=3)
Bng 3.6: T l dc cht gii phng (%SD) t cc mu N6

38

42

(n=3)
14

Bng 3.7: Thnh phn cng thc cc mu M1, M2, M3, M4, M5

44

15

Bng 3.8: Thnh phn vin nhn

46

16

Bng 3.9: Thnh phn cng thc cc mu M6, M7, M8, M9

47

17

Bng 3.10: Thnh phn cng thc cc mu M7, M10, M11

49

18

Bng 3.11: cng ca vin nhn (kP)

57

19

Bng 3.12: mi mn vin nn nhn

57

20

Bng 3.13: Khi lng vin sau khi bao

58

21

Bng 3.14: Kch thc ming gii phng dc cht

58

Bng 3.15: Kt qu nh lng mu vin la chn bng phng

59

22

23

24
25

php HPLC
Bng 3.16: T l felodipin gii phng (%SD) mu vin la
chn (n=3)
Bng 3.17: Kt qu phn tch d liu ha tan mu vin la chn

60

bng phn mm S Splus 8.0

Bng 3.18: Bng tiu chun vin thm thu felodipin 5mg

59

61

DANH MC CC HNH V V TH
STT
1

Tn hnh v, th
Hnh 1.1: Bm thm thu Rose Nelson, Higuchi-Leeper,
Higuchi Theeuwe.

Trang
2

Hnh 1.2: Bm thm thu c bn (EOP)

Hnh 1.3: Bm thm thu ko y

Hnh 1.4: Bm thm thu kim sot xp mng

Hnh 1.5: Bm thm thu dng nhiu lp

Hnh 1.6: Bm thm thu OROS-CT

Hnh 1.7: Bm thm thu Liquid OROS

Hnh 1.8: H nang lng gii phng chm

Hnh 2.1: Nguyn tc khoan laze

30

10

Hnh 2.2: Gi ng vin

34

11

12

13

Hnh 3.1: th biu din mi tng quan gia nng

felodipin v mt quang o ti bc sng 238nm.
Hnh 3.2: th biu din mi tng quan gia nng v din
tich pic
Hnh 3.3: th biu din % felodipin gii phng t cc mu
vin N1, N2

37

38

40

Hnh 3.4: th biu din % felodipin gii phng t cc mu

14

15

41

N3,N4,N5
Hnh 3.5: th biu din % felodipin gii phng t N1, N2,
N6

43

16

17

18

19

20

21

22
23

Hnh 3.6: th gii phng dc cht cc mu M1, M2, M3,

M4,M5
Hnh 3.7: th gii phng dc cht t cc mu M6, M7, M8,
M9
Hnh 3.8: th gii phng dc cht t cc mu vin c t l
NaCl khc nhau
Hnh 3.9: th gii phng dc cht t vin c dy mng
bao khc nhau
Hnh 3.10: th gii phng dc cht t cc mu vin c kch
thc ming gii phng khc nhau
Hnh 3.11: th gii phng dc cht mu M6 trong cc mi
trng pH khc nhau
Hnh 3.12: th gii phng dc cht t mu M6 vi tc
cnh khuy khc nhau
Hnh 3.14: th gii phng dc cht t mu vin la chn

10

45

47

49

51

52

54

55
60

T VN
Hin nay trn th trng dc phm cc dng bo ch theo hng kim sot
gii phng dc cht ang pht trin rt mnh m. u im chnh ca cc dng bo
ch ny l gip ngi bnh tun th iu tr tt hn, ti a tc dng iu tr v gim
thiu tc dng bt li. C nhiu phng php khc nhau kim sot gii phng
dc cht nh bo ch dng ct tr v ct trng n, bao mng polyme khuych
tn, bo ch dng vin thm thuTrong s dng nguyn l bm thm thu l
mt hng c nhiu u im, c tnh kh thi cao trong nghin cu v trin khai.
Hin nay nhiu thuc s dng trn lm sng ng dng cng ngh bm thm thu
kim sot gii phng dc cht nh cc thuc h ng huyt v ri lon chuyn
ha

(metformin,

glipizid,

lovastatin),

cc

thuc

khng

histamin

(chlorpheniramin), thuc tc ng ln th th adrenergic (salbutamol,

pseudoephedrin, phenylpropranolamin), v c bit cc thuc tim mch
(nifedipin, prazosin, doxazosin, verapamin, isradipin, diltiazem, verapamil,
felodipin, nicardipin).
Felodipin l mt thuc h huyt p nhm chn knh calci, c tc dng chn
lc ln c trn h tiu ng mch, lm h huyt p, khng gy tt huyt p th
ng, an ton, ph hp s dng di ngy v vi ngi gi nn n ngy cng
dng s dng rng ri. Trn th gii, felodipin c nhiu nc pht trin thnh
cng dng thuc gii phng c kim sot theo c ch bm thm thu cha 5 mg
felodipin tc dng ko di 24 gi. Tuy nhin, trong nc cha c nghin cu no
tip cn vn bo ch vin thm thu felodipin. V vy chng ti t vn
nghin cu ti: Nghin cu bo ch vin gii phng ko di theo c ch bm
thm thu cha felodipin vi mc tiu sau y:
- Xy dng c cng thc bo ch vin thm thu 2 lp cha 5 mg felodipin
gii phng ko di 12 gi v nh gi cc c tnh ca vin bo ch c.

11

Chng 1. TNG QUAN

1.1. Thuc gii phng ko di theo c ch bm thm thu
1.1.1. Tng quan v h bm thm thu
Hin tng thm thu l qu trnh chuyn dch ca cc phn t dung mi t
ni c nng cht tan thp n ni c nng cao qua mng bn thm. Hin
tng ny c Abbe Nollet ghi nhn vo nm 1748. Cc nghin cu v p sut
thm thu bt u t nhng nm 1960 v gn lin vi s pht trin ca khoa hc v
mng bn thm. Ngy nay, hin tng thm thu c ng dng vi nhiu mc
ch khc nhau nh: lc nc, x l nc thi, loi mui khi nc bin, cng ngh
thc phm, bo ch thuc gii phng ko di v.v
Trong lnh vc bo ch dc phm, c nhiu nghin cu tm cch ng dng
nguyn l p sut thm thu pht trin cc dng bo ch kim sot gii phng
dc cht. H kim sot gii phng dc cht da trn nguyn l p sut thm thu
gi chung l h bm thm thu. Lch s pht trin ca h bm thm thu c th
chia thnh 2 loi l h thm thu cy di da v h thm thu ng ung.
a. H thm thu cy di da
H thm thu cy di da u tin c nghin cu l bm thm thu Rose
Nelson (1955), c cu to gm mt v cng, c 3 khoang c mng ngn cch:
khoang dc cht, khoang mui v khoang nc. Sau bm Rose Nelson c
ci tin thnh bm Higuchi-Leeper v bm Higuchi Theeuwe bng cch b
khoang mui hoc thay v cng bng mng bn thm bn [29], [38], [45].

Hnh 1.1: Bm thm thu Rose Nelson, Higuchi-Leeper, Higuchi Theeuwe.

12

b. H thm thu ng ung

C th phn loi h thm thu ng ung thnh cc loi sau:
* Bm thm thu mt ngn:
-

Bm thm thu c bn (Elementary osmotic pump EOP): c Theeuwe

pht trin vo nm 1974, n l mt loi bm Higuchi Theeuwe ci tin bng cch

b khoang ring cha mui i v tc nhn to p sut thm thu c trn ng
nht vi dc cht v mng bn thm c bao bn ngoi vin nhn (hnh 1.2).
Nc trong ng tiu ha s c ht qua mng bn thm, ha tan dc cht v
dung dch dc cht s c bm qua ming gii phng [29],[40],[45].

Hnh 1.2: Bm thm thu c bn (EOP)

* Bm thm thu nhiu ngn:
-

Bm thm thu ko y (push-pull osmotic pump PPOP): c pht trin

khc phc nhc im ca bm thm thu c bn. Bm thm thu ko y

c p dng bo ch cc thuc gii phng ko di, c ng hc gii phng bc
0, s dng ngy 1 ln, i vi cc dc cht kh tan (nhm thuc h huyt p,
chuyn ha, h hp) v c cc dc cht c tan cao (hnh 1.3).

Hnh 1.3: Bm thm thu ko y

V mt cu to, bm thm thu ko y c bo ch di dng vin 2 lp,
trong :

13

+ Lp th nht cha dc cht, t dc to p sut thm thu v cc t

dc khc khi thm nc c th d dng to thnh dung dch, hn dch hoc dng
gel cha dc cht di dng tiu phn phn tn mn.
+ Lp th hai gm cc t dc to p sut thm thu, polyme c kh nng
trng n khi gp nc v cc t dc khc.
+ Vin c bao bi mng bn thm, c khoan ming gii phng dc cht
chnh gia mt vin lp cha dc cht
Khi s dng, bm tip xc vi nc, lp th nht ht nc v to thnh dung
dch, hn dch hoc dng phn tn mn ca dc cht trong gel c th bm qua
ming gii phng dc cht. Lp th 2 cng ht nc v lm trng n polyme to
ra p sut y dc cht lp th nht qua ming gii phng ra ngoi [10],
[29],[40],[45].
-

Bm thm thu c ngn th 2 khng trng n: Ngn th 2 c s dng

pha long dung dch dc cht trc khi c gii phng ra ngoi. H ny c s
dng v c mt s trng hp dc cht gii phng dng dung dch bo ha gy
kch ng ng tiu ha. H gm 2 ngn cng, ngn th nht cha tc nhn thm
thu nh ng hoc NaCl, ngn th 2 cha dc cht. Nc c ko vo c 2
ngn qua mng bn thm, ha tan tc nhn thm thu trong ngn 1, dung dch ny
c y qua ngn dc cht qua l lin kt 2 ngn v pha long dung dch dc
cht trc khi dung dch dc cht c gii phng ra ngoi qua cc l xp to ra
trn b mt mng bn thm bao quanh h [29],[40].
* Cc dng c bit khc:
-

Bm thm thu kim sot xp ca mng (Controlled porosity osmotic

pumps CPOP): loi bm ny s dng mng bn thm c thm cc thnh phn c

kh nng ha tan trong nc, khi s dng do tip xc vi nc cc thnh phn b
ha tan lm cho mng c xp nht nh. Mng khi va c kh nng thm
nc va cho dch ha tan thm qua. Cc nghin cu cho thy ng hc gii phng
dc cht ca loi bm ny cng theo c ch bm thm thu quy c, gii phng
theo c ch khuch tn ch ng vai tr nh (hnh 1.4) [10], [29],[40].

14

Hnh 1.4: Bm thm thu kim sot xp mng

-

H thm thu ng nht (Monolithic osmotic systems): Cu to ca h l dng

phn tn n gin ca cc tc nhn tan trong nc trong ct polyme. Khi h tip

xc vi mi trng nc, qu trnh ht nc ca cc tc nhn hot ng din ra qu
trnh ph v cu trc ct polyme bao quanh dc cht, gii phng dc cht ra
ngoi mi trng [29],[40].
-

H cha pellet thm thu: loi ny mi n v liu gm nhiu pellet cha

dc cht, c hoc khng c tc nhn to p sut thm thu, c bao bng mng
bn thm . Khi s dng pellet thm nc trng n lm cng mng to cc l xp
gii phng dc cht [5].
-

Bm thm thu bng mng (Osmotic bursting osmotic pump): Loi bm ny

khng c ming gii phng dc cht hoc ming gii phng dc cht qu nh khi
s dng p lc trong vin tng lin tc n khi rch mng bao gii phng dc
cht. Loi bm thm thu ny c thi gian tim tng di v thch hp bo ch
dng thuc gii phng theo nhp [29],[40].
-

Bm thm thu dng nhiu lp (Sandwiched osmotic tablet SOTS): c

bo ch di dng vin ba lp gm mt lp ng vai tr y gia v hai lp cha

dc cht hai bn, c bao bng mng bao bn thm. Ming gii phng dc cht
c khoan c hai mt vin. Cc dc cht c tnh kch ng ng tiu ha khi
bo ch di dng ny c th lm gim tc dng ph (hnh 1.5) [29], [40].
Ming gii phng dc
Lp dc cht
Lp y
Hnh 1.5: Bm thm thu dng nhiu lp

15

Bm thm thu ti ch i trng (OROS CT): c s dng bo ch cc

thuc s dng ngy 1-2 ln vi mc ch a thuc ti gii phng ti ch l i

trng. OROS CT c th l vin thm thu n cng c th gm 5-6 vin thm thu
ko - y c bao ngoi bng mt lp polyme tan trong rut, np trong nang cng.
Khi ung vo d dy v nang gelatin b ha tan nhng nh lp bao tan trong rut
nn vin khng b thm dch tiu ha. Khi n rut non lp polyme bn ngoi b
ha tan v vin bt u gii phng theo c ch gii phng ca vin thm thu ko
y (hnh 1.6) [29],[40].

Hnh 1.6: Bm thm thu OROS CT

-

H thm thu lng (Liquid OROS): y l loi bm thm thu ci tin s

dng kim sot gii phng dc cht di dng lng hoc bo ch di dng
lng. Dc cht c th l cht lng thn du hoc bo ch di dng dung dch du,
c th thm cc tc nhn nh ha bo ch di dng t nh ha. V mt cu to
loi bm ny c th l L-OROS Hardcap hoc L-OROS Softcap (hnh 1.7)
[29],[40].

Hnh 1.7: Bm thm thu Liquid OROS

16

H nang lng gii phng chm (Telescopic capsule for delayed release): c

hng Alza Corporation (Palo Alto, CA) pht trin. H ny gm 2 ngn: ngn th
nht cha dc cht v c 1 cng gii phng, ngn th 2 cha tc nhn thm thu.
Hai ngn ny c nm trong 2 lp v nang, c ng np li vi nhau. Khi nc
c hp thu vo bn trong h lp thm thu trng n to p lc trc tip ln
thanh trt ni gia phn v th nht v th hai, np nang c m ra v gii
phng dc cht. Trong sut thi gian tr hon ny th tch ngn cha dc cht
khng i nn chnh lch p sut gia trong v ngoi ngn cha khng ng k, do
tc ht nc t mi trng vo ngn cha dc cht rt nh v dc cht
khng c gii phng trong giai on ny (hnh 1.8) [10], [29], [40].

Hnh 1.8: H nang lng gii phng chm

1.1.2. Cc thnh phn c bn ca mt h thm thu
- Dc cht: Nhng dc cht c thi gian bn thi ngn (2 6h), c hiu lc cao
hoc c s dng iu tr ko di thng c s dng trong h thm thu nh
diltiazem HCl, carbamazepin, metoprolol, oxprenolol, nifedipin, glipizid
- Tc nhn to p sut thm thu: c vai tr ch yu to ra p sut thm thu bn
trong h ko nc vo ha tan dc cht. Bao gm cc mui v c v cc
carbohydrat. Thng thng s dng kt hp cc tc nhn thm thu tng hiu
qu to ra p sut thm thu trong h (bng 1.1).
- Mng bn thm: c vai tr quan trng i vi h thm thu, ch cho nc thm
qua mt chiu v khng cho dc cht v cc thnh phn khc i qua mng. Mng
bn thm nn tr v lun nguyn vn v kch thc duy tr p lc thm thu hng
nh trong qu trnh gii phng. Cc polyme thng c s dng l cc este

17

cellulose nh cellulose acetat, cellulose acetat butyrat, cellulose triacetat v ethyl

cellulose. Trong thng dng nht l cellulose acetat c nng acetyl 32 38%.
Bng 1.1: Mt s cht hay dng to p sut thm thu [33]
Tc nhn to p sut thm thu

V d

Mui tan ca cc acid v c

MgCl2, MgSO4, NaCl, KCl, LiCl, Na2SO4,

Mui tan ca cc acid hu c

Natri v kali acetat, magnesi succinat, kali

benzoat, natri citrat

Carbohydrat

Arabinose, ribose, xylose, glucose, lactose,

fructose, galactose

Cc amino acid tan trong nc

Glycin, leucin, alanin

Cc polyme hu c

NaCMC, HPMC, HEPC, PEO, carbopol

- Cc polyme thn nc v k nc: cc polyme ny c vai tr to cc ct cha

dc cht. Cc polyme thn nc hay dng nh HPMC, hydroxyl ethyl cellulose,
carboxy methyl cellulose. Cc polyme k nc nh ethyl cellulose, cc loi sp.
- Tc nhn to xp vin nhn: c vai tr vn chuyn nc, to ra mng li l
xp ko nc vo bn trong vin nhn. Cc tc nhn to l xp gm silicon dioxid,
kaolin, titan dioxid, alumina, niaciamid, natri lauryl sulfat.
- Cht ha do: Ci thin do dai ca mng bn thm, nh polyethylen glycol,
ethylen glycol monoacetat v diacetat, triethylcitrat, diethyl tartarat
- Tc nhn iu chnh kh nng thm nc qua mng (Flux regulators): c thm
vo thnh phn mng bao tng hoc gim tnh thm ca mng bn thm. Cc hp
cht thn nc nh PEG (300600Da), polyhydric alcohol, polyalkylen glycol ci
thin tnh thm nc ca mng. Cc hp cht s nc nh diethyl phthalat,
dimethoxy ethylphthalat c khuynh hng lm gim tnh thm nc.
- Tc nhn to l: cc tc nhn ny s dng trong cc h thm thu cha dc cht
kh tan trong nc v trong h thm thu kim sot xp ca mng, to ra cc l
siu nh trn mng. Cc tc nhn ny c th l cc cht v c hoc hu c, cht
lng hoc cht rn. V d cc mui natri clorid, natri bromid, kali clorid, kali

18

sulphat, kali phosphat, cc carbohydrat sucrose, glucose, fructose, mannose,

lactose, sorbitol, manitol v cc polyol nh polyvinyl pyrolidon [16],[28].
1.1.3. Cc yu t nh hng n kh nng GPDC t bm thm thu
Bm thm thu gii phng dc cht theo cch ht nc qua mng bn thm,
ha tan dc cht v bm ra ngoi qua ming gii phng dc cht. Tc thm
nc vo bm thm thu c m t bng phng trnh [5], [9], [33]:
dv A
= L p ( . p)
dt h

Trong :
dv
: Tc thm nc
dt

A, h: Din tch b mt, dy mng bn thm

L p : H s bn thm c hc

: H s phn nh tnh bn thm ca mng bao

, p : Chnh lch p sut thm thu, p sut thy tnh trong v ngoi mng.

