B Y T

TRNG I HC DC H NI

NGUYN TH HNG

NGHIN CU BO CH VIN

THEOPHYLIN GII PHNG THEO NHP

BNG PHNG PHP BAO BT KH

KHA LUN TT NGHIP DC S

H NI 05/2014

B Y T

TRNG I HC DC H NI

NGUYN TH HNG

NGHIN CU BO CH VIN

THEOPHYLIN GII PHNG THEO NHP

BNG PHNG PHP BAO BT KH

KHA LUN TT NGHIP DC S

Ngi hng dn:

1. TS. Nguyn Thch Tng

2. ThS. Nguyn Huy Tun

Ni thc hin:

B mn Bo Ch

Trng i hc Dc H Ni

H NI 05/2014

LI CM N

Trc tin, em xin gi li bit n su sc n PGS.TS. Phm Th Minh Hu,

T.S Nguyn Thch Tng v ThS. Nguyn Huy Tun lun lun tn tm hng

dn, ng vin v gip em trong qu trnh hc tp v nghin cu khoa hc.

Em xin c gi li cm n ti ton th thy c gio, cc anh ch k thut vin

B mn Bo ch ht lng quan tm, gip v to iu kin tt nht em hon

thnh c kha lun ny.

Em cng xin chn thnh cm n ti Ban gim hiu, cc thy c gio trng i

hc Dc H Ni cng vi tri thc v tm huyt, truyn t cho em nhng kin

thc qu bu trong sut thi gian hc tp ti trng.

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

anh, ch, em lun bn, quan tm, ng vin em vt qua kh khn trong cuc

sng v hc tp, l ng lc em hc tp, rn luyn v nghin cu ti Trng i

hc Dc H Ni.

H Ni, ngy 14 thng 05 nm 2014

Sinh vin

Nguyn Th Hng

MC LC

DANH MC CC K HIU V CC CH VIT TT

DANH MC CC BNG

DANH MC CC HNH V V TH

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

CHNG 1: TNG QUAN ..................................................................................... 2

1.1. i cng v theophylin ............................................................................................. 2

1.1.1. Cng thc ha hc ........................................................................................ 2

1.1.2. Tnh cht ....................................................................................................... 2

1.1.3. c im dc ng hc .............................................................................. 2

1.1.4. Tc dng dc l .......................................................................................... 2

1.1.5. Ch nh, chng ch nh ............................................................................... 2

1.1.6. Liu dng ...................................................................................................... 3

1.1.7. Mt s ch phm ca theophylin c trn th trng ..................................... 3

1.2. i cng v thuc gii phng theo nhp ................................................................ 3

1.2.1. Khi nim thuc gii phng theo nhp sinh hc ........................................... 3

1.2.2. u nhc im ca thuc gii phng theo nhp sinh hc ............................ 4

1.2.3. Phn loi thuc gii phng theo nhp sinh hc ............................................ 4

1.2.4. Mt s nghin cu v theophylin gii phng theo nhp ................................ 6

1.3. i cng v phng php bao bt kh ................................................................. 7

1.3.1. Khi nim ...................................................................................................... 7

1.3.2. u, nhc im............................................................................................. 7

1.3.3. Phn loi phng php bao bt kh ............................................................ 7

1.3.4. C ch hnh thnh lp v bao ....................................................................... 9

1.3.5. Mt s yu t nh hng ti hnh thnh lp v bao ................................... 10

1.3.6. Mt s nghin cu v phng php bao bt kh ........................................ 12

CHNG 2. I TNG V PHNG PHP NGHIN CU ...................... 14

2.1. Nguyn liu v thit b .............................................................................................. 14

2.1.1. Nguyn liu ................................................................................................. 14

2.1.2. Thit b nghin cu ..................................................................................... 15

2.2. Ni dung nghin cu ................................................................................................. 15

2.3. Phng php thc nghim ...................................................................................... 15

2.3.1. Phng php xy dng ng chun ......................................................... 15

2.3.2. Phng php bo ch ................................................................................. 16

2.3.2.1. Phng php bo ch vin nhn ......................................................... 16

2.3.2.2. Phng php bao lp kim sot gii phng (phng php bao bt kh) . 16

2.3.3. Phng php nh gi ............................................................................... 17

2.3.3.1. Phng php nh gi vin nhn ....................................................... 17

2.3.3.2. Phng php nh gi vin bao ......................................................... 19

2.3.3.3. Phng php o nhit chuyn ha thy tinh .................................. 20

2.3.3.4. Phng php nh gi hnh nh b mt v mt ct ngang lp v bao ..... 21

CHNG 3. THC NGHIM, KT QU V BN LUN ............................ 22

3.1. Xy dng ng chun v mi tng quan gia nng v mt quang .. 22

3.2. Xy dng cng thc bo ch vin theophylin gii phng theo nhp bng

phng php bao bt kh ............................................................................................... 22

3.2.1. Xy dng cng thc vin nhn cha 100 mg theophylin ............................ 23

3.2.1.1. nh hng ca t dc r ................................................................... 23

3.2.1.2. nh hng ca t dc n ................................................................ 24

3.2.2. Xy dng cng thc lp v bao theophylin gii phng theo nhp bng

phng php bao bt kh ..................................................................................... 26

3.2.2.1. nh hng ca talc ............................................................................. 27

3.2.2.2. nh hng ca loi HPMC ................................................................. 29

3.2.2.3. nh hng ca t l khi lng lp v bao ......................................... 30

3.2.2.4. nh hng ca cht to knh .............................................................. 31

3.2.2.5. nh hng ca cht ha do ............................................................... 34

3.3. nh gi nh hng ca yu t thuc quy trnh ti gii phng dc cht t

vin bao .............................................................................................................................. 37

3.3.1. nh hng ca nhit ........................................................................... 37

3.3.1.1. nh hng ca nhit ti nhit chuyn ha thy tinh ca mng

phim HPMC K4M ............................................................................................. 37

3.3.1.2. nh hng ca nhit ti hnh nh b mt v mt ct lp v bao .. 38

3.3.1.3. nh hng ca nhit ln gii phng dc cht .......................... 40

3.3.2. nh hng ca thi gian ......................................................................... 41

3.3.3. nh hng ca thi gian sau ................................................................... 43

KT LUN V XUT .................................................................................... 45

TI LIU THAM KHO ........................................................................................ 1

PH LC 1

PH LC 2 ................................................................................................................ 5

DANH MC CC K HIU V CC CH VIT TT

BP Dc in Anh

CAP Cellulose acetat phtalat

CHD Cht ha do

CT Cng thc

DBP Dibutyl phtalat

DVN IV Dc in Vit Nam IV

KT iu kin thng

EC Ethyl cellulose

Gp hoc gp Gii phng

GPDC Gii phng dc cht

GPKD Gii phng ko di

GPTN Gii phng theo nhp

HEC Hydroxylethyl cellulose

HPC Hydroxypropyl cellulose

HPMC Hydroxyl propyl methyl cellulose

L-HPC Hydroxypropyl cellulose trng lng phn t thp

SD lch chun

SSG Natri starch glycolat

T,t Thi gian

TB Trung bnh

TEC Trietyl citrate

Tg Nhit chuyn ha thy tinh

TKHH Tinh khit ha hc

Tlag, tlag Thi gian tim tng

TLVB T l khi lng lp v bao

TPL Theophylin

USP Dc in M

DANH MC CC BNG

Trang

Bng 1.1. Mt s nghin cu v phng php bao bt kh 12

Bng 2.1. Nguyn liu s dng 14

Bng 3.1. Cng thc vin nhn vi mt s loi t dc khc nhau 23

Bng 3.2. Phn trm TPL gii phng t vin nhn s dng t dc r khc nhau 23

Bng 3.3: Phn trm TPL gii phng t vin nhn s dng t dc n khc nhau 25

Bng 3.4. Thnh phn cng thc vin nhn 25

Bng 3.5. cng, mi mn, hm lng trung bnh vin, khi lng

trung bnh vin CT4

26

Bng 3.6. Cng thc lp v bao vi mt s loi t dc khc nhau 27

Bng 3.7. Phn trm TPL gii phng t vin bao c t l talc lp v bao

khc nhau

28

Bng 3.8. Phn trm TPL gii phng t vin bao bng cc loi HPMC

khc nhau

29

Bng 3.9. Phn trm TPL gii phng t vin bao CT 4.3 cc TLVB khc nhau 30

Bng 3.10. Phn trm TPL gii phng t vin bao c cc cht to knh khc nhau 31

Bng 3.11. Phn trm TPL gii phng t vin bao c t l cht to knh khc nhau 33

Bng 3.12. Phn trm TPL gii phng t vin bao s dng cc loi cht ha

do khc nhau

36

Bng 3.13. Hnh nh b mt v hnh nh ct ngang ca vin bao KT

v 80oC trong 24 gi

39

Bng 3.14. Phn trm TPL gii phng t vin bao nhng nhit khc

nhau trong 24 gi

40

Bng 3.15. Phn trm TPL gii phng t vin bao 60oC trong cc

thi gian khc nhau

42

Bng 3.16. Phn trm TPL gii phng t vin bao 60oC trong 24 gi sau

cc khong thi gian sau khc nhau

47

DANH MC CC HNH V V TH

Trang

Hnh 1.1. M hnh thuc gii phng thuc theo nhp 3

Hnh 1.2. H bao mng gii phng theo nhp 4

Hnh 1.3. H nt gii phng theo nhp 5

Hnh 1.4. H bm thm thu gii phng theo nhp 5

Hnh 1.5. S minh ha cc my bao kh cht ha do 8

Hnh 1.6. S minh ha my bao kh da trn nhit kt dnh 9

Hnh 1.7. Minh ha c ch hnh thnh mng phim trong bao bt kh 9

Hnh 3.1. th biu din mi tng quan gia nng TPL v mt quang

o ti bc sng 272 nm.

