B Y T

TRNG I HC DC H NI

MN VN HNG

NGHIN CU BO CH VIN NN

R NHANH CHA FELODIPIN

KHA LUN TT NGHIP DC S

H NI - 2013

B Y T TRNG I HC DC H NI

MN VN HNG

NGHIN CU BO CH VIN NN R NHANH CHA FELODIPIN

KHA LUN TT NGHIP DC S

Ngi hng dn: 1. PGS.TS. Phm Th Minh Hu 2. TS. Nguyn Thch Tng Ni thc hin: B mn Bo ch

H NI 2013

LI CM N

Vi tt c lng knh trng v s chn thnh, ti xin c by t nim bit n

su sc tic gio PGS.TS. Phm Th Minh Hu, ti thy gio TS. Nguyn Thch

Tng Ging vin B mn Bo ch, Trng i hc Dc H Ni, nhng ngi

trc tip hng dn, ch bo tn tnh, gip v truyn t nhng kinh nghim

qu bu cho ti hon thnh kha lun ny.

Ti cng xin gi li cm n ti cc thy c gio, cc anh ch k thut vin

b mn Bo Ch nhit tnh gip , to mi iu kin thun li cho ti trong thi

gian lm thc nghim ti b mn.

Cui cng, xin by t lng bit n su sc ti gia nh v bn b, nhng ngi

lun ng vin ng h ti trong sut qu trnh hc tp, rn luyn v nghin cu

ti Trng i hc Dc H Ni.

H Ni, ngy 21 thng 5 nm 2013

Sinh vin

Mn Vn Hng

MC LC LI CM N

DANH MC CC K HIU V CH VIT TT

DANH MC BNG

DANH MC CC HNH V, TH

T VN ............................................................................................................ 1

CHNG I: TNG QUAN ................................................................................ 2

1.1. Tng quan v felodipin. ................................................................................. 2

1.1.1. Cng thc cu to ......................................................................................... 2 1.1.2. Tnh cht l ha ............................................................................................ 2

1.1.3. Dc ng hc .............................................................................................. 2

1.1.4. Tc dng dc l .......................................................................................... 3

1.1.5. Ch nh, chng ch nh, liu dng, tc dng ph .................................... 3

1.1.6.Mt s dng bo ch cha felodipin trn th trng .................................. 4

1.2. i cng v h phn tn rn ....................................................................... 4

1.2.1. Khi nim ...................................................................................................... 4

1.2.2. u nhc im ............................................................................................. 4

1.2.3. Cu trc l ha .............................................................................................. 5

1.2.4. Cc cht mang thng dng ........................................................................ 5

1.2.5. C ch lm tng tan v tc ha tan ................................................... 5

1.2.6. Cc phng php bo ch h phn tn rn ................................................ 6

1.2.6.1.Phng php un chy ............................................................................... 6

1.2.6.2.Phng php dung mi ............................................................................... 6

1.2.6.3.Phng php un chy kt hp vi dung mi ............................................ 6

1.2.7.Phng php nh gi HPTR ..................................................................... 6

1.2.8. n nh ca HPTR .................................................................................. 7

1.2.9. Mt s nghin cu v h phn tn rn cha felodipin trn th gii ......... 7

1.3. Khi qut v vin nn r nhanh .................................................................. 10

1.3.1. Khi nim .................................................................................................... 10

1.3.2. u nhc im ........................................................................................... 10

1.3.3. Phng php bo ch vin nn r nhanh ................................................. 11

1.3.4.Mt s nghin cu v vin nn r nhanh cha felodipin trn th gii .... 12

CHNG II: NGUYN LIU V PHNG PHP NGHIN CU ......... 15

2.1. Nguyn liu v thit b ................................................................................. 15

2.1.1.Nguyn liu ................................................................................................. 15

2.1.2. Thit b ........................................................................................................ 15

2.2. Ni dung nghin cu .................................................................................... 16

2.2.1. Nghin cu bo ch HPTR cha felodipin ............................................... 16

2.2.2. Nghin cu bo ch v ti u vin nn r nhanh cha HPTR ca felodipin .................................................................................................................... 16

2.3. Phng php ................................................................................................. 16

2.3.1. Kho st s ph thuc ca nng dc cht ti hp th quang ..... 16

2.3.2. Phng php bo ch HPTR ..................................................................... 17

2.3.2.1.Phng php dung mi ............................................................................. 17

2.3.2.2.Phng php un chy kt hp dung mi ................................................ 17

2.3.3. Phng php bo ch vin nn r nhanh ................................................. 18

2.3.3.1.Phng php dp tng vin ...................................................................... 18

2.3.3.2.Phng php to ht t .......................................................................... 18

2.3.3.3.Phng php ti u ha ........................................................................... 19

2.4. Phng php nh gi ................................................................................. 19

2.4.1.Phng php nh gi HPTR ................................................................... 19

2.4.1.1.nh lng hm lng dc cht trong HPTR ........................................ 19

2.4.1.2.nh gi tc ha tan ca felodipin trong HPTR ................................. 19

2.4.1.4.Ph hng ngoi (IR) ................................................................................. 20

2.4.1.5.Phn tch nhit vi sai (DSC) ..................................................................... 20

2.4.1.6.nh gi n nh ca HPTR ............................................................... 20

2.4.2. Phng php nh gi vin nn r nhanh ............................................... 21

2.4.2.1.nh lng hm lng dc cht trong vin nn .................................... 21

2.4.2.2.nh gi thi gian r ............................................................................... 21

2.4.2.3.nh gi mi mn ............................................................................... 21

2.4.2.4.nh gi tc ha tan ca felodipin trong vin nn r nhanh ............. 22

2.5. Phng php x l s liu ........................................................................... 22

CHNG III: THC NGHIM, KT QU V BN LUN ..................... 23

3.1. Kt qu thc nghim v bn lun ............................................................... 23

3.1.1. Kho st s ph thuc ca hp th quang vi nng dc cht ..... 23

3.1.2. Nghin cu bo ch HPTR cha felodipin ............................................... 23

3.1.2.1.Kho st nh hng ca cc loi polyme khc nhau ............................... 24

3.1.2.2.nh gi nh hng ca t l felodipin v HPMC trong h phn tn rn ti tc ha tan ca felodipin trong HPTR ............................................................ 26

3.1.2.3.Kho st nh hng ca khi lng phn t HPMC khc nhau ............. 27

3.1.2.4.Kho st nh hng ca kch thc tiu phn HPTR ti tc ha tan ca felodipin trong HPTR ......................................................................................... 28

3.1.2.5.Kho st nh hng ca cc loi t dc hp ph khc nhau ti tc ha tan ca felodipin trong HPTR ............................................................................ 29

3.1.2.6.o ph hng ngoi (ph IR) ..................................................................... 30

3.1.2.7.Phn tch nhit vi sai (DSC) ..................................................................... 31

3.1.2.8.nh gi n nh ................................................................................. 32

3.1.3. Nghin cu bo ch vin nn r nhanh cha h phn tn rn ca felodipin .................................................................................................................... 33

3.1.3.1.Kho st nh hng ca phng php bo ch ti thi r ca vin nn.....35

3.1.3.2.Kho st nh hng ca t dc n, t dc siu r, v cc t c khc ti thi gian r ca vin nn ............................................................................. 36

3.1.3.3.Kho st nh hng ca kch thc chy ci ti thi gian r ca vin nn.37

3.1.3.4.Kho st nh hng ca cng ti thi gian r v mi mn ca vin nn.38

3.1.3.5.Ti u ha cng thc ................................................................................ 39

KT LUN V XUT ................................................................................ 46

1. Kt lun ........................................................................................................... 46

2. xut ............................................................................................................. 47

TI LIU THAM KHO .................................................................................. 48

PH LC I .......................................................................................................... 50

1. Nghin cu bo ch HPTR ca felodipin ..................................................... 50

2. Nghin cu bo ch vin nn r nhanh cha HPTR ca felodipin ............ 53

DANH MC CC K HIU V CH VIT TT

K hiu Cm t y SKD Sinh kh dng TLTK Ti liu tham kho TKHH Tinh khit ha hc TC NSX Tiu chun nh sn xut BP Dc in Anh USP Dc in M CT Cng thc STT S th t TB LC Trung bnh lch chun TG Thi gian HPTR H phn tn rn PEG Polyethylen glycol PVP Polyvinyl pyrrolidon HPMC Hydroxypropylmethylcellulose HP -CD Hydroxypropyl beta cyclodextrin CP Crosspovidon NSG Natri starch glycolat NLS Natri lauryl sulfat KTMR Kch thc mt ry

DANH MC CC BNG

Tn bng Trang Bng 1.1. Mt s dng bo ch ca felodipin trn th trng 4 Bng 1.2. Mt s nghin cu v h phn tn rn cha felodipin trn th

gii 8

Bng 1.3. Mt s nghin cu v vin nn r nhanh chafelodipin trn th

gii 12

Bng 2.1. Nguyn liu s dng cho nghin cu 15 Bng 3.1. Cng thc bo ch h phn tn rn cha felodipin 24 Bng 3.2. Phn trm ha tan ca felodipin t HPTR thi im mi bo

ch (ban u) v sau khi lo ha cp tc 1 thng ( 40 2o C, m 75%) 32

Bng 3.3. Cng thc bo ch vin nn r nhanh cha felodipin bng

phng php dp tng vin 34

Bng 3.4. Cng thc bo ch vin nn r nhanh cha felodipin bng

phng php to ht t 35

Bng 3.5. nh hng ca phng php bo ch ti thi gian r ca vin

nn 35

Bng 3.6. nh hng ca cc loi t dc ti thi gian r ca vin nn 36 Bng 3.7. nh hng ca cng ti thi gian r v mi mn ca vin

nn 39

Bng 3.8. Mc trn v mc di ca manitol v CP trong thit k cng

thc nh gi 39

Bng 3.9. Cng thc nh gi nh hng ca manitol v CP c thit k

bng phn mm MODDE 8.0 40

Bng 3.10. nh hng ca manitol v CP ti phn trm gii phng ca

felodipin t vin nn r nhanh 40

Bng 3.11. nh hng ca lng manitol v CP ti thi gian r v mi

mn ca vin nn r nhanh 41

Tn bng Trang Bng 3.12. Cng thc ti u vin nn r nhanh cha felodipin c thit

k bng phn mm INFORM 3.1 44

Bng 3.13. Thi gian r v mi mn ca vin nn bo ch theo cng

thc ti u 45

Bng 4.1. Phn trm gii phng ca felodipin t HPTR vi cht mang l

PVP K30, PEG 4000, HPMC E6, c t l felodipin vi cht mang l 1:1 51

Bng 4.2.Phn trm gii phng ca felodipin t HPTR vi cht mang l

PEG 4000, HPMC E6, c t l felodipin vi cht mang l 1:3 51

Bng 4.3. Phn trm gii phng ca felodipin t HPTR vi cht mang l

HPMC E6, c t l felodipin vi cht mang l 1:1, 1:3, 1:4, 1:6 52

Bng 4.4. Phn trm gii phng ca felodipin t HPTR vi cht mang l

HPMC E6, HPMC K4M, HPMC K15M, c t l felodipin vi cht mang l

1:3.

52

Bng 4.5. Phn trm gii phng ca felodipin t HPTR vi cht mang l

HPMC E6, c t l felodipin vi cht mang l 1:3, kch thc tiu phn l

:180, 350, 600, 800 m 53

Bng 4.6. Phn trm gii phng ca felodipin t HPTR vi cht mang l

HPMC E6, c t l felodipin vi cht mang l 1:3, t dc hp ph:

lactose, Aerosil 53

Bng 4.7. nh hng ca kch thc chy ci ti thi gian r ca vin nn 54 Bng 4.8. Tc gii phng felodipin t vin nn bo ch theo cng thc

ti u 54

DANH MC CC HNH V, TH

Tn hnh Trang

Hnh 1.1. Qu trnh thay i cu trc l ha ca HPTR trong thi gian

bo qun 7

Hnh 3.1. th ph thuc ca hp th quang vi nng dc cht 23 Hnh 3.2. th so snh tc ha tan ca felodipin trong HPTR s dng

3 loi polyme HPMC E6, PEG 4000, PVP K30 vi t l dc cht v

polyme l 1:1, (n= 3, TB LC) 24

Hnh 3.3. th so snh tc ha tan ca felodipin t HPTR s dng

cht mang l HPMC E6 v PEG 4000 vi t l dc cht v polyme l 1:3

(n=3, TB LC) 25

Hnh 3.4. th nh hng ca t l polyme ti tc gii phng ca

felodipin trong HPTR (n=3, TB LC) 26

Hnh 3.5. th nh hng ca khi lng phn t HPMC ti tc ha

tan ca felodipin trong HPTR (n=3, TB LC) 27

Hnh 3.6. th nh hng ca kch thc tiu phn ti tc ha tan

ca felodipin trong HPTR (n=3, TB LC) 28

Hnh 3.7. th nh hng ca t dc hp ph ti tc ha tan ca

felodipin t HPTR (n=3, TB LC) 29

Hnh 3.8. Ph hng ngoi ca felodipin, HPTR c t l felodipin v HPMC

E6 l 1:1, 1:3, 1:6 v HPMC E6 30

Hnh 3.9. Kt qu phn tch nhit vi sai (DSC) ca (a) felodipin,(b) HPMC

E6,(c) SD5 mi bo ch, (d) SD5 lo ha 1 thng diu kin thng 31

Hnh 3.10. nh hng ca kch thc chy ci ti thi gian r ca vin

nn.(n=3, TB LC) 38

Tn hnh Trang Hnh 3.11. Mt p3D nh hng ca lng manitol v lng CP ti tc

ha tan ca felodipin t vin nn sau 5 pht 41

Hnh 3.12. Mt p 3D nh hng ca lng manitol v lng CP ti thi

gian r ca vin nn 42

Hnh 3.13. Mt p 3D nh hng ca lng manitol v lng CP ti

mi mn ca vin nn 43

Hnh 3.14. Tc gii phng ca felodipin trong vin nn bo ch theo

trong cng thc ti u (n=3,TB LC) 45

1

T VT Vi s pht trin ngy cng hin i ca cng ngh bo ch, nhiu dng bo ch

mi c ra i, qua gip cho vic s dng thuc ngy cng an ton, hiu qu

v tin dng hn. Vin nn r nhanh l mt dng bo ch mi, c rt nhiu s

quan tm trong vi nm tr li y. iu ny c minh chng bng vic xut hin

ngy cng nhiu ch phm trn th trng. Dng bo ch ny c nhiu u im ni

bt so vi vin nn quy c nh: sinh kh dng (SKD) ca dc cht c tng ln

ng k, ung khng cn nc, hng v d chu V c bit thch hp vi

trng hp cn tc dng nhanh.