Vi mng bn thm chun, l hng nh. Trong hu ht cc h thm thu,

khi kch thc ming gii phng tng, p sut thy tnh trong h nh nht v
>> p , p sut thm thu bn ngoi dch tiu ha khng ng k so vi bn

trong vin do c th thay th cho . Phng trnh trn tr thnh [5], [9], [33]
dv A
= k vi k = L p .
dt h

Tc gii phng dc cht ra ngoi mi trng theo phng trnh:

dM dv
= .C
dt
dt

C: nng dc cht c phn phi trong 1 n v th tch dung dch.

Kt hp 2 phng trnh trn:
dM
A
= .k . .C
dt
h

Nh vy, t c hng nh tc gii phng dc cht t h thm thu

phi la chn thch hp v ti u mng bn thm ( duy tr A,h,k hng nh) v
duy tr mt dung dch bo ha ca dc cht trong vin nhn (cho n khi mt
19

lng d cht rn cha ha tan cn tn ti trong nhn th c v C c th c duy

tr mc khng i).
Cc yu t nh hng n qu trnh gii phng dc cht t h thm thu
gm:
- tan dc cht.
- Kch thc ming gii phng dc cht.
- p sut thm thu to ra trong vin nhn.
- Cc yu t thuc v mng bao: dy, din tch, c tnh mng bao, cht ha
do.
tan dc cht:
T l gii phng dc cht ph thuc vo tan ca cc cht tan trong h, do
tan dc cht cn phi thch hp gii phng c qua h thm thu. Vi
dng vin thm thu c bn (EOP), dc cht c tan cao qu hay thp qu u
khng thch hp bo ch. Cc dc cht c tan thp khng to ra c p sut
thm thu mnh gii phng dc cht t n nng iu tr. Nu dc cht
c tan cao h d t c ng hc bc 0 ban u nhng ngn nn kh ko di
c tc dng iu tr v tc gii phng khng n nh. C nghin cu cho rng
thy tan dc cht trong khong 50 300 mg/ml l thch hp bo ch vin
thm thu c bn (EOP).
Vi cc dc cht c tan thp, c th s dng cc bin php ci thin
tan nh s dng kt hp vi cc t dc tng tan, s dng dng mui tan, to h
phn tn rnhoc s dng cc polyme trng n phn tn cc dc cht t tan
di dng hn dch. c bit, h thm thu ko y (PPOP) c th p dng cho c
cc dc cht c tan rt thp v c dc cht c tan rt cao [5],[9],[16],[38].
Kch thc ming gii phng dc cht:
Ming gii phng l ni dc cht c gii phng ra ngoi mi trng. Kch
thc ming gii phng nh hng ti tc gii phng dc cht.
+ Vi h thm thu ming gii phng c to ra nh khoan laser, khoan c hc
hoc to l khi dp vin, kch thc ming phi c thit k trong khong ph
hp.
20

Nu kch thc ming qu b: kh gii phng dc cht t kt qu iu tr

v p sut thy tnh trong vin nhn ln nn khng th b qua trong qu trnh gii
phng dc cht do qu trnh gii phng khng tun theo ng hc bc 0.
Nu kch thc ming qu ln: dc cht ngoi gii phng do p sut thm
thu m cn do qu trnh khuch tn, do cng khng gii phng theo ng hc
bc 0.
ng knh ca ming gii phng dc cht thng t 0,250 0,500 mm l
thch hp i vi nhiu dc cht.
+ Vi h thm thu ming gii phng c to ra nh cc tc nhn tan trong
nc (v d h CPOP). Vi h ny mng bao l hn hp ca polyme to mng bn
thm trn vi cc t dc tan trong nc (PG, PEG, NaCl, HPMC), khi tip xc
vi mi trng nc s ha tan cc t dc to ra cc l nh ng vai tr l ming
gii phng dc cht. Mt l ng vai tr quan trng do mng phi c thit
k sao cho mt l va to tnh thm v kh nng gii phng nhng vn m
bo tnh bn thm v tnh nguyn vn ca mng [5],[9],[16],[38].
p sut thm thu to ra trong vin nhn:
T phng trnh ta thy tc gii phng dc cht t l thun vi p sut
thm thu to ra trong vin nhn. Mun dc cht gii phng theo ng hc bc 0
cn phi duy tr p sut thm thm thu trong vin nhn t gi tr hng nh, do
phi duy tr nng bo ha ca cc cht to p sut thm thu. Nu dc cht
khng t to ra c p sut thm thu mnh th phi thm vo cng thc cc
cht to p sut thm thu. Tuy nhin, mt s dc cht t tan hoc khng tan
trong nc d thm t dc to p sut thm thu nhng gii phng dc cht
cng khng t hiu qu iu tr do t l dc cht trong tng thnh phn gii
phng thp. Khi , phi p dng cc bin php lm tng tan dc cht hoc c
th bo ch thnh h thm thu nhiu ngn [5],[9],[16],[38].
Bng 1.2: p sut thm thu to ra bi cc dung dch bo ha [16], [40]
Tc nhn to ASTT

ASTT

Tc nhn to ASTT

21

ASTT

Lactose Fructose

500

Manitol Sucrose

170

Dextrose Fructose

450

Sucrose

150

Sucrose Fructose

430

Manitol Lactose

130

Manitol Fructose

415

Dextrose

82

Natri clorid

356

Kali sulphat

39

Fructose

335

Manitol

38

Lactose Sucrose

250

Na3PO4.12H2O

36

Kali clorid

245

Na2HPO4.7H2O

31

Lactose Dextrose

225

Na2HPO4.12H2O

31

Manitol Dextrose

225

NaH2PO4.H2O

28

Dextrose Sucrose

190

Na2HPO4

21

Mng bao:
Mng bao c nh hng rt ln n tc gii phng dc cht, th hin

cc yu t sau:
+ c tnh mng bao:
Mng bao l mng polyme bn thm: mng ch cho nc thm qua m khng
cho cc cht tan i qua. Mng bao c tnh thm cng cao th tc thm nc cng
cao nn tc gii phng dc cht cng cao. Tnh thm ca mng c th tng hay
gim bng cch la chn loi polyme to mng v loi, lng cht ha do thch
hp. Cc tnh cht ca mng bn thm cn c:
9 C bn duy tr nguyn vn hnh dng trong qu trnh gii phng
dc cht
9 C kh nng thm nc duy tr tc ht nc theo nh thit k
9 Tng hp sinh hc
9 Cng v khng trng n
9 dy chu c p sut trong h [38].
Cc polyme thng c s dng to mng bn thm gm: cc este ca
cellulose nh cellulose acetat, cellulose propionat, cellulose acetat butyrat; cc
ether cellulose nh ethyl cellulose; cc Eudragit. Trong cellulose acetat hay
22

c s dng nht do c tnh bn thm cao, chn lc v c tnh d bin i khi

thm cht ha do. Ethyl cellulose, Eudrgit cng hay c dng v ph bin, r
nhng kh nng thm nc thp hn cellulose acetat [5].
Cc cht ha do c cho thm vo ci thin tnh cht c l cho mng.
Cc cht ha do tan trong nc hay c s dng nh PEG, HPMCv nhanh
to ra cu trc l xp, rt ngn thi gian tim tng gii phng dc cht; loi
khng tan trong nc nh du thu du, triacetin cng hay c dng v gip
qu trnh gii phng hng nh hn.
Dung dch mng bao hay s dng l dung dch cellulose acetat 2 4% trong
aceton (w/v) vi t l cht ha do ph hp ty thuc vo mc ch s dng.
+ dy mng bao: cng thc trn ch ra tc gii phng dc cht t l
nghch vi dy mng bao v cc kt qu thc nghim chng minh iu ny.
+ Din tch mng bao: thng khng thay i nn t nh hng n tc gii
phng dc cht [5],[9],[16],[38].
1.1.4. u, nhc im ca h thm thu
u im
-

C ng hc gii phng dc cht bc 0 sau thi gian tim tng

C th thit k gii phng chm hoc theo nhp

Gii phng dc cht khng ph thuc vo pH ng tiu ha, thc n, nhu

ng rut.

C ch gii phng dc cht khng ph thuc vo dc cht.

C s tng quan cao gia gii phng invitro v invivo.

T l gii phng cao hn so vi cc cc h gii phng theo c ch khuch

tn thng thng.

Tc gii phng c th d on trc v c th thay i theo chng trnh

bng cch iu chnh cc thng s kim sot qu trnh gii phng [16],[38].

Nhc im
-

K thut bo ch phc tp, gi thnh sn phm t.

C nguy c qu liu cao nu qu trnh bao phim b li gy khuyt tt trn

mng.
23

Khoan ming gii phng l mt vn kh khn [16],[38].

Trong cc dng bm thm thu th bm thm thm thu ko - y (PPOP)

c ng dng v thng mi ha rng ri hn so vi cc dng bm thm
thu khc. Mt s u, nhc im ca bm PPOP gm:
- u im:
+ ng hc gii phng bc 0 v duy tr ng hc bc 0 cho n khi gii phng
ht dc cht.
+ Thch hp bo ch h gii phng ko di cho cc dc cht c tan
khc nhau, c bit cc dc cht c tan rt thp v nhng dc cht c tan
rt cao.
+ C th nng cp ln quy m sn xut cng nghip
-

Nhc im:

+ Cn thit b dp vin 2 lp.

+ Cn s dng thm t dc mu phn bit 2 lp.
+ Cn thit b khoan ming gii phng dc cht c kh nng t ng xc nh
ng mt cn khoan.
Zhi-hong Zhang v cng s (2009) nghin cu khc phc kh khn trong
vic khoan ming gii phng ng mt cha dc cht ca vin thm thu loi ko
- y. Cc tc gi s dng cc dc cht khng tan trong nc (indapamid,
gliclazid v dipyridamol) lm m hnh nghin cu, thit k cc cng thc v s
dng cc k thut truyn thng. Nghin cu kh nng gii phng dc cht Invitro.
S liu gii phng dc cht t cc vin khoan ming gii phng dc cht trn mt
cha dc cht v khoan ming cng ng knh trn c 2 mt khng c s khc
bit. Do vy c th gii quyt bng cch khoan ming gii phng dc cht trn c
2 mt vin [47].
Bng 1.3: Mt s sn phm vin gii phng ko di theo c ch bm thm
thu ko y hin nay.
Tn thng

Dc cht

Dng thit

24

Hm lng

S dng

mi

(mg)

Alpress LP

Prazosin

PPOP

2,5 5mg

H huyt p

Cardura XL

Doxazosin

PPOP

4, 8 mg

H huyt p

Covera HS

Verapamil

PPOP

180, 240 mg

H huyt p

Ditropan XL

Oxybutinin chlorid

PPOP

5, 10 mg

Gin c bng quang

Dynacirc CR

Isradipin

PPOP

5, 10 mg

H huyt p

Invega

Paliperidon

PPOP

3, 6, 9 mg

Tm thn phn lit

Glucotrol XL

Glipizid

PPOP

5, 10 mg

H ng huyt

Procardia XL

Nifedipin

PPOP

30, 60, 90mg

H huyt p

1.2. FELODIPIN
1.2.1. Cng thc
CTPT: C18H19Cl2NO4
Khi lng phn t: 384,259 g/mol
Tn

khoa

hc:

3-ethyl-5-methyl-4(2,3-

dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine3,5-dicarboxylate [17], [41], [42].

1.2.2. Tnh cht
Felodipin tn ti di dng bt tinh th mu trng hoc vng nht, nhit
nng chy 145oC, rt t tan trong nc, tan trong nc 19,17 mg/lt 250C, tan
trong dicloromethan v methanol [41]. Felodipin thuc phn nhm II theo phn loi
sinh dc hc. Felodipin l mt hn hp racemic [42].
1.2.3. Dc ng hc:
a) Hp thu v phn b:
- Felodipin hp thu hon ton qua ng tiu ha sau khi ung, sinh kh dng
khong 15%
- Nng nh trong huyt tng sau khi ung t c sau 2,5 5 gi
- C nng nh trong huyt tng v din tch di ng cong (AUC) tng
tuyn tnh vi liu ln n 20 mg.
- Gn vi protein huyt tng xp x 99%, ch yu l albumin
25

b) Chuyn ha v thi tr:

- Felodipin c chuyn ha phn ln gan thnh cc cht khng c hot tnh.
- Felodipin c thanh thi trong mu cao, trung bnh 1200ml/pht, khng c s
tch ly ng k khi s dng di ngy.
- Thi tr ch yu qua thn, khong 70% di dng cc cht chuyn ha, phn cn
li qua phn, thi gian bn thi t1/2=11 25 gi.
1.2.4. Tc dng v ch nh:
a) Tc dng:
- L thuc chn knh canxi c tnh chn lc cao trn mch lm gim huyt p ng
mch, khng tc dng ln c trn tnh mch nn khng lm gim huyt p th ng
- Chng au tht ngc v chng thiu mu cc b do ci thin s cn bng cung
cu oxy tim
b) Ch nh:
- iu tr tng huyt p
- iu tr au tht ngc.
1.2.5. Tc dng khng mong mun v chng ch inh:
a) Tc dng khng mong mun:
- Thng gp: bng mt, nhc u; ph ngoi bin nh ph c chn, ph li
- t gp: nhp tim nhanh, nh trng ngc, chong vng, bun nn, nga, mt mi
b) Chng ch nh:
- Ph n c thai.
- Qu mn vi felodipin v cc thnh phn khc.
- Suy tim mt b.
- Nhi mu c tim cp.
- au tht ngc khng n nh.
1.2.6. Liu lng, cch dng:
- Tng huyt p: Liu c iu chnh theo tng bnh nhn. Liu duy tr thng
thng 5 10 mg, 1 ln /1 ngy.
- au tht ngc: Nn bt u bng 5mg, 1 ln/ngy, tng ln 10 mg,1 ln/ngy nu
cn.
26

- Vin nn nn c dng vo bui sng, nut vi nc v khng c chia nh.