22

Hnh 3.2. Phn trm TPL gii phng t vin nhn s dng cc loi t dc r

khc nhau

24

Hnh 3.3. Phn trm TPL gii phng t vin nhn s dng cc loi t dc n

khc nhau

25

Hnh 3.4. Phn trm TPL gii phng t vin bao c t l talc trong lp v bao

khc nhau

28

Hnh 3.5. Phn trm TPL gii phng t vin bao bng cc loi HPMC khc nhau 29

Hnh 3.6. Phn trm TPL gii phng t vin bao CT4.3 cc TLVB khc nhau 30

Hnh 3.7. Phn trm TPL gii phng t vin bao c cc loi cht to knh khc nhau 32

Hnh 3.8. Phn trm TPL gii phng t vin bao c t l cht to knh khc nhau 33

Hnh 3.9. Nhit chuyn ha thy tinh ca mng phim K4M vi cc loi

cht ha do khc nhau

34

Hnh 3.10. Phn trm TPL gii phng t vin bao s dng cc loi CHD

khc nhau

36

Hnh 3.11. Nhit chuyn ha thy tinh ca mng phim K4M s dng DBP

v cc iu kin khc nhau

38

Hnh 3.12. Phn trm TPL gii phng t vin bao 24 gi nhng nhit

khc nhau

40

Hnh 3.13. Phn trm TPL gii phng t vin bao 60oC trong cc thi gian

khc nhau

42

Hnh 3.14. Phn trm TPL gii phng t vin bao 60oC trong 24 gi sau

cc khong thi gian khc nhau

43

Hnh PL1. S bo ch vin nhn theophylin 100 mg PL 1

Hnh PL2. S bao vin bng phng php bao bt kh PL2

1

T VN

Hen ph qun l bnh vim mn tnh ng h hp kh ph bin nc ta cng

nh nhiu nc trn th gii. Cc nghin cu gn y ch ra rng, hen ph qun l

mt bnh c din bin theo chu k sinh hc th hin cc triu chng ca hen tr nn

trm trng hn trong khong thi gian t na m v sng [20]. V vy yu cu a

thuc ng thi im ng vai tr quan trng kim sot bnh.

Theophylin (TPL) l thuc gin ph qun dng cha hen, tuy hin nay khng

cn gi v tr nh trc y, nhng do gi r v d kim nn hin vn c dng ph

bin v c mt trong danh mc thuc thit yu. Trn th gii c nhiu nghin cu

v dng thuc gii phng theo nhp (GPTN) cha theophylin [4], [19], [37], tuy nhin

Vit Nam vn cha c nghin cu no c thc hin.

Trong lnh vc sn xut dc phm, c rt nhiu k thut bo ch vin kim

sot gii phng trong cng ngh bao vin c ra i t rt sm v c p dng

kh ph bin. Tuy nhin, cng ngh bao bng dung mi c cc nhc im l s

dng nhiu dung mi, tiu tn nhiu nng lng, hin tng lo ha trong qu trnh

bo qun. Vit Nam, k thut bao kh ch yu ng dng trong bao ng v hu

nh cha c nghin cu no nhm ng dng k thut bao kh trong kim sot gii

phng dc cht.

Xut pht t nhng vn trn, chng ti thc hin ti Nghin cu bo ch

vin theophylin gii phng theo nhp bng phng php bao bt kh vi mc tiu

sau: Xy dng cng thc v quy trnh bo ch vin theophylin 100 mg gii phng theo

nhp bng phng php bao bt kh c thi gian tr hon gii phng khong 6-7 gi.

2

CHNG 1: TNG QUAN

1.1. i cng v theophylin

1.1.1. Cng thc ha hc

Tn khoa hc: 1,3-dimethyl-3,7 dihydro-1H-purin-2,6-dion [2], [38].

1.1.2. Tnh cht

Bt tinh th trng, kh tan trong nc, hi tan trong ethanol, tan trong cc dung

dch hydroxyd kim, amoniac v cc acid v c [2], [38].

1.1.3. c im dc ng hc

- Hp thu ng ung b chm li nhng khng b gim bi thc n.

- Sau khi ung nang theophylin hoc vin nn khng bao, thng t nng nh

trong huyt thanh sau 1 - 2 gi.

- Thi gian bn thi theophylin bin thin rng.

- Theophylin chuyn ha gan v bi tit cng nhng cht chuyn ha qua thn.

Lng nh theophylin khng chuyn ha c bi tit trong phn [3], [36].

1.1.4. Tc dng dc l

Thuc lm gin c trn, nht l c ph qun, kch thch h thn kinh trung ng,

kch thch c tim v tc dng trn thn nh mt thuc li tiu [3], [36].

1.1.5. Ch nh, chng ch nh

1.1.5.1. Ch nh

Hen ph qun: hin nay dng thuc theophylin ung gii phng nhanh khng c

ch nh lm gim co tht ph qun trong hen ph qun cp hoc vim ph qun

mn, cc ch phm theophylin gii phng chm vn c ch kim sot cn hen ban

m v th kh kh bui sng.

3

1.1.5.2. Chng ch nh

Qu mn vi bt c mt thnh phn no ca ch phm thuc, bnh lot d dy t

trng ang hot ng, co git, ng kinh khng kim sot c [3], [36].

1.1.6. Liu dng

Trong iu tr lu di co tht ph qun mn, liu ung t 300 1000 mg/ngy,

mi liu cc nhau 6-8 gi. Dng bin i gii phng liu 175 500 mg mi 12 gi

hoc dng 1 ln 1 ngy liu 400-600 mg [36].

1.1.7. Mt s ch phm ca theophylin c trn th trng

- Theophylin 100 mg (cng ty CPDP Tirpharco) vin nn bao phim 100 mg.

- THEOSTAT LP (PIERRE FABRE MEDICAMENT PRODUCTION) vin nn

gii phng chm 100 mg.

- Diaphyllin (Gedeon Richer): dung dch tim 240 mg/5 ml theophylin ethylendiamin.

- Theophylin 200 mg (cng ty dc phm qun 8): vin nn bao ng 200 mg.

1.2. i cng v thuc gii phng theo nhp

1.2.1. Khi nim thuc gii phng theo nhp sinh hc

H GPTN l h gii phng thuc nhanh, hon ton trong thi gian ngn sau mt

khong thi gian khng gii phng nh trc hay gi l thi gian tim tng (tlag). H

c thit k da trn nhp hay ng h sinh hc ca c th nhm mc ch vn

chuyn thuc ti ng ni, ng lng do tng hiu qu iu tr v tng kh nng

tun th ca bnh nhn [5], [14], [19], [23].

Hnh 1.1. M hnh thuc gii phng thuc theo nhp [5], [23]

tlag

Gi

i p

h

ng

th

u

c

A: gii phng thuc hon ton sau tlag

B: gii phng thuc tr hon sau tlag

C: gii phng thuc ko di saut lag

4

1.2.2. u nhc im ca thuc gii phng theo nhp sinh hc

1.2.2.1. u im

- Tng hiu qu iu tr do thuc c gii phng ti v tr ch, hoc thi im gii

phng thuc ph hp vi nhp sinh hc hay bnh trong c th.

- Gim liu, gim c s ln dng thuc, do c th gim c chi ph iu tr.

- Trnh kch ng, hoc gim tc dng ti mt v tr no trong ng tiu ha khi

s dng ng ung [5].

1.2.2.2. Nhc im

- Thit k dng bo ch i hi cc k thut phc tp, chi ph sn xut c th cao hn.

- Thit k v nh gi th nghim in vitro, in vivo phc tp, cn nhiu k thut v

thit b hin i nh: cng hng t ht nhn [5].

1.2.3. Phn loi thuc gii phng theo nhp sinh hc

C nhiu cch phn loi thuc gii phng theo nhp, trong phn loi theo

phng php thit k h GPTN d dng p dng trong thc t, gm 3 loi:

- H GPTN da trn mng bao kim sot gii phng.

- H GPTN da trn nt kim sot gii phng.

- H GPTN bng bm thm thu [18].

1.2.3.1. H gii phng theo nhp da trn mng bao kim sot gii phng

- c im: h gm nhn cha dc cht c bao mt lp mng kim sot gii

phng c c tnh trng n, n mn; nt v hoc c kh nng tng tnh thm. M

hnh:

Hnh 1.2. H bao mng gii phng theo nhp

(a): li cha thuc (vin nn, nang, )

(b): mng bao kim sot gii phng:

- Mng trng n/n mn.

- Mng c kh nng nt v.

- Mng tng tnh thm [18].

- Tlag ph thuc vo dy mng bao [5], [18].

- Nguyn liu:

+ Polyme to mng nt v: ethyl cellulose, Eudragit RS, Eudragit RL,

5

+ Polyme to mng trng n, n mn: HPMC, HPC, Eudragit L, ...

cc loi sp c kh nng nng chy hoc n mn nh sp ong, sp Carnauba,

+ Eudragit RS, Eudragit RL c kh nng tng tnh thm khi c mt cc acid hu

c nh: acid acetic, acid succinic, [18].

1.1.3.2. H gii phng theo nhp da trn nt kim sot gii phng

H nang cha nt kim sot gii phng, khi tip xc vi mi trng, np nang

nhanh chng b ha tan, tip theo nt c y ra khi thn nang do p lc t trong

hoc t trng n, n mn.

M hnh:

Hnh 1.3. H nt gii phng theo nhp

(a): dc cht v t dc.

(b): np nang tan trong nc.

(c): thn nang khng thm hoc bn thm.

(d): nt kim sot gii phng.

(e): liu gii phng nhanh [18].

- Nguyn liu: HPMC, PVA, to nt trng n, hoc t dc thn du nh

glucire,to nt t bt ra khi nang [18].

1.2.3.3. H kim sot gii phng bng bm thm thu

- H gm vin nn hai lp: cha dc cht v polyme trng n bao ton b bng

mng bn thm vi cc l khoan lase. Gia lp mng bn thm v nhn c thm

mt lp bao thn nc ko di tr hon gii phng.

- M hnh:

Hnh 1.4. H bm thm thu gii phng theo nhp

(a): cng thc thuc.

(b): polyme trng n.

(c) : lp bao thn nc.

(d): lp bao thm thu.

(e) : l khoan lase [18].

- Nguyn liu: polyme bao mng bn thm: cellulose acetat,

T dc tng p lc thm thu: NaCl, KCl, [18].