Felodipin l mt thuc chng tng huyt p thuc nhm dihydropyridin. Thuc

hp thu tt qua ng tiu ha. Tuy nhin, thuc b chuyn ha qua gan bc mt

v km tan trong nc, nn SKD ng ung thp ch 16%. Vn kh khn t ra

l ci thin tan v tng SKD ca thuc. To HPTR l phng php ci thin tc

ha tan kh ph bin trong bo ch. Vin nn r nhanh gip dc cht phn tn

nhanh. Kt hp HPTR vi vin nn r nhanh l mt hng i mi gip ci thin tc

ha tan v thi gian tc dng, dc cht trnh c chuyn ha qua gan bc

mt qua lm tng SKD ca thuc. V vy trong kha lun ny, chng ti tin

hnh:

Nghin cu bo ch vin nn r nhanh cha felodipin

Vi mc tiu chnh nh sau:

1. Nghin cu bo ch h phn tn rnci thin tc ha tan ca

felodipin.

2. Nghin cu bo ch vin nn r nhanh cha h phn tn rn ca

felodipin.

2

CHNG I: TNG QUAN 1.1. Tng quan v felodipin 1.1.1. Cng thc cu to - Cng thc cu to:

- Cng thc phn t: C18 H19Cl2NO4 [4].

- Tn khoa hc:

Ethyl methyl (4RS)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-

dicarboxylate [4].

- Khi lng phn t: 384,3 [4].

1.1.2. Tnh cht l ha - Cm quan v tan: bt kt tinh mu trng n vng, tan t do trong aceton,

ethanol, methanol, methylene chlorid, rt t tan trong heptan, thc t khng tan

trong nc [4][23].

- Hp th UV- VIS, hp th quang cc i bc sng = 238 nm v = 361

nm, t s hp th A 361 / A238= 0,34 ti 0,36. im chy t 142 145o C [4].

1.1.3. Dc ng hc Hp thu:

Felodipin c hp thu hu nh hon ton qua ng tiu ha. Qu trnh hp thu

khng b nh hng bi thc n. Tuy nhin SKD ng ung ca felodipin thp,

ch khong 16%, do thuc b chuyn ha qua gan bc mt [8][22].

Phn b: Felodipin lin kt mnh vi protein huyt tng, ti 99% ch yu l albumin.

Th tch phn b Vd l 9,7 (L/Kg). H s thanh thi ton phn l 12 (mL/pht/kg).

3

Nng thuc trong mu t hiu qu iu tr do tng huyt p tm trng t 1 ti

50g/ml. nng 3g/ml c tc dng gim 50% cc trng hp tng huyt

p[8][22].

Chuyn ha v thi tr: Felodipin chuyn ha gn nh hon ton qua gan ch yu ti enzym CYP450.

Felodipin thi tr ch yu qua nc tiu di dng mt hot tnh khong 70 % liu

dng. Trong nc tiu khng qu 0,5 % liu dng c thi tr di dng cn hot

tnh. Phn cn li c thi tr qua phn. Thi gian bn thi t 11 ti 16 gi

[8][22].

1.1.4. Tc dng dc l Felodipin l thuc chn knh calci thuc nhm dihydropyridin. Thuc gy h

huyt p do lm gin mch ngoi vi. Thuc tc dng theo c ch c ch s vn

chuyn ca ion Ca++ vo trong lng t bo c trn mch mu gy gin c v gim

sc cn ngoi vi [22].

1.1.5. Ch nh, chng ch nh, liu dng, tc dng ph Ch nh: iu tr tng huyt p, au tht ngc n nh [22]. Chng ch nh: mn cm vi felodipin, ph n c thai, suy tim mt b, nhi

mu c tim cp tnh, cc trng hp au tht ngc khng n nh [8].

Tc dng ph. - Thuc dung np tt. Tc dng ph thng gp l mt, ph ngoi bin, nh

trng ngc v mt mi. Tc dng ny thng xut hin khi mi iu tr hay khi tng

liu [8].

Liu dng. - iu tr tng huyt p: liu ban u l 5mg/ngy (vi ngi gi l 2,5 mg/ ngy)

vo bui sng. Liu thng thng l 5 10 mg/ngy. Him khi s dng liu ln hn

20 mg/ngy [5][22].

- iu tr au tht ngc: liu 5mg/ ngy, tng ln 10mg/ ngy nu cn thit [5][22].

4

1.1.6. Mt s dng bo ch cha felodipintrn th trng Bng 1.1. Mt s dng bo ch ca felodipin trn th trng

Tn bit dc Hot cht Hm lng

Hng sn xut Dng bo ch

Plendil Plus Felodipin 5 mg

AstraZeneca Vin nn gii phng ko di Metoprololtartrat 50 mg

Plendil ER Felodipin 2 mg 5mg 10 mg

AstraZeneca Vin nn bao phim gii phng ko di

Felobeta Felodipin 5 mg 10 mg BetapharmArzneimittel

Vin nn tc dng chm.

Felodipin STADA 5mg retard

Felodipin 5 mg Stadapharm GmbH Vin nn tc dng chm.

Nhn xt: qua bng 1.1 cho thy, hu ht cc dng bo ch ca felodipin trn

th trng l tc dng ko di. Vin nn tc dng nhanh cn s dng trong trng

hp cp tnh cha c cp. V vy, nghin cu bo ch vin nn r nhanh cha

felodipin l mt vn cn mi.

1.2. i cng v h phn tn rn 1.2.1. Khi nim H phn tn rn (HPTR) l mt h rn m trong mt hay nhiu dc cht

c phn tn trong mt hay nhiu cht mang tr v tc dng dc l v c bo

ch bng phng php thch hp [1][3][14].

1.2.2. u nhc im u im:

- Tng SKD ca dc cht [15][19].

- Tng tan v tc ha tan ca dc cht [15][19].

- D ch to v d s dng hn cc phng php ci thin tan khc [3][14].

Nhc im: HPTR khng c ng dng rng ri trong cng nghip do:

- Bo ch HPTR mt nhiu thi gian v kinh ph.

5

- HPTR km n nh trong qu trnh bo qun, dc cht d chuyn trng thi

t dng v nh hnh sang dng kt tinh.

- HPTR c dnh cao nn kh kt hp vo cc dng bo ch [14][15].

1.2.3. Cu trc l ha H phn tn rn c cc loi cu trc c bn sau y:

- Hn hp eutectic n gin.

- Dung dch rn.

- To thnh hp cht v phc cht mi [3][21].

1.2.4. Cc cht mang thng dng Nhng yu cu chnh ca cht mang s dng cho bo ch HPTR bao gm:

- Tan tt trong nc.

- Khng c v khng c tc dng dc l.

- n nh vi nhit v c nhit nng chy thp i vi phng php un

chy.

- C kh nng lm tng tan ca dc cht t tan.

- Khng c tng tc ha hc v khng to thnh phc bn vng vi dc

cht.

- Tan trong nhiu dung mi khc nhau v nhit chuyn knh cao i vi

phng php dung mi [14].

Cht mang s dng l cc polyme thn nc nh: polyethylen glycol (PEG)

polyvinyl pyrrolidon (PVP), hydroxypropylmethylcellulose (HPMC).

1.2.5. C ch lm tng tan v tc ha tan HPTR c tc dng ci thin tan v tc ha tan theo hai c ch chnh:

- c ch qu trnh chuyn t dng v nh hnh sang dng tinh th ca dc

cht. Dc cht dng kt tinh c tan km. Nhng khi chng tn ti trng thi

v nh hnh th tan tng ln ng k, do khng cn cung cp nng lng ph

v mng tinh th [15].

6

- Gim kt t tiu phn: mt s polyme dng lm cht mang trong HPTR c

kh nng gy thm. Do , lm gim vn cc v tng din tch tip xc ca tiu

phn HPTR vi mi trng ha tan [15].

1.2.6. Cc phng php bo ch h phn tn rn 1.2.6.1. Phng php un chy

Phng php un chy thng p dng vi dc cht v cht mang c nhit

nng chy thp v bn vi nhit . Hn hp vt l ca dc cht v cht mang

thn nc c un nng ti khi chy lng hon ton. Hn hp chy lng sau

c lm lnh nhanh bng nc . Cht rn thu c sau c em nghin v

ry qua ry c kch thc mt ry thch hp [14][15][19].

1.2.6.2. Phng php dung mi

Phng php dung mi p dng vi dc cht v cht mang khng bn vi

nhit hoc c nhit nng chy cao. Dc cht v cht mang thn nc c

ha tan trong mt hoc hn hp dung mi d bay hi. Sau c loi b dung

mi theo nhiu cch khc nhau nh: bc hi dung mi trong ni cch thy, trong t

sy hay bay hi nhit phng, phun sy [14][15][19].

1.2.6.3. Phng php un chy kt hp vi dung mi

p dng khi phng php un chy v phng php dung mi kh thc

hin. Cht mang hay s dng trong phng php ny l PEG, do chng c nhit

nng chy trung bnh (di 70o C). u tin, dc cht c ha tan trong dung

mi d bay hi. Cht mang c un nng ti khi chy lng. Phi hp dung dch

dc cht vo cht mang chy lng, khuy ti khi thu c hn hp ng nht. Hn

hp thu c em loi b dung mi [14][15][19].

1.2.7. Phng php nh gi HPTR nh gi tng tc dc cht v cht mang

- Phn tch nhit vi sai (DSC).

- Nhiu x tia X (pXRD).

- Ph FT-IR.

nh gi hnh thi cu trc HPTR

7

Knh hin vi in t qut (Scanning electron microscopy).

nh gi n nh

- Phn tch nhit vi sai (DSC).

- nh gi tc ha tan ca dc cht trong HPTR [15].

1.2.8. n nh ca HPTR Trong HPTR, dc cht tn ti ch yu di dng v nh hnh. iu ny dn

ti cu trc l ha ca HPTR khng bn v mt nhit ng hoc. Thc t, trong

HPTR lun tn ti mt lng nh dc cht tn ti di dng nhng ht tinh th.

Nhng ht tinh th ny to mm kt tinh ca qu trnh chuyn dng dc cht trong

thi gian bo qun HPTR. V vy tc gii phng dc cht s gim i sau mt

thi gian bo qun [16].

Cht mang s dng trong HPTR l cc polyme thn nc. Chng c kh nng

ht m mnh. Hm lng nc cao thc y nhanh qu trnh chuyn sang dng tinh

th ca dc cht trong HPTR [19].

Hnh 1.1. Qu trnh thay i cu trc l ha ca HPTR trong thi gian bo qun

Nh vy, HPTR km n nh nn vn m bo n nh l vn cn

c u tin gii quyt. V vy, trong ti ny, chng ti bc u tin hnh nh

gi n nh ca HPTR.

1.2.9. Mt s nghin cu v h phn tn rn cha felod[ipin trn th gii Ci thin tan ca dc cht kh tan bng to HPTR l mt phng php

c t kh lu. Do nhng u im ni bt so vi nhng phng php ci thin tan

khc nn phng php to HPTR c ng dng kh rng ri trong bo ch. Trn

8

th gii c nhiu cng trnh nghin cu v HPTR ca nhiu c cht khc nhau.

Bng di y xin nu ln mt s cng trnh nghin cu tiu biu trn th gii.

Bng 1.2. Mt s nghin cu v h phn tn rn cha felodipintrn th gii

STT Dc

cht

Phng

php Kt qu nghin cu TLTK

1 Felodipin - Dung mi

- Cht mang s dng l PVP K30, HPMC

K4M.