C th ung lc i hoc sau khi n nh khng c cht bo hoc carbohydrat [2],
[3], [4], [8], [39].
1.2.7. Cc sn phm cha felodipin trn th trng:
Bng 1.4: Cc sn phm cha felodipin trn th trng
Tn thng mi
Plendil
Plendil Plus
Felodipin extended
release
Felodipin Stada 10mg
retard
Felop SR 5mg
Standard

Hm lng
2,5mg, 5mg

Nh sn xut
AstraZeneca

Felodipin 5 mg + metoprolol
succinat 47,5 mg
2,5mg;5mg;10 mg
10 mg

AstraZeneca
Mutual pharmaceutical
Co.inc
Stada VN
Standard Chem & Pharm

5 mg

Co., Ltd

Flodicar 5mg MR

5 mg

Pymepharco

Felodipin HEXAL

5 mg

HEXAL Pharma Ltd

Enfelo 5

5 mg

Aegis. Ltd

Felutam CR

5 mg

Vellpharm Vit Nam

1.3. Cc nghin cu v felodipin

1.3.1. Cc nghin cu ci thin tan ca felodipin
Chu Qunh Anh (2013) nghin cu nh hng ca cc cht mang PVP
K30, HPMC E5 LV, PEG 4000, PEG 6000 v nh hng ca poloxamer kt hp
vi cc cht mang n tan v ha tan ca felodipin trong HPTR. nh gi c
ch ci thin tan v ha tan bng nghin cu nhiu x tia X v phn tch nhit
vi sai. Kt qu, HPTR bo ch vi cc cht mang trn u c tan tng so vi
nguyn liu, cao nht l 2,7 ln vi HPTR felodipin:PEG 4000 t l 1:4. Khi kt
hp poloxamer v cc cht mang th tan v ha tan ca felodipin u tng ln,

27

cao nht l HPTR ca felodipin:PEG 4000:PLX t l 1:4:1,5 tng tan 3,5 ln

nguyn liu v ha tan sau 5 gi n 98,6% [1].
Murali Monohar Pandey v cng s (2012) nghin cu ci thin tan ca
felodipin bng phng php to HPTR bng phng php dung mi vi Soluplus,
l mt polyme phc ca polyvinyl caprolactum polyvinyl acetat PEG. H phn
tn rn c nh gi bng phn tch nhit vi sai (DSC), nhiu x tia X, quang ph
hng ngoi (FT-IR). Kt qu nghin cu ch ra tan ca felodipin trong hn hp
vt l v h phn tn rn vi Solupus u tng. H phn tn rn vi t l
felodipin:Soluplus (1:10) c tan felodipin tng gp 30 ln felodipin tinh khit.
Tc gi kt lun y l phng php rt hu ch ci thin tan v sinh kh dng
ca felodipin [27].
Krit Suknunthaa v cng s (2012) nghin cu bo ch HPTR felodipin
trong PVP K90 bng phng php bc hi dung mi, s dng dicloromethan v
ethanol vi cc t l khc nhau. Nghin cu phn tch nhit vi sai (DSC) cho thy
nhit chuyn ha thy tinh (Tg) ca HPTR felodipin/PVP thay i, chng t c
s tng tc gia felodipin v PVP, v Tg ca HPTR felodipin/PVP s dng h
dung mi dicloromethan:ethanol (5:5) l cao nht. Cc tc gi gii thch nguyn
nhn do mch PVP b ko di hn nn s tng tc vi felodipin tt hn. Nghin
cu quang ph hng ngoi (FT-IR) cng cho kt qu tng t. Cc tc gi kt
lun HPTR felodipin/PVP s dng h dung mi dicloromethan:ethanol (5:5) c
n nh tt nht, duy tr trng thi v nh hnh trong thi gian 2 thng [25].
B.Bhavani v cng s (2012) nghin cu bo ch phc h ca felodipin vi
betacyclodextrin(-CD) v hydroxypropyl -cyclodextrin(HP -CD) vi mc ch
tng t l ha tan v sinh kh dng ca felodipin. Phc h gm 2 thnh phn
felodipin-cyclodextrin theo cc t l khc nhau c bo ch bng cc phng php
khc nhau. nh gi c tnh ca phc h bng quang ph hng ngoi (FT-IR) v
nghin cu ha tan invitro theo USP XXII kt hp vi o quang bc sng
362 nm. Kt qu nghin cu ch ra rng h phc 2 thnh phn c th ci thin tan
ca felodipin t 2,5 120 ln, ph thuc vo c loi cyclodextrin s dng v

28

phng php tin hnh. Phc h ca felodipin - HP-CD t l 1:1 bo ch bng

phng php nho trn c tan cao nht v cao hn dc cht tinh khit [14].
Aniket Ashokbhai Ladani v cng s (2011) nghin cu ci thin tan v
ha tan ca felodipin bng k thut to phc vi cyclodextrin, s dng -CD v
HP -CD vi t l khc nhau v lng PVP K30 khc nhau. Kt qu nghin cu
DSC chng minh felodipin n cht chuyn sang trng thi to phc vi -CD
v HP -CD. Kt qu nghin cu gii phng invitro ch ra rng phc h felodipin v
HP -CD gii phng 95% dc cht trong 30 pht so vi felodipin ch gii phng
55%. Hn hp bao gm phc h ca felodipin v HP -CD vi s c mt ca PVP
K30 c t l ha tan tt hn so vi c felodipin v phc ca n vi HP -CD [11].
A.R. Tapas v cng s (2009) nghin cu ci thin t l ha tan ca
felodipin bng k thut ng t s dng aceton, nc v dicloromethan l dung mi
ha tan, dung mi khng ha tan v cht lng to cu tng ng. Kt qu nghin
cu FTIR v DSC ch ra khng c s thay i dc cht sau qu trnh kt tinh.
Nghin cu nhiu x tia X cho thy ph nhiu x ca vi cu c s gim chiu cao
ca cc pic. Kch thc vi cu khong 134,33 13,57m, n=3 v ha tan ca
felodipin tng 4 ln trong m phosphat pH 6,8 cha 1,8% Tween 80 trong 120
pht. Kt qu nghin cu ch ra k thut ng t ci thin ha tan ca
felodipin so vi bt thng thng, c th do s chuyn cc b t th kt tinh sang
th v nh hnh [12].
Lee KR v cng s (2008) chng minh nh hng ca HPMC v
poloxamer n ha tan ca felodipin v t pht trin dng vin nn kim sot
gii phng s dng ct polyme trng n. Cc tc gi ch ra rng vic nghin
felodipin v polyme lm tng nh t l ha tan so vi hn hp vt l. Kt qu
nghin cu nhiu x tia X cho thy felodipin vn duy tr dng tinh th sau khi
nghin cng vi poloxamer. Do vic tng t l ha tan sau khi nghin felodipin
cng HPMC hoc poloxamer c gy ra bi tc dng tng tan ca cc polyme
v c vic nghin. nh hng ca poloxamer nhiu hn so vi HPMC. T cc
tc gi nghin cu dng vin s dng poloxamer ci thin ha tan v
Carbopol l polyme to ct kim sot gii phng [26].
29

Bhanudas Shankar Kuchekara v cng s (2007) kho st s nh hng ca

HPMC, PVP, PEG 6000 ln tan v kh nng to phc h ca felodipin vi -CD
v HP-CD. Cc tc gi cho rng vic thm mt lng nh polyme thn nc (0,25
0,5%)rt hiu qu ci thin tan v kh nng to phc vi cyclodextrin v vy
ch cn t cyclodextrin hn tng tan cho felodipin. Tt c cc polyme nghin
cu trn u c tc dng tng tan ca felodipin - cyclodextrin bng cch tng
hiu qu phc hp ha. tan cao nht c ci thin ln 81,8% vi h 3 cht cha
-CD v 0,25% (w/v) PVP [13].
Vasilios I.Teberekidis v cng s (2007) nghin cu cc lin kt hydro
trong cc h phn tn rn ca felodipin vi cc polyme tan trong nc nh PVP
hoc PEG. Mc lin kt hydro trong h phn tn rn c th nh hng n kh
nng gii phng dc cht t h. Cc tc gi nhn thy felodipin c lin kt hydro
vi PVP mnh hn vi PEG, iu ny th hin s khc nhau v tc ha tan
felodipin t h phn tn rn s dng polyme khc nhau [44].
Evangelos Karavas v cng s (2006) nghin cu c ch gii phng dc
cht t HPTR ca felodipin v PVP K30 da trn tng quan lin kt hydro gia
chng v cng tng tc. H phn tn rn c to ra bng phng php dung
mi, s dng ethanol tuyt i ha tan PVP v felodipin. Tng tc c nh
gi bng ph cng hng t ht nhn (NMR) v ph UV. Nghin cu ch ra tng
tc gia PVP v felodipin xy ra tng ng vi s xut hin lin kt hydro v tng
tc tng ln ng k khi nng PVP cao hn 75%(w/w). Tc gi kt lun tng
tc lin kt hydro trong h phn tn rn felodipin/PVP l nguyn nhn chnh lm
tng ha tan ca felodipin v khi c nng th c tnh thn nc ca PVP
khng cn c ngha trong tng ha tan [22].
Eun-Jung Kim v cng s (2006) nghin cu ch to HPTR ca felodipin
v PVP, HPMC, poloxamer bng phng php dung mi. Kt qu nghin cu nhiu
x tia X v phn tch nhit ch ra felodipin chuyn sang trng thi v nh hnh
trong HPTR. ha tan ca felodipin trong cc HPTR cng tng so vi cc hn
hp vt l tng ng, ph thuc vo cht mang s dng v t l felodipin/cht
mang . Tc ra ch ra cht mang HPMC lm tng ha tan thp nht so vi PVP
30

v poloxamer. Trong khi s dng sorbitol v mannitol lm cht mang th

felodipin khng thay i dng th hnh v t l ha tan cng khng thay i [20].
E.Karavas v cng s (2001) nghin cu bo ch HPTR ca felodipin vi
NaCMC, HEC v HPMC vi cc t l khc nhau (50:50, 75:25, 90:10) bng
phng php dung mi. Tng tc gia dc cht v polyme c nghin cu bng
phng php phn tch nhit vi sai v ph IR. nh gi gii phng dc cht invitro
bng thit b th ha tan c a c nh, cnh khuy 100rpm, mi trng ha tan
500 ml 0,1M m phosphat pH 6,5 cha 2% Tween. nh lng hm lng
felodipin bng phng php quang ph UV bc sng 237 nm. Kt qu nghin
cu cho thy khng c s tng tc v phn hy ca dc cht sau thi gian bo
qun 3 thng nhit 40oC. Kt qu cng ch ra HPTR ca felodipin v HPMC
tc dng ko di v gii phng tuyn tnh hn vi HEC [21].
1.3.2. Cc nghin cu v cc dng gii phng ko di cha felodipin
1.3.2.1. Gii phng ko di theo c ch bm thm thu
Wichan Ketjinda v cng s (2011) nghin cu bo ch vin thm thu 2
lp gii phng theo c ch ko y (PPOP) cha felodipin s dng phc h
polyme chitosan (CS) v polyacrylic acid (PPA) nh l polyme thm thu
(osmopolymer), nghin cu c ch gii phng dc cht ca vin. nh lng hm
lng felodipin trong vin bng phng php HPLC theo chuyn lun trong USP
31, nghin cu gii phng dc cht invitro bng thit b th ha tan t ng , c
kt ni vi my o quang ph hp th bc sng 362 nm. Kt qu nghin cu cho
thy dc cht gii phng t h PPOP theo ng hc gii phng bc 0 v c th ko
di ln 12-24 gi ph thuc vo cht ha do s dng, s dng cht ha do l
dibutyl sebacate c thi gian lag-time di hn v gii phng dc cht chm hn s
dng PEG 400. Trong trng hp s dng PEG 400, tng t l CS s lm tng t l
gii phng dc cht. Lc dp khng c nh hng n gii phng dc cht t h
PPOP. Tc gi cng gii thch c ch gii phng dc cht c iu khin bi 2
c ch ni tip nhau: bm thm thu y lp dc cht trong vin v sau qu
trnh n mn v ho tan lp dc cht trong mi trng ha tan. Tc gi cng

31

chng minh c tnh tng ng gia d on v kt qu thu c da trn m

hnh ton hc ng hc bc 0 [46].
1.3.2.2. Gii phng ko di theo cc c ch khc
L Huy Ngh (2013) nghin cu bo ch vin nn felodipin 5 mg gii
phng ko di. Tc gi s dng PVP K30 v poloxamer lm cht mang trong
HPTR theo t l felodipin:PVP:PLX l 1:9:1,5 bng phng php dung mi. Kt
hp vi HPMC E4M v HPMC K4M kim sot gii phng. Kt qu nghin cu
cho thy HPTR vi PVP v poloxamer ci thin tan v ha tan ca felodipin
v CT11 c bo ch bng phng php dp thng cho d liu ha tan gn ging
vin i chiu Plendil 5mg nht (f2=75,54%). Tc gi cng chng minh t l t
dc trn v lc dp khng nh hng n tc gii phng dc cht [7].
S. Kiran Kumar v cng s (2013) nghin cu bo ch vin felodipin gii
phng 24h s dng ct s nc l glyceryl monostearat v sp Carnauba. Mu vin
c nh gi ng u khi lng, cng, gii phng invitro. Nghin cu
FT-IR, DSC s dng nh gi tng tc gia dc cht v t dc. Cc tc gi
a ra 1 cng thc ti u nht, gii phng 100% felodipin sau 24h. Cc tc gi
kt lun dc cht gii phng theo m hnh ng hc Higuchi, theo c ch khuch
tn v n mn [37].
Bhanu P Sahu v cng s (2011) nghin cu dng thuc dng qua ng
mi bng ct thn nc cha felodipin tng sinh kh dng. Dc cht c cha
trong gel HPMC trng n. Cc c tnh l ha ca gel c nh gi nh pH ca
gel, nht, nng dc cht, tc thm qua mng. Kt qu nghin cu cho
thy ct HPMC c hnh thi b mt tt, cho hiu qu thm dc cht qua nhanh.
nht ca gel nm trong khong thch hp khi dng qua ng mi. Cng thc gel
cha PEG 400 c tc thm nhanh hn cng thc cha Tween 80. Nghin cu
ph FT-IR v phn tch nhit vi sai(DSC) cho thy khng c tng tc gia HPMC
v felodipin. Kt qu ch ra tnh kh thi ca vic pht trin h ct thn nc gii
phng felodipin qua ng mi v ci thin sinh kh dng ca thuc [15].
Rares I.Iovanov v cng s (2009) nghin cu nh hng ca cc yu t
n qu trnh gii phng felodipin t vin gii phng ko di dng ct thn nc.
32

Cc polyme c s dng l HPMC v PEO. S dng phn mm ti u ha Modde

6.0 thit k th nghim. Cc bin c lp bao gm: t l phn trm cc polyme,
loi HPMC v t l gia cc polyme trong vin. Nghin cu kt lun yu t quan
trng nht nh hng ti gii phng felodipin l t l polyme thn nc (HPMC v
PEO) trong vin, nu tng t l polyme s ko di ng k thi gian gii phng
felodipin t vin. Cc tc gi cng bo ch c 1 cng thc ti u nht c s
gii phng felodipin tng t nh vin i chiu Plendil 10mg v ko di gii
phng invitro ln n 10 gi [34].
Pradeep R.Patil v cng s (2009) nghin cu bo ch h t to nano nh
tng (SNES) cha felodipin nhm mc ch tng ha tan ca felodipin. Kt qu
ch ra, t l khi lng cht du:cht din hot:cht ng din hot l 3,5:1:1 tng
ng c kh nng nh tng ha tt, kch thc tiu phn trung bnh 421 nm v gii
phng nhanh (>90% trong 15 pht). ko di gii phng, gel SNES c bao
bng mt cht khng thm nc Gelucire43/01(GEL) vi Caprol PGE 860
(CAP) c thm vo mng bao tng gii phng dc cht. nh gi nh hng
ca tc nhn to gel Aerosil200(A200) v tc nhn tng gii phng(CAP) cho
thy CAP c tc dng nh nh knh to ra trong mng GEL gii phng dc
cht v A200 ko di gii phng bng cch to th gel. Cc tc gi kt lun pht
trin h gel SNES bao trong GEL c th c ng dng gii phng ko di cc
dc cht thn du khc [30].
Rares I.Iovanov v cng s (2008) nghin cu bo ch v ti u ha vin
gii phng ko di dng ct cha felodipin s dng Kollidon SR, so snh vi vin
i chiu Plendil 10 mg. Thit k th nghim vi 2 bin c lp l phn trm
Kollidon SR s dng v t dc n, vi 3 mc khc nhau mi bin. Tin hnh
bo ch cc mu vin, nh gi cc c tnh ca cc vin bo ch c ( cng,
mi mn, gii phng dc cht invitro). Kt qu nghin cu ch ra phn trm
Kollidon SR nh hng ln nht n gii phng dc cht. T cc d liu th
nghim, cc tc gi cng ti u ha c 1 cng thc bo ch c c tnh gii
phng tng t sn phm i chiu (cha 31% Kollidon SR v Ludipress l t dc
n), c h s f2=66,23 [35].
33