6

Nhn xt: nguyn liu v phng php bo ch h gii phng theo nhp ngy cng

c nghin cu rng ri, c nhiu ng dng trong thc t. Trong , h c mng

bao trng n n mn c m hnh thit k kh n gin (c th ch cn 1 loi polyme

bao mt lp mng kim sot gii phng), qui trnh bo ch n gin (c th bao

dp to vin nn hoc bao mng phim mt lp polyme kim sot gii phng) ph hp

p dng phng php bao bt kh.

1.2.4. Mt s nghin cu v theophylin gii phng theo nhp

Nm 2007, Mastiholimath V.S. v cng s tin hnh bo ch thn nang

khng thm nc cha vi nang (TPL, Eudragit L100, Eudragit S100) c bo ch

bng phng php nh ha bc hi dung mi. Nt ng thn nang cha cc khi

lng khc nhau hoc HPMC, natri alginat hoc gm guar. Thn v np nang c

dnh bng dung dch EC 5% trong cn. C h c bao nhng trong dung dch CAP

5%, dung mi l hn hp aceton: ethanol = 8:2, cht ha do l DBP (0,75%).

Kt qu: h t c mc tiu gii phng ti i trng, tlag ph thuc thi gian v pH,

c th t c t 2-24 gi [19].

Nm 2010, Tekade A. R. v cng s nghin cu bo ch ht kp TPL lin kt

cho c chun b bng cch nh hn dch theophylin, delonix regiagum v natri

alginat vo dung dch CaCl2 sau vo dung dch AlCl3 cc nng khc nhau.

Cc ht tip tc c bao bng Eudragit L100 v Eudragit S100.

Kt qu: h t gii phng theo nhp vi tlag th trn in vitro 5-7 ting, kt qu chp

hunh quang trn th cho thy vin cn nguyn vn trong 6 ting [37].

Nm 2011, Bhat v cng s tin hnh bao hn hp cha TPL, aerosil v ng

ln li ng s dng t dc dnh l dung dch PVP K30, pellet thu c mang i

sy. Cc nt nn hoc nng chy bng gm xanthan, PVP lin kt cho, carrageen

hoc veegum c bao nhng hoc nn vi p lc khc nhau, t v tr trn cng ca

thn nang cha y thuc. Cc nt nng chy c a vo bng pipet. Vin nang

c bao bng nhng trong dung dch 5% ethyl cellulose trong ethanol.

Kt qu: h GPTN vi tlag t 2 -36.Thi gian tim tng c th c iu chnh bng

cch thay i lng v thnh phn ca nt, lp bao bn ngoi [4].

7

Nhn xt: cc nghin cu trn c phng php bo ch kh phc tp, s dng

nhiu loi ha cht v qui trnh bo ch cn nhiu bc tin hnh th cng.V vy

chng ti la chn bo ch vin theophylin gii phng theo nhp vi cu trc gm

vin nhn cha dc cht bo ch bng phng php xt ht t v lp v bao kim

sot gii phng bo ch bng phng php bao bt kh.

1.3. i cng v phng php bao bt kh

1.3.1. Khi nim

Bao bt kh l cng ngh bao trong bt nguyn liu c bao trc tip ln cc

dng bo ch rn khng s dng hoc s dng rt t dung mi, v s dng nhit trong

qu trnh to thnh mt lp v bao [17], [35].

1.3.2. u, nhc im

- u im:

Khng s dng dung mi hu c nn an ton trong qu trnh sn xut, gim

c chi ph.

Khng s hoc s dng rt t nc nn gim c thi gian quy trnh bao (ch yu

bc sy kh), ph hp vi bo ch cc dc cht nhy cm vi m [7], [17].

- Nhc im:

Kh c th bao c mt lp rt mng.

Bo qun v x l bt bao i hi kim sot iu kin mi trng c bit.

Kh m bo dy lp v bao ng u.

Nhit cn thit cho mt s bt qu cao vi cc thnh phn nhy cm nhit .

1.3.3. Phn loi phng php bao bt kh

Da vo thnh phn cng thc lp v bao v quy trnh bao, c th chia lm ba

loi nh sau:

- Bao bt kh cht ha do (CHD) (Plasticizer-dry-coating).

- Bao bt kh da trn kt dnh nhit (Heat-dry-coating).

- Bao bt kh tnh in (Electrostatic coating) [17], [31].

8

1.3.3.1. Bao bt kh c cht ha do

a. Nguyn tc

Nguyn liu dng bt v cht ha do c phun ng thi ln b mt dng bo

ch bng cc vi phun ring bit. Cht ha do lng s lm t bt v b mt bao,

thc y s lin kt ca cc bt ln b mt bao. Sau sn phm c trong mt

thi gian xc nh trc, vi nhit trn nhit chuyn ha thy tinh (tg) ca

polyme to thnh mt lp v bao ng nht [17].

Thnh phn cng thc bao bt kh cht ha do c yu cu kh c bit: mc

cht ha do cao, kch thc ht v nhit chuyn ha thy tinh ca bt bao thp [31].

b. Thit b bao

Mt s thit b s dng l: my ly tm to ht, my sy tng si, my bao vin

nn vi ni bao c l. S minh ha trong hnh 1.5.

1.3.3.2. Bao bt kh da trn kt dnh nhit

- Nguyn tc: b mt bao c duy tr nhit cao to iu kin lm mm v

phn b u bt bao. Lc c hc lm cho bt bm chc trn b mt bao [31].

Ht polyme phn b lin tc trn b mt vin nn cha trong my to cu, m

khng s dng bt k dung mi v cht ha do no. Polyme nng chy nh mt

n hng ngoi t trn nh ca my to cu. Bt bm dnh ln b mt vin c

thc y ch bi s nng chy mt phn ca cc polyme, to ra lc lin kt gia

cc ht vi nhau v gia cc ht vi b mt bao [17].

A B C

Hnh 1.5. S minh ha mt s thit b bao kh cht ha do: (A) bao kh bng my ly

tm to ht [21], (B) my sy tng si [21], (C) my bao vin nn vi ni bao c l [21].

Cht ha

do

Hn hp bt

B phn cp bt

u phun

dch

Cht ha

do

B phn cp bt

Hn hp bt

Cht ha do

B phn cp bt

Hn hp bt

bKh

nn

9

- Thit b: thit b c s dng ph bin l thit b sy tng si quay v my to

cu [29]. S minh ha trong hnh 1.6.

Hnh 1.6. S minh ha mt s thit b bao kh da trn kt dnh nhit:(A)

my sy tng si quay [11],(B) my to cu cho qu trnh bao bt vi n hng

ngoi qui m phng th nghim [8].

1.3.3.3. Bao tnh in

- Nguyn tc: da trn lc ht tnh in gia cc thnh phn mang in tri du

thc y bm dnh ca bt bao ln b mt bao. Ti mt thi im ch c mt mt

ca vin c bao vi cng sut ln ti 25000 n v/gi. Bc cui cng l

hnh thnh lp v bao [31]

- Thit b cu to kh phc tp c th bao tnh in tng mt ca vin nn.

1.3.4. C ch hnh thnh lp v bao

Theo Sauer Dorothea v cc cng s, qu trnh hnh thnh lp v bao bng

phng php bao bt kh tri qua cc bc sau y: (1) nng chy v lin kt ca

cc ht polyme, (2) nn lm mn b mt bao, (3) gim nhit lm cng mng bao

[31]. C ch c m t nh trong hnh 1.7.

Hnh 1.7. Minh ha c ch hnh thnh lp v trong bao bt kh [31]

A B

Lp bt bao

Nng chy v lin kt

Nn

Gim nhit

10

1.3.5. Mt s yu t nh hng ti hnh thnh lp v bao

1.3.5.1. Kch thc bt bao

i vi bao bt kh, kch thc nguyn liu bao l mt yu t quan trng nh

hng ti s ng nht ca lp v bao. Bt siu mn c u im l tng din tch b

mt ln, v vy kh nng thm t bi cht kt dnh, kh nng mm hoc chy lng

bi nhit d dng hn. Tuy nhin, lc ht vanderwaals gia cc ht bt ln, lm bt

km trn chy, b mt bao khng u. Khi khc phc c kh nng trn chy, s

dng bt siu mn bao bt kh s kim sot c b dy v mc ng nht ca

lp v bao tt hn khi dng bt mn (kch thc < 100m). Do vy qu trnh x l

nguyn liu trc khi bao ht sc quan trng. Kch thc bt thng c yu cu

nh hn 1% din tch b mt bao, m bo b mt bao ng nht, ci thin kh

nng lin kt, cm quan b mt v thi gian bao [17], [31].

1.3.5.2. Nhit chuyn ha thy tinh v c im bin dng do ca nguyn liu

Trong qu trnh bao, nhit b mt bao thng cao hn nhit chuyn ha

thy tinh ca nguyn liu to iu kin cho nguyn liu chuyn trng thi mm

hn v lin kt tt hn vo b mt bao. Trong bao bt kh, lng cht lng a vo

b gii hn, qu trnh chuyn trng thi ca nguyn liu din ra kh khn hn. V vy,

nhit chuyn ha thy tinh v c im bin dng do l 2 yu t quan trng

la chn nguyn liu bao [31].

Khi bao nhit cao hn nhit chuyn ha thy tinh, nguyn liu trng

thi ging nh cht lng (liquid like) v d b bin dng. Ty vo nhit chnh

lch, nht ca nguyn liu bao c th gim dn ti hnh thnh lc mao dn,

thc y lin kt ca nguyn liu ln b mt bao [31].

Trong qu trnh bao bt kh, lc nn c hc cng c vai tr trong thc y lin

kt gia nguyn liu v b mt bao. i vi nguyn liu n hi, bin dng ca

nguyn liu c th o ngc, dn n lin kt b mt km. Khi lp bao biu hin

c tnh nha (plastic behavior), bin dng khng o ngc, lc nn c hc thc

y kh nng lin kt ca nguyn liu ln b mt do tng din tch tip xc gia b

11

mt v nguyn liu hoc do cc nguyn liu t lin kt c hc (mechanical

interlocking) vi nhau [31].