- Dung mi: dichloromethan v methanol

Kt qu:

- Ph IR cho thy khng c tng tc v

mt ha hc gia felodipin v cht mang.

- Nhiu x tia X (pXRD) v phn tch

nhit vi sai (DSC) cho thy, trong HPTR

cht mang c kh nng c ch qu trnh

kt tinh ca dc cht

- HPTR c t l felodipin : PVP K30 l 1

: 3 c kh nng ci thin tc ha tan

ca felodipin tt nht (90,43%felodipin

gii phng sau 90 pht).

[20]

2 Felodipin

- Phng

php dung

mi p dng

vi PVA.

- Phng

php un

chy kt

hp vi

dung mi p

- Cht mang s dng: PEG 6000, PVA

- Dung mi: ethanol.

- Kt hp HPTR c t l felodipin : PVA

l 1:6 vo vin nn, bo ch bng phng

php dp thng.

Kt qu:

HPTR: - Nhiu x tia X (pXRD) v phn tch

nhit vi sai (DSC) cho thy, cht mang c

[6]

9

dng vi

PEG 6000.

kh nng c ch qu trnh kt tinh ca

dc cht.

- HPTR c t l felodipin : PVA l 1:6, c

kh nng ci thin tc ha tan ca

dc cht tt nht (95 % felodipin gii

phng sau 85 pht).

Vin nn: - Thi gian r l 10,0 pht

- cng 4,20kp

- mi mn 0,79 %

3 Felodipin

- Phng

php dung

mi p dng

vi PVP

K30

- un chy

kt hp vi

dung mi p

dng vi

PEG 4000

- Cht mang: PVP K30, PEG 4000

- Dung mi: ethanol.

Kt qu:

- Ph hng ngoi (IR) cho thy, gia

felodipin v cht mang c xy ra tng

tc. Tng tc ny c th l lin kt hydro

ca nhm N-H vi nhm carbonyl ca

cht mang.

- Nhiu x tia X (XRPD) cho thy cht

mang c kh nng c ch qu trnh kt

tinh ca dc cht.

- HPTR c t l felodipin v PVP K30 l

1: 9, c kh nng ci thin tc ha tan

l tt nht (felodipin gii phng hon ton

sau 30 pht).

[10]

10

Nhn xt: qua bng 1.2 cho thy, phn ln cc nghin cu v HPTR ca

felodipin u chn cht mang l PVP K30. HPTR to vi PVP K30 ht m mnh v

b vn cc trong qu trnh bo qun. Cc nghin cu u cha nh gi nh hng

ca kch thc tiu phn, t dc hp ph ti tc ha tan ca felodipin. n

nh ca HPTR cha c cp v nh gi. Cc nghin cu ch dng li bo

ch HPTR, cha kt hp vo vin nn hoc kt hp mi ch dng li bc u.

Vin nn kt hp c thi gian r ln (10 pht) [6], khng phi dng vin nn r

nhanh. Do vy, vic kt hp HPTR vi vin nn r nhanh l mt hng mi.

1.3. Khi qut v vin nn r nhanh 1.3.1. Khi nim

Theo nhiu ti liu nh ngha:

Vin nn r nhanh l dng thuc rn, mi vin cha mt n v phn liu, v

r nhanh vi mt lng nh nc khi t trong ming. Dc cht c gii phng

v phn tn trong nc bt. Sau c nut v hp thu qua ng tiu ha

[9][25].

Theo nhiu ti liu th thi gian r ca vin nn r nhanh phi di 1 pht

[9][25]. Nhng theo cc qun l thuc v thc phm M (FDA), thi gian r ca

vin nn phi di 30 giy [2].

1.3.2. u nhc im u im Vin nn r nhanh c tt c nhng u im ca vin nn thng thng nh m

bo v n nh, ng u phn liu, d ng gi vn chuyn v bnh nhn d

dng s dng [25].

Do r trong khoang ming nn n cng c u im ca dng thuc lng nh:

khng b mc nghn khi nut. Thch hp s dng cho bnh nhn nhi khoa, lo khoa,

bnh nhn nm lit ging, bnh nhn nn lin tc [25].

Dc cht c gii phng v phn tn trong nc bt. Nn chng c th c

hp thu ti khoang ming nn trnh c chuyn ha qua gan bc mt. Qua

lm tng nhanh tc dng ca thuc v tng SKD ca thuc [25].

11

Nhc im - Vin c gi thnh cao [2].

1.3.3. Phng php bo ch vin nn r nhanh C nhiu phng php bo ch vin nn ra nhanh nh:phng php dp vin

qua to ht t, phng php dp thng, phng php ng kh v phng php

c khun... Trong phng php dp thng l ph bin nht. Sau y trnh by

mt s phng php chnh:

Phng php dp thng Phng php dp thng pht trin hn so vi cc phng php dp vin khc

do gim chi ph v thi gian sn xut. Trong phng php ny, dc cht v t

dc c a trc tip vo vin nn khng thng qua giai on lm cm, nn

khng thng qua giai on r trong. V vy, vin d r hn.

u im ni bt ca phng php ny l n p ng c vi dc cht

khng bn vi nhit v m [25].

Phng php dp vin qua to ht t Cc thnh phn gm poly-alcohol (v d: mannitol, xylitol..), acid hu c (nh:

acid citric, acid tartaric), t dc r, dc cht vi t dc khc, c trn kh.

Khi bt c em to ht t vi t dc dnh l dung dch hay h phn tn ca

polyme (nh: polyethylene glycol, carrageenan) trong nc. Ht c to thnh

em dp vin. Tuy nhin, vin bo ch theo phng php ny c thi gian r lu

hn phng php dp thng do tri qua giai on r trong [25].

Phng php ng kh L phng php loi b dung mi nh thng hoa. Dung mi c loi b t

dung dch dc cht v h t dc to ct. Vin nn bo ch theo phng php ny

thng nh v c xp cao. iu ny lm cho vin d r. Khi t vin thuc ln

li, vin nn gn nh ngay lp tc tan r v gii phng dc cht [2][25].

Phng php c khun (Molding) Trong phng php ny, hn hp bt c nho m bng dung mi (thng

l ethanol hoc nc). Khi m c em dp vin lc dp thp hn so vi lc

12

dp khi dp thng. Vin nn sau c loi b ht dung mi bng cch sy kh

[25].

Vin nn bo ch theo phng php ny c thi gian r km hn vin bo

ch theo phng php ng kh. Tuy nhin n d sn xut hn phng php ng

kh [25].

1.3.4. Mt s nghin cu v vin nn r nhanh cha felodipin trn th gii Vin nn r nhanh c rt nhiu s quan tm trong vi nm tr li y.

Ngy cng c nhiu cng trnh nghin cu v vin nn r nhanh trn th gii. Dng

bo ch ny p dng vi nhiu dc cht nh : piroxicam, meloxicam, nimodipin

Tuy nhin, vin nn r nhanh cha felodipin cn t cng trnh nghin cu. c bit

l dng kt hp gia vin nn r nhanh vi HPTR. Bng di y xin gii thiu mt

s cng trnh nghin cu v vin nn r nhanh cha felodipin.

Bng 1.3. Mt s nghin cu v vin nn r nhanh chafelodipin trn th gii

STT Dc cht

Phng php Kt qu nghin cu TLTK

1 Felodipin - Dp thng

- cng: t 3,9 ti 4,4 kg/cm2

- mi mn: t 0,3 ti 0,8 %

- Trong 3 t dc siu r l

crosspovidon, disolcel, natristarch

glycolat, th vin s dng CP lm

t dc r cho thi gian r tt

nht (18,3 giy).

- Tc gii phng: phn trm

gii phng dc cht sau 5 pht

cao nht t 38,0 %

[11]

2 Felodipin

Bc 1: bo ch HPTR ca felodipin vi mt trong cc cht mang l HP -CD Bc 2: kt hp

Kt hp HPTR c t lfelodipin:

HP -CD l 1:1 vi vin nn r

nhanh. Kt qu

- cng ca tt c cc cng

[7]

13

HPTR vi vin nn r nhanh. Vin nn c bo ch theo phng php dp thng

thc nh gi 3 -4 kg/cm2,

- mi mn t 0,120,34 % - Nng dc cht t 99,23ti 100,15%.

- Thi gian r: vin bo ch vi

crosspovidon c thi gian r thp

nht (42 giy) thi gian thm thp

nht (26 giy) so vi vin s dng

disolcel v natri starch glycolat.

- Tc gii phng: vin bo

ch vi CP cho tc gii phng

dc cht nhanh nht (90 % dc

cht c gii phng trong 10

pht u tin).

3 Felodipin

Bc 1: bo ch HPTR ca felodipin vi mt trong cc cht mang l PVP, PEG, manitol cc t l gia felodipin vi cht mang l 1:1, 1:2, 1:4, 1:9.

Bc 2: kt hp HPTR vi vin nn r nhanh. Vin nn c bo ch theo phng php dp thng v thng hoa

- mi mn: t 0,26 ti 0,64 %

- cng: t 2,00 ti 6,05 (kp),

thp nht vi vin bo ch theo

phng php thng hoa.

- Thi gian r t 12 ti 600 giy.

Thi gian thm t t 8 ti 660

giy.

+ Vin bo ch theo phng php

thng hoa cho thi gian r nhanh

nht (12 giy).

+ vin bo ch bng phng php

dp thng: trong 3 loi cht mang

s dng cho HPTR, manitol ci

thin tan tt nht (45 giy).

[17]

14

- Tc gii phng ca dc

cht:

+ Phng php thng hoa: 90 %

dc cht gii phng sau 0,58

pht.

+ Phng php dp thng: 90%

dc cht gii phng sau 3,6

pht.

Nhn xt: t bng 1.3 cho thy, c hai hng da dc cht vo vin nn r nhanh:

- a trc tip felodipin nguyn liu vo vin nn r nhanh: hng ny tuy

thi gian r ca vin nn nhanh (18,3 giy) [11], nhng khng ci thin c tan

ca felodipin (phn trm gii phng sau 5 pht u tin cao nht ch t 38,0 %).

- Kt hp HPTR cha felodipin vo vin nn r nhanh:

+ Vi HPTR s dng HP -CD lm cht mang: thi gian r nhanh nht l 42

giy. Tuy nhin, HP -CD l t dc kh t tin, do vy kh ng dng vo trong

cng nghip.

+ Vi HPTR s dng PVP, PEG, manitol: thi gian r nhanh nht l 45 giy

vi manitol, nhng manitol khng phi l polyme kim sot gii phng. Vi

phng php thng hoa, tuy c thi gian r nhanh (12 giy) [17]. Tuy nhin phng

php ny khng kh thi khi ng dng trong cng nghip.Hn na, vin kt hp vi

HPTR bo ch theo phng php dp thng, tuy c thi gian r (t 40 ti 45 giy)

[7][17] di1 pht nhng vn cha t theo tiu chun ca dc in M (thi gian

r ca vin phi di 30 giy) [2].

Cc cng trnh nghin cu trncng cha tin hnh sng lc cc yu t nh

hng ti thi gian r ca vin nn nh: loi t dc n, kch thc chy ci,

cng v cha tin hnh ti u ha cng thc bo ch. V vy, vic nghin cu mt

cch y v h thng v vin nn r nhanh cha HPTR ca felodipin l cn thit.

15

CHNG II: NGUYN LIU V PHNG PHP NGHIN CU

2.1. Nguyn liu v thit b

2.1.1. Nguyn liu Bng 2.1. Nguyn liu s dng cho nghin cu

STT Tn nguyn liu Ngun gc Tiu chun 1 Felodipin Trung Quc BP 2 Polyvinylpyrrolidon (PVP K30) Trung Quc BP 3 Polyethylene Glycol 4000 c USP 4 Hydroxypropylmethylcellulose E6 M TC NSX 5 Hydroxypropylmethylcellulose K4M M TC NSX 6 Hydroxypropylmethylcellulose K15M M TC NSX 7 -lactosemonohydrat Trung Quc TC NSX 8 Manitol Trung Quc TC NSX 9 Dextran* Trung Quc TC NSX 10 Avicel PH 101 Trung Quc TC NSX 11 Natri starch glycolat Trung Quc TC NSX 12 Crosspovidon c USP

13 Natricroscarmellose (Disolcel) c USP 14 Polyethylene Glycol 6000 c USP 15 Natri lauryl sulfat Trung Quc TC NSX 16 Aerosil Trung Quc TC NSX 17 Magnesistearat Trung Quc TC NSX 18 Dinatrihydrophosphat Trung Quc TC NSX 19 Ethanol tuyt i Trung Quc TKHH 20 Dicloromethan Trung Quc TKHH 21 Natrihydroxyd Trung Quc TC NSX 22 Acid hydrocloric Trung Quc TC NSX

(*: dextran kch thc ht 350 m,)

2.1.2. Thit b - Ni cch thy BUCHI 461

- T sy BINDER

16

- My nghin ba KIKA LABORTECHNIK

- My th tan ERWEKA DT 600

- My o quang ph UV-VIS heios

- Cn phn tch Sartorius BP 121S

- Cn k thut Sartorius TE3102S

- My dp vin tm sai KORSCH model VFD007S21A

- My o cng Pharmatesttyp PTB511E

- My phn tch nhit Mettler Toledo

- T lo ha cp tc Climacell

- My o mi mnpharmatesttyp PTF20E

- My th thi gian r ERWEKA typ E/RSL 10209

2.2. Ni dung nghin cu 2.2.1. Nghin cu bo ch HPTR cha felodipin

- Kho st nh hng ca cc loi polyme,t l dc cht v polyme, kch

thc tiu phn HPTR, t dc hp ph, khi lng phn t cht mang ti tc

ha tan ca felodipin trong HPTR.