Jeong-Sook Park v cng s (2007) nghin cu nh gi v pht trin cc

pellet bao mng Eudragit da trn th nghim ha tan s dng phng php cnh
khuy. Hai loi Eudragit (RS v RL) c s dng cho 2 dng gii phng ko
di v gii phng nhanh. Kt qu cho thy ha tan felodipin 30 pht t pellet
bao Eudragit RS v RL tng ng l 0,96% v 99,6%. Tc gi ch ra t l mng
bao l yu t chnh nh hng n t l gii phng v tm ra 1 t l Eudragit RS
30D ti u nht c ha tan tng t nh sn phm i chiu Plendil [24].
1.3.3. Cc nghin cu khc
Mn Vn Hng (2013) nghin cu bo ch HPTR ca felodipin vi cc
cht mang PVP K30, PEG 4000, HPMC E6 v xy dng cng thc vin nn r
nhanh t HPTR . Tc gi kt lun HPTR ca felodipin vi cht mang HPMC E6
t l 1:3 bng phng php dung mi c ha tan tt nht. HPTR c nh gi
bng nghin cu ph hng ngoi IR v phn tch nhit vi sai chng minh c ch
ci thin ha tan felodipin l s chuyn sang trng thi v nh hnh. nh gi nh
hng ca cc loi t dc, phng php bo ch, kch thc chy ci, cng ti
thi gian r ca vin nn. S dng phn mm MODDE 8.0 thit k th nghim v
INFORM 3.1 ti u ha tc gi a ra c mt cng thc ti u c tc
gii phng sau 5 pht l 87,141,35%, thi gian r 26,671,15 giy, mi mn
0,3% [6].
D SandeepKumar v cng s (2011) nghin cu bo ch vin r nhanh
cha felodipin bng phng php dp thng s dng cc t dc crosspovidon ,
avicel v manitol iu v. Cc c tnh ca vin c nh gi bao gm cng,
mi mn, ng u hm lng, thi gian thm m, t l hp th nc v thi
gian r invitro. Da trn thi gian r invitro (xp x 8 14 giy) chn ra c 1
cng thc nh gi gii phng dc cht invitro v nghin cu tng tc dc
cht t dc bng ph IR. Kt qu ch ra cng thc c cha 2% crospovidon v
15% MCC c kt qu gii phng 98,751,42% dc cht trong 10 pht, t l hp
th nc 70,55 0,44%, thi gian r Invitro 10,020,15 giy [19].
Sagar Balaso Sangale v cng s (2011) nghin cu bo ch vi cu ni
cha felodipin bng phng php bc hi dung mi. Vi cu to ra c nh gi
34

kh nng gi dc cht, t trng, gc ngh, kch thc tiu phn v gii phng dc
cht invitro. Kt qu nghin cu ch ra kch thc ca vi cu trong khong 130
140nm. nh chp knh hin vi v kin hin vi in t qut cho thy cc tiu phn c
hnh dng hnh cu. Hm lng dc cht trong vi cu t 86 88%, v c th gii
phng ko di ln n 8 gi [36].
Hariprasanna R.C v cng s(2010) nghin cu bo ch vin gii phng
nhanh cha felodipin s dng t dc siu r natri croscarmelose v h phn tn rn
s dng polyvinyl alcohol (PVA) l cht cht mang. Trc khi dp vin cc ch s
gc ngh, % h s nn, h s Houness c nh gi. Sau khi dp vin cc ch s v
cng, mi mn, thi gian r invitro, thi gian ht m v gii phng dc cht
invitro c nh gi. Nghin cu n nh c tin hnh theo hng dn ca
ICH trong thi gian 3 thng. Kt qu nghin cu ch ra vin c to bi HPTR
ca felodipin vi cht mang PVA t l 1:9 c kt qu tt nht, tc ha tan invitro
nhanh nht( t90%= 5,32 0,42). nh gi n nh cng cho thy cc ch s trn
khng thay i sau thi gian bo qun [23].
Raghavendra Rao N.G v cng s (2010) nghin cu bo ch vin
felodipin gii phng nhanh bng phng php dp thng, s dng cc k thut khc
nhau: dp thng felodipin v cc t dc, to HPTR ca felodipin ri mi dp thng
v k thut thng hoa camphor. Nghin cu nhiu x tia X v quang ph FT-IR ch
ra rng tt c cc h phn tn rn u c dng v nh hnh v khng c tng k
gia dc cht v cc t dc s dng. Cc tc gi kt lun t l ha tan ca
felodipin c th c ci thin bng phng php bo ch cha HPTR ca felodipin
v PVP (1:4), PEG (1:4) hoc manitol (1:9) hoc bng k thut thng hoa camphor
th vin cha 40% camphor c t l ha tan tt nht [31].
Raghavendra Rao N.G v cng s (2010) nghin cu bo ch vin gii
phng nhanh s dng ng thi cc t dc siu r bng phng php bc hi dung
mi. Crospovidon v natri starch glycolat c s dng theo cc t l khc
nhau(1:1, 1:2 v 1:3). Trong cc cng thc bo ch, cng thc cha 4% (w/w) h
ng siu r (t l crospovidon v natri starch glycolat l 1:1) cho kt qu tt nht,
c thi gian gii phng 50% dc cht (t50%) l 1,97 pht. Nghin cu n nh
35

cho thy khng c s thay i ng k no v nng dc cht v thi gian phn

tn invitro (p<0,05). Cc tc gi kt lun ha tan ca felodipin c th c ci
thin trong vin gii phng nhanh bng cch s dng ng t dc siu r [32].
Upendra Kulkarni v cng s (2010) nghin cu dng bo ch t di li
bng phng php khun. nh lng hm lng felodipin trong mi mnh 11
cm2 bng phng php o quang bc sng 362 nm trong dung dch m
phosphat pH 6,5 cha 0,1% SLS. Kt qu nghin cu cho thy cc film ngm di
li m bo cc c tnh v ton vn, s mm do, phn tn dc cht v cc ch
tiu cht lng khc. Kt qu ch ra 25,54% dc cht c hp thu qua nim mc
li trong 5 pht liu s dng 5 mg. Nghin cu gii phng dc cht invitro cc
cng thc cho kt qu gii phng t 71,68% n 97,27% trong 90 pht. Kt qu
nghin cu n nh cho thy hm lng dc cht gim t 1,15 1,9% khi bo
qun 402oC, m 755% trong 30 ngy [43].
Chinna Reddy Palem v cng s (2010) nghin cu bo ch mng kt dnh
nim mc ming 2 lp gii phng felodipin di li bng k thut khun.
Cc tc gi a ra 1 cng thc c t l gii phng dc cht 94,6% theo ng
hc gii phng bc 0, tnh thm 41,6% dc cht vi lu lng 0,113 mg/h/cm2 qua
mng di li ln. Nghin cu ph FTIR cho thy khng c bt k tng tc no
gia felodipin v cc polyme. Nghin cu n nh cho thy c dc cht v
mng u n nh trong dch nc bt ngi [18].
Nh vy, phn ln cc nghin cu tp trung nghin cu ci thin tan v ha
tan ca felodipin trc khi a vo dng bo ch v phn ln theo hng bo ch
HPTR ca felodipin vi cc polyme thn nc. Cc nghin cu v dng gii phng
ko di cng rt hn ch, ch yu s dng ct polyme thn nc. Do , nghin cu
bo ch vin thm thu felodipin gii phng ko di theo c ch ko y l mt
hng mi, c tnh kh thi cao to ra mt dng bo ch kim sot qu trnh gii
phng dc cht c tnh n nh cao v c nhiu ngha lm sng.
Chng 2: I TNG V PHNG PHP NGHIN CU
2.1. Nguyn vt liu v thit b

36

2.1.1. Nguyn vt liu

Bng 2.1: Nguyn vt liu
STT

Tn nguyn liu

Ngun gc

Tiu chun

Felodipin

Trung Quc

USP 32

Gm Xanthan

Trung Quc

USP 32

Disolcel

Trung Quc

NSX

Natri starch glycolat

Trung Quc

BP

Crospovidon

NSX

Natri clorid

Vit Nam

DVN IV

PVP K30

Trung Quc

BP

Avicel pH 101

Trung Quc

BP

Lactose

Vit Nam

BP

10

Magnesi stearat

Vit Nam

BP

M (Colorcon)

NSX

M (Colorcon)

NSX

M (Colorcon)

NSX

11
12
13

PEO 200.000 (POLYOX

WSR N-80)
PEO 5.000.000 (POLYOX
WSR Coagulant)
PEO 7.000.000 (POLYOX
WSR 303)

14

Cellulose acetat (Opadry CA)

M (Colorcon)

NSX

15

Oxid st

Trung Quc

NSX

16

Aceton

Trung Quc

Tinh khit ha hc

17

Ethanol 90%

Vit Nam

DVN IV

18

Nc ct

Vit Nam

DVN IV

2.1.2. Thit b
- My dp vin tm sai Korsch (Php), b chy ci ng knh =9 mm
- My bao phim t ng Vanguard
- Thit b khoan laze EPILOG Helix

37

- Cn phn tch Mettler Toledo AB 204S (Thy S)

- Cn k thut Sartorius TE 3102 S (c)
- My quang ph UV VIS Hitachi U1800 (Nht Bn)
- H thng sc k lng hiu nng cao (HPLC)
- My th ha tan ValKen Varian 7010
- My o pH InoLab PH 730
- My o m Precisa XM 60 (Thy S)
- My o cng vin nn ERWEKA TBH 20 (c)
- My th mi mn ERWEKA TA 10
- T sy tnh
- Ry, bt s, dng c thy tinh cc loi v.v
2.2. Phng php nghin cu
2.2.1. Phng php bo ch vin nhn
Bo ch vin nn 2 lp, mi m 100 vin:
-

Phng php bo ch lp dc cht: xt ht t

+ Nghin, ry cc nguyn liu qua ry 0,18 mm. Cn felodipin v cc t dc.

+ Phn tn felodipin vo dung dch ethanol 90%, khuy 5 pht cho felodipin tan
ti a
+ Cho PVP K30 vo dch trn, khuy trn cho n khi PVP tan ht
+ Nho m hn hp bt t dc v dch trn trong ci s. Xt ht qua ry 0,8 mm
+ Sy ht 40 50oC n khi ht c m t t 1- 3%, sa ht qua ry 0,6 mm.
+ T dc trn c nghin, ry qua ry 0,18 mm. Trn t dc trn vi cm thu
c sau khi sa ht.
-

Phng php bo ch lp y: Nghin, ry cc nguyn liu qua ry 0,18 mm

Cn cc t dc lp y, trn u hn hp bt theo nguyn tc trn bt kp. Hn

hp bt c em dp thng.
-

Dp vin: Dp vin 2 lp bng my dp vin tm sai Korsch vi chy ci ng

knh =9 mm.

38

+ Cn lp dc cht cho vo ci, dp s b lp dc cht. a chy trn ra khi

ci nhng khng y chy di ln, lp dc cht vn nm trong ci
+ Cn lp y, cho vo trn lp dc cht, dp hon ton vin thu c vin nn 2
lp
+ iu chnh lc dp cng vin trong khong 10 12kP.
2.2.2. Phng php bao phim
a) Chun b dch bao phim:
Opadry CA (CA:PEG 3350=9:1)

Cng thc dch bao:

Nc ct

14 g
6,7 g

Aceton

300 ml

Dch bao c chun b theo phng php sau:

+ Ha tan nc ct v aceton vi nhau thnh hn hp dung mi
+ Rc t t bt Opadry CA vo hn hp dung mi
+ Khuy trn lin tc bng my khuy t trong 1h n khi polyme tan ht v duy
tr khuy trn trong sut qu trnh bao.
b) Tin hnh bao phim:
S dng my bao phim t ng, mi m bao khong 0,5 kg gm 50 vin th v cc
vin tr n thm. Theo di khi lng vin tng ln trong qu trnh bao. Sau khi
bao xong n nh mng bao 24h 40oC. Cc thng s ca qu trnh bao:
+ Nhit gi vo: 50oC
+ Nhit gi ra: 40oC
+ Tc ni bao: 15 vng/pht
+ Vn tc gi vo: 12m3/h
+ Vn tc gi ra: 15m3/h
+ Tc bm dch nhu ng: 15 vng/pht
+ p sut kh nn phun dch bao: 8 Pa
c) Phng php tnh khi lng mng bao:
Khi lng mng bao l phn khi lng vin tng ln sau khi bao mng.
Phn trm khi lng tng ca vin trc v sau khi bao c tnh theo cng thc:

39

h=

m1 m2
100%
m1

Trong : m1, m2 ln lt l khi lng vin trc v sau khi bao (mg)
2.2.3. Phng php to ming gii phng dc cht
Vin sau khi bao t c dy mng bao thch hp c n nh mng bao
24h nhit 40oC, sau tin hnh khoan ming gii phng dc cht bng thit
b khoan laze EPILOG Helix. Ci t thng s ng knh l khoan mong mun,
iu chnh tc bn tia v cng tia laze to c ming gii phng theo
yu cu.

Hnh 2.1: Nguyn tc khoan laze

2.2.4. Phng php nh gi
2.2.4.1.

Phng php phn tch nng lng nhit vi sai

Nhm xc nh trng thi ca felodipin nguyn liu, hn hp bt v ht trc khi

dp vin. S dng thit b DSC vi cho nhm cha mu 40 l, c thng np,
khi lng mu t 1 20 mg. Nhit qut t 25 190oC, tc gia nhit
10o/pht. Trong qu trnh th, thi nit vi lu lng 50 ml/pht.
2.2.4.2. Phng php nh gi cng ca vin nhn
+ Thc hin bng my o cng Erweka THB 20.
+ t tng vin dc theo ng knh vin, tc ng 1 lc qua ng knh vin n
lc vin b v, ghi li lc gy v vin.
+ Thc hin vi 12 vin
Yu cu: cng nm trong khong 10 12kP

40

2.2.4.3. Phng php nh gi mi mn vin nhn

+ Ly 20 vin bt k, ry loi bt dnh vin, cn tng khi lng c m1 (g).
+ Cho vin vo trng quay, quay 100 vng vi tc 25 vng/pht.
+ Ly vin ra, ry loi bt mn. Cn li khi lng vin sau khi ry c m2 (g).
+ Thc hin 3 ln ly gi tr trung bnh.
+ Tnh mi mn vin theo cng thc:
mi mn =

m1 m2
100%
m1

Yu cu: mi mn <1%
2.2.4.4. Phng php nh lng
nh lng felodipin trong vin bng phng php HPLC theo dc in M USP
35.
-

Dung dch m: ha tan 6,9 g natri dihydro phosphat khan trong khong 800 ml
nc ct trong bnh 1000 ml, iu chnh pH bng dung dch acid phosphoric n
pH=3,00,05, b sung nc n th tch, khuy trn.

Pha ng: Hn hp dung dch m: acetonitrile: methanol (2:2:1).

Dung dch chun: Cn chnh xc 1 lng felodipin khong 20 mg, ha tan trong
100 ml methanol, em siu m trong 5 pht. Ht chnh xc 10 ml dung dch
bng pipet vo bnh nh mc 100 ml, pha long bng hn hp pha ng n
th tch c dung dch c nng khong 20 g/ml. Lc qua mng PTFE
0,45 m, b 4 ml dch lc u.

Dung dch th:

Chun b dung dch th:
+ Nghin mn 10 vin bng my nghin bi. Cn lng bt tng ng khong 10
mg felodipin. Ha tan vo 40 ml acetonitrile, 20 ml methanol trong bnh nh
mc 100 ml. em siu m 5 pht. Thm khong 30 ml dung dch m. Lc u
khong 30 pht. B sung dung dch m n va th tch 100 ml.
+ em 1 phn i ly tm tc 5.000 vng/pht trong 15 pht, gn ly dch
trong trn.

41

+ Ly 10 ml dung dch trong bng pipet vo bnh nh mc 50 ml, b sung pha

ng n va th tch.
+ Lc qua mng lc PTFE 0,45 m, b 4 ml dch lc u
- iu kin HPLC:
+ Ct C18: 4,6 mm 15 cm, nhi ht L1(5 m)
+ Tc dng: 1 ml/pht
+ Detector 362 nm
+ Th tch tim mu: 40 l
-

Tnh hm lng felodipin trong vin so vi nhn theo cng thc:!

Trong :
mchun: l khi lng felodipin chun
mtb: l khi lng trung bnh 10 vin th
mcn: l khi lng cn mu th
Sth,Schun l din tch pic thu c t dung dch th v dung dch chun tng ng.
2.2.4.5. Phng php nh gi b mt mng bao
Phng php chp knh hin vi in t qut (SEM), quan st b mt mng bao,
nh gi ng u mng bao, s khc nhau trc v sau khi gii phng dc
cht.
2.2.4.6. Phng php o ng knh ming gii phng dc cht
S dng knh hin vi quang hc, o vt knh 4x o ng knh ming gii
phng dc cht s dng 1 ngun sng chiu t trn xung. Tin hnh o 12 vin,
tnh gi tr trung bnh, RSD.
2.2.4.7. Phng php nh gi kh nng gii phng dc cht
- iu kin: S dng thit b th ha tan t ng VanKen Varian 7010.
+ Thit b cnh khuy, 6 cc th, ch th vin bng tay, lp thm gi ng
vin.

42

+ Nhit mi trng: 370,5oC

+ Tc cnh khuy: 50 vng/pht
+ Thi gian th 24 gi, thi gian ht mu 1gi/ln, thi gian bm 120 giy/ln
+ Mi trng th ha tan: 500 ml dung dch m phosphat 0,1M pH 6,5 c 1%
natri lauryl sulfat
+ o quang bc sng 238 nm
-

Dung dch chun nng 10 g/ml:

Cn chnh xc khong 10 mg felodipin vo bnh nh mc 100 ml, thm 80 ml
dung dch m phosphat 0,1M pH 6,5 c 1% natri lauryl sulfat, siu m 45 pht.
B sung thm m cho va th tch, lc u. Lc qua giy lc th, b 20 ml
dch lc u. Ht chnh xc 10 ml dch lc bng pipet vo bnh nh mc 100
ml, thm m th tch, lc u c dung dch felodipin chun 10 g/ml.