1.3.5.3. Nhit trong qu trnh bao

Theo phng trnh thi gian (t) cn thit hai ht bt lin kt ph thuc vo

nht ca mng bao (), bn knh ca ht (R) v sc cng b mt ca lp bao ( ), k

l hng s: =

T phng trnh trn, nht gim lm tng kh nng lin kt gia cc ht, thc

y hnh thnh lp v bao. i vi bt nhit do (thermoplastic powder), nht

ph thuc vo trng lng phn t ca polyme v nhit . V vy, cc sn phm

bao bt kh gn nh ng dng cho c dng bo ch gii phng ngay lp tc v gii

phng c kim sot t c mt lp bao t yu cu v cm quan v kim sot

gii phng.

V nht gim khi nhit tng, bao v nhit cao c th c s dng

to ra mt mng phim ng nht, mc d hin tng lo ha cng c th c

thc y nhanh hn.

gim nhit qu trnh bao v rt ngn giai on , polyme m c tg qu

cao (tg > 60C) c kt hp vi cht ho do c th gim tg ca bt bao [31].

1.3.5.4. Bao lt (subcoat)

Bao lt nhm thay i nng lng b mt tip xc do to thun li cho lin

kt ca lp bt vi b mt bao. Cc polyme bao lt c la chn c th nng

chy mt phn nhit bao, thc y s bm dnh ca bt bao bng cch hnh thnh

cu cht lng lin kt vi b mt bao. V kh nng phn b ca lp bao lt trn b

mt ca cc li bao l rt quan trng, nn nguyn liu bao lt tt nht c la chn

bng cch o gc tip xc (contact angel) vi b mt bao v vi cc polyme c

bao. Gi tr gc tip xc cng nh, hiu qu lin kt cng cao [31], [33].

12

1.3.6. Mt s nghin cu v phng php bao bt kh

Vi cc u im v chi ph, thi gian v an ton trong sn xut, phng php bao

bt kh ngy cng c nghin cu rng ri c bit l ng dng trong bo ch cc

dng thuc kim sot gii phng. Di y l mt s v d minh ha.

Bng 1.1. Mt s nghin cu v phng php bao bt kh

Dc cht Nguyn liu Dang bo ch Nm

1. Phng php bao bt kh cht ha do

Pancreatin [21] Polyme: HPMCAS

CHD: triacetin, TEC, ATBC,..

Bao tan rut 1999

Propanolol hydrochlorid

[24], [26]

Polyme: Eudragit RS, EC

CHD: TEC, AMG, ATBC

Gii phng ko

di (GPKD) 2003

Theophylin [11], [12] Polyme: HPMCAS

CHD: TEC, AMG Bao tan rut

2006,

2008

Theophylin [35] Polyme: EC, HPMCAS

CHD: triacetin, TEC, ATBC, GPKD 2011

Theophylin [15] Polyme: Eudragit RL

CHD: nc

GPKD 2013

2. Phng php bao kh da trn kt dnh nhit

Theophylin [8] Polyme: Eudragit EPO

Vin bao che v

v trnh m 2004

Chlorpheniramin maleat,

theophylin [32]

Polyme: Eudragit L 100-55

CHD: TEC GPKD 2007

Chlorpheniramin maleat,

natri valproat [33]

Polyme: Eudragit L 100-55

CHD: TEC

Cha c m

hnh gii phng

dc cht

2009

3. Phng php bao kh tnh in

Ibuprofen [27] Polyme: Eudragit RS, Eudragit

RL

CHD: TEC

GPKD 2010

Ibuprofen [28] Polyme: Eudragit EPO

CHD: glycerol: nc (1:1),

glycerol 5%:NaCl (1:1),

Vin gii phng

nhanh 2010

Acid ascorbic [7] Polyme: Polyethylene (PE) wax Vin bao bo v 2014

13

C th thy phng php bao bt kh ang ngy cng c quan tm nhiu hn

v p dng rng ri. Trong , phng php bao bt kh cht ha do s dng nguyn

liu, quy trnh, thit b n gin ang c p dng ngy cng nhiu. Cc nguyn

liu c p dng trong cc nghin cu trn c: HPMCAS, EC, cc loi Eudragit

v nhiu loi cht ha do kh ph bin bo ch dng vin kim sot gii phng.

Theophylin c s dng kh nhiu do r tin v d kim, tuy nhin cc nghin cu

a phn bo ch dng gii phng ko di. V vy, ti c thc hin vi mc ch,

p dng phng php bao mi - phng php bao bt kh cht ha do bo ch

dng gii phng theo nhp cha theophylin.

14

CHNG 2. I TNG V PHNG PHP NGHIN CU

2.1. Nguyn liu v thit b

2.1.1. Nguyn liu

Bng 2.1. Nguyn liu s dng

STT Nguyn liu, t dc, dung mi Ngun gc Tiu chun

1 Theophylin khan Trung quc USP 32

2 Avicel PH 101 Trung quc BP 2009

3 Lactose monohydrat Trung quc BP 2009

4 Natri croscarmelose Trung quc BP 2009

5 Crospovidon Trung quc BP 2009

6 Natri starch glycolat Trung quc BP 2009

7 Talc Trung Quc BP 2009

8 Magnesi stearat Trung Quc BP 2009

9 Polyvinyl pyrolidon K30 Trung Quc USP 32

10 Hydroxy propyl methyl cellulose K100M Nht USP 32

11 Hydroxy propyl methyl cellulose K4M Nht USP 32

12 Hydroxy propyl methyl cellulose E6 Trung Quc BP 2009

13 Dibutyl phtalat Trung Quc BP 2009

14 Triethyl citrat Trung Quc BP 2009

15 Acid fumaric Trung Quc BP 2009

16 Acid hydroclorid c Trung Quc TKHH

17 Trinatri phosphat Trung Quc TKHH

18 Natri hydroxyd Trung Quc TKHH

19 Ethanol 96% Trung Quc TKHH

20 Diclomethan Trung Quc TKHH

15

2.1.2. Thit b nghin cu

- My dp vin tm sai Korsch model VFD007S21A vi b chy ci =7mm.

- My o cng ca vin nn Erweka TBH20.

- Knh hin vi in t qut S4800 NIHE 10000kV.

- Cn k thut Sartorius TEC 31025.

- Cn phn tch Sartorius BP 121S.

- Cn xc nh m nhanh Precica.

- Ni bao truyn thng.

- T sy chn khng LVO Labtech (Hn Quc).

- My phn tch nhit Mettler Toledo.

- Cn phn tch Mettler Toledo.

- My siu m LC 60H.

- My o quang Hitachi U-1800.

- My th ha tan Erweka DT 60.

- My o mi mn Pharmatest PTF 20E (c)

- V mt s dng c th nghim khc.

2.2. Ni dung nghin cu

- Pht trin quy trnh bao bt kh bo ch vin theophylin gii phng theo nhp.

- nh gi nh hng cc yu t cng thc mng bao ti gii phng dc cht

t vin bao.

- nh gi nh hng ca thi gian, nhit v thi gian sau ti gii phng

dc cht t vin bao.

2.3. Phng php thc nghim

2.3.1. Phng php xy dng ng chun

Chun b dy chun: cn chnh xc 100 mg theophylin ha tan vi khong 50 ml

mi trng (pH 1,0; pH 6,8; nc ct) trong cc c m, siu m 10 pht, chuyn dung

dch thu c vo bnh nh mc 100ml. Pha long bng mi trng tng ng

c cc dung dch c nng chnh xc: 4,0; 6,0; 8,0; 10,0; 12,0 g/ml.

16

o mt quang ca dy dung dch chun bc sng 272 nm. Mu trng l

cc mi trng tng ng.

2.3.2. Phng php bo ch

2.3.2.1. Phng php bo ch vin nhn

Bo ch vin nhn bng phng php xt ht t:

- Nghin TPL, lactose (nu c), ry TPL, lactose, Avicel, mt phn t dc r (60%

lng TD r) qua ry 250 m.

- Trn bt kp theo nguyn tc ng lng.

- Phn tn u PVP 10% trong ethanol 70o vo khi bt. Xt ht qua ry 800 m.

- Sy 600C trong 30 pht, sa qua ry 1mm, tip tc sy cho n khi vin t hm

m 3-4%.

- Ry t dc trn magnesi stearat, talc, phn t dc r cn li (40% lng TD r)

qua ry 180 m, trn vi cm thu c trn.

- Dp vin bng my dp vin tm sai vi chy ci ng knh 7 mm, iu chnh

t c khi lng vin 180 mg ( 7,5%), lc gy v vin 6-8 kP.

2.3.2.2. Phng php bao lp kim sot gii phng (phng php bao bt kh)

- Chun b nh tng cht ha do:

Ha tan HPMC E6 trong nc to dung dch HPMC E6 10% (kl/tt).

Phn tn DBP/TEC vo dung dch E6 10%, siu m 30 pht, hnh thnh

nh tng. Lc nh tng thu c qua ry 180 m.

- Chun b bt bao: cn, ry nguyn liu qua ry 125 m theo cng thc. Trn u

theo nguyn tc ng lng.

- Chun b thit b: lp sng phun dch, bm nhu ng, ni bao, my sy.

- Chun b vin nhn bao: cn khi lng vin nhn dng bao theo cng thc.

Tnh khi lng trung bnh ca mt vin.

- Bao vin:

Cho ni bao quay 5 pht trc khi bt u qu trnh bao, thi kh loi bi.

Bao lt: bng nh tng cht ha do, ng thi phun dch v thi kh nng.

Bao lt ti khi vin tng 5-6% khi lng vin nhn th chuyn sang bao bt.

17

Bao bt: phun nh tng cht ha do, rc bt bao, cho ni quay khong 1 pht

bt bm chc vo vin, thi kh nng trong 2-3 pht. Lp li qu trnh trn

cho ti khi vin t c khi lng mong mun.

- Sy vin trong t sy tnh: iu kin nhit v thi gian kho st [25].

2.3.3. Phng php nh gi

2.3.3.1. Phng php nh gi vin nhn

a. nh gi cng ca vin nn

S dng my o cng vin nn Erweka THB20. Th vi 10 vin, ly gi tr

trung bnh, lc gy v vin trung bnh c tnh ra kP.

Yu cu: lc gy v vin trung bnh nm trong khong 6-8 kP.

b. nh gi ng u khi lng: theo DVN IV (ph lc 11.3)

Cn khi lng ca 20 vin trn cn phn tch Sartorius BP 121S, tnh khi lng

trung bnh ca mt vin (mtb). Cn khi lng ca tng vin, tnh phn trm lch

khi lng (% m) so vi mtb.