- o ph IR, phn tch nhit vi sai (DSC).

- Bc u nh gi n nh ca HPTR.

2.2.2. Nghin cu bo ch v ti u vin nn r nhanh cha HPTR ca felodipin

- Kho st nh hng ca phng php bo ch, t dc n, t dc r, t

dc khc, kch thc chy ci ti thi gian r ca vin nn r nhanh.

- Kho st nh hng ca cng ti thi gian r v mi mn ca vin

nn.

- Ti u ha cng thc.

2.3. Phng php 2.3.1. Kho st s ph thuc ca hp th quang vi nng dc cht

Tin hnh:

17

Pha dung dch gc (dung dch S): cn chnh xc 50 mg felodipin chun. Ha

tan trong 50ml ethanol, cho vo bnh nh mc 200ml. Thm ethanol ti vch, lc

u. c dung dch S c nng 250 g/ml.

Pha dy dung dch chun: t dung dch gc, tin hnh pha dy dung dch

chun c nng 8, 10, 20, 30, 40, 50 g/ml bng ethanol. Dy dung dch chun

em o hp th quang bc sng = 362 nm.

2.3.2. Phng php bo ch HPTR HPTR c bo ch vi mt trong s cc cht mang: PEG, HPMC hay PVP. Ty

theo cht mang s dng m HPTR c ch theo phng php thch hp.

2.3.2.1. Phng php dung mi

p dng vi cc cht mang l HPMCv PVP K30.

- Cn cc thnh phn theo trong cng thc (bng 3.1).

- Trn hn hp felodipin vi cht mang.

- Ha tan hn hp dc cht vi cht mang trong dung mi (vi HPMC l hn

hp dicloromethan v ethanol, vi PVP K30 l ethanol).

- Thm t dc hp ph, khuy u.

- Hn hp thu c em bc hi dung mi mt phn 40o C trong ni cch

thy 1 gi.

- Hn hp sau bc hi dung mi, em sy trong t sy nhit 50o C ti khi

bay ht dung mi.

- Cht rn thu c sau khi sy, n nh trong bnh ht m trong 24h. Sn

phm nghin v ry qua ry c kch thc mt ry thch hp.Bo qun HPTR trong

l thy tinh c nt v bao kn bng giy parafilm, trong bnh ht m, trnh nh

sng.

2.3.2.2. Phng php un chy kt hp dung mi

p dng vi cht mang l PEG 4000.

- Cn cc thnh phn theo cng thc (bng 3.1).

- Ha tan felodipin trong ethanol trong cc c m (cc 1).

18

- Cho PEG 4000 vo 1 cc c m khc (cc 2), un cch thy cho ti khi PEG

4000 tan chy hon ton nhit 70o C.

- Rt dung dch cc 1 sang cc 2 khuy u trong ni cch thy. Trng cc 1

bng ethanol.

- Thm t dc hp ph, khuy u.

- Hn hp thu c em bay hi dung mi 40o C trn ni cch thy trong 1

gi.

- Cht rn thu c em sy nhit 50o C ti khi bay hi ht dung mi.

- Cht rn thu c sau khi sy, n nh v lm kh trong bnh ht m

trong 24 gi. Sn phm em nghin v ry qua ry c kch thc mt ry thch hp.

Bo qun HPTR trong l thy tinh kn, bao giy parafilm, trong bnh ht m,

trnh nh sng.

2.3.3. Phng php bo ch vin nn r nhanh Vin nn r nhanh cha 10mg felodipin c bo ch theo hai phng php:

phng php dp tng vin v phng php to ht t.

2.3.3.1. Phng php dp tng vin

- Cn cc thnh phn theo cng thc (bng 3.3).

- Nghin v ry PEG 6000, NLS qua ry 180 m.

- Ry Aerosil, magnesistearat qua ry 180 m.

- Trn HPTR ln lt vi PEG 6000 (hoc NLS), t c n, t dc siu r,

magnesistearat, Aerosil theo nguyn tc ng lng.

- Hn hp bt sau khi nho trn em dp vin vi cng v ci chy

thch hp.

2.3.3.2. Phng php to ht t

Cn cc thnh phn theo cng thc (bng 3.4)

Bo ch t dc dnh cha HPTR: Ha tan felodipin trong ethanol. Thm ln lt HPMC E6, dicloromethan

khuy ti khi thu c dung dch ng nht. Thm lactose, trn u.

Trn bt kp:

19

- Nghin PEG 6000, ry qua ry 180 m.

- Trn ln lt t dc n, t dc siu r, PEG 6000 theo nguyn tc ng

lng.

To ht: - Khi bt thu c em nho m bng t dc dnh. Khi m thu c to

ht qua ry 350 m. Sy ht nhit 60o C trong 15 pht. Sa ht qua ry 350 m

- Ry Aerosil, magnesistearat qua ry 180 m.

- Trn ht vi Aerosil, magnesistearat.

- Ht sau khi trn vi t dc trn c em dp vin vi cng 3 4 kp v

kch thc chy ci thch hp.

2.3.3.3. Phng php ti u ha

Cng thc nh gi nh hng ca lng manitol v CP c thit k bng

phn mm MODDE 8.0, vi hai binl manitol v CP. nh gi trn ba bin u ra

l tc ha tan ca felodipin sau 5 pht, thi gian r, mi mn.Kt qu kho st

c s dng thit k cng thc ti u bng phn mm INFORM 3.1.

2.4. Phng php nh gi

2.4.1. Phng php nh gi HPTR 2.4.1.1. nh lng hm lng dc cht trong HPTR

Mu chun: t dung dch S (mc 2.3.1), tin hnh pha long bng ethanol

c dung dch c nng 20 g/ml.

Mu th:cn chnh xc mt lng mu tng ng cha 5mg felodipin. Cho

lng bt cn vo bnh nh mc dung tch 100ml. Thm 50ml ethanol vo bnh

nh mc, lc u, siu m 15 pht. Thm ethanol ti vch, lc u. Dung dch thu

c em lc, b 20ml dch lc u. Ht chnh xc 10ml dch lc, cho vo bnh

nh mc 25ml. Pha long dch lc bng ethanol va 25ml, lc u.

Mu chun v mu th c em o quang bc sng = 362 nm. Mu th

c so snh vi mu chun.

2.4.1.2. nh gi tc ha tan ca felodipin trong HPTR

20

Tin hnh theo phng php th tc ha tan ca Karavas E. v cng s

[10]. nh gi trn my th tc ha tan ERWEKA DT 600 kiu cnh khuy.

Thng s:

- Thit b: my o tc ha tan kiu cnh khuy.

- Tc quay: 100 vng/ pht.

- Nhit : 37 0,5o C.

- Mi trng th: 500 ml m phosphat pH 6,5 cha 0,5 % NLS.

- Thi gian th: 60 pht.

Tin hnh: cn chnh xc mt lng HPTR (tng ng khong 10mgfelodipin)

cho vo cc th tc ha tan. Vn hnh my. Ly mu nhng thi im 5, 15,

30, 45, 60 pht. Mi ln ly mu, ht khong 10ml dung dch mu, ng thi b

sung vo cc th mt th tch mi trng mi bng vi th tch mu ht. Mu

sau khi ht c lc qua giy lc, b 4ml dch lc u. Dch lc em o hp th

quang bc sng = 362 nm. Dung dch th ha tan c so snh vi mu chun

nng 20 g /ml (pha theo cch pha mu chun mc 2.4.1.1).

2.4.1.4. Ph hng ngoi (IR)

Ph hng ngoi Fourier c tin hnh trn thit b Model IFS-66/S, Bruker

Optics, Germany. Mt n hai mg mu c trn vi 150 mg KBr v nn thnh a

ng knh 12 mm bng my nn thy lc (Model No. 3912, Carver Inc., U.S.A).

Mu c phn tch trong khong 600-4000 cm-1 vi phn gii l 0,1 cm-1.

2.4.1.5. Phn tch nhit vi sai (DSC)

Cc th nghim DSC c thc hin trn thit b phn tch nhit Mettler Toledo.

Tin hnh nh gi vi cc mu felodipin nguyn liu, HPMC E6, HPTR bo ch

theo cng thc SD5 mi bo ch v lo ha sau 1 thng nhit phng. Mu

chun v mu th c p trn a nhm v chy khong nhit t 40oC n 200oC

vi tc gia nhit 10oC/pht, tc kh nitrogen tc 50 ml/pht.

2.4.1.6. nh gi n nh ca HPTR

Tin hnh lo ha cp vi cc cng thc SD3(1:1), SD5(1:3), SD6(1:4),

SD8(1:6). Bt HPTR ng trong a pettri v c lo ha cp tc trong t vi kh

21

hu iu kin 40 2oC, m 75 0,5 % trong 4 tun. nh gi tc ha tan

ca dc cht trong HPTR thi im tun th 4.

2.4.2. Phng php nh gi vin nn r nhanh 2.4.2.1. nh lng hm lng dc cht trong vin nn

Cn chnh xc 10 vin nn, tnh gi tr trung bnh khi lng ca mt vin.

Tin hnh nghin mn 10 vin. Bt vin c nh lng theo phng php nh

lng hm lng dc cht trong HPTR (mc 2.4.1.1).

2.4.2.2. nh gi thi gian r

Theo phng php th thi gian r ci tin ca dc in M [25].

Tin hnh trn thit b th thi gian r ERWEKA vi thng s:

- ng thy tinh hnh tr di 75,0 - 80,0 mm, ng knh trong 21,5 mm.

- Mt di c gn tm li c mt li kch thc 2,00 mm.

- Th tch mi trng: 900ml nc ct.

- Khong cch gia mt li vi b mt nc trong cc 6 8 cm.

- Nhit : 37 0,5oC

Tin hnh:

nh gi trong iu kin tnh khng c rung lc. Cho mt vin vo ng thy tinh.

Vin r hon ton khi khng cn nhn con hoc bt vin qua ht li. Kim tra nhn

con bng a thy tinh. Thi gian r c ghi bng ng h bm giy.

2.4.2.3. nh gi mi mn

Theo phng php ca dc in M 30 [23]. nh gi trn thit b

pharmatesttyp PTF20E. Thng s:

- S dng trng quay c ng knh 287,0 4,0 mm, dy 38,0 2,0 mm,

ng knh cnh cung 80,5 5,0 mm.

- S vng quay: 100 vng.

- Tc quay: 25 1 vng /pht.

Tin hnh: ly 20 vin nn bt k, sng loi b bt vin. Cn chnh xc 20 vin

(tng ng vi 8g) sng (M1). Lau sch trng quay v cho 20 vin vo trng.

Vn hnh my. Mu sau khi quay, sng loi b bt. Cn li mu (M2).

22

mi mn c tnh theo cng thc:

2.4.2.4. nh gi tc ha tan ca felodipin trong vin nn r nhanh

Tin hnh nh gi tc ha tan ca vin nn r nhanh cha felodipin

ging vi phng php nh gi tc ha tan ca HPTR cha felodipin. Thay

mu HPTR bng vin nn r nhanh (mc 2.4.1.2).

2.5. Phng php x l s liu

D liuctnhton nh phnmm Excel 2007 (Microsoft., USA). Cc

th nghimctinhnh ba ln v biu th bng gi tr trung bnh

lchchun.

Cng thc nh gi nh hng ca manitol v CP ti tc ha tan ca

felodipin, mi mn, thi gian r ca vin nn r nhanh c thit k trn phn

mm MODDE 8.0. Kt qu nh gi c x l v thit k cng thc ti u trn

phn mm INFORM 3.1

23

CHNG III: THC NGHIM, KT QU V BN LUN

3.1. Kt qu thc nghim v bn lun 3.1.1. Kho st s ph thuc ca hp th quang vi nng dc cht la chn c khong nng felodipin ph hp cho nh lng v th

ha tan, tin hnh nh gi mi thng quan gia nng felodipin v mt

quang bc sng = 362 nm.

Hnh 3.1. th ph thuc ca hp th quangvi nng dc cht

Nhn xt:t hnh 3.1 cho thy, gi tr hp th quangtuyn tnh vi nng

dc cht trong khong t 10g/ml ti 40 g/ml bc sng 362 nm, vi h s

tng quan R2 = 0,999. Nh vy, nh lng felodipin bng phng php o quang

m bo chnh xc khong nng t 10 g/ml ti 40 g/ml.