Mu trng: dung dch m phosphat 0,1M pH 6,5 c 1% natri lauryl sulfat

Phn trm dc cht gii phng ti mi thi im c tnh theo cng thc:
%gii phng=

( D D0 ) mchuan M lt
100 (%)
( Dchuan D0 ) 2 mlt M tt

Trong :
D0, Dchuan, D: hp th ca mu trng, dung dch chun, dung dch th.
mchuan, mlt:

Khi lng felodipin chun, khi lng l thuyt trong vin.

Mlt,Mtt: Khi lng vin theo l thuyt, khi lng vin thc t
-

Ti nhng thi im gii phng u tin, nh lng felodipin gii phng trong
mi trng ha tan bng phng php thm chun: Ti mi thi im ly mu
ht 10 ml dch ha tan, pha long vi 10 ml dung dch chun 10 g/ml, lc qua
giy lc, o quang dch lc bc sng 238 nm. Tin hnh o quang song song
1 mu chun nng 10 g/ml. T kt qu o quang tnh ton nng
felodipin trong dch ha tan v tnh t l felodipin gii phng.

43

Hnh 2.2: Gi ng vin [42]

-

Yu cu v ha tan theo Test 1 - USP 35:

Bng 2.2.: Yu cu v ha tan theo Test 1 USP 35
Thi gian (gi)
2
6
10

Lng dc cht gii phng

10% - 30%
42% - 68%
75%

2.2.4.8. Phng php nh gi ng hc gii phng

-

Phng php so snh 2 ng cong gii phng:

S dng ch s f2: th hin s ging nhau ca 2 ng cong gii phng dc cht,

c quy nh bi C quan qun l thuc v thc phm M (FDA) v C quan
nh gi cc sn phm y hc Chu u (EMEA ) a ra:

Trong :
n

: S im ly mu

Ri, Ti : % gii phng dc cht ti thi im i ca mu i chiu v mu th.

44

Gi tr f2 cng gn 100 th 2 th cng ging nhau, f2 = 100 khi 2 th ging

nhau hon ton, f2 = 50 th s sai khc trung bnh ti mi im l 10%, f2 nm trong
khong 50 100 th 2 th c coi l ging nhau.
-

Nghin cu m hnh ng hc gii phng

S dng phn mm Splus 8.0, phn tch d liu ha tan ca cc cng thc theo m
hnh ng hc bc 0, bc 1, Higuchi, Weibuill, Hixson Crowell, Korsmeyer
Peppas. Cn c vo gi tr AIC xc nh m hnh gii phng ph hp vi dng bo
ch nht. Cng thc tnh gi tr AIC:
Trong : n c mu; phng sai; p s tham s trong m hnh.
So snh gi tr AIC khi khp vo cc m hnh ng hc, gi tr AIC nh nht tng
ng vi m hnh ph hp nht.
Cc m hnh ng hc:
+ ng hc bc 0:

Qt = Q0 + K0t

Trong : Q0: lng thuc gii phng ban u

Qt: lng thuc gii phng thi im t
k: hng s tc gii phng bc 0
+ ng hc bc 1:
Trong :

C = Cn(1 e-kt)

C: % gii phng thi im t

C0: % gii phng thi im tv cng(100%)
K: hng s tc gii phng bc 1

+ M hnh Weibuill: %Q=100*(1-e(-k*t^n))

+ M hnh Higuchi:

Q t = KH

KH hng s gii phng theo ng hc Higuchi

+ M hnh Hixson Crowell: Q = Q0(1-(1-Kst)3)
Trong : Q: lng thuc gii phng ti thi im t
Q0: lng thuc ban u
Ks: hng s lin quan n b mt din tch
+ M hnh Korsmeyer Peppas: Qt/Q = Kktn
45

n: h s gii phng
Cn c vo cc gi tr ca h s gii phng n c th xc nh c ch gii phng
thuc
Bng 2.3: Gii thch c ch gii phng thuc theo h s n
T l theo hm ca thi
H s gii phng (n)
C ch vn chuyn thuc
gian
0,45
Khuch tn theo nh lut Fick
t-1/2
0,45< n < 0,89
Vn chuyn khng theo quy tc
tn-1
0,89
Vn chuyn theo trng hp II
ng hc bc 0
n > 0,89
Siu vn chuyn trng hp II
tn-1

46

Chng 3: KT QU NGHIN CU
3.1. Xy dng ng chun
3.1.1. Phng php o quang ph hp th UV - VIS
Pha cc dung dch felodipin c nng khc nhau, t 0,5 g/ml n 10,0 g/ml
trong mi trng m phosphat 0,1M pH 6,5 c 1% natri lauryl sulfat; o quang
bc sng =238 nm.
Tin hnh: Cn chnh xc 10mg felodipin vo bnh nh mc 100 ml, thm
khong 80 ml mi trng ha tan. Lc u, siu m trong 45 pht. B sung thm
dung dch m ti th tch. Lc u, lc qua giy lc, b 20 ml dch lc u. Pha
long bng dung dch m c cc dung dch felodipin c nng chnh xc
0,5; 2; 4; 6; 8; 10 g/ml. o mt quang ca cc dung dch ny bc sng 238
nm. Kt qu thu c bng 3.1 v hnh 3.1.
Bng 3.1: S ph thuc mt quang v nng felodipin o bc sng 238 nm
STT

Nng C(g/ml)

Mt quang(D)

0,5

0,040

0,087

0,166

0,240

0,307

10

0,384

Hnh 3.1: th biu din mi tng quan gia nng felodipin v mt quang
o ti bc sng 238nm.
47

Nhn xt: T th ta thy nng felodipin trong dung dch m phosphat 0,1M
pH 6,5 c 1% natri lauryl sulfat v mt quang ti bc sng 238 nm c s tng
quan tuyn tnh trong khong nng kho st t 0,5 g/ml n 10,0 g/ml vi h
s tng quan R2 1. Nh vy, c th s dng phng php o quang bc sng
238 nm nh lng hm lng dc cht gii phng ra mi trng ha tan l
m phosphat 0,1M pH6,5 c 1% natri lauryl sulfat.
3.1.3. Phng php HPLC
Tin hnh pha dy dung dch chun felodipin chun c nng 10, 15, 20, 25,
30 g/ml, chy sc k cc dung dch chun ny vi cc iu kin theo mc 2.2.4.4.
Kt qu c trnh by trong bng 3.2 v hnh 3.2.
Bng 3.2: S ph thuc din tch pic v nng felodipin trong phng php
HPLC
STT

Nng C(g/ml)

Din tch pic(mAU.s)

10

1.490.559

15

2.335.831

20

3.181.118

25

3.716.397

30

4.661.662

Hnh 3.2: th biu din mi tng quan gia nng v din tich pic
48

Nhn xt
T th ta thy c s tng quan tuyn tnh gia nng felodipin v din
tich pic thu c trong khong nng 10 30 g/ml, vi h s R2 1. Nh vy c
th s dng phng php HPLC nh lng cc dung dch felodipin c nng
trong khong trn bng phng php HPLC.
3.2. Nghin cu ci thin ha tan felodipin
Theo cu to ca vin thm thu ko y, vin nhn l vin nn 2 lp, trong
felodipin trong lp dc cht s c y ra ngoi mi trng ha tan dn dn
khi polyme trong lp y ht nc v trng n. Do dc cht felodipin rt t tan
trong nc, nn gii phng ht dc cht phi ci thin ha tan felodipin
trong lp dc cht. La chn t dc PVP K30 va c tc dng ci thin ha
tan va lm t dc dnh trong phng php xt ht t. Tin hnh nghin cu 2
yu t nh hng l phng php bo ch v t l t dc tng ha tan.
3.2.1. nh hng ca phng php bo ch ti ha tan felodipin
nh gi nh hng ca phng php bo ch ti ha tan felodipin, tin
hnh bo ch cc mu vin nn c cc thnh phn sau:
Felodipin

mg

PVP K30

mg

Avicel PH 101

80

mg

Magnesi stearat

0,5

mg

Ethanol 90%

0,05 ml

Phng php 1: xt ht t vi t dc dnh l dung dch PVP/ethanol 90% (N1)

Phng php 2: xt ht t vi t dc dnh l hn hp felodipin v PVP c
phn tn trong ethanol 90% (N2).
Dp cc vin nn c cng 7 8 kP.
Tin hnh th ha tan theo mc 2.2.4.7. Kt qu th ha tan c trnh by
trong bng 3.3 v hnh 3.3:

49

Bng 3.3: T l dc cht gii phng(%SD) t cc mu N1, N2 (n=3)

Mu

Thi gian(pht)
0

N1

N2

10

15

20

25

30

35

40

30,1

60,2

70,0

72,6

73,2

74,1

75,0

75,4

2,5

3,2

3,5

3,6

2,8

3,4

3,0

2,4

51,0

92,8

97,2

98,1

99,0

100,0

2,4

2,5

3,1

3,2

2,6

3,6

Hnh 3.3: th biu din % felodipin gii phng t cc mu vin N1, N2

Nhn xt
Kt qu nghin cu cho thy phng php bo ch nh hng ti tc gii
phng dc cht. Mu N2 gii phng hon ton dc cht sau 30 pht trong khi
mu N1 ch gii phng 74,1%. C th gii thch do phng php 2 thay th cho
bc ch to h phn tn rn ca felodipin bng phng php dung mi, tng t l
felodipin chuyn t trng thi kt tinh sang v nh hnh, do vy tan ca
felodipin cng tng ln. Gin DSC (Ph lc 3) ca cm N2 cng chng minh
iu ny: ng DSC ca cm N2 mt pic thu nhit ca felodipin ti im chy
145oC, chng t felodipin c s chuyn dng t kt tinh sang v nh hnh. Nh
vy, phng php xt ht t vi t dc dnh l hn hp felodipin v PVP c
phn tn trong ethanol 90% ci thin ha tan ca felodipin.
3.2.2. nh hng ca t l PVP/felodipin ti ha tan felodipin
50

 nh gi nh hng ca t l PVP/felodipin ti ha tan ca felodipin tin

hnh bo ch cc mu vin N3, N4 trong thay i t l PVP/felodipin t
0,5/1(N3); 2/1(N4) theo phng php 2 trn, so snh vi mu vin N2(1/1).
Kt qu th ha tan c trnh by bng 3.5 v hnh 3.4 sau:
Bng 3.4 : Thnh phn cng thc lp dc cht mu N3, N4, N5
Cng thc

T dc

N2

N3

N4

Felodipin (mg)

PVP K30 (mg)

2,5

10

Avicel pH101 (mg)

80

82,5

75

Magnesi stearat (mg)

0,5

0,5

0,5

Bng 3.5: T l dc cht gii phng (%SD) t cc mu N2, N3, N4(n=3)

Thi gian (pht)

Mu

10

15

20

25

N2

51,12,3 92,83,1 97,22,4 98,24,5 99,04,2 1001,2

N3

29,02,2 58,53,5 75,43,4 80,63,6 81,53,5 822,1

N4

30,83,0 71,92,6 84,73,6 86,54,0 87,52,3 88,13,6

Hnh 3.4: th biu din % felodipin gii phng t cc mu N2,N3,N4

51

30

Nhn xt
Kt qu nghin cu cho thy t l PVP/felodipin nh hng ti tc gii
phng felodipin t cc mu vin. Mu N2 vi t l PVP/felodipin l 1/1 c tc
ha tan cao nht, sau 30 pht gii phng 100% dc cht. T l PVP/felodipin
cao hn hay thp hn u lm gim ha tan ca felodipin. C th gii thch khi
lng PVP cng tng th lng felodipin dng kt tinh cng gim, dng v nh
hnh cng nhiu, do mu N2 c ha tan cao hn mu N3. Nhng khi PVP
tng nhiu th ha tan li c xu hng gim, c th do tng nht, tng lin
kt hydro gia felodipin v PVP, lm gim ha tan ca felodipin. Nh vy, t l
PVP/felodipin thch hp nht trong nghin cu l 1/1.
3.2.3. nh hng ca PEO 200.000 n ha tan ca felodipin
PEO 200.000 l polyme thn nc, c khi lng phn t thp nn c th ci
thin ha tan dc cht t tan trong nc. nh gi nh hng ca PEO n
ha tan ca felodipin tin hnh bo ch mu vin N5 c thnh phn nh sau theo
phng php xt ht t vi t dc dnh l PVP/ ethanol 90%.
Felodipin

mg

PVP K30

mg

PEO 200.000

90

mg

Magnesi stearat

0,5

mg

Ethanol 90%

0,05 ml

Tin hnh th ha tan theo mc 2.2.4.7. So snh kt qu th ha tan vi

mu N1, N2. Kt qu c trnh by trong bng 3.6 v hnh 3.5:
Bng 3.6: T l dc cht gii phng (%SD) t cc mu N5 (n=3)
Thi
gian(pht)
% gp
Thi
gian(pht)
% gp

172,0

35

40

89,23,5

10

20

25

30

32,32,3 48,53,3 60,83,5 72,441 80,52,5

45

50

55

60

94,63,6 96,82,4 98,03,9 98,54,2 1004,1

52

15

Hnh 3.5: th biu din % felodipin gii phng t N1, N2, N5

Nhn xt
T kt qu thc nghim ta thy mu N5 gii phng 100% dc cht sau 60
pht, ha tan cao hn mu N1, do s dng PEO 200.000 vi t l 90 mg/5 mg
felodipin cng c kh nng ci thin ha tan felodipin. So snh vi mu N2 ta
thy thi gian gii phng ca N6 ko di hn mc d vn gii phng 100% dc
cht nh N2. Nguyn nhn do PEO 200.000 l polyme thn nc nn gii phng
dc cht cn thi gian ht nc, trng n v ha tan nhng do c tnh thn nc
nn to lp o nc bao quanh tiu phn dc cht, lm tng tan ca felodipin.
Nh vy, tng cng kh nng ci thin ha tan ca felodipin trong vin
thm thu, trong cc nghin cu tip theo lp dc cht s dng PEO 200.000
(POLYOX WSR N-80) lm t dc trng n v bo ch bng phng xt ht
t vi t dc dnh l hn hp felodipin v PVP (t l 1:1) phn tn trong ethanol
90%.
3.3. Nghin cu xy dng cng thc vin thm thu
3.3.1. La chn t dc lp y v lp dc cht
la chn cc t dc s dng trong cng thc tin hnh bo ch cc mu
vin c thnh phn khc nhau nh trong bng 3.7. Cc mu M1, M2, M3 c lp
dc cht khc nhau ln lt s dng natri croscarmelose (Disolcel), crospovidone,
natri starch glycolat; lp y cng s dng gm xanthan lm t dc trng n. Cc
53

mu M4, M5 c lp dc cht ging nhau PEO 200.000 (POLYOX WSR N-80),

lp y s dng ln lt PEO 5.000.000 (POLYOX WSR Coagulant) v PEO
7.000.000 (POLYOX WSR 303).
Bng 3.7: Thnh phn cng thc cc mu vin M1, M2, M3, M4, M5
Thnh phn 1 vin (mg)

Lp
dc
cht

M1

M2

M3

M4

M5

Felodipine

PVP K30

Natri croscarmelose (Disolcel)

40

Crospovidone

40

Natri starch glycolat

PEO 200.000(POLYOX WSR

90

90

Natri clorid

30

30

30

Lactose

40

40

40

45

45

Magnesi stearat

0,6

0,6

0,6

0,6

0,6

Gm Xanthan

60

60

60

PEO

75

75

PVP K30

Natri clorid

20

20

20

35

35

Avicel PH101

40

40

40

Lactose

30

30

Oxid st

0,2

0,2

0,2

0,2

0,2

Magnesi stearat

0,6

0,6

0,6

0,6

0,6

40

N-80)

5.000.000(POLYOX

WSR Coagulant)
PEO
Lp
y

7.000.000(POLYOX

WSR 303)

Khi lng mng bao so vi vin nhn

8,50 0,15%

Kch thc ming GPDC

0,5 0,025 mm

54

Tin hnh th ha tan cc mu vin theo phng php 2.2.4.7. Kt qu c

trnh by trong hnh 3.6.

Hnh 3.6: th gii phng dc cht cc mu M1, M2, M3, M4,M5

Nhn xt
T kt qu th th nghim ha tan ta thy thnh phn lp dc cht, lp y
khc nhau cho kt qu gii phng dc cht khc nhau. Mu M3 s dng natri
starch glycolat trong lp dc cht lm cn tr qu trnh gii phng dc cht, ch
gii phng c 74,3% sau 12 gi. Nguyn nhn do natri starch glycolat khi gp
nc trng n thnh dng keo dnh ly ming gii phng dc cht, kh b tri ra
nn cn tr qu trnh gii phng dc cht.
Cc mu vin M1, M2, M4, M5 u gii phng hn 90% dc cht sau 12 gi
nhng mu M4, M5 c ng hc gii phng khc so vi mu M1, M2. Mu M4 v
M5 phn ln dc cht c gii phng theo ng hc bc 0, c khong tuyn tnh
trong th gii phng, cn mu M1, M2 cha khong tuyn tnh ngn, khng c
trng cho tnh cht ca vin thm thu l gii phng theo ng hc bc 0.
-

Mu M4: phng trnh ng hc gii phng

y=13,82x 6,775; h s

R2=0,991 trong khong 1 8 gi.