%m = (mi mtb)/mtb x 100%

Yu cu: theo c in Vit Nam IV, % chnh lch so vi khi lng trung bnh

vin c khi lng t 80 250 mg l 7,5%.

c. nh gi mi mn

Theo BP 2013 (phng php 2.9.7)

S dng my o mi mn PHARMATEST PTF E. Cn mt khi lng vin

khong 6,5 g, lm sch bi bm trn vin. Cn chnh xc khi lng vin (m1 gam)

cho vo my quay 100 vng. Sau ly vin ra, lm sch bi v cn li (m2 gam).

mi mn c tnh theo cng thc:

X% = (m1 m2)/ m1 x 100%

Yu cu: mi mn khng c qu 1%.

d. nh lng

Nghin 20 vin, cn chnh xc mt lng mth (mg) tng ng vi khi lng

trung bnh mt vin (~ 180 mg) vo cc c m 100 ml. Thm khong 40 ml nc ct,

siu m 30 pht. Chuyn dch thu c vo bnh nh mc 100 ml, b sung nc ct

18

va 100 ml, lc u, lc loi b 20ml dch lc u. Ly chnh xc 1ml dch lc

trn cho vo bnh nh mc 100ml, thm nc va 100 ml, lc u. o quang

bc sng 272 nm. So snh vi mu chun c pha vi nng tng t (khong

10 g/ml). Mu trng l nc.

CT tnh:

X % =Cchun DthDchun x 100

x 10 x 100%

Trong :

Cchun : nng dung dch chun (g/ml)

Dchun, Dth : mt quang tng ng ca

dung dch chun, dung dch th

X%: hm lng so vi l thuyt

Th vi 3 mu bt ly 3 v tr khc nhau.

Theo qui nh trong DVN IV, gii hn cho php hm lng vin nn cha khi

lng dc cht trn 50 - 100 mg l 7,5 %. Vy hm lng TPL trong vin phi

nm trong khong 92,5%-107,5% so vi lng theo l thuyt.

e. nh gi kh nng gii phng dc cht t vin nhn

Th theo chuyn lun vin nn theophylin trong DVN IV:

- Thit b: kiu cnh khuy.

- iu kin th: mi trng ha tan: 900 ml nc, 50 1 vng/ pht, 37 0,5oC,

th trong 60 pht.

- Cch tin hnh: ti cc thi im 5, 15, 30, 45, 60 pht, ht chnh xc 10 ml dch,

pha long ti nng thch hp, b sung 10 ml sau mi ln ht. Dch pha long

v dung dch chun pha vi nng chnh xc khong 10 g/ml o quang bc

sng 272 nm. Mu trng l nc.

Xy dng cng thc tnh nng gii phng dc cht ti mi thi im

- Nng TPL trong mu th l dch rt t mi trng ha tan ti thi im t (Ct)

tnh theo cng thc: Ct = Cc x Dt /Dc x k.

Trong : Ct , Cc l nng mu th v chun

Dt, Dc l mt quang mu th, mu chun

k l h s pha long

- Khi lng TPL trong 10 ml dch ht ra ti thi im t l: m10(t) = Ct x 10

19

- Khi lng TPL trong 900 ml dch ti thi im t l: m900(t) = m10(t) x 90

- Khi lng TPL gii phng ti thi im t l:

mt = 900() + m10(i)1

=0 (vi t=1 th m10(i) = 0)

- Phn trm TPL gii phng ti thi im t l:

% =mt

mvin x X % x 100% Trong :

- mvin: khi lng vin nhn th ha tan

- X%: hm lng dc cht trong vin.

Mi cng thc th vi 3 vin, ly kt qu trung bnh.

Yu cu: sau 30 pht, vin nhn phi gii phng trn 85% dc cht.

2.3.3.2. Phng php nh gi vin bao

a. T l khi lng lp v bao

T l khi lng lp v bao (TLVB) c tnh bng % khi lng lp v bao so

vi khi lng vin nhn.

TLVB = [ (m2 - m1) x 100% / m1] Trong : m1, m2: khi lng vin trc v sau

khi bao (mg)

b. nh lng theophylin t vin bao

Do vin sau bao mng chc nn s dng my nghin bi nghin vin. Ly 5 vin

c cng t l khi lng v bao cho vo my nghin bi. Bt thu c tin hnh v

tnh ton tng t nh vi nh lng vin nhn mc 2.3.3.1.d.

Yu cu: gii hn hm lng cho vin bao: 92,5% - 107,5% hm lng theo l thuyt.

c. nh gi kh nng gii phng dc cht t vin bao

Th theo BP2013 ph lc XII B

- Thit b: kiu cnh khy.

- Mi trng: 2 gi u trong 750 ml mi trng acid HCl 0.1 M, sau thm

250 ml dung dch trinatri phosphat 0.2 M, iu chnh pH bng acid HCl 2M hoc

dung dch NaOH 2M t c pH 6,8 0,05.

- Nhit : 37 0,5oC, tc cnh khuy: 100 1 vng/ pht.

20

- Ht 10 ml dch mi trng ha tan ti cc thi im 1, 2, 3, 4, 5, 6, 7, 8 gi, b

sung 10 ml mi trng ha tan sau mi ln ht mu.

- Pha long ti nng thch hp, o quang mu th v mu chun (nng pha chnh

xc khong 10 g/ml) bc sng 272 nm, mu trng l mi trng th ha tan.

- Cch xy dng CT tnh tng t nh trong phn xy dng CT tnh phn trm

gii phng dc cht t th ha tan vin nhn trong mc 2.3.3.1.e.

Yu cu: vin c thi gian tim tng 6-7 gi, sau 8 gi trn 85% dc cht gii phng.

2.3.3.3. Phng php o nhit chuyn ha thy tinh

Th nghim c thit k nhm nh gi nh hng ca loi cht ha do v iu

kin nhit sy ln tg ca HPMC K4M trong mng phim.

- Quy trnh bo ch mng phim:

Pha 40ml dung dch HPMC K4M 2% (kl/tt) trong hn hp dung mi ethanol:

dichlomethan t l 1:1. Cht ha do (nu c) c thm vo dung dch trn vi lng

tng ng 30% (kl/kl) so vi khi lng ca HPMC K4M. Khuy u dung dch

bng khuy t trong 1 gi. Cc dung dch thu c ra cc a petri c ng knh

10cm, bc hi dung mi trong cc iu kin khc nhau: sy chn khng LVO Labtech

trong 6 gi (t nhit 30oC) v sy 60oC trong 24 gi, bo qun trong ti nilon

kn trong bnh ht m trc khi phn tch nhit vi sai.

- Tin hnh phn tch nhit vi sai:

Cc mng phim thu c trn c ct nh, cn 1 lng mu tng ng

khong 7 mg HPMC K4M, p mu trong a nhm dung tch 40 l. Mu trng

l chn ng rng.

S dng my phn tch nhit Mettler Toledo trong iu kin c kh nitrogen vi

lu lng dng 50 ml/pht, qu trnh phn tch nhit gm 2 giai on:

Giai on 1: tng nhit t 30oC ti 150oC vi tc 10oC/pht, sau h

nhit xung 30oC vi tc 10oC/pht lm bay hi ht nc trong mu.

Giai on 2: tng nhit ln 200oC vi tc 10oC/pht.

Phn tch ph bng phn mm c ci sn, ghi li kt qu tg [26].

21

2.3.3.4. Phng php nh gi hnh nh b mt v mt ct ngang lp v bao

S dng phng php chp knh hin vi in t qut (SEM). Vin bao c ct

dc bng mt li dao co, mu sau x l quan st v chp li di knh hin vi in

t qut S4800 NIHE 10000 kV [26].

22

CHNG 3. THC NGHIM, KT QU V BN LUN

3.1. Xy dng ng chun v mi tng quan gia nng v mt quang

xc nh mi tng quan gia nng v mt quang ca dung dch TPL

trong cc mi trng pH 1,2; pH 6,8; nc ct: tin hnh pha dy dung dch chun

v o bc sng 272 nm nh nu trong mc 2.3.1, kt qu nh trong hnh sau:

Hnh 3.1: th biu din mi tng quan gia nng TPL v mt quang

o ti bc sng 272 nm

- Nhn xt: Kt qu thu c t hnh 3.1 cho thy nng ca TPL trong cc mi

trng v mt quang ti bc sng 272 nm c s tng quan tuyn tnh trong

khong nng kho st t 4,0 g/ml n 12 g/ml vi h s tng quan trong mi

trng pH 1,0; pH 6,8; nc ct tng ng l R2 = 0,999; 0,998 v 0,999 hay R2 1.

- Kt lun:

C th s dng phng php o quang bc sng 272 nm nh lng TPL.

nh lng TPL trong cc mi trng trn bng phng php o quang ti

bc sng 272 nm cn pha long mu th v chun c nng nm trong

khong tuyn tnh kt qu nh lng c chnh xc hn.

3.2. Xy dng cng thc bo ch vin theophylin gii phng theo nhp bng

phng php bao bt kh

Vi mc tiu xy dng c vin gii phng theo nhp c: thi gian tim tng 6-7

gi (dc cht gii phng di 10%), sau 8 gi trn 85% dc cht gii phng.

y = 0,044x + 0,012

R = 0,999

y = 0,054x + 0,017

R = 0,999y = 0,052x + 0,004

R = 0,998

0

0.2

0.4

0.6

0.8

0 5 10 15

Mt

q

uan

g (

D)

Nng ( g/ml)

pH 1,0

pH 6,8

nc ct

23

Tin hnh bo ch vin gii phng theo nhp gm 2 phn: vin nhn v lp v bao

kim sot gii phng.

3.2.1. Xy dng cng thc vin nhn cha 100 mg theophylin

Mc tiu la chn vin nhn c kh nng gii phng dc cht tt nht.

Tin hnh kho st mt s thnh phn t dc nh hng ti kh nng gii phng

dc cht t vin nhn.