3.1.2. Nghin cu bo ch HPTR cha felodipin la chn HPTR ph hp cho cng thc bo ch vin nn r nhanh xt v kh

nng ci thin tc ha tan ca felodipin, tin hnh xy dng cng thc bo ch

HPTR theo bng 3.1.

24

Bng 3.1. Cng thc bo ch h phn tn rn cha felodipin

CT* (g) SD 1 SD 2

SD 3

SD 4

SD 5

SD 6

SD 7

SD 8

SD 9

SD 10

SD 11

SD 12

SD 13

SD 14

Felodipin 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50 0,50

PVP K30 0,50 - - - - - - - - - - - - -

PEG 4000 - 0,50 - 1,50 - - 3,00 - - - - - - -

HPMC E6 - - 0,50 - 1,50 2,00 - 3,00 - - 1,50 1,50 1,50 1,50 HPMC K4M - - - - - - - - 1,50 - - - - -

HPMC 15M - - - - - - - - - 1,50 - - - -

- Lactose 4,00 4,00 4,00 4,00 4,00 4,00 4,00 4,00 4,00 4,00 4,00 4,00 4,00 -

Aerosil - - - - - - - - - - - - - 4,00 KTMR** (m)

180 180 180 180 180 180 180 180 180 180 350 600 800 180

(*: cng thc, **: kch thc mt ry)

3.1.2.1. Kho st nh hng ca cc loi polyme khc nhau

HPTR thng s dng cc polyme thn nc lm cht mang. Mi polyme

khc nhau vi nhng dc cht khc nhau c kh nng c ch qu trnh kt tinh ca

dc cht l khc nhau. V vy cn tin hnh sng lc chn ra loi cht mang c

kh nng ci thin tc ha tanca dc cht tt nht. Kt qu c th hin

hnh 3.2 v bng 4.1 (ph lc 1).

Hnh 3.2. th so snh tc ha tan ca felodipin trong HPTR s dng 3 loi polyme

HPMC E6, PEG 4000, PVP K30 vi t l dc cht v polyme l 1:1, ( n= 3, TB LC)

25

Nhn xt: t hnh 3.2 cho thy, mc gii phng dc cht trong h HPTR

vi cht mang l PVP K30 sau 5 pht l thp nht (69,44 %)so vi cht mang l

HPMC E6 (75,32 %) v PEG 4000 (73,15 %). iu ny c th do PVP K30 kh

nng c ch qu trnh kt tinh ca dc cht l km nht. Trong qu trnh bo qun,

HPTR s dng cht mang l PVP K30 ht m mnh v b vn cc.

T kt qu ny tip tc kho st tc ha tan ca felodipin trong HPTR vi

cht mang l PEG 4000 v HPMC E6. Kt qu kho st c th hin hnh 3.3 v

bng 4.2 (ph lc 1).

Hnh 3.3. th so snh tc ha tan ca felodipin t HPTR s dng cht mang

l HPMC E6 v PEG 4000 vi t l dc cht v polyme l 1:3 (n=3, TB LC)

Nhn xt:t hnh 3.3 cho thy, mc gii phng dc cht sau 5 pht t

HPTR vi cht mang l HPMC E6 (92,51%) cao hn so vi HPTR c cht mang l

PEG 4000 (88,55 %). Do nht ca PEG 4000 ( 20o C, dung dch 2% PEG 4000

l 13,123mPas [12]) cao hn HPMC E6 ( 20o C, dung dch 2% l 6 mPas [18]).

Kh nng c ch chuyn t trng thi v nh hnh sang trng thi tinh th felodipin

ca HPMC E6 tt hn PEG 4000. Qua bc kho st ny, la chn HPMC E6 lm

cht mang cho bo ch HPTR cha felodipin.

26

3.1.2.2. nh gi nh hng ca t l felodipin v HPMC trong h phn tn

rn ti tc ha tan ca felodipin trong HPTR

la chn c t l dc cht v cht mang cho tc ha tan ca

felodipin trong HPTR cao nht, tin hnh kho st nh hng ca t l felodipin

v HPMC E6. Kt qu c th hin hnh 3.4 v bng 4.3 (ph lc 1).

Hnh 3.4. th nh hng ca t l polyme ti tc gii phng ca felodipin

trong HPTR (n=3, TB LC)

Nhn xt: t hnh 3.4 cho thy, t l dc cht v cht mang l 1:3 th tc

ha tan ca felodipin trong HPTR l cao nht (thi im 5 pht, phn trm ha

tan ln ti 92,51 %). S chnh lch tc ha tan ca felodipin t l 1:3 v 1:4 l

khng nhiu. Tc ha tan thp nht t l 1:1 (thi im 5 pht, phn trm ha

tan l 73,15 %). iu ny c th gii thch nh sau. t l thp, lng HPMC E6

khng c ch hon ton qu trnh kt tinh ca dc cht trong HPTR. Do

trong HPTR vn cn mt lng ln dc cht tn ti di dng tinh th. t l 1:6,

lng HPMC E6 nhiu, nht cao, lng polyme d tha bao ph bn ngoi dc

cht. Khi tiu phn HPTR tip xc vi mi trng ha tan, lp bn ngoi hnh thnh

27

lp dung dch c nht cao. Do cn c thi gian nc ha tan ht lp

polyme bn ngoi, tc gii phng dc cht chm. Qua bc kho st ny, la

chn t l dc cht v cht mang l 1:3 lm t l bo ch HPTR.

3.1.2.3. Kho st nh hng ca khi lng phn t HPMC khc nhau

la chn c khi lng phn t HPMC thch hp nht, tin hnh kho

st nh hng ca khi lng phn t HPMC ti tc ha tan ca felodipin trong

HPTR. Cn c vo iu kin thc t, ch c th chn c HPMC E6, HPMC K4M,

HPMC K15M sng lc. Kt qu kho st c trnh by hnh 3.5 v bng 4.4

(ph lc 1).

Hnh 3.5. th nh hng ca khi lng phn t HPMC ti tc ha tan ca

felodipin trong HPTR (n=3, TB LC)

Nhn xt: t th 3.5 cho thy, tc gii phng felodipin ra khi HPTR trong

5 pht u tin gim dn theo th t SD5 (92,51 %) > SD9(63,81 %) > SD10

(57,24 %). iu ny c th gii thch nh sau, khi lng phn t HPMC cng cao

th nht ca chng cng cao ( nht 20o C, dung dch 2% ca HPMC E6 l 6

mPas,HPMC K4M l 4000 mPas, HPMC K15M l 15000 mPas [18]). Khi tiu phn

HPTR tip xc vi mi trng ha tan, lp polyme bn ngoi ha tan trc to ra

28

lp v bao xung quanh tiu phn HPTR. Lp v ny c nht cao. iu ny cn

tr s xm nhp ca nc vo bn trong tiu phn HPTR v lm chm tc gii

phng ca felodipin trong HPTR

Ngoi ra, thc nghim bo ch cho thy, khi lng phn t tng th thi gian v

lng dung mi s dng ha tan cng tng. Sau th nghim ny, la HPMC E6

lm cht mang bo ch HPTR.

3.1.2.4. Kho st nh hng ca kch thc tiu phn HPTR ti tc ha

tan ca felodipin trong HPTR

nh gi nh hng ca kch thc tiu phn ti tc ha tan ca dc

cht v la chn c kch thc tiu phn ti u em bo ch vin nn, tin hnh

kho st nh hng ca kch thc tiu phn HPTR ti tc ha tan ca felodipin

trong HPTR. Kt qu kho st c trnh by hnh 3.6 v bng4.5 (ph lc 1).

Hnh 3.6. th nh hng ca kch thc tiu phn ti tc ha tan ca

felodipin trong HPTR (n=3, TB LC)

29

Nhn xt: t hnh 3.6 cho thy, tc gii phng ca ca felodipin t HPTR

ti thi im 5 pht gim dn theo th t SD5 (180) > SD11 (350) > SD12 (600) >

SD13 (800). Thi im 60 pht, tc ha tan khng c s khc bit nhiu. S

khc bit v thi im ban u c th gii thch nh sau. Kch thc tiu phn

HPTR cng ln th din tch tip xc gia dc cht v mi trng ha tan gim. V

vy tc gii phng dc cht chm. Qua th nghim ny, la chn tiu phn c

kch thc qua mt ry 180 m lm kch thc bo ch HPTR do c tc gii phng

dc cht l cao nht (thi dim 5 pht l 92,51%).

3.1.2.5. Kho st nh hng ca cc loi t dc hp ph khc nhau ti tc

ha tan ca felodipin trong HPTR

Nhng t dc hp ph c bn cht khc nhau th nh hng ti tc ha

tan ca felodipin trong HPTR l khc nhau. la chn c t dc hp ph ci

thin c tc ha tan ca felodipin trong HPTR tt nht, tin hnh kho st nh

hng ca t dc hp ph. Kt qu kho st c th hin trong hnh 3.7 v trnh

by trong bng 4.6 (ph lc 1).

Hnh 3.7. th nh hng ca t dc hp ph ti tc ha tan ca felodipin t

HPTR. (n=3, TB LC)

30

Nhn xt: t hnh 3.7 cho thy, tc ha tan ca felodipin t HPTR trong 5

pht u gim theo th t SD5 (92,51 %)> SD14 (68,79 %). Aerosil l t dc trn

c bn cht s nc. Trong cng thc ng vai tr l t dc hp ph. lng ln

so vi dc cht (t l dc cht v t dc n l 1:8), gy cn tr s thm ca

nc vo tiu phn HPTR, lm chm tc gii phng dc cht ra khi HPTR.

Cn lactose l t dc hp ph c bn cht thn nc. Khi tip xc vi mi trng

ha tan s ko nc vo bn trong tiu phn. Do , tc gii phng dc cht

cao hn. Qua y, la chn lactose lm t dc hp ph bo ch HPTR.

Sau khi tin hnh kho st nh hng ca cc yu t, la chn cng thc

SD5 c t l felodipin v HPMC E6 l 1:3 lm cng thc ti u. HPTR c bo

ch theo cng thc ny c s dng nh ph IR v o DSC.

3.1.2.6. o ph hng ngoi (ph IR)

Kt qu o ph hng ngoi ca felodipin nguyn liu, HPMC E6, HPTR c

t l felodipin v HPMC E6 l 1:1, 1:3, 1:6 c th hin hnh 3.8.

3000 3250 3500 3750

30

40

50

60

70

80

90

100

HPMC

FEL:HPMC=1:6

FEL:HPMC=1:3

FEL:HPMC=1:1

Inte

nsity

Wavelength (cm-1)

FEL

3371

3384

3388

Hnh 3.8. Ph hng ngoi ca felodipin, HPTR c t l felodipin v HPMC E6 l

1:1, 1:3, 1:6 v HPMC E6.

Nhn xt: t hnh 3.8 cho thy, felodipin nguyn liu c im hp th ti s

sng 3371 cm-1. im ny c th l ca nhm N-H. Ph ca HPMC E6 nguyn liu

31

khng c im hp th ti s sng 3371 cm-1 v cu trc phn t khng c nhm N-

H. Khi tng t l HPMC E6 trong HPTR ln th im hp th ny dch chuyn theo

hng tng s sng hp th. Tuy nhin, s dch chuyn ny l khng nhiu v

cng khng cao. HPTR c t l felodipin vi HPMC E6 l 1:1 th im hp th

th hin khng r rng trn ph. S dch chuyn tn s hp th ny c th d on

do nh hng ca lin kt hydro to thnh gia nhm N-H ca felodipin vi nhm

O-R ca HPMC E6. S nh hng ny cnh mnh khi felodipin tn ti dng v

nh hnh. V dng v nh hnh, nhm N-H linh ng hn v d hnh thnh lin

kt hydro hn. V vy, t l HPMC E6 cng tng th kh nng c ch qu trnh

chuyn t dng v nh hnh sang dng tinh th cng mnh.

3.1.2.7. Phn tch nhit vi sai (DSC)

Hnh 3.9. Kt qu phn tch nhit vi sai (DSC) ca (a)felodipin,(b) HPMC E6, (c)

HPTR (SD5) mi bo ch,(d) HPTR (SD5) lo ha 1 thng nhit phng

Nhn xt: t hnh 3.9 cho thy, xut hin mt nh peak ca felodipin

nguyn liu (a) 145,84oC, vi enthalpy l 81,95 J/g. HPMC E6 (b) khng c peak

145oC. HPTR (SD5) (c) mi bo ch khng c peak 145,84oC, u ny chng

t s tn ti ca trng thi v nh hnh ca dc cht trong HPTR. Nh vy,

HPMC E6 c kh nng c ch tt qu trnh kt tinh ca dc cht. SD5 (d)sau khi

lo ha nhit phng, trn th cng khng c im peak 145,84oC. iu

32

ny chng t HPMC E6 c kh nng c ch tt qu trnh kt tinh tr li ca dc

cht v cu trc l ha ca HPTR c n nh.

Nh vy, c ch lm tng tc ha tan ca HPTR l chuyn dng felodipin

t tinh th sang v nh hnh v HPTR ct l felodipin v HPMC E6 l 1:3 n nh

v mt nhit ng hc.