-

Mu M5: phng trnh ng hc gii phng y=18,23x 13,88; h s

R2=0,997 trong khong 1 6 gi.

55

So snh gia M4 v M5 ta thy s dng loi PEO khc nhau th kh nng gii
phng dc cht cng khc nhau. PEO 7.000.000 c khi lng phn t cao hn
PEO 5.000.000 nn tc trng n ca PEO 7.000.000 mnh hn PEO 5.000.000,
dn n tc y nhanh hn do dc cht c gii phng nhanh hn. Mt
khc PEO 7.000.000 ht m hn, kh xt ht hn PEO 5.000.000 nn PEO
5.000.000 c la chn l t dc trng n trong lp y.
Nh vy, sau qu trnh kho st, mu M4 c la chn nghin cu tip v
thnh phn vin nhn bao gm:
Bng 3.8: Thnh phn vin nhn
Dc cht/t dc

Vai tr

V tr s dng

Felodipin

Dc cht

Lp dc cht

PVP K30

T dc dnh, ci thin ha C 2 lp
tan

PEO

200.000(POLYOX

T dc trng n

Lp dc cht

T dc trng n

Lp y

Natri clorid

T dc to ASTT

C 2 lp

Lactose

T dc n

C 2 lp

Avicel pH 101

T dc r, n

C 2 lp

Magnesi stearat

T dc trn

C 2 lp

Oxid st

T dc to mu

Lp y

WSR N-80)
PEO 5.000.000(POLYOX
WSR Coagulant)

3.3.2. Nghin cu t l PEO 200.000 v PEO 5.000.000 trong vin nhn

Tin hnh bo ch cc mu vin thm thu theo cng thc trong bng 3.9 theo
cc phng php trong mc 2.2.1. Tin hnh th ha tan cc mu vin M6, M7,
M8, M9 theo mc 2.2.4.7. Kt qu c trnh by trong hnh 3.7.

56

Bng 3.9: Thnh phn cng thc cc mu vin M6, M7, M8, M9
Thnh phn 1 vin (mg)

Lp dc cht

Lp y

M6

M7

M8

M9

Felodipin

PVP K30

PEO 200.000

90

90

70

70

Natri clorid

15

15

15

15

Avicel

25

25

45

45

Lactose

45

45

45

45

Magnesi stearat

0,9

0,9

0,9

0,9

PEO 5.000.000

50

40

50

40

Natri clorid

15

15

15

15

Avicel PH101

15

25

15

25

Lactose

30

30

30

30

Oxid st

0,55

0,55

0,55

0,55

Magnesi stearat

0,55

0,55

0,55

0,55

Khi lng mng bao so vi vin nhn

12,5 0,15%

Kch thc ming GPDC

0,5 0,025 mm

Hnh 3.7: th gii phng dc cht t cc mu M6, M7, M8, M9

57

Nhn xt
T kt qu th ha tan ta thy khi thay i t l PEO 200.000 v PEO
5.000.000 trong lp dc cht v lp y th kh nng gii phng dc cht thay
i.
-

Mu M6 c t l PEO 200.000 v PEO 5.000.000 tng ng l 90 mg v 50

mg c thi gian lag time 1 gi, gii phng 95% dc cht sau 12 gi, th gii
phng tuyn tnh trong khong 1 10 gi theo phng trnh ng hc bc 0: y =
9,810x 6,318; h s R2=0,992.
-

Mu M7 c t l PEO 200.000 v PEO 5.000.000 tng ng l 90 mg v 40

mg c thi gian lag time 2 gi, gii phng 75,8% dc cht sau 12 gi, th gii
phng tuyn tnh trong khong 2 14 gi theo phng trnh ng hc bc 0: y =
7,345x 13,23; h s R2=0,998.
-

Cc mu M8 (t l PEO 200.000 v PEO 5.000.000 tng ng l 70 mg/50

mg) v M9 (t l PEO 200.000 v PEO 5.000.000 tng ng l 70 mg/40 mg) gii

phng dc cht rt thp (ch c 22,5% v 18,5% tng ng sau 12 gi), nguyn
nhn do lp dc cht c t PEO 200.000 hn nn kh nng trng n ca lp dc
cht km hn.
Nh vy t l cc PEO trong vin nhn c nh hng rt ln n tc gii
phng dc cht. Trong tt c cc mu trn th mu M6 c t l gii phng dc
cht cao nht, 95% dc cht sau 12 gi. Do , cng thc M6 (vi t l PEO
200.000 trong lp dc cht 90mg v PEO 5.000.000 trong lp y 50mg) l thch
hp nht s dng trong cc nghin cu tip theo.
3.3.3. Nghin cu nh hng ca t l natri clorid n tc GPDC
p sut thm thu trong vin nhn c vai tr rt quan trng ko nc qua
mng bn thm, do quyt nh c ch cng nh tc gii phng dc cht.
nh gi nh hng ca t l natri clorid trong vin nhn n tc gii phng
dc cht tin hnh bo ch cc mu vin thm thu c t l NaCl khc nhau theo
cng thc trong bng 3.10. Tin hnh th ha tan theo mc 2.2.4.7, so snh vi
mu M6. Kt qu c trnh by trong hnh 3.8.

58

Bng 3.10: Thnh phn cng thc cc mu vin M6, M10, M11
Thnh phn 1 vin (mg)

Lp dc cht

Lp y

M6

M10

M11

Felodipin

PVP K30

PEO 200.000

90

90

90

Natri clorid

15

40

Avicel

25

40

Lactose

45

45

45

Magnesi stearat

0,9

0,9

0,9

PEO 5.000.000

50

50

50

Natri clorid

15

40

Avicel PH101

15

30

Lactose

30

30

20

0,55

0,55

Oxid st

0,55

Magnesi stearat

0,55

0,55

0,55

Khi lng mng bao so vi vin nhn

12,5 0,15%

Kch thc ming GPDC

0,5 0,025 mm

Hnh 3.8: th gii phng dc cht t cc mu vin c t l NaCl khc nhau

59

Nhn xt:
T kt qu gii phng dc cht ta thy so snh cc mu M6, M10, M11 c s
khc nhau r rt v tc gii phng dc cht.
-

Mu M10 khng c NaCl trong c lp dc cht v lp y nn chnh lch p

sut thm thu gia 2 bn mng bn thm thp, nc c ht vo bn trong vin

nhn chm nn tc trng n ca cc polyme chm, dn n tc gii phng
dc cht chm hn nhiu so vi mu M6, v ch gii phng khong 40,9% dc
cht sau 12 gi. th gii phng tuyn tnh trong khong 2 12 gi theo phng
trnh y=3,609x 2,326; h s R2=0,993.
-

Mu M11 sau 12 gi gii phng 45,8% dc cht nhng trong khong 1 6

gi gii phng rt chm ch c 10,1%, sau gii phng mnh dc cht. th

gii phng tuyn tnh trong khong 6 12 gi theo phng trnh y=6,201 27,86;
h s R2=0,998. C th do mu M11 khng c avicel nn tc dn nc vo khi
polyme chm do thi gian trng n ca polyme ko di. Do ha tan ca
M11 cng thp hn nhiu so vi M6.
Nh vy, t dc to p sut thm thu c vai tr rt quan trng, nh hng
n tc gii phng dc cht. qu trnh gii phng dc cht n nh theo
ng hc bc 0 cn phi duy tr p sut thm thm thu trong vin nhn t gi tr
hng nh, do phi duy tr nng bo ha ca cc cht to p sut thm thu.
Nu s dng t l NaCl nhiu qu s kh khn trong qu trnh bo ch v NaCl ht
m mnh, kh nng chu nn km. Kt qu th nghim chng t t l NaCl trong
mu M6 ph hp s dng cho cc nghin cu tip theo.
3.3.4. Nghin cu nh hng ca dy mng bao n tc GPDC
Mng bao c vai tr rt quan trng trong kim sot gii phng dc cht t
vin thm thu, do c im l mng bn thm nn dy mng bao nh hng n
tc ht nc t mi trng vo vin nhn. Do dy mng bao t l thun vi
khi lng mng bao nn c th theo di khi lng mng bao tng ln kim
sot qu trnh bao.
nh gi nh hng ca b dy mng bao n tc gii phng dc cht
tin hnh bo ch cc mu vin thm thu cng thc vin nhn nh M6, bao mng
60

bn thm theo phng php trong mc 2.2.2 c khi lng mng bao tng ln so
vi vin nhn tng ng l 10% (M12), 12,5% (M6) v 15% (M13), v c cng
kch thc ming gii phng dc cht 0,50,025 mm.
Tin hnh th ha tan theo mc 2.2.4.7. Kt qu c trnh by trong hnh 3.9.

Hnh 3.9: th gii phng dc cht t vin c dy mng bao khc nhau
Nhn xt:
T kt qu th ha tan cc mu vin c b dy mng bao khc nhau ta thy
b dy mng bao nh hng ti thi gian tim tng v tc gii phng dc cht.
Khi lng mng bao cng ln th thi gian tim tng cng di, tc gii phng
dc cht cng chm v ngc li. Th t v tc gii phng dc cht cc mu
nghin cu: M12>M6>M13. Nguyn nhn do khi khi lng mng bao cng ln th
dy mng bn thm cng ln dn n tc ht nc vo vin nhn cng gim,
thi gian ha tan, trng n cc thnh phn trong vin nhn tng ln, do dc
cht b y ra ngoi chm hn.
-

Mu M12 sau 10 gi gii phng 100% dc cht, khong tuyn tnh t 1 7

gi c phng trnh y=15,22x 11,68; h s R2=0,999.

-

Mu M13 gii phng 81,5% sau 12 gi, c khong gii phng tuyn tnh t 2

13 gi theo phng trnh y=7,88x 12,64; h s R2=0,998.

61

Nh vy, sau thi gian lag time khc nhau, tt c cc mu vin u gii phng
theo ng hc bc 0, ch khc nhau v tc gii phng dc cht, do c th
thy mng bn thm cellulose acetat c kh nng kim sot gii phng rt tt, tc
ht nc qua mng n nh. So snh vi mu M6 th M12 gii phng nhanh qu,
khng ko di c 12 gi, mu M13 ko di gii phng hn 12 gi nhng mng
bao dy, kh phn bit 2 lp khoan ming GPDC. Do vy, khi lng mng bao
so vi vin nhn 12,5% c la chn cho cc nghin cu tip theo.
3.3.5. Nghin cu nh hng ca kch thc ming gii phng n tc
GPDC
Ming gii phng dc cht l ni dc cht c y ra ngoi, do kch
thc ming gii phng nh hng n tc gii phng. la chn kch thc
ming gii phng dc cht thch hp tin hnh bo ch cc mu vin c cng thc
vin nhn nh M6 c cng dy mng bao 12,50,15%, kch thc ming gii
phng thay i 0,5 mm (M6), 0,8 mm (M14), 1,0 mm (M15). Tin hnh th ha
tan theo phng php trong mc 2.2.4.7. Kt qu th ha tan c trnh by
trong hnh 3.10.

Hnh 3.10: th gii phng dc cht t cc mu vin c kch thc ming gii
phng khc nhau

62

Nhn xt:
T kt qu th ha tan cc mu vin c kch thc ming gii phng khc
nhau ta thy kch thc ming gii phng t nh hng n thi gian tim tng, nh
hng nhiu n tc gii phng dc cht, ng knh ming gii phng cng
ln th dc cht c gii phng cng nhanh. V cng mt tc ht nc vo
vin nhn, cng mt tc trng n ca polyme th ming gii phng cng ln
dc cht c y ra cng nhiu, do tc gii phng dc cht cng tng ln.
Th t v tc gii phng dc cht t cc mu nghin cu: M6<M14<M15.
-

Mu M14 gii phng 99% sau 12 gi, th gii phng tuyn tnh trong

khong 1 9 gi theo phng trnh y=12,04x 10,34; h s R2=0,998.

-

Mu M15 gii phng 100% sau 10 gi, th gii phng tuyn tnh trong

khong 1 8 gi theo phng trnh y=14,06x 12,23; h s R2=0,998.

So snh cc mu M14, M15 vi mu M6 th mu M6 ko di gii phng hn,
khong tuyn tnh trong th di hn(1 10 gi). Do kch thc ming gii
phng 0,5 mm c la chn cho cc nghin cu tip theo.
La chn cng thc bo ch
T cc kt qu cc nghin cu trn cng thc vin thm thu c la chn nh
sau:
-

Lp dc cht
Felodipin
PVP K30

PEO 200.000

90 mg

Natri clorid

15

Avicel PH 101

mg
mg

25 mg

Lactose

45 mg

Magnesi stearat

0,9

mg

PEO 5.000.000

50

mg

Natri clorid

15

mg

Avicel PH 101

15 mg

Lp y

63

5 mg

Lactose

30

mg

Oxid st

0,55

mg

Magnesi stearat

0,55

mg

Cng thc dch bao

Opadry CA (CA:PEG 3350=9:1)

14 g

Nc ct

6,7 g

Aceton

300 ml

Khi lng mng bao so vi vin nhn:12,5%

Kch thc ming GPDC: 0,5 mm

3.4. nh gi nh hng ca cc yu t mi trng ha tan n kh nng gii

phng dc cht
u im ca dng bo ch vin thm thu l qu trnh gii phng dc cht
khng ph thuc vo cc yu t mi trng bn ngoi h nh pH v nhu ng
ng tiu ha, tuy nhin p sut thm thu mi trng li c nh hng. nh
gi nh hng ca cc yu t mi trng tin hnh th ha tan mu vin M6 trong
cc mi trng c pH, tc khuy v p sut thm thu khc nhau.
3.4.1. nh hng ca pH mi trng ha tan
So snh kt qu th ha tan mu vin M6 cc mi trng pH khc nhau:
pH 1,2; 4,5 v 6,5. Thay i pH mi trng bng dung dch NaOH 40%. Kt qu
c trnh by trong hnh 3.11.

Hnh 3.11: th gii phng dc cht mu M6 trong mi trng pH khc nhau

64

Nhn xt:
T kt qu th ha tan mu M6 trong cc mi trng pH khc nhau tnh gi
tr f2 tng quan gia cc th ta thy f2 (pH 4,5/6,5)=79,65, f2 (pH 1,2/4,5)=64,63,
f2 (pH 6,5/1,2)=76,61, cc gi tr f2 u nm trong khong 50 100, chng t cc
th gii phng dc cht ging nhau. Do pH mi trng ha tan khng nh
hng n t l gii phng dc cht t vin thm thu.
3.4.2. nh hng ca tc cnh khuy
So snh kt qu th ha tan mu vin M6 vi tc khuy khc nhau: 50
vng/pht, 75 vng/pht v 100 vng/pht. Kt qu c trnh by trong hnh 3.12.

Hnh 3.12: th gii phng dc cht mu M6 vi tc cnh khuy khc nhau

Nhn xt
T kt qu th ha tan tnh gi tr f2 tng qua gia 2 th gii phng dc
cht ta c f2 (50rpm/75rpm)=81,87, f2 (75rpm/100rpm)=88,93, f2 (50rpm/100rpm)
=73,08. Cc gi tr f2 nm trong khong 50 100, do vy cc th gii phng trn
l ging nhau. Nh vy tc khuy khng nh hng n t l gii phng dc
cht t vin thm thu.
3.4.3. nh hng ca p sut thm thu mi trng ha tan
to cc mi trng ha tan c p sut thm thu khc nhau cho vo mi mi
trng ha tan lng NaCl khc nhau: 20 mg, 40 mg. Tin hnh th ha tan mu

65

vin M6 cc mi trng ny. So snh vi mu M6 mi trng ha tan khng

cho NaCl. Kt qu c trnh by trong hnh 3.13.