Bng 3.1. Cng thc vin nhn vi mt s loi t dc khc nhau

Thnh phn CT1 CT2 CT3 CT4

1. Theophyllin (mg) 100 100 100 100

2. TD n Avicel (mg) 66 66 66 33

Lactose (mg) - - - 33

3. TD r

Crospovidon (mg) 10 - - -

SSG (mg) - 10 - -

Natri croscarmelose (mg) - - 10 10

4. TD trn Magnesi stearar (mg) 2 2 2 2

Talc (mg) 2 2 2 2

5. TD dnh PVP 10% trong ethanol 70o (ml) 12 12 12 12

Vin nn c bo ch bng phng php xt ht t theo phng php ghi

mc 2.3.2.1 (m 100 vin). Tin hnh th gii phng dc cht theo phng php

ghi mc 2.3.3.1.

Tiu ch la chn: sau 30 pht trn 85% dc cht gii phng.

3.2.1.1. nh hng ca t dc r

Tin hnh kho st vi 3 loi t dc r l: crospovidon, natri starch glycolat

(SSG), natri croscarmelose. Kt qu nh sau:

Bng 3.2. Phn trm TPL gii phng t vin nhn s dng cc t dc r khc nhau

T (pht) % TPL gii phng ((TB SD)

CT1 ( crospovidon) CT2 ( SSG) CT3 (natri croscarmelose)

5 9,84 2,24 5,84 0,78 35,01 0,39

15 13,75 1,86 10,93 1,14 66,84 1,40

30 21,33 3,04 23,43 7,06 97,07 1,35

45 31,67 0,59 48,54 5,97 98,95 0,42

60 58,96 3,07 70,54 8,49 101,27 0,74

24

Hnh 3.2. Phn trm TPL gii phng t vin nhn s dng cc t dc r khc nhau

- Nhn xt:

Khi s dng cc t dc r khc nhau cho tc gii phng dc cht t vin

nhn khc nhau.

Mc gii phng dc cht sau 5 pht u tin ca vin nhn tng dn theo

th t CT3 (natri croscarmelose) > CT2 (crospovidon) > CT1 (SSG).

Vin nhn CT3 ti thi im 30 pht gii phng c 97,07% dc cht.

- Gii thch:

Theo kt qu nghin cu ca mt s tc gi khi tip xc vi mi trng: vin

s dng natri croscarmelose r ngay lp tc to thnh ht mn, vin s dng

SSG r chm hn v to thnh cc ht th hn, vin s dng crospovidon

trng n ngay lp tc nhng kh nng trng n c gii hn to thnh cc

mng ln, lin kt lng lo.

Kh nng r ca natri croscarmelose khi to ht dp vin l tt nht. Kt qu

trn cng ph hp vi kt qu ca mt s nghin cu [39].

- Kt lun: la chn CT3 c cha natri croscarmelose l t dc r tin hnh

kho st tip.

3.2.1.2. nh hng ca t dc n

Avicel v lactose l 2 t dc n c la chn kho st tip. Kt qu nh sau:

0

30

60

90

120

0 20 40 60 80

% T

PL

gi

i p

h

ng

Thi gian (pht)

CT1

CT2

CT3

25

Bng 3.3. Phn trm TPL gii phng t vin nhn s dng cc t dc n khc nhau

T (pht) % TPL gii phng (TB SD)

CT3 (Avicel) CT4 (Avicel : lactose = 1:1)

5 35,01 0,39 85,34 4,99

15 66,84 1,40 100,29 0,43

30 97,07 1,35 102,26 1,02

45 98,95 0,42 103,80 1,14

60 101,27 0,74 104,65 1,46

Hnh 3.3. Phn trm TPL gii phng t vin nhn s dng cc t dc n khc nhau

- Nhn xt: c 2 cng thc u cho phn trm gii phng dc cht sau 30 pht t

trn 85%. Tuy nhin cng thc CT4 (Avicel : lactose = 1:1), % TPL gii phng

5 pht l 85,34% cao hn nhiu so vi cng thc CT3 (Avicel) l 35,01%.

- Gii thch: lactose thuc nhm t dc n tan trong nc, Avicel thuc nhm t

dc n khng tan trong nc [1]. Do vy CT4 c kh nng r, gpdc tt hn.

- Kt lun: la chn hn hp Avicel : lactose = 1:1 kho st tip.

Kt lun:

T nhng kt qu thu c, chng ti a ra cng thc cho mt vin nhn nh sau:

Bng 3.4.Thnh phn cng thc vin nhn

Thnh phn Khi lng

1. Theophylin (mg) 100

2. TD n Avicel (mg) 33

Lactose (mg) 33

3. TD r Natri croscarmelose (mg) 10

4. TD trn Magnesi stearat (mg) 2

Talc (mg) 2

5. TD dnh dd PVP 10% trong ethanol 70o (ml) 12

0

30

60

90

120

0 20 40 60 80

% T

PL

gi

i p

h

ng

Thi gian ( pht)

CT4 CT3

26

Vin nn TPL c bo ch bng phng php xt ht t vi quy trnh nh

mc 2.3.1.1. Tin hnh dp m 1000 vin bng my dp vin tm sai Korsch model

VFD007S21A. Vin sau khi bo ch c nh gi mt s tiu ch cht lng theo

phng php ghi trong mc 2.3.3.1. Kt qu nh trong bng 3.5.

Bng 3.5. cng, mi mn, hm lng trung bnh vin, ng u khi lng CT4

Ch tiu Kt qu

cng trung bnh (Kp) (n=10) (TBSD) 7,25 0,57

mi mn (%) (n=3) (TBSD) 0,79 0,07

Hm lng trung bnh (%) (n =3) (TBSD) 103, 45 2,01

ng u khi lng (n=20) 96,43% - 106,21%

- Nhn xt:

Vin t yu cu ng u khi lng theo quy nh trong DVN IV.

cng vin nm trong gii hn t ra l t 6-8 Kp, mi mn thp (< 1%),

hm lng nm trong gii hn cho php (t 92,5 % - 107,5 %).

- Kt lun: vin dp theo cng thc CT4 t y cc ch tiu yu cu v cht

lng, iu kin tin hnh cc giai on bo ch tip theo.

3.2.2. Xy dng cng thc lp v bao theophylin gii phng theo nhp bng

phng php bao bt kh

Sau khi tham kho ti liu [6], [21] v xem xt iu kin tin hnh th nghim ti

b mn, chng ti tin hnh la chn:

- Bt bao: polyme bao lp v kim sot gii phng l HPMC, talc tng trn chy,

chng dnh trong qu trnh bao, cc cht to knh c th c: lactose, HPMC E6,

acid fumaric.

- Nh tng cht ha do l dibutyl phtalat hoc triethyl citrat trong dung dch

HPMC E6 10%.

- Khi lng vin nhn cho mt m bao l 40g

- T l khi lng lp v bao d kin l 100% so vi khi lng vin nhn.

- 60oC trong 24 gi.

27

- V nh gi mt s yu t v thnh phn cng thc lp v bao nh hng ti gii

phng dc cht t vin bao.

- Tiu ch la chn: tlag 6-7 gi (gii phng dc cht < 10%), sau 8 gi t trn

85% gii phng dc cht.

Bng 3.6. Cng thc lp v bao vi mt s loi t dc khc nhau

3.2.2.1. nh hng ca talc

La chn lp v bao trng n n mn c thnh phn bt bao c bn gm HPMC

K100M v talc, tin hnh kho st t l talc trong cng thc bt bao.

Kt qu nh bng 3.7.

Thnh phn

CT

4.1

CT

4.2

CT

4.3

CT

4.4

CT

4.5

CT

4.6

CT

4.7

CT

4.8

CT

4.9

1. Bt bao

Loi

HPMC

HPMC

K100M 90% 80% - - - - - - -

HPMC

K4M - - 80% 50% 50% 50% 60% 70% 60%

Cht to

knh

Lactose - - - 30% - - - - -

HPMC

E6 - - - - - 30% - - -

Acid

fumaric - - - 30% 30% - 20% 10% 20%

Talc 10% 20% 20% 20% 20% 20% 20% 20% 20%

2. Nh tng cht ha do

Dung dch 10%

(kl/tt) HPMC E6

(kl/kl)

80%

CHD

(kl/kl)

Dibutyl

phtalat 20% -

Triethyl

citrat - 20%

28

Bng 3.7. Phn trm TPL gii phng t vin bao c t l talc trong lp v bao khc nhau

T (gi) % TPL gii phng (TB SD)

CT4.1 (10%) CT4.2 (20%)

2 0,57 0,03 0,96 0,06

4 1,04 0,06 2,08 0,13

6 2,61 0,09 4,90 0,25

7 3,65 0,28 6,58 0,28

8 5,32 0,38 8,63 0,34

Hnh 3.4. Phn trm TPL gii phng t vin bao c t l talc trong lp v bao khc nhau

- Nhn xt:

o Vin bao s dng HPMC K100M v talc 2 t l khc nhau kt qu gii phng

dc cht ti thi im 8 gi u nh hn 10%, tlag > 8 gi.

o Vin bao vi cng thc CT4.2 (20% talc) cho kt qu gii phng dc cht ti

cc thi im cao hn so vi vin bao vi cng thc CT4.1 (10% talc).

- Gii thch:

o Do HPMC K100M c nht cao [29], khi trong mi trng ha tan, s

trng n to lp gel dy, ko di thi gian n mn lp v bao, tlag ln.

o Lng talc tng ln, tng ng lng HPMC gim xung, do talc t trng ln

nn vi cc vin c cng t l khi lng lp v bao, vin c thnh phn talc

trong bt bao l 20% lp v bao mng hn, lp gel khi tip xc vi mi trng

mng hn v vy dc cht khuch tn ra ngoi nhiu hn. Mt khc, do talc s

0

5

10

15

20

0 2 4 6 8 10

% T

PL

gii

ph

n

g

Thi gian (gi)

CT 4.1

CT 4.2

CT 4.2

CT 4.1

29

nc do lin kt trong lp v bao CT4.2 (t l talc 20%) lng lo hn nn

dc cht s khuch tn ra ngoi nhiu hn so vi vin bao bng CT4.1 (t l

talc 10%).

o Mt khc, quan st trong qu trnh bao vin, khi s dng t l talc thp, bt bao

trn chy km.