3.1.2.8. nh gi n nh

HPTR thng km n nh. mi mt t l ca dc cht v cht mang

khc nhau th kh nng c ch li qu trnh kt tinh ca dc cht l khc nhau.

la chn c t l thch hp nht bo m n nh ca HPTR, tin hnh s b

nh gi n nh trong 1 thng ca HPTR trong iu kin lo ha cp tc (40

2o C, m75 5%.). Kt qu nh gi n nh c trnh by bng 3.2.

Bng 3.2. Phn trm ha tan ca felodipin t HPTR thi im mi bo ch (ban

u) v sau khi lo ha cp tc 1 thng 40 2o C, m 75 5 %

Thi gian

(pht)

SD3 (1:1) SD5(1:3) SD6(1:4) SD8(1:6)

Ban u (%)

1 thng (%)

Ban u (%)

1 thng (%)

Ban u (%)

1 thng (%)

Ban u (%)

1 thng (%)

0 0 0 0 0 0 0 0 0

5 73,15 (2,75)

75,68 (4,67)

92,51 (0,15)

74,51 (4,85)

85,62 (2,40)

72,35 (7,40)

81,14 (2,70)

43,59 (13,22)

15 80,16 (2,01)

82,24 (2,95)

88,98 (1,94)

89,15 (1,85)

89,14 (0,76)

83,60 (1,24)

81,40 (0,45)

61,25 (10,04)

30 77,26 (3,07)

83,85 (1,12)

85,89 (1,97)

88,23 (1,68)

88,00 (0,03)

84,01 (1,88)

78,90 (1,66)

68,73 (4,02)

45 76,85 (2,91)

84,57 (1,89)

83,30 (2,34)

87,30 (1,69)

88,38 (0,66)

82,79 (1,64)

78,38 (2,20)

71,64 (0,86)

60 75,24 (1,74)

83,85 (2,66)

82,19 (1,42)

86,00 (1,77)

88,57 (1,78)

84,28 (5,08)

77,52 (2,49)

71,43 (1,39)

(n=3, TB LC)

Nhn xt: tbng 3.2 cho thy, thi im 5 pht u, phn trm gii phng

ca felodipin trong h phn tn rn cc cng thc SD5, SD6, SD8 sau lo ha u

33

gim so vi thi im ban u. C th gii thch s st gim ny nh sau, bt

HPTR c lo ha trong iu kin m cao. Phn t HPMC ht m v hnh

thnh lin kt gia cc tiu phn HPTR. Hm lng HPMC cng ln th cc tiu

phn lin kt vi nhau cng nhiu. Do xc sut phn t HPMC tip xc vi nhau

l rt ln. Nhng lin kt ny lm chm gii phng dc cht ra khi HPTR.

cng thc SD3, thi im 5 pht, s thay i v tc ha tan l khng nhiu.

Trong cng thc SD3, lng HPMC nh v c phn tn trong lng ln lactose,

nn mc lin kt gia cc tiu phn thp. nhng thi im tip theo, cng thc

SD3, SD5, SD6, s thay i v tc ha tan l khng ng k. cng thc SD8

chng kin s st gim mnh v tc gii phng dc cht. Ngoi nguyn nhn

hnh thnh lin kt gia cc tiu phn. Trong cng thc SD8 lng HPMC cao, ht

m mnh, m thc y qu trnh chuyn dng ca dc cht, t dng v nh

hnh khng bn v mt nhit ng hc sang dng tinh th bn hn. V vy, hm

lng dc cht tn ti di dng v nh hnh trong mu SD8 sau khi lo ha mt

thng thp hn mu SD8 ban u. Qua th nghim ny, chng t HPTR c bo

ch vi cht mang l HPMC E6, c t l dc cht v cht mang l 1:3, m bo

n nh v mt tc ha tan.

Nh vy, la chn cng thc SD5 lm cng thc bo ch HPTR cha

felodipin do c kh nng ci thin tc ha tan v n nh nht. Bt HPTR bo

ch theo cng thc SD5 c chn lm nguyn liu bo ch vin nn r nhanh

cha felodipin.

3.1.3. Nghin cu bo ch vin nn r nhanh cha h phn tn rn ca felodipin

Cng thc bo ch vin nn r nhanh cha HPTR ca felodipin bo ch theo

phng php p tng vin c trnh by trong bng3.3 v phng php to ht

t c trnh by trong bng 3.4.

34

Bng 3.3. Cng thc bo ch vin nn r nhanh cha felodipin bng phng php

dp tng vin

Cng thc ODT

1

ODT

2

ODT

3

ODT

4

ODT

5

ODT

6

ODT

7

ODT

8

ODT

9

ODT

10

ODT

11

HPTR cha

felodipin (SD 5)

(mg)

120 120 120 120 120 120 120 120 120 120 120

Avicel PH 101

(mg) 110 110 110 110 110 110 110 110 110 110 110

Manitol (mg) 110 - - 110 110 110 110 110 110 110 110

Dextran (mg) - 110 - - - - - - - - -

Lactose (mg) - - 110 - - - - - - - -

CP (mg) 30 30 30

- 30 30 30 30 30 30

NSG (mg) - - - 30 - -

- - - -

Disolcel (mg) - - - - 30 -

- - - -

PEG 6000 10 10 10 10 10 - - 10 10 10 10

NLS (mg) - - - - - - 10 - - - -

Aerosil (mg) 10 10 10 10 10 10 10 10 10 10 10

Magnesistearat

(mg) 10 10 10 10 10 10 10 10 10 10 10

Khi lng vin

(mg) 400 400 400 400 400 390 400 400 400 400 400

cng (Kp) 3 - 4 3 - 4 3 4 3 - 4 3 4 3 - 4 3 -4 5 - 6 8 - 9 3 - 4 3 4

Kch thc chy

ci (mm) 10 10 10 10 10 10 10 10 10 12 13

35

Bng 3.4. Cng thc bo ch vin nn r nhanh cha felodipin bng phng php

to ht t

Thnh phn Khi lng n v Felodipin 10 mg HPMC E6 30 mg Lactose 80 mg Avicel PH 101 110 mg Manitol 110 mg CP 30 mg PEG 6000 10 mg Aerosil 10 mg Magnesistearat 10 mg Ethanol 0,5 ml Dicloromethan 0,5 ml Tng khi lng vin 400 mg cng 3 - 4 Kp Kch thc chy ci 10 mm

3.1.3.1. Kho st nh hng ca phng php bo ch ti thi gian r ca

vin nn

la chn phng php thch hp nht bo ch vin nn r nhanh, tin

hnh so snh hai phng php dp tng vin v to ht da trn tiu ch thi gian r

ca vin nn.

Bng 3.5. nh hng ca phng php bo ch ti thi gian r ca vin nn

Phng php Dp tng vin To ht t Thi gian r (giy) 45,33 (2,52) 600,67(1,78)

(n=3, TB LC)

Nhn xt: t bng 3.3 cho thy,vin nn bo ch theo phng php to ht

t c thi gian r cao hn rt nhiu (gp 13,25 ln) so vi vin nn bo ch theo

phng php dp tng vin. iu ny c th l gii nh sau. Vin nn bo ch theo

phng php dp tng vin c xp cao hn vin nn bo ch theo phng php

to ht. Trong phng php to ht, lng polyme ng vai tr lm t dc dnh l

kh nhiu, do khi to ht, lng polyme s bm dnh trn b mt cc ht lm

36

tng kt dnh khi dp vin. Do lm tng thi gian r ca vin. Trong phng

php dp tng vin, HPTR c bo ch di dng bt. Chng c phn tn u

trong mt lng ln t dc n v t dc siu r. Nn kh nng tip xc v lin

kt gia cc tiu phn HPTR vi nhau khi dp vin l rt thp. V vy, vin c

xp cao v d r hn. T kt qu ny chn phng php dp tng vin lm phng

php bo ch vin nn r nhanh.

3.1.3.2. Kho st nh hng ca t dc n, t dc siu r, v cc t c

khc ti thi gian r ca vin nn

Thi gian r ca vin nn ngoi chu nh hng ca phng php bo ch, cn

chu nh hng rt ln ca cc loi t dc n, t dc r, t dc khc. V vy,

tin hnh kho st nh hng ca cc loi t dc ti thi gian r. Kt qu c

trnh by bng 3.6.

Bng 3.6. nh hng ca cc loi t dc ti thi gian r ca vin nn

Cc yu t nh hng CT Loi t dc Thi gian r ( giy) T dc n

ODT1 Manitol 45,33 (2,52) ODT2 Dextran 48,00 (2,00) ODT3 -lactosemonohydrat 85,67 (2,08)

T dc siu r

ODT1 CrossPovidon (CP). 45,33 (2,52) ODT4 Natri starch glycolat (NSG) 226,00 (5,29) ODT5 Disolcel 142,33 (2,52)

T dc khc

ODT1 PEG 6000 45,33 (3,21) ODT6 Khng c PEG v NLS 73,67 (2,52) ODT7 Natri lauryl sulfat (NLS) 339,33 (1,15)

(n= 3, TB LC)

Nhn xt: t bng 3.6 cho thy

nh hng ca t dc n: thi gian r ca vin nn tng theo th t sau

ODT1 (manitol) < ODT2 (dextran) < ODT3 (lactose). iu ny c th gii thch

nh sau, tc ha tan ca manitol trong nc v kh nng ht nc ca chng vo

trong vin nn nhanh hn -lactose. Dextran s dng trong cng thc c kch thc

350 m. Do , vin bo ch vi dextran c xp cao hn vin bo ch vi

lactose. Do c xp cao ln kh nng ht nc vo trong vin nhanh hn lactose.

Thi gian r ca vin ODT1 v ODT2 chnh lch nhau khng nhiu. Nhng thc

37

nghim cho thy, trong qu trnh dp vin, vin bo ch vi dextran km t v

ng u khi lng hn vin bo ch vi manitol.

nh hng ca t dc siu r: thi gian r ca vin nn gim theo th t

ODT4 (NSG)> ODT5 (disolcel) > ODT1 (CP). iu ny c th do NSG, disolcel

r theo c ch trng n. Khi trng n, chng to gel c nht nht nh.

nht ca gel to bi NSG v disolcel ty thuc vo hm lng ca chng trong vin

nn. Lp gel ny cn tr s xm nhp ca nc vo bn trong vin nn. Nhng

disolcel c mc to gel v nht ca gel thp hn NSG. ng thi kh nng

ht nc ca chng mnh hn so vi NSG. Vin bo ch vi t dc siu r CP c

thi gian r l tt nht, c th do cu trc c xp cao, r theo c ch ht nc v

trng n mnh, nhng khng to gel [13].

nh hng ca t dc khc: thi gian r ca vin nn tng theo th t

ODT1 (PEG 6000) < ODT6 (khng c PEG 6000 v NLS) < ODT7 (NLS). PEG

6000 bao ph quanh cc tiu phn HPTR, khi dp vin. N s gy ra phn lc c

chiu ngc vi chiu ca lc dp. V vy, PEG 6000 c vai tr chng dnh gia

cc tiu phn HPTR v tng xp cho vin nn. ng thi, PEG 6000 l mt

polyme thn nc v c tc ha tan trong nc nhanh. Thc nghim cho thy,

NLS d chy lng v dnh bt khi nghin nh. Khi dp vin, tiu phn NLS ny s

lin kt vi tiu phn HPTR, lm cho vin c xp km v kh r.

Qua kho st ny, chn manitol lm t dc n, CP lm t dc r, v PEG

6000 cho bc kho st tip theo.

3.1.3.3. Kho st nh hng ca kch thc chy ci ti thi gian r ca vin

nn

Kch thc ca chy ci em dp vin cng c nh hng nht nh ti thi

gian r ca vin nn. thy c s nh hng ny v la chn c kch thc

thch hp em dp vin, tin hnh kho st nh hng ca kch thc chy ci ti

thi gian r ca vin nn. Kt qu kho st c th hin trong hnh 3.10 v trnh

by trong bng 4.7 (ph lc 1).

38

Hnh 3.10. nh hng ca kch thc chy ci ti thi gian r ca vin nn (n=3,

TB LC)

Nhn xt:thi gian r ca vin nn gim theo th t: 10 (45,33 giy) >

12 (36,33 giy) > 13 (29,67 giy). Kch thc chy ci cng ln th thi gian r

ca vin nn cng gim. Do cng mt lng bt em dp vin, khi kch thc chy

ci tng th lc nn ti tm vin nn gim. Ngoi ra, kch thc chy ci tng, vin

mng hn v din tch tip xc vi mi trng ha tan tng. Do vy, vin d r hn.

T kt qu ny, chn chy ci c kch thc 12 mm lm chy ci dp vin cng

thc ti u.

3.1.3.4. Kho st nh hng ca cng ti thi gian r v mi mn ca

vin nn

cng ca vin nn nh hng rt ln ti thi gian r v mi mn ca

vin nn. Nu vin c dp vi cng qu cao th khng t v thi gian r.

Vin c cng thp th khng t v mi mn. V vy, cn phi tin hnh kho

st la chn cng ca vin nn thch hp tha mn hai tiu ch thi gian r v

mi mn. Kt qu c trnh by trong bng 3.7.