Hnh 3.13. th gii phng dc cht mu M6 trong cc mi trng c nng

NaCl khc nhau
Nhn xt
T kt qu th ha tan cho thy s c mt NaCl trong mi trng ha tan
lm gim tc gii phng dc cht, nng NaCl cng cao th tc gii phng
cng gim. Nguyn nhn do c NaCl trong mi trng ha tan lm gim chnh lch
p sut thm thu gia trong v ngoi mng, nn nc b ko vo bn trong vin
nhn chm li, lm tc gii phng chm i, thm ch khng gii phng dc cht
c. Hu nh mu M6 khng gii phng dc cht c khi thm 20 mg v 40
mg NaCl. Do , nng cht to p sut thm thu trong mi trng ha tan cng
cao tc gii phng dc cht cng gim.
3.5. nh gi cc c tnh ca vin v xut tiu chun
Tin hnh bo ch 100 vin theo cng thc chn theo cc phng php
trong mc 2.2.1, 2.2.2, 2.2.3.
3.5.1. nh gi cc c tnh ca vin bo ch c
nh gi hnh thc vin

66

Vin thm thu sau khi bao b mt nhn, mng bao trong, 2 lp c mu khc
nhau nn c th phn bit. Ming gii phng dc cht l l nh, chnh gia vin,
c khoan xuyn qua mng bao.
Hnh nh chp SEM b mt mng bao cho thy trc khi gii phng b mt
mng bao c cc l t hn v nh hn so vi b mt mng bao sau khi gii phng.
Do cu trc mng bn thm thay i sau khi nc thm qua.
nh gi cng ca vin nhn:
Bng 3.11: cng ca vin nhn (kP)
Vin

cng (kP)

Vin

cng (kP)

10,51

10,74

11,02

10,84

11,87

11,28

11,84

10

11,22

11,05

11

10,65

10,64

12

11,66

cng:

11,150,58 kP

Nhn xt: Tt c cc vin th nghim c cng u nm trong trong gii

hn 10 12kP.
nh gi mi mn vin nhn
Bng 3.12: mi mn vin nn nhn
mi mn (%)
Ln 1

0,72

0,51

0,67

Ln 2

0,70

0,52

0,58

Ln 3

0,62

0,71

0,66

Trung bnh

0,68

0,58

0,63

Nhn xt: Tt c c cc mu vin bo ch u c mi mn < 1%.

nh gi ng u khi lng vin sau khi bao

67

Bng 3.13: Khi lng vin sau khi bao

STT

Khi

STT

lng (mg)

STT

Khi
lng (mg)

Khi

STT

lng (mg)

Khi
lng (mg)

335,11

332,55

11

335,23

16

332,22

330,74

333,80

12

332,02

17

334,34

333,64

332,29

13

329,23

18

329,25

331,81

331,52

14

334,21

19

334,65

329,54

10

335,45

15

333,33

20

334,86

Khi lng vin: 332.78 2,00 mg

RSD:

0,3%
Nhn xt: ng u khi lng vin sau khi bao c RSD<5%

nh gi ng u kch thc ming gii phng dc cht

Bng 3.14: Kch thc ming gii phng dc cht
Vin

ng knh (mm)

Vin

ng knh (mm)

0,521

0,525

0,585

0,512

0,554

0,535

0,588

10

0,546

0,533

11

0,542

0,542

12

0,577

Kch thc ming GPDC: 0,546 0,025 mm

RSD:

4,5%

Nhn xt: ng u kch thc ming gii phng c RSD<5%

nh lng vin thm thu
Tin hnh nh lng vin bao v khoan ming gii phng dc cht nh mc
2.2.4.4, kt qu nh lng bng HPLC nh bng sau:

68

Bng 3.15: Kt qu nh lng mu vin la chn bng phng php HPLC

Mu chun

Mu th

Thi gian

Din tch

Thi gian

Din tch

lu

pic(mAU.s)

lu

pic(mAU.s)

Ln 1

10,545

3.181.118

10,627

3.113.329

Ln 2

10,552

3.249.121

10,443

3.153.545

Ln 3

10,550

3.270.432

10,502

3.072.479

Trung bnh 10,549

3.233.557

10,524

3.113.117

Vi mchun=20,1mg Cc=20,1g/ml
Mcn =0,676 g
Phn trn hm lng felodipin trong vin th so vi nhn l:
%felodipin so vi nhn = 96,76%
Nhn xt: hm lng felodipin trong vin th nm trong khong 90 110% so vi
hm lng ghi trn nhn.
Th ha tan
S dng thit b th ha tan t ng VanKen Varian 7010
Kt qu th ha tan trnh by trong bng 3.16.
Bng 3.16: T l felodipin gii phng (%SD) mu vin la chn (n=3)
Thi gian (gi)

% felodipin gii

Thi gian (gi)

phng

phng

64,13,3

73,71,1

12,21,2

82,33,5

21,11,5

10

90,32,8

31,82,0

11

93,52,7

42,82,5

12

95,01,6

53,83,1

69

% felodipin gii

Hnh 3.14: th gii phng dc cht t mu vin la chn

-

Thi gian lag time: 1h

t yu v ha tan theo Test 1 USP 35.

Khp m hnh ng hc: S dng phn mn S-Plus 8.0 phn tch d liu ha
tan trong khong thi gian 1 10 gi, kt qu c trnh by trong bng 3.17.
Bng 3.17: Kt qu phn tch d liu ha tan mu vin la chn bng phn
mm S Splus 8.0
M hnh ng hc

Phng trnh ng hc gii phng

AIC

trong khong 1 10h

Bc 0

Qt=10,14*t 8,6

1,45

11,43

Bc 1

Qt=100(1 e-0,136*t)

10,82

49,62

Higuchi

Qt=43,08*t 49,6

3,93

31,37

Weibull

Qt=100(1-e0,028*t^1,86)

1,9

16,83

Hixson Crowell

Qt=100(1-(1-0.039*t)3)

8,88

45,67

Korsmeyer Peppas

Qt/Q=6,24*t1.17

3,03

26,17

Nhn xt:
T kt qu phn tch d liu ha tan bng phn mm S-Plus 8.0 ta thy m
hnh ng hc bc 0 c gi tr AIC nh nht, do m hnh ng hc bc 0 l ph
hp nht cho qu trnh gii phng dc cht t mu vin la chn.

70

3.5.2. xut tiu chun vin thm thu felodipin 5mg

T cc nghin cu nh gi mu vin la chn, xut tin chun vin thm
thu felodipin 5mm nh bng 3.18.
Bng 3.18: Bng tiu chun vin thm thu felodipin 5mg
Cc ch tiu

Yu cu

Phng php

Vin bao 2 lp, mt mt mu

Hnh thc

trng mt mt mu nu. B

Cm quan

mt nhn, mng bao u. Ming

gii phng chnh gia b mt vin

Kch thc
ming GPDC
Hm lng

Soi knh hin vi quang hc

0,5 mm

ngun sng bn ngoi

Hm lng felodipin t t 90

HPLC

110% hm lng ghi trn nhn

- Thit b cnh khuy, 6 cc

th, ch th vin bng tay,
lp thm gi ng vin.
- Mi trng th ha tan:
T l dc cht gii phng ti cc
thi im:
ha tan

dung dch m phosphat

0,1M pH 6,5 c 1% natri
lauryl sulfat.

2h: 10% - 30%

- Nhit mi trng:

6h: 40 60%

370,5oC

10h: khng t hn 80%

- Tc cnh khuy: 50
vng/pht
- o quang bc sng 238
nm.

71

Chng 4: BN LUN
4.1. V phng php bo ch
4.1.1. Phng php ci thin ha tan ca dc cht
Trong dng bo ch vin thm thu ko y dc cht c gii phng di
cc dng: dung dch (vi dc cht d tan), hn dch hoc tiu phn phn tn trong
gel ca cc polyme (vi cc dc cht t tan). Do c tnh ca felodipin rt t tan
trong nc ( tan 19,17 mg/l 250C) nn nghin cu ci thin tan v ha tan
ca felodipin c rt nhiu tc gi tp trung nghin cu, phn ln theo hng to
h phn tn rn vi polyme thn nc hoc to phc h vi dn cht ca
cyclodextrin. ci thin ha tan ca felodipin khi a vo h thm thu cn la
chn phng php bo ch v t l t dc ci thin ha tan thch hp.
Bo ch lp dc cht s dng kt hp 2 phng php: phng php xt ht
t vi t dc dnh l hn hp felodipin v PVP K30 t l 1:1 c phn tn trong
ethanol 90% v s dng PEO 200.000 ci thin ha tan ca feodipin. Hai
phng php ny c c ch ci thin ha tan khc nhau. Phng php xt ht t
vi t dc dnh l hn hp felodipin v PVP phn tn trong ethanol 90% thay th
cho bc ch to h phn tn rn ca felodipin vi cht mang PVP bng phng
php dung mi, lm tng t l felodipin chuyn t trng thi kt tinh sang v nh
hnh, do vy tan v ha tan ca felodipin cng tng ln. Phng php s dng
PEO 200.000 ci thin ha tan felodipin do PEO 200.000 l polyme thn nc
c khi lng phn t thp, do to lp o nc bao quanh cc tiu phn dc
cht, lm tng tan ca felodipin.
4.1.2. Phng php dp vin
L dng bo ch vin thm thu ko y nn vin nhn l vin 2 lp, do
s dng phng php dp vin 2 lp. Do thit b s dng l my dp vin tm sai
Korsch nn vic dp vin phi qua 2 bc: cho lp dc cht vo ci trc, dp s
b lp dc cht trc sau cho lp y vo ci v dp hon ton. Vi thao tc
dp nh vy mt nhiu thi gian, cng ca vin khng ng u v kh a ra 1

72

tiu chun v lc dp vin. Ti v tr tip xc gia s c s xen k, an xen vo

nhau gia thnh phn 2 lp, tuy nhin iu ny khng nh hng n kh nng gii
phng dc cht v kh nng trng n ca polyme trong lp y mnh hn nn
dc cht vn b y ht ra ngoi. Phng php ny ch s dng trong quy m
phng th nghim, khi dp vi s lng nhiu phi s dng my dp vin 2 lp t
ng.
4.1.3. Phng php bao mng bn thm
m bo ng u cht lng mng bao qu trnh bao mng bn thm c
tin hnh bng my bao phim t ng. Cellulose acetat l polyme s dng ph bin
to mng bn thm trong cng thc vin thm thu, trong thnh phn dch bao
thng cho thm cht ha do, cht chng dnh. Chng ti s dng cellulose acetat
c trn sn vi cht ha do l PEG 3350 theo t l CA:PEG 3350=9:1, c
hng dc phm Colorcon thng mi ha vi tn gi Opadry CA. S dng
Opadry CA c nhiu u im: d ha tan trong dung mi aceton, khng phi thm
cht ha do, cht chng dnh, cht lng mng bao tt, ng u, b mt nhn, d
sy kh. Tuy nhin khi s dng Opadry CA trong dch bao c thm nc nn nc
d b ht vo vin nhn lm mm vin nhn v d xut hin lp bt trng ca PEG
trn b mt vin khi nhit cao qu. Do phi kim sot nhit thch hp (thp
hn 500C) trong qu trnh bao.
4.2.3. Phng php khoan ming gii phng dc cht
C nhiu phng php to ming gii phng dc cht nh to ming gii
phng ngay trong qu trnh dp vin, khoan c hc, khoan laze. Trong khoan
laze l phng php mi, c k thut cao, s dng thit b khoan t ng. Phng
php c nhiu u im, ni bt nht l c th iu chnh ng knh ming gii
phng d dng v c th p dng sn xut quy m cng nghip. S dng my khoan
laze EPILOG LAZER Helix l thit b tin tin, gn nh, d vn hnh. My s dng
ngun laser CO2 cng sut 25W, ch cn s dng mc cng sut 4 10% cng
sut my l c th khoan thu c ming gii phng dc cht thch hp. Trong
qu trnh khoan iu chnh hai thng s thch hp l cng pht tia v thi gian
73

tc ng thu c ming gii phng dc cht kch thc v su ph hp. T

kt qu nh gi ng u kch thc ming gii phng ta thy phng php
khoan laze c ng u kch thc ming gii phng cao. Do c th n nh
c quy trnh bo ch v kch thc ming gii phng nh hng n tc gii
phng dc cht.
4.2. V xy dng cng thc vin thm thu
Do dc cht felodipin c thi gian bn thi di(t1/2=11 25 gi) nn hu ht
cc nghin cu v dng gii phng ko di ch xy dng ko di gii phng n 10
12 gi. C nhiu yu t nh hng n tc gii phng dc cht t dng bo
ch vin thm thu, trong nghin cu ny chng ti ch kho st, xy dng cng
thc vin nhn, la chn dy mng bn thm v kch thc ming gii phng
dc cht. C s ca vic la chn cng thc vin thm thu cn c trn tc gii
phng dc cht ca cc mu th (t l dc cht gii phng sau 12 gi phi >
80%), di khong tuyn tnh trong th gii phng, thun li trong qu trnh
bo ch v cc yu t v cm quan, hnh thc vin bn ngoi.
4.2.1. Xy dng cng thc vin nhn
La chn polyme trng n trong vin nhn
Theo c ch gii phng ca vin thm thu ko y, do chnh lch p sut
thm thu gia trong v ngoi mng nc c ko vo trong vin, dc cht c
phn tn trong dng gel ca polyme lp dc cht v c y ra ngoi khi polyme
lp y trng n to lc y tc ng ln lp dc cht. Theo , thnh phn
khng th thiu trong c lp dc cht v lp y l t dc to p sut thm thu
v t dc trng n. T dc to p sut thm thu s dng ph bin l natri
clorid. T dc trng n l cc polyme thn nc. Kt qu nghin cu cho thy s
dng t dc PEO 200.000 trong lp dc cht v PEO 5.000.000 trong lp y c
kh nng kim sot tc gii phng dc cht tt nht, gii phng > 90% dc
cht sau 12 gi v qu trnh gii phng tun theo ng hc bc 0. Nh vy c th
thy u im ca t dc PEO trong dng bo ch vin thm thu.

74

Vic la chn t dc PEO lm t dc trng n trong cng thc vin nhn

c vai tr quan trng bi PEO c kh nng kim sot gii phng dc cht tt, kh
nng trn chy v chu nn cao, c th bo ch bng phng php dp thng hoc
xt ht. Hn na PEO khi lng phn t thp cn c kh nng ci thin ha tan
ca cc dc cht t tan. Do hin nay PEO c s dng rng ri trong cng
ngh bo ch, c bit l dng vin thm thu. Tuy nhin cc PEO c th ko di
thi gian tim tng ca dng bo ch do tc hp th nc v hydrat ha chm.
T l PEO trong vin nhn
Theo nguyn tc th t l PEO trong 2 lp cng nhiu th tc gii phng cng
cao. Th nghim cho thy mu M6 c t l PEO 200.000 trong lp dc cht v
PEO 5.000.000 lp y tng ng 90 mg v 40 mg c thi gian lag time 1 gi,
gii phng 95% dc cht sau 12 gi, c th gii phng tuyn tnh trong khong
1 10 gi. Cc mu vin M7, M8, M9 sau 12 gi gii phng <80%. Do tc gii
phng dc cht t vin thm thu ph thuc vo nhiu yu t nn t l PEO thch
hp nht trong vin nhn c th thay i, khi phi thay i dy mng bao v
kch thc ming gii phng dc cht tng ng vn p ng c t l gii
phng nh mong mun. Trn c s th nghim ha tan ca mu vin M6 nh vy
chng ti la chn cng thc mu vin M6 tin hnh cc nghin cu tip
theo.
V t l t dc to p sut thm thu
T l t dc to p sut thm thu trong vin nhn c vai tr quan trng v n
to ra chnh lch p sut thm thu trong v ngoi mng, ko nc t mi trng
bn ngoi qua mng bn thm vo vin nhn, t mi ha tan cc thnh phn v
lm trng n cc polyme. Theo l thuyt, qu trnh gii phng dc cht n
nh theo ng hc bc 0 cn phi duy tr p sut thm thu trong vin nhn t gi
tr hng nh, do phi duy tr nng bo ha ca cc cht to p sut thm thu.
T kt qu nghin cu cho thy khng s dng NaCl trong c lp dc cht v lp
y th tc gii phng dc cht chm, ch gii phng khong 40,9% dc cht
sau 12 gi, khi lactose ng vai tr t dc to p sut thm thu chnh, nhng
75

chnh lch p sut thm thu lactose to ra khng ln, lm gim tc gii
phng dc cht. Nu s dng t l NaCl nhiu qu s kh khn trong qu trnh bo
ch v NaCl ht m mnh, kh nng chu nn km Mu vin M6 c t l NaCl
ph hp nht c s dng trong cc nghin cu tip theo.
4.2.2. La chn dy mng bao
Do c im l mng bn thm nn dy mng bao nh hng n tc ht
nc t mi trng vo vin nhn. dy mng bao t l thun vi khi lng
mng bao. Do c qu trnh gii phng dc cht nh mong mun cn phi la
chn c khi lng mng bao thch hp. T kt qu thc nghim so snh kh
nng gii phng dc cht cc mu vin c khi lng mng bao tng ln khc
nhau 100,12%, 12,50,15% v 150,16% ta thy tng khi lng mng bao
cng ln th thi gian tim tng cng di, tc gii phng dc cht cng chm v
ngc li. Tt c cc mu vin u gii phng theo ng hc bc 0, ch khc nhau
v tc gii phng dc cht, khng c hin tng nt mng. Do c th thy
s dng Opadry CA to ra mng bn thm rt do dai, c kh nng kim sot gii
phng rt tt, c tc ht nc qua mng n nh d c dy khc nhau. T kt
qu nghin cu, tng khi lng mng bao so vi vin nhn 12,50,15% l ti
u nht va m bo tc gii phng, hnh thc vin p v rt ngn thi gian
bao, nguyn liu mng bao.
4.2.3. La chn kch thc ming gii phng dc cht
Do mng cellulose acetat l mng bn thm nn cc phn t dc cht khng b
khuch tn qua mng m ch c gii phng qua ming gii phng dc cht. Do
kch thc ming gii phng nh hng n tc gii phng dc cht. So
snh kt qu nghin cu ha tan cc mu vin c kch thc ming gii phng
khc nhau 0,50,025 mm, 0,80,02 mm, 10,03 mm ta thy kch thc ming gii
phng t nh hng n thi gian tim tng, nh hng nhiu n tc gii phng
dc cht, ng knh ming gii phng cng ln th dc cht c gii phng
cng nhanh. Kt qu ch ra kch thc ming gii phng 0,50,025 mm l thch hp
nht trong nghin cu ny v ko di nht thi gian gii phng v c khong tuyn
76

tnh di nht trong th gii phng dc cht. Phn ln cc nghin cu v vin

thm thu u khoan ming gii phng c ng knh 0,25 0,5mm. Trong nghin
cu ny nu khoan nh hn 0,5mm c th ko di hn gii phng dc cht nhng
k thut khoan kh hn v ng u kch thc gim.
4.3. V nh gi mu vin bo ch c
4.3.1. Cc phng php nh gi
-