- Kt lun: la chn CT4.2 tin hnh cc th nghim tip theo.

3.2.2.2. nh hng ca loi HPMC

Theo kt qu mc 3.2.1.1, khi s dng HPMC K100M kt qu th ha tan c

tlag > 8 gi, nn chng ti s dng HPMC K4M c nht thp hn kho st

tip. Kt qu th ha tan nh trong bng sau.

Bng 3.8. Phn trm TPL gii phng t vin bao bng cc loi HPMC khc nhau

T

(gi)

% TPL gii phng (TB SD)

CT4.2 (K100M) CT4.3 (K4M)

2 0,96 0,06 0,48 0,05

4 2,08 0,13 2,20 0,07

6 4,90 0,25 60,24 4,37

7 6,58 0,28 92,29 3,52

8 8,63 0,34 93,96 1,90

Hnh 3.5. Phn trm TPL gii phng t vin bao bng cc loi HPMC khc nhau

- Nhn xt: khi thay HPMC K100M bng HPMC K4M, vin bao t c m hnh

gii phng theo nhp vi tlag = 5 - 6 gi.

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

h

ng

Thi gian (gi)

CT 4.1

CT 4.3

CT 4.2

30

- Gii thch: HPMC K4M c nht thp hn [29], do vy vi cng mt t l khi

lng lp v bao, khi trng n to gel trong mi trng ha tan th lp gel ca

HPMC K4M mng hn, lng lo hn. Kt qu l lp v bao b n mn, ha tan

nhanh hn to iu kin cho vin nhn bung lp v bao gii phng dc cht. Tuy

nhin vi tlag = 5-6 gi, vn cha t c mc tiu ra.

- Kt lun: la chn HPMC K4M l polyme kim sot gii phng, tin hnh kho

st t l khi lng lp v bao dy hn.

3.2.2.3. nh hng ca t l khi lng lp v bao

Tin hnh th ha tan cng thc CT4.3 t l khi lng lp v bao so vi vin

nhn l 100% (TLVB 100%), 120% (TLVB 120) v 150% (TLVB 150%).

Kt qu nh sau:

Bng 3.9. Phn trm TPL gii phng t vin bao CT4.3 cc TLVB khc nhau

T (gi) % TPL gii phng (TB SD)

TLVB 100% TLVB 120% TLVB 150%

2 0.48 0.05 0.27 0.05 0.32 0.06

4 2.20 0.07 0.93 0.17 0.98 0.13

6 60.24 4.37 3.66 0.43 3.61 0.25

7 92.29 3.52 6.18 0.42 6.07 0.28

8 93.96 1.90 32.97 3.07 8.49 0.28

Hnh 3.6. Phn trm TPL gii phng t vin bao CT4.3 cc TLVB khc nhau

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

hn

g

Thi gian (gi)

TLVB 100%

TLVB 120%

TLVB 150%

31

- Nhn xt:

o Khi khi lng lp v bao tng, tlag tng, c th tng ng ca vin c TLVB

100%, 120%, 150% tlag l 5-6 gi, 7-8 gi v hn 8 gi.

o HPMC K4M cho mt m hnh gii phng theo nhp TLVB 120% vi tlag l

7-8 gi, lu hn so vi tlag mc tiu l 6-7 gi. 8 gi c 32,97% dc cht

gii phng.

- Gii thch: khi khi lng lp v bao tng, lp gel hnh thnh khi tip xc vi mi

trng dy hn, cn nhiu thi gian hn n mn lp gel yu to iu kin bung

mng gii phng nhanh dc cht.

- Kt lun:

o La chn HPMC K4M l polyme bao lp kim sot gii phng, TLVB la

chn kho st tip l 120%.

o Thm mt s t dc to knh cho vo thnh phn lp v bao gim tlag v

ci thin kh nng gii phng dc cht sau pha tim tng.

3.2.2.4. nh hng ca cht to knh

a. nh hng ca loi cht to knh

La chn 3 loi cht to knh: lactose, acid fumaric, HPMC E6 a vo bt bao

vi t l HPMC K4M : cht to knh : talc = 50% : 30% : 20%.

Tin hnh th ha tan cc vin bao mc 120%, thu c kt qu nh bng 3.10.

Bng 3.10. Phn trm TPL gii phng t vin bao c cc cht to knh khc nhau

T(gi) % TPL gii phng (TB SD)

CT4.3 CT4.4 (lactose) CT4.5 (acid fumaric) CT4.6 (HPMC E6)

2 0,27 0,05 0,48 0,08 0,76 0,26 0,34 0,14

4 0,93 0,17 2,72 0,04 3,12 0,10 1,53 0,02

6 3,66 0,43 81,86 18,31 94,07 3,31 69,80 3,21

7 6,18 0,42 103,12 0,80 101,57 0,70 101,78 0,32

8 32,97 3,07 104,81 1,08 102,48 3,22 102,42 1,23

32

Hnh 3.7. Phn trm TPL gii phng t vin bao c cc loi cht to knh khc nhau

- Nhn xt:

So vi CT4.3 lp v bao ch c HPMC K4M v talc, c 3 cng thc thm cht

to knh t l 30% tlag ngn hn (5-6 gi), dc cht gii phng nhanh sau pha

tim tng (7 gi % gii phng dc cht u 100%).

% gii phng theophylin lc 6 gi gim dn theo th t CT4.5 (acid fumaric)

(94,07%) > CT4.4 (lactose) (81,86%) > CT4.6 (HPMC E6) (64,80%).

lch chun v % theophylin gii phng lc 6 gi ca CTT 4.4 (lactose) kh

cao SD = 18,31%

- Gii thch:

Cc cht to knh thm vo u c kh nng tan tt trong mi trng, to cc knh

dn nc vo pha trong, ng thi lng HPMC K4M gim i (t 80% -50%)

khin cho lp gel to ra mng v lng lo hn, do tlag ngn li v dc cht

gii phng sau pha tim tng nhanh hn.

Acid fumaric c tnh acid nn tan d dng trong pH 6,8; sau ti lactose,

HPMC E6 l polyme trng n v tan chm trong mi trng. Do c s khc

nhau v kh nng hnh thnh cc knh dn nc vo bn trong nhn, tc n

mn ca lp v bao, nh hng ti tlag.

Bt lactose c t trng ln hn so vi bt HPMC K4M, khi ry nguyn liu qua

ry 125 m, bt lactose qua ry d dng, cn HPMC K4M xp kh qua ry hn,

do trong qu trnh bao bt c th b tch lp, phn b khng u ln cc vin

0

20

40

60

80

100

120

0 2 4 6 8 10

%T

PL

gi

i p

hn

g

Thi gian (gi)

CT4.3CT4.4CT4.5CT4.6

33

bao, lm cho cc vin bao gii phng khng u, lch chun v % dc cht

gii phng ngay sau pha tim tng cao.

Ngoi ra, acid fumaric tan ph thuc pH, do thi gian lu gi ti d dy s nh

hng ti tlag. Lactose v HPMC E6 kim sot gii phng ch ph thuc thi gian.

- Kt lun: Thm cht to knh lm cho tlag ngn li, qu trnh gii phng sau pha tim

tng nhanh, la chn HPMC E6 l cht to knh tin hnh cc th nghim tip theo.

b. nh hng ca t l cht to knh

Theo kt qu th ha tan ca CT4.6 cha 30% HPMC E6 trong thnh phn bt

bao tlag l 5-6 gi nh hn so vi tlag mc tiu l 6-7 gi. V vy chng ti tin hnh

kho st vi cc t l HPMC E6 10%, 20% khi lng bt bao.

Kt qu th ha tan nh sau:

Bng 3.11. Phn trm TPL gii phng t vin bao c t l cht to knh khc nhau

T

(gi)

% TPL gii phng

CT4.6 (30%) CT4.7 (20%) CT4.8 (10%) CT4.3 (0%)

2 0,34 0,14 0,41 0,09 0,56 0,15 0,27 0,05

4 1,53 0,02 1,79 0,49 1,07 0,20 0,93 0,17

6 69,80 3,21 6,53 0,97 4,51 0,34 3,66 0,43

7 101,78 0,32 95,26 0,45 8,32 0,50 6,18 0,42

8 102,42 1,23 103,38 3,77 34,70 4,70 32,97 3,07

Hnh 3.8. Phn trm TPL gii phng t vin bao c t l cht to knh khc nhau

- Nhn xt:

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

hn

g

Thi gian ( gi)

CT4.6

CT4.7

CT4.8

CT4.3

34

Khi gim t l HPMC E6, tlag tng. C th ng CT4.6 (30%); CT4.7 (20%);

CT4.8(10%); CT4.3(0%) th thi gian tlag ln lt l 5-6 gi, 6-7 gi, 7-8 gi

v 7-8 gi.

CT 4.7 (20%) tlag 6-7 ting, % TPL gii phng dc cht lc 8 gi l 103,38%.

- Gii thch:

HPMC E6 c vai tr l cht to knh, nn khi gim lng HPMC E6, gim hnh

thnh nhng knh dn nc lm suy yu lp v bao.

ng thi lng HPMC K4M tng, s lm cho lp v bao to lp gel dy,

nht cao hn khi tip xc vi mi trng ha tan, cn nhiu thi gian lp v

bao yu i,do ko di pha tim tng

- Kt lun: la chn CT 4.7 tin hnh cc th nghim tip theo.

3.2.2.5. nh hng ca cht ha do

Cht ha do lm gim nhit chuyn ha thy tinh ca polyme, nn nh

hng n hnh thnh mng phim, ngoi ra cc c im khc nh, mc thn

nc, thn du, nht cng nh hng ti gii phng dc cht t vin bao.

a. nh hng ca cht ha do ln nhit chuyn ha thy tinh

Chun b mng phim ca 3 mu HPMC K4M, HPMC K4M + DBP, HPMC K4M

+ TEC nh trong mc 2.3.3.3. Sau mng phim c sy chn khng 30oC

trong 6 gi cho bay ht dung mi.

o nhit chuyn ha thy tinh kt qu nh trong hnh sau:

Hnh 3.9. Nhit chuyn ha thy tinh ca mng phim K4M vi cc loi cht ha do

khc nhau

35

- Kt qu: Nhit chuyn ha thy tinh ca mng phim HPMC K4M khng c cht

ha do l 181,03 oC; mng phim HPMC K4M c DBP l 157,81 oC v mng

phim HPMC K4M c TEC l 103,44 oC.