39

Bng 3.7. nh hng ca cng ti thi gian r v mi mn ca vin nn

cng (kp) 3 - 4 5 - 6 8 - 9

Kch thc chy ci (mm) 10 10 10

Thi gian r (giy) 45,33 (2,52) 73,67 (3,21) 122,67 (2,52)

mi mn (%) 2,96 1,17 0,17

(n=3, TB LC )

Nhn xt:t bng 3.7 cho thy, cng ca vin nn cng tng th thi gian

r cng tng v mi mn ca vin nn cng gim. Khi cng tng th lc lin

kt gia cc tiu phn tng ln, lc nn ti tm vin nn tng ln ng thi xp

ca vin nn gim i, dn ti thi gian r ca vin nn tng ln. Qua th nghim

ny, chn cng 5 - 6 kp lm cng cho vin nn cng thc ti u. V c mi

mn gn vi gii hn cho php (di 1%) v c thi gian r gn vi mc 1 pht.

3.1.3.5. Ti u ha cng thc

Sau khi tin hnh kho st v la chn c cc loi t dc, kch thc chy

ci, cng thch hp, tin hnh thit k cng thc nh gi nh hng ca manitol

v CP bng phn mm MODDE 8.0. Mc trn v mc di ca manitol v CP s

dng thit k c trnh by trong bng 3.8.

Bng 3.8. Mc trn v mc di ca manitol v CP trong thit k cng thc nh

gi

Tn t dc n v Mc di Mc trn Manitol mg 80 200 CP mg 14 40

Sau khi c c cc gi tr khc nhau ca tng bin u vo, tnh ton v xy

dng cng thc nh gi hon chnh. Cng thc hon chnh c trnh by trong

bng 3.9.

40

Bng 3.9. Cng thc nh gi nh hng ca manitol v CP c thit k bng

phn mm MODDE 8.0

Cng thc TU 1

TU 2

TU 3

TU 4

TU 5

TU 6

TU 7

TU 8

TU 9

TU10

TU11

HPTR ca felodipin (SD5) (mg)

120 120 120 120 120 120 120 120 120 120 120

Avicel (mg) 110 110 110 110 110 110 110 110 110 110 110 Manitol (mg) 80 200 80 200 80 200 140 140 140 140 140 CP (mg) 14 14 40 40 27 27 14 40 27 27 27 PEG 6000 (mg) 10 10 10 10 10 10 10 10 10 10 10

Aerosil (mg) 10 10 10 10 10 10 10 10 10 10 10 Magnseiumstearat (mg) 10 10 10 10 10 10 10 10 10 10 10

Khi lng vin (mg) 354 474 380 500 367 487 414 440 427 427 427

Kch thc chy ci (mm) 12 12 12 12 12 12 12 12 12 12 12

cng (kp) 5-6 5-6 5-6 5-6 5-6 5-6 5-6 5-6 5-6 5-6 5-6

nh gi trn cc tiu ch tc gii phng dc cht sau 5 pht, thi gian r,

mi mn. Kt qu c th hin trong bng 3.10 v bng 3.11.

Bng 3.10. nh hng ca manitol v CP ti phn trm gii phng ca felodipin t

vin nn r nhanh TG* pht

TU 1

TU 2

TU 3

TU 4

TU 5

TU 6

TU 7

TU 8

TU 9

TU 10

TU 11

0 0 0 0 0 0 0 0 0 0 0 0

5 82,69 (0,53)

87,30 (2,09)

80,80 (1,26)

81,61 (2,05)

88,96 (1,61)

88,35 (1,31)

89,13 (2,01)

85,21 (1,80)

86,18 (2,88)

87,60 (0,48)

88,84 (1,47)

15 92,41 (3,72)

92,50 (0,79)

91,83 (0,99)

88,92 (4,95)

91,86 (1,07)

91,45 (1,66)

95,10 (1,17)

92,79 (2,28)

90,32 (1,20)

91,27 (0,84)

92,09 (0,85)

30 90,73 (3,56)

91,13 (0,84)

90,70 (0,39)

90,60 (2,14)

91,02 (1,07)

91,10 (0,93)

92,21 (1,76)

90,41 (0,72)

87,65 (0,84)

87,41 (0,84)

88,74 (0,85)

45 89,40 (3,76)

90,86 (0,16)

89,83 (0,36)

89,89 (2,35)

89,90 (1,28)

89,15 (1,07)

90,29 (2,11)

87,58 (2,20)

84,79 (1,68)

86,13 (0,69)

88,19 (0,90)

60 87,37 (3,72)

88,67 (1,38)

89,32 (3,09)

88,04 (2,30)

87,37 (0,92)

88,97 (0,61)

90,67 (1,82)

87,13 (1,90)

83,51 (1,12)

84,57 (0,55)

86,89 (1,21)

(*: thi gian, n =3, TB LC )

41

Bng 3.11. nh hng ca lng manitol v CP ti thi gian r v mi mn ca

vin nn r nhanh Cng thc

TU 1

TU 2

TU 3

TU 4

TU 5

TU 6

TU 7

TU 8

TU 9

TU 10

TU 11

mi mn (%) 0,12 0,45 0,19 0,49 0,29 0,48 0,24 0,31 0,47 0,43 0,52

Thi gian r (giy)

72,00 (3,61)

62,67 (7,02)

32,00 (3,00)

25,67 (3,06)

30,67 (1,15)

27,67 (0,58)

58,00 (3,00)

23,67 (2,08)

37,67 (2,08)

36,00 (3,61)

38,33 (2,52)

(n=3, TB LC)

Trn c s cc d liu bng 3.10 v bng 3.11 tin hnh nh gi nh

hng hip ng ca CP v manitol ti tc gii phng dc cht sau 5 pht, thi

gian r, mi mn.

nh hng ca CP v manitol c th hin trn hnh 3.11:

Hnh 3.11. Mt p3D nh hng ca lng manitol v lng CP ti tc ha

tan ca felodipin t vin nn sau 5 pht

Nhn xt:t mt p 3D hnh 3.11 cho thy nh hng ca CP v manitol ti tc

gii phng ca felodipin trong vin nn thi im 5 pht u:

- nh hng ca CP: ban u khi lng CP tng dn th tc gii phng ca

dc cht tng dn. Khi lng CP tng ti khong 19,2 mg n 24,4 mg th tc

gii phng dc cht khng tng na mc d lng CP tip tc tng. Tuy nhin, khi

lng CP tng trong khong t 29,6 ti 34,8 mg th tc gii phng dc cht

gim mnh. iu ny do ban u, khi tng lng CP th tc ht nc vo vin

nn tng, do tc gii phng dc chttng. Tc gii phng dc cht dn

42

t ti gi tr ti a. V CP khng tan trong nc, khi tng thm lng CP th s gy

cn tr tc ha tan ca felodipin. V vy tc gii phng ca felodipin gim.

- nh hng ca manitol: t mt p cho thy, ban u khi lng manitol tng

dn th tc gii phng dc cht cng tng dn. Nhng khi tng ti ngng gn

128 mg th tc gii phng khng tng na mc d lng manitol vn tip tc

tng. Ban u khi tng lng manitol ln th tc ko nc vo bn trong vin

nn cng tng, nn tc gii phng ca dc cht tng. Tc gii phng s tng

dn v t ti mt gi tr ti da v duy tr mc ny mc d lng manitol tip tc

tng.

nh hng ca CP v manitol ti thi gian r c th hin trn hnh 3.12:

Hnh 3.12. Mt p 3D nh hng ca lng manitol v lng CP ti thi gian r

ca vin nn

Nhn xt: t mt p 3D hnh 3.12 cho thy:

- nh hng ca lng CP ti thi gian r: ban u, khi tng lng CP th

thi gian r ca vin nn khng i. Tng lng CP ti khong t 24,4 mg n 29,6

mg th thi gian r ca vin nn gim ti cc tiu. Thi gian r ny li tng dn khi

tip tc tng lng CP.

- nh hng ca lng manitol ti thi gian r: khi tng dn lng manitol th

thi gian r khng thay i. Tng lng manitol trong khong t 176 mg ti 200

mg th thi gian r bt u gim dn.

43

iu ny c th gii thch nh sau, c hai c ch chi phi thi gian r ca

vin nn. C ch ht nc trng n to lc y ca CP v c ch ha tan v ko

nc vo vin ca manitol. Ban u, thi gian r b chi phi ch yu bi CP v nh

hng ca manitol nh. Vin nn mi cng nht nh th tn ti nhng khong

gi tr lc lin kt gia cc tiu phn nht nh. Khong gi tr ny gi cho vin nn

r trong mt khong thi gian. Khi tng lng CP ln trong khong t 24,4 ti 29,6

mg th lc y do CP to ra vt qu khong gi tr lc ny v thi gian r ca vin

gim t ngt. Do CP khng tan trong nc, nn khi tip tc tng CP th thi gian

r tng ln nhng khng nhiu. Khi lc y ca CP vt qu khong gi tr lc lin

kt gia cc tiu phn th thi gian r ch yu ph thuc vo tc ha tan v ko

nc vo trong vin ca manitol. V vy, khi tng lng manitol t 176 mg ln 200

mg th tc ha tan v ko nc vo tng nn thi gian r gim xung.

nh hng ca CP v manitol ti mi mn c th hin trong hnh 3.13:

Hnh 3.13. Mt p 3D nh hng ca lng manitol v lng CP ti mi mn ca

vin nn

Nhn xt: t mt p 3D hnh 3.13 cho thy

- nh hng ca CP: ban u, khi tng lng CP ln t 14 mg ti 19,2 mg th

mi mn ca vin nn tng dn. Tip tc tng lng CP ln vt ngng 24,4 th

mi mn ca vin nn khng i.

44

- nh hng ca manitol: ban u, khi lng manitol tng dn th mi mn

ca vin khng i. Tng manitol ln ti khong 128 mg th mi mn tng ti

mt gi tr nht nh. V gi tr ny khng i khi lng manitol tip tc tng.

nh hng ca CP v manitol c th c gii thch nh sau: trong qu trnh

dp vin s hnh thnh mt khong gi tr lc lin kt gia cc tiu phn vi nhau

(gia tiu phn HPTR vi HPTR, HPTR vi t dc v t dc vi t dc).

Khong gi tr ny s gi cho mi mn ca vin nn mt mc nht nh.

Khi lng CP v manitol tng ln, khong gi tr lc ny s gim i v mi mn

s tng ln ti mt gi tr trn (do cng l khng i). V vy cng khng

tng thm na mc d tip tc tng lng t dc.

Kt qu nh gi nh hng ca CP v manitol c s dng thit kt cng

thc ti ubng phn mm INFORM 3.1 vi yu cu ca bin u ra nh sau:

- Tc gii phng sau 5 pht tin ti cc i (100%).

- Thi gian r tin ti nh nht (di 30 giy).

- mi mn tin ti nh nht (di 1%)

Bng 3.12. Cng thc ti u vin nn r nhanh cha felodipin c thit k

bng phn mm INFORM 3.1

Thnh phn Khi lng n v HPTR ca Felodipin SD5 120 mg Avicel 110 mg Manitol 200 mg CP mg 28,5 mg PEG 6000 10 mg Aerosil 10 mg Magnesistearat 10 mg Khi lng vin 488,5 mg cng 5 - 6 kp Kch thc chy ci 12 mm

Kt qu nh gi cng thc ti u c trnh by trong hnh 3.14, bng 3.8

v bng 4.8 (ph lc 1).

45

Hnh 3.14. Tc gii phng ca felodipin trong vin nn bo ch theo trong cng

thc ti u (n=3,TB LC)

Bng 3.13. Thi gian r v mi mn ca vin nn bo ch theo cng thc ti u

Thi gian r (giy) 26,67 (1,15) mi mn (%) 0,30

(n=3, TB LC)

Nhn xt: nh vy, cng thc ti u m bo tc gii phng ca

felodipin trong vin nn sau 5 pht l 87,14 1,35 %. Thi gian r (26,67 1,15

giy) di 30 giy, t theo yu cu ca dc in M. V m bo v mi mn

(0,30%) di 1%.

46

KT LUN V KIN NGH

1. Kt lun Mt s kt qu thu c qua qu trnh thc nghim:

1.1. Nghin cu bo ch HPTR cha felodipin Sau khi tin hnh sng lc v la chn c cc yu t nh hng ti tc ha tan v n nh ca HPTR cha felodipin, HPTR c bo ch theo cng

thc sau:

Thnh phn Khi lng n v

Felodipin 0,50 g

HPMC E6 1,50 g

Lactose 4,00 g

Kch thc mt ry 180 m

Tin hnh nh gi ph hng ngoi (IR) v phn tch nhit vi sai (DSC) vi cng thc HPTR. Bc u kt lun c c ch lm tng tan ca HPTR l c

ch chuyn dng dc cht t v nh hnh sang tinh th.

nh gi s b n nh ca HPTR. Bc u kt lun HPTR m bo n nh v tc ha tan sau 4 tun lo ha cp tc ( 40 2o C, m 75 5 %).