Phng php nh lng v th ha tan:

T kt qu xy dng ng chun ca felodipin khi nh lng bng phng

php UV VIS v phng php HPLC c th s dng c 2 phng php ny

nh lng felodipin. Dc in M USP 35 quy nh phng php nh lng
bng HPLC. y l phng php cho kt qu c chnh xc cao. Tuy nhin s
dng phng php ny nh lng hm lng felodipin gii phng trong 12 gi kh
thc hin. Phn ln trong cc nghin cu v felodipin cc tc gi u s dng
phng php o quang 2 bc sng cc i l 238 nm hoc 362 nm. Phng php
ny c chnh xc khng cao, do hm lng dc cht thp nn mt quang
thp, c bit trong nhng gi gii phng u tin. Tuy nhin phng php o
quang d thc hin, c th kt hp th ha tan v o quang t ng nn thun li
cho th nghim nh tc gii phng dc cht 12 gi. Do chng ti la chn
phng php o quang bc sng 238 nm khi nh gi tc gii phng dc
cht trong 12 gi bng thit b th ha tan t ng VanKel Varian 7010 c kt
hp my th ha tan v my o quang. Phng php HPLC c s dng
nh lng hm lng felodipin trong vin thm thu theo USP 35.
nh khc phc nhc im v mt quang thp nhng gi u tin s
dng phng php thm chun kt qu nh lng chnh xc hn, t xc nh
ng t l dc cht gii phng.
-

Cc phng php nh gi khc

S dng cc phng php nh gi thng thng. Trong phng php o

kch thc ming gii phng bng knh hin vi quang hc s dng ngun sng bn

77

ngoi chiu xung c chnh xc km nht, tuy nhin c th thc hin c.

o chnh xc kch thc ming gii phng phi s dng knh hin vi in t qut
(SEM) tuy nhin nh gi 12 mu phng php chp SEM cng khng thun
li.
4.3.2. nh gi nh hng ca cc yu t mi trng ha tan n kh nng
gii phng dc cht
Kt qu th nghim chng t tc gii phng dc cht mu th khng thay
i khi tin hnh mi trng pH v tc cnh khuy khc nhau. iu ny
chng minh rng vin thm thu gii phng dc cht khng b nh hng bi pH
ng tiu ha v nhu ng rut, y l u im ca vin thm thu so vi cc
dng bo ch s dng ng ung khc. Tuy nhin p sut thm thu ca mi
trng li nh hng n tc gii phng. Kt qu thc nghim cho thy nu cho
thm vo mi trng ha tan mt t l NaCl th lm gim tc gii phng.
Nguyn nhn do s c mt NaCl trong mi trng ha tan lm gim chnh lch p
sut thm thu trong v ngoi mng, nc b ko vo bn trong chm hn nn tc
gii phng chm i.
4.3.3. Kt qu nh gi mu vin c la chn
Mu vin c la chn cui cng M6 c nh gi cc c tnh v mi
mn, cng, ng u khi lng sau khi bao, ng u kch thc ming gii
phng, hm lng felodipin v kh nng gii phng dc cht 12 gi. Kt qu cc
tiu ch nh gi u nm trong khong gii hn yu cu. Kt qu th nghim ha
tan cho thy mu vin M6 p ng c yu cu v ha tan trong USP 35, hn
na ko di gii phng 12 gi, trong c khong tuyn tnh t 1 10 gi, gii
phng dc cht theo ng hc bc 0. Nh vy mu vin M6 p ng c cc
yu cu ca dng bo ch vin thm thu.
T kt qu th ha tan vin Felutam CR (Vellpharm Vit Nam, ngy sn
xut: 18/01/2013, s l 0030113, hn dng: 01/2016) cc mi trng pH khc
nhau (Hnh 1 Ph lc 6) ta thy mi trng pH khc nhau th vin Felutam gii

78

phng khc nhau. Vi mi trng pH 1,2; 4,5 v 6,5 ngay gi u tin gii
phng khc nhau rt nhiu, 30,22,2%; 45,62,8%; 19,12,1% tng ng. So vi
vin Felutam, mu vin la chn c qu trnh gii phng dc cht khng b nh
hng bi pH mi trng ha tan.
So snh th gii phng mu vin M6 v vin i chiu Felutam CR (Hnh 2
Ph lc 6) cho thy mu vin M6 v vin i chiu c tc gii phng dc
cht sau thi gian lag time tng g nhau, ch khc nhau v liu gii phng gi
u tin do vin i chiu s dng khong 20% dc cht mng bao bo v bn
ngoi mng bn thm, bi dng bo ch vin thm thu ko y kh t c t l
gii phng nh vy ngay gi u tin v phi c khong thi gian lag time.

79

KT LUN V KIN NGH

Kt lun
Sau mt thi gian thc nghim nghin cu bo ch vin gii phng ko di theo
c ch bm thm thu cha felodipin chng ti thu c mt s kt qu sau:
1. xy dng c cng thc bo ch vin thm thu 2 lp cha 5 mg
felodipin gii phng ko di trong 12 gi theo c ch bm thm thu ko y t
ha tan theo USP 35. Cng thc vin nh sau:
Vin nhn(1 vin)
Lp dc cht

Lp y

Felodipin

mg

PVP K30

mg

PEO 200.000

90

mg

Natri clorid

15

mg

Avicel PH 101

25

mg

Lactose

45

mg

Magnesi stearat

0,9 mg

PEO 5.000.000

50

mg

Natri clorid

15

mg

Avicel PH 101

25

mg

Lactose

30

mg

Oxid st

0,55 mg

Magnesi stearat

0,55 mg

Cng thc dch bao

Opadry CA (CA:PEG 3350=9:1)
Nc ct

6,7 g

Aceton

300 ml

Khi lng mng bao: 12,5% so vi vin nhn

Kch thc ming GPDC: 0,5 mm
80

14 g

2. nghin cu mt s yu t nh hng n kh nng gii phng dc cht

ca vin bo ch c.
- Khi dy mng bao tng th tc gii phng dc cht gim.
-

Khi ng knh ming gii phng dc cht tng th tc gii phng dc

cht tng.

- pH v tc cnh khuy khng nh hng n tc gii phng dc cht

- Nng cht to p sut thm thu trong mi trng ha tan cng cao th tc
gii phng cng gim.
Kin ngh
- Trin khai bo ch vin thm thu quy m ln hn.
- Tin hnh theo di n nh, xc nh tui th ca ch phm.

81

TI LIU THAM KHO

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ca felodipin, Kha lun tt nghip dc s, Trng i hc dc H Ni.
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525.
4. B Y t (2007), Ha dc, tp 1, Nh xut bn Y hc, tr.154.
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s, Trng i hc Dc H Ni.
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felodipin, Kha lun tt nghip dc s, Trng i hc Dc H Ni.
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8. Vidal Vit Nam (2009), tr.525 529.
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ko di theo c ch bm thm thu, Lun vn thc s dc hc, Trng i hc
Dc H Ni.
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Aqueous Solubility and

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biopharmaceutics, 64(2), p. 200205.
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84

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86

PH LC
PH LC 1: PH HP TH UV-VIS
1.

Ph UV-VIS ca dung dch felodipin 20g/ml trong m phosphat 0,1M

pH 6,5 c 1% natri lauryl sulfat

2.

Ph UV-VIS ca dung dch m phosphat 0,1M pH 6,5 c 1% natri lauryl

sulfat

87

PH LC 3: HNH NH DSC
1.

Hnh nh DSC ca cm N2 v felodipin nguyn liu

2.

Hnh nh DSC ca hn hp vt l felodipin v PEO 200.000 v felodipin

nguyn liu

88

PH LC 4: THIT B KHOAN LAZE EPILOG Helix

1. Hnh nh thit b khoan laze trng thi khng hot ng

89

2. Hnh nh thit b khoan laze khi hot ng

PH LC 5: HNH NH VIN

1. Hnh nh vin trc khi gii phng

90

2. Hnh nh vin sau khi gii phng

Hnh nh SEM b mt mng bao trc v sau khi gii phng

Trc khi gii phng

Sau khi gii phng

91

PH LC 6: KT QU TH HA TAN

Danh mc cc bng kt qu th ha tan:

Bng 1: Kt qu th ha tan cc mu M1, M2, M3, M4, M5
Bng 2: Kt qu th ha tan cc mu M6, M7, M8, M9
Bng 3: Kt qu th ha tan cc mu M10, M11
Bng 4: Kt qu th ha tan cc mu c kch thc ming gii phng khc nhau
Bng 5: Kt qu th ha tan cc mu c kch thc ming gii phng khc nhau
Bng 6: : Kt qu th ha tan mu M6 cc mi trng pH khc nhau
Bng 7: Kt qu th ha tan mu M6 vi tc cnh khuy khc nhau
Bng 8: Kt qu th ha tan mu M6 cc mi trng nng NaCl khc nhau
Bng 9: Kt qu th ha tan vin Felutam trong cc mi trng pH khc nhau

92

Hnh 1: th gii phng dc cht t vin Felutam cc mi trng pH khc

nhau
Hnh 2: So snh ha tan gia mu vin la chn v vin Felutam mi trng
pH 6,5

Bng 1: Kt qu th ha tan cc mu M1, M2, M3, M4, M5 (n=3)

Thi gian(gi)
0
1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

M1
M2
M3
M4
M5
0
0
0
0
0
0
1,40,2
0
4,30,2
2,30,2
13,20,1 12,50,8
0
19,40,6 23,41,0
28,41,1 25,10,8 11,90,5 34,61,3 42,22,0
42,41,5 37,31,6 20,10,9 51,32,6 60,52,3
55,32,3 50,02,3 26,81,5 66,12,7 79,61,6
65,82,0 61,52,3 34,21,1 71,33,0 93,23,3
72,52,0 71,82,5 42,02,0 90,01,1 98,03,5
78,63,1 79,42,8 50,13,1 98,51,9 100,02,8
83,21,6 85,53,5 57,92,2 99,53,5
87,62,5 91,53,1 65,42,6 100,03,6
90,53,1 96,02,9 70,23,3
93,13,5 98,33,6 74,33,2

93

Bng 2: Kt qu th ha tan cc mu M6, M7, M8, M9(n=3)

Thi
gian(gi)

T l felodipin gii phng(%SD)

0
1
2
3
4
5
6
7
8
9
10
11
12

M6

M7

M8

M9

0
0
12,21,2
21,11,5
31,82,0
42,82,5
53,83,1
64,13,3
73,71,1
82,33,5
90,32,8
93,52,7
95,01,6

0
0
3,20,5
9,02,2
15,61,6
21,83,2
29,12,5
37,32,6
45,72,0
54,13,4
61,73,6
68,61,9
75,81,5

0
0
0,50,1
2,80,5
5,51,2
7,31,5
9,01,6
11,02,0
12,82,1
15,31,3
17,81,5
20,02,4
22,52,6

0
0
0
2,70,1
5,00,1
6,90,1
8,60,1
10,10,6
11,71,2
13,41,3
15,10,6
16,80,4
18,51,1

Bng 3: Kt qu th ha tan cc mu M10, M11 (n=3)

Thi gian(h)

1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

M10

M11

0
2,91,8
7,00,6
11,90,4
16,01,0
20,21,5
24,62,8
27,72,3
31,62,4
34,92,5
37,93,5
40,93,3

1,80,1
3,50,2
4,90,2
6,30,5
7,80,5
10,10,6
16,31,1
21,81,2
27,51,3
33,22,1
39,43,2
45,83,5

Bng 4: Kt qu th ha tan cc mu M12, M13 (n=3)

94

Thi gian(h)
0
1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

M12(100,12%) M13(150,16%)
0
0
3,50,3
0
17,51,6
34,42,0
50,22,4
65,31,8
80,12,5
93,62,6
97,54,0
99,03,1
100,02,6

2,80,5
10,51,5
18,41,5
26,32,0
34,92,6
43,12,5
51,41,8
59,01,9
67,33,2
75,52,4
81,52,5

Bng 5: Kt qu th ha tan cc mu c kch thc ming gii phng khc nhau

(n=3)
Thi gian(h)
0
1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

M14(0,80,02 mm) M15(1,00,03 mm)
0
0
1,50,2
12,51,1
25,32,2
37,51,3
49,82,5
633,1
75,23,0
87,52,6
95,62,6
97,52,8
98,51,6
99,03,5

95

3,50,2
14,51,1
29,21,3
43,32,2
57,42,5
73,82,8
88,22,9
98,53,3
99,53,0
100,03,5

Bng 6: Kt qu th ha tan mu M6 cc mi trng pH khc nhau, (n=3)

Thi gian(h)
0
1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

pH 1,2
pH 4,5
pH 6,5
0
0
0
0
1,30,5
0
9,51,1
11,41,0
12,21,2
19,51,2
23,21,5
21,11,5
28,81,3
35,12,2
31,82,0
39,62,3
46,62,1
42,82,5
48,93,1
57,83,1
53,83,1
59,63,5
68,33,2
64,13,3
70,23,6
78,51,5
73,71,1
80,32,8
88,03,3
82,33,5
87,82,8
92,42,5
90,32,8
93,22,9
96,42,6
93,52,7
95,53,4
96,32,4
95,01,6

Bng 7: Kt qu th ha tan mu M6 vi tc cnh khuy khc nhau (n=3)

Thi gian(h)
0
1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

50 rpm
75 rpm
100 rpm
0
0
0
0
0
1,50,5
12,21,2
11,01,1
12,61,2
21,11,5
23,52,3
26,21,6
31,82,0
35,82,5
37,73,2
42,82,5
46,03,4
47,53,3
53,83,1
56,43,5
58,53,5
64,13,3
67,52,6
68,52,6
73,71,1
76,31,7
78,32,8
82,33,5
85,12,7
87,73,6
90,32,8
92,63,7
93,33,8
93,52,7
94,53,5
95,03,1
95,01,6
95,52,5
95,43,4

96

Bng 8: Kt qu th ha tan mu M6 cc mi trng nng NaCl khc nhau

(n=3)
Thi gian(h)
0
1
2
3
4
5
6
7
8
9
10
11
12

T l felodipin gii phng(%SD)

0 mg NaCl 20 mg NaCl 40 mg NaCl
0
0
0
0
0
0
12,21,2
0
0
21,11,5
0
0
31,82,0
0,50,1
0
42,82,5
1,10,1
0,50,1
53,83,1
1,80,4
0,80,1
64,13,3
2,60,5
1,20,2
73,71,1
3,50,4
1,60,3
82,33,5
4,50,5
2,00,1
90,32,8
5,30,3
2,10,2
93,52,7
6,21,1
2,30,3
95,01,6
7,11,0
2,50,3

Bng 9: Kt qu th ha tan vin Felutam trong cc mi trng pH khc nhau

Thi gian(h) pH 1,2
0
0
30,22,2
1
39,62,3
2
49,43,3
3
59,63,3
4
68,43,5
5
76,73,2
6
85,73,5
7
95,92,3
8
98,12,4
9
100,02,8
10

pH 4,5
0
45,62,8
54,42,6
59,53,5
65,93,4
72,02,1
80,12,4
90,02,2
95,42,3
97,43,2
100,03,3

97

pH 6,5
0
19,12,1
28,22,3
38,92,0
49,82,3
60,73,2
70,73,5
80,13,6
90,53,6
98,23,8
100,02,4

Hnh 1: th gii phng dc cht t vin Felutam cc mi trng pH khc

nhau

98

Hnh 2: So snh ha tan gia mu vin la chn v vin Felutam mi trng

pH 6,5

99