1.2. Nghin cu bo ch vin nn r nhanh cha HPTR ca felodipin nh gi c nh hng ca cc loi t dc, phng php bo ch, kch thc chy ci, cng ti thi gian r ca vin nn. T chn manitol lm t

dc n, CP lm t dc r, PEG 6000 v phng php dp tng vin bo ch

vin nn r nhanh.

S dng phn mm MODDE 8.0 thit k th nghim qua nh gi mi tng quan gia lng manitol v CP ti tc gii phng dc cht sau 5 pht,

thi gian r v mi mn.

47

S dng phn mm INFORM 3.1 chn ra cng thc ti u sau: Thnh phn Khi lng n v HPTR ca Felodipin SD5 120 mg Avicel 110 mg Manitol 200 mg CP mg 28,5 mg PEG 6000 10 mg Aerosil 10 mg Magnesistearat 10 mg Khi lng vin 488,5 mg cng 5 - 6 kp Kch thc chy ci 12 mm

Cng thc vin nn r nhanh c ti u bng phn mm INFORM 3.1 c tc

gii phng sau 5 pht l 87,14 1,35 %. Thi gian r v mi mn tng ng

l 26,67 1,15 giy v 0,30 % ph hp vi tiu chun ca dc in M.

2. Kin ngh Tip tc nh gi n nh ca HPTR. nh gi n nh ca vin nn r nhanh bo ch theo cng thc ti u.

48

TI LIU THAM KHO

Ti liu ting vit

1. o Hu Doanh, (2012), Nghin cu h phn tn rn ca glipizid, Kha lun tt nghip dc s i hc, Trng i hc Dc H Ni.

2. Nguyn Th Loan, (2010), Nghin cu bo ch vin Proxicam r trong ming bng phng php ng kh, Kha lun tt nghip dc s i hc, Trng i hc Dc H Ni.

3. Phan Th Nga, (2009), Nghin cu h phn tn rn ca itraconazol, Kha lun tt nghip dc s i hc, Trng i hc Dc H Ni.

Ti liu ting Anh. 4. British Pharmacopoeia 2009, monogaphs Felodipin, p.2443 2447.

5. British National Formulary 57, (2009), p.115.

6. Bhole P. G. et al., (2009), Enhancement of water solubility of felodipine by preparing solid dispersion using poly-ethylene glycol 6000 and poly-vinyl alcohol, Asian Journal of Pharmaceutics, 3(3), 240-244.

7. BhavaniBoddeda et al., (2012), Formulation and Evaluation of Fast Dissolving Tablets of Felodipine, International Journal of Engineering Research & Technology, 1(9), 1 - 16.

8. Cvetkovic, Plosker, (2005), Ramipril/Felodipine Extended-Release Fixed-Dose Combination A Review of its Use in the Management of Essential Hypertension, Drugs 2005, 65(13), 1851-1868.

9. Hirani et al., (2009), Orally Disintegrating Tablets: A Review, Tropical Journal of Pharmaceutical Research, 8(2), 161-172.

10. Karavas E. et al., (2007), Investigation of the release mechanism of a sparingly water soluble drug from solid dispertions in hydrophilic carriers based on physical state of drug, particle size distribution and drug polymer interactions, EuropeanJournal of Pharmaceutics and Biopharmaceutics, 66, 334- 347.

11. Kulkarni et al., (2010), Formulation and development of fast disintegatingfelodipin tablets: funtionality of superdisintegrants,

49

International Journal of Pharmaceutical Sciences and Research, 1(8), 93 99.

12. Le-He Mei et al., (1995), Densities and Viscosities of Polyethylene Glycol + Salt + Water Systems at 20o C, Journal of Chemical&EngineeringData, 40(6), 1168 -1171.

13. MohitMangal et al., (2012), Superdisintegrants: An Updated Review, International Journal of Pharmacy and Pharmaceutical Science Research, 2(2), 26-35.

14. NiranjanChivate et al., (2012), A Complete Review on Solid Dispersion Technology and Factorial Design, Current Pharma Research, 2(4), 659-667.

15. Praveen Kumar D. et al., (2012), Solid dispersion: a review, Journal of Pharmaceutical and Scientific Innovation, 1(3), 27-34.

16. Patidar K. et al., (2011), Solid Dispersion Technology: A Boon for Poor Water Soluble Drugs, Indian Journal of Novel Drug Delivery, 3(2), 83-90.

17. Raghavendra Rao N. G. et al., (2010), Comparative study on effect of diferent techniques use in the formulation of felodipin fast dissolving tablets, International Journal of Pharmacy and Pharmaceutical Sciences, 2(2), 152-159.

18. Raymond C Rowe, (2009), Handbook of Pharmaceutical Excipients sixth edition, Pharmaceutical Press.

19. Singh S. et al., (2011), A review on solid dispersion, International Journal of Pharmacy and Life Sciences, 2(9), 1078-1095.

20. Sandeep Pawar et al., (2009), Studies on solid dispersion of Felodipine, Journal of Pharmacy Research, 2(4),768-774.

21. SandrienJanssens et al., (2009), Review physical chemistry of solid dispersions, Journal of Pharmacy and Pharmacology, 61,1571-1586.

22. Sean C Sweetman, (2009), Martindale 36th The Complete Drug Reference, Pharmaceutical Press.

23. The United Stated Pharmacopoeia (USP 30 NF 25), (2007), monographs Felodipin.

50

24. William R. et al., (2005), Orally Disintegrating Tablets, Products,Technologies, and Development Issues,Pharmaceutical technology,130-150.

25. Yourong Fu et al., (2004), Orally Fast Disintegrating Tablets: Developments, Technologies, Taste-Masking and Clinical Studies,Critical Reviews in Therapeutic Drug Carrier Systems, 21(6), 433-475.

PH LC I 1. Nghin cu bo ch HPTR ca felodipin

51

Bng 4.1. Phn trm gii phng ca felodipin t HPTR vi cht mang l PVP K30,

PEG 4000, HPMC E6, c t l felodipin vi cht mang l 1:1

Thi gian (pht)

Phn trm gii phng ca felodipin t HPTR SD1 (PVP K30) SD2 (PEG 4000) SD3 (HPMC E6)

0 0 0 0

5 69,44 (1,05)

75,32 (2,65)

73,15 (2,75)

15 75,16 (1,12)

78,06 (2,06)

80,16 (2,01)

30 71,94 (0,70)

76,13 (1,33)

77,26 (3,07)

45 70,73 (0,78)

75,56 (0,50)

76,85 (2,91)

60 72,58 (0,24)

75,16 (1,01)

75,24 (1,74)

(n=3, TB LC) Bng 4.2.Phn trm gii phng ca felodipin t HPTR vi cht mang l PEG 4000,

HPMC E6, c t l felodipin vi cht mang l 1:3

Thi gian Phn trm gii phng ca felodipin t HPTR

SD4 (PEG 4000) SD5 (HPMC E6) 0 0 0

5 88.55 (2,46)

92.51 (0,15)

15 83.22 (0,39)

88.98 (1,94)

30 82.19 (0,75)

85.89 (1,97)

45 79.86 (0,79)

83.30 (2,34)

60 78.92 (0,39)

82.19 (1,42)

(n=3, TB LC)

Bng 4.3. Phn trm gii phng ca felodipin t HPTR vi cht mang lHPMC E6,

c t l felodipin vi cht mang l 1:1, 1:3, 1:4, 1:6

Thi gian (pht) Phn trm gii phng ca felodipin t HPTR

52

SD3 (1:1) SD5 (1:3) SD6 (1:4) SD8 (1:6) 0 0 0 0 0 5 73,15

(2,75) 92,51 (0,15)

85,62 (2,40)

81,14 (2,70)

15 80,16 (2,01)

88,98 (1,94)

89,14 (0,76)

81,40 (0,45)

30 77,26 (3,07)

85,89 (1,97)

88,00 (0,00)

78,90 (1,66)

45 76,85 (2,91)

83,30 (2,34)

88,38 (0,66)

78,38 (2,20)

60 75,24 (1,17)

82,19 (1,42)

88,57 (1,78)

77,52 (2,49)

(n=3, TB LC)

Bng 4.4. Phn trm gii phng ca felodipin t HPTR vi cht mang lHPMC E6,

HPMC K4M, HPMC K15M, c t l felodipin vi cht mang l 1:3

Thi gian (pht)

Phn trm gii phng ca felodipin t HPTR SD5 (HPMC E6) SD10 (HPMC K15M) SD9 (HPMC K4M)

0 0 0 0

5 92.51 (0,15)

57,24 (4,21)

63,81 (4,18)

15 88.98 (1,94)

64,10 (4,63)

69,71 (5,05)

30 85.89 (1,97)

68,00 (8,43)

71,71 (4,31)

45 83.30 (2,34)

70,38 (8,33)

73,71 (4,72)

60 82.19 (1,42)

71,24 (5,87)

74,57 (5,21)

(n=3, TB LC)

Bng 4.5.Phn trm gii phng ca felodipin t HPTR vi cht mang lHPMC E6,

c t l felodipin vi cht mang l 1:3, kch thc tiu phn l :180, 350, 600, 800

m

53

Thi gian (pht)

Phn trm gii phng ca felodipin t HPTR

SD5 (180) SD11 (350) SD12 (600) SD13 (800)

0 0 0 0 0

5 92.51 (0,15)

65,54 (1,75)

45,02 (0,58)

37,32 (5,06)

15 88.98 (1,94)

80,44 (1,63)

78,11 (2,86)

66,39 (8,20)

30 85.89 (1,97)

79,99 (1,87)

90,04 (1,88)

81,34 (2,70)

45 83.30 (2,34)

77,67 (1,88)

83,75 (4,06)

84,16 (0,56)

60 82.19 (1,42)

78,29 (2,68)

80,96 (3,29)

83,12 (0,56)

(n=3, TB LC)

Bng 4.6. Phn trm gii phng ca felodipin t HPTR vi cht mang lHPMC E6,

c t l felodipin vi cht mang l 1:3, t dc hp ph: lactose, Aerosil

Thi gian (pht)

Phn trm gii phng ca felodipin t HPTR SD5 (lactose) SD14 (Aerosil)

0 0 0

5 92.51 (0,15)

68,79 (2,49)

15 88.98 (1,94)

80,78 (3,02)

30 85.89 (1,97)

82,21 (2,00)

45 83.30 (2,34)

79,45 (0,59)

60 82.19 (1,42)

77,83 (0,72)

(n=3, TB LC)

2. Nghin cu bo ch vin nn r nhanh cha HPTR ca felodipin

Bng 4.7. nh hng ca kch thc chy ci ti thi gian r ca vin nn

54

Kch thc chy ci (mm) 10 12 13

Thi gian r (giy) 45,33 (2,52)

36,33 (1,53)

29,67 (1,53)

(n=3, TB LC)

Bng 4.8.Tc gii phng felodipin t vin nn bo ch theo cng thc ti u

Thi gian (pht) Phn trm gii phng (%) 0 0

5 87,14 (1,35)

15 89,90 (1,78)

30 88,22 (0,68)

45 85,47 (0,61)

60 85,17 (2,26)

(n=3, TB LC)

B Y TTRNG I HC DC H NIMN VN HNGKHA LUN TT NGHIP DC SH NI - 2013B Y TNGHIN CU BO CH VIN NN R NHANH CHA FELODIPINKHA LUN TT NGHIP DC SNgi hng dn:1. PGS.TS. Phm Th Minh Hu2. TS. Nguyn Thch TngNi thc hin:H NI 2013LI CM NVi tt c lng knh trng v s chn thnh, ti xin c by t nim bit n su sc tic gio PGS.TS. Phm Th Minh Hu, ti thy gio TS. Nguyn Thch Tng Ging vin B mn Bo ch, Trng i hc Dc H Ni, nhng ngi trc tip hng dn...Ti cng xin gi li cm n ti cc thy c gio, cc anh ch k thut vin b mn Bo Ch nhit tnh gip , to mi iu kin thun li cho ti trong thi gian lm thc nghim ti b mn.Cui cng, xin by t lng bit n su sc ti gia nh v bn b, nhng ngi lun ng vin ng h ti trong sut qu trnh hc tp, rn luyn v nghin cu ti Trng i hc Dc H Ni.H Ni, ngy 21 thng 5 nm 2013Sinh vinT VT CHNG I: TNG QUANTng quan v felodipinCng thc cu toTnh cht l haDc ng hcTc dng dc lCh nh, chng ch nh, liu dng, tc dng phMt s dng bo ch cha felodipintrn th trngi cng v h phn tn rnKhi nimu nhc imCu trc l haCc cht mang thng dngC ch lm tng tan v tc ha tanCc phng php bo ch h phn tn rnPhng php un chyPhng php dung miPhng php un chy kt hp vi dung miPhng php nh gi HPTR n nh ca HPTRMt s nghin cu v h phn tn rn cha felod[ipin trn th giiKhi qut v vin nn r nhanhKhi nimTheo nhiu ti liu nh ngha:u nhc imPhng php bo ch vin nn r nhanhMt s nghin cu v vin nn r nhanh cha felodipin trn th giiBng 1.3. Mt s nghin cu v vin nn r nhanh chafelodipin trn th gii

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