- Nhn xt:

Khi s dng cht ha do, nhit chuyn ha thy tinh ca mng phim

HPMC K4M u gim.

TEC lm gim nhit chuyn ha thy tinh nhiu hn DBP.

- Gii thch:

Cht ha do lm gim lc lin kt gia cc phn t polyme, tng lng

polyme t do, do cc phn t polyme chuyn ng t do hn, nhit

chuyn pha s thp hn [10]. V vy, iu kin u tin la chn cht ha

do l kh nng khuch tn vo trong v tng tc vi polyme [9].

HPMC K4M l mt polyme thn nc [34]. Nn nhiu nghin cu s dng

cht ha do cng c bn cht thn nc tng tng tc vi HPMC [13],

[16], [22], [30]. TEC thn nc hn DBP (trong cng thc c nhm hydroxy

[29]). V vy mng phim HPMC K4M s dng TEC nhit chuyn ha thy

tinh thp hn so vi mng s dng DBP, qu trnh hnh thnh mng phim s

dng TEC c thc y nhanh hn v mng phim ng nht hn.

b. nh hng ca cht ha do ln gii phng dc cht

Tip tc nh gi nh hng ca cht ha do ln gii phng dc cht t vin

bao s dng TEC hoc DBP trong thnh phn nh tng cht ha do.

Lp v bao s dng TEC v DBP lm cht ha do, cc thnh phn khc trong

cng thc ging nhau v 60oC trong 24 gi.

Kt qu ha tan nh bng 3.12.

36

Bng 3.12. Phn trm TPL gii phng t vin bao s dng cc loi CHD khc nhau

T(gi) % TPL gii phng

CT4.7 (DBP) CT4.9 (TEC)

2 0,41 0,70

4 1,79 44,33

6 6,53 66,04

7 95,26 78,50

8 103,38 81,07

Hnh 3.10. Phn trm TPL gii phng t vin bao s dng cc loi CHD khc nhau

- Nhn xt:

S dng DBP hay TEC lm cht ha do trong thnh phn mng bao th c 2

u cho m hnh gii phng theo nhp.

Tlag CT4.9 (TEC) thp hn ca CT4.7 (DBP) nhiu.

- Gii thch: Tuy TEC lm gim mnh nhit chuyn ha thy tinh ca HPMC

K4M, khi lp v bao s dng TEC s hon thin tt hn v kim sot gii

phng tt hn. Nhng TEC thn nc hn, nht km hn DBP [29] nn lp

v bao thn nc hn, lm cho qu trnh ha tan, xi mn ca lp gel sau khi tip

xc vi mi trng din ra nhanh hn nn pha tim tng li ngn li.

- Kt lun: la chn DBP lm cht ha do trong thnh phn nh tng ha do

ca mng bao.

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

hn

g

Thi gian ( gi)

CT 4.7

CT 4.9

37

Kt lun:

T kt qu cc th nghim mc 3.2.1.1 n mc 3.2.1.6 chng ti a ra cng

thc cho mt lp v bao vin theophylin gii phng theo nhp l:

- Khi lng vin bao cho mt m: 40 (g).

- Bt bao: 30 (g) HPMC K4M, 10 (g) HPMC E6, 10 (g) talc.

- Nh tng CHD: 82,5 (g) DPB trong dung dch 300 (ml) dung dch HPMC E6

10% (kl/tt) trong nc.

- T l khi lng lp bao v l 120% so vi vin nhn.

i vi phng php bao bt kh th nhit v thi gian c nh hng n

hnh thnh lp v bao, v vy chng ti tip tc nh gi nh hng ca yu t quy

trnh l nhit v thi gian , thi gian sau ti kh nng gii phng dc cht.

3.3. nh gi nh hng ca yu t thuc quy trnh ti gii phng dc cht

t vin bao

Qu trnh vi mc ch t c nhit m polyme chuyn t trng thi knh

glass sang trng thi mm do, linh hot hn soften. Tham kho ti liu [25] kt

hp vi iu kin th nghim ti b mn chng ti la chn kho st :

- 4 mc nhit l iu kin thng (KT) (khong 30oC), trong t sy cc

nhit 40oC, 60oC, 80oC.

- Thi gian : 0 gi, 15 gi, 24 gi.

- Thi gian vin sau : 1 ngy, 7 ngy, 30 ngy.

Vin bao CT4.7 c bo ch theo phng php ghi mc 2.3.2.2, ly vin bao

mc bao tng 120% nh gi nh hng ca yu t thuc v quy trnh ln gii

phng dc cht.

3.3.1. nh hng ca nhit

3.3.1.1. nh hng ca nhit ti nhit chuyn ha thy tinh ca mng phim

HPMC K4M

Chun b mng phim HPMC K4M v DBP, sy 2 iu kin khc nhau: sy chn

khng (30oC) trong 6 gi v sy 60oC trong 24 gi. Mu o DSC theo phng php

nh trong mc 2.3.3.3. Kt qu nh trong hnh sau:

38

Hnh 3.11. Nhit chuyn ha thy tinh ca mng phim HPMC K4M

s dng cht ha do l dibutyl phtalat v cc iu kin khc nhau

- Nhn xt: Mng phim s dng DBP 60oC trong 24 gi c nhit chuyn ha

thy tinh l 95,22oC thp hn nhiu so vi mng bao ch sy chn khng (30oC)

trong 6 gi l 157,81oC.

- Gii thch:

nhit cao, nht ca cht ha do v polyme gim, nn polyme v cht

ha do c th d dng trn ln v tng tc vi nhau, lm gim nhit chuyn

ha thy tinh ca mng phim [31].

- ng dng:

p dng qu trnh vi phng php bao bt kh c bit vi nhng polyme

c nhit chuyn ha thy tinh cao.

La chn thi gian v nhit thch hp thc y nhanh qu trnh hnh

thnh lp v bao, tit kim thi gian, tit kim in nng v an ton th nghim.

3.3.1.2. nh hng ca nhit ti hnh nh b mt v mt ct lp v bao

nh gi nh hng ca nhit ti hnh thnh lp v bao, chng ti tin

hnh th nghim nh trong mc 2.3.3.5, mu o l hnh nh ct ngang v hnh nh b

mt vin ca vin CT4.7 iu kin thng (KT) v vin CT4.7 c 80 oC

trong 24 gi. Kt qu nh sau.

39

Bng 3.13. Hnh nh b mt v hnh nh ct ngang ca vin bao iu kin thng

v 80oC trong 24 gi

KT (30oC) trong 24 gi 80oC trong 24 gi

B mt

Ct ngang

- Nhn xt:

So snh hnh nh b mt lp v bao: Vin 80oC trong 24 gi c b mt ng

nht hn vin ch iu kin thng.

iu kin thng b mt lp v cho thy hnh nh x x, nhiu l, cn nhit

cao 80 oC cc polyme chuyn sang trng thi mm hn, cc ht polyme lin

kt vi nhau to b mt mn, t l hn.

Tuy nhin 80oC cc ht polyme vn cha hon ton chy lng v ng

nht.

So snh hnh nh mt ct: Kt qu cng tng t, vin nhit 80 oC trong

24 gi, hnh nh ct ngang ca vin ng nht hn, khng b phn thnh nhiu

lp ring, t xp hn.

40

- Kt lun: Nhit c nh hng ti cht lng lp v bao. Khi c nhit

thch hp, lp v bao s hnh thnh nhanh hn v ng nht hn.

- ng dng:

Vin bao bng phng php bao bt kh cn kho st iu kin thch hp

thc y hnh thnh lp v bao nhanh hn.

Vi lp v bao ang kho st, cn ko di thi gian hoc tng nhit

thc y qu trnh hnh thnh lp v bao ng nht hn.

3.3.1.3. nh hng ca nhit ln gii phng dc cht

Kt qu th ha tan cc cng thc CT4.7 sau khi bao c iu kin thng

v 40oC, 60oC, 80oC thu c nh sau:

Bng 3.14. Phn trm TPL gii phng t vin bao nhit khc nhau trong 24 gi

T

( gi) %TPL gii phng

80o 60oC 40oC KT

2 0,97 0,41 0,62 0,69

4 2,43 1,79 33,27[A1] 2,10

6 36,11 6,53 68,30 4,80

7 70,68 95,26 100,09 29,11

8 105,26 103,38 102,64 81,58

Hnh 3.12. Phn trm TPL gii phng t vin bao nhit khc nhau trong 24 gi

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

hn

g

Thi gian ( gi)

80oC

60oC

40oC

KT

41

- Nhn xt:

C s khc bit v tlag v kt qu gii phng dc cht gia cc cng thc nhng

khng tun theo qui lut.

iu kin thng v 60oC cho tlag l 6-7 gi, cn 40oC l 2-3 gi, 80oC

cho tlag l 5-6 gi.

Cha ph hp vi kt qu nghin cu trong mt s ti liu tham kho [25] khi

nhit tng thc y lin kt gi cc ht polyme trn lp v bao, lm cho lp

v bao ng nht v kim sot gii phng tt hn.

- Gii thch:

S khc bit khi iu kin thng c th c gii thch l do sau khi bao,

lp v bao vn cn mt hm lng m ng k, nc cng ng vai tr l mt

cht ha do. V vy khi vin iu kin thng, lp v bao chu tc ng

ca 2 CHD l nc v DBP, s c mt ca nc c th l nguyn nhn thc

y hnh thnh lp v bao ng nht hn. V vy c th vin iu kin

thng lp v bao kim sot gii phng dc cht tt hn. Vai tr ca nc

phun thm vo qu trnh tng c cp trong nghin cu [21].

Da vo kt qu o tg ca mng phim K4M trong mc 3.3.1.1, c 3 nhit

u thp hn nhit chuyn ha thy tinh ca K4M trong mng phim. Hnh

nh lp v bao 80oC trong 24 gi cc ht polyme vn cha thc s chy

lng v ng nht.

- Kt lun:

Vi cc iu kin hin ti, lp v bao vn cha thc s n nh, s khc bit

v gii phng dc cht t vin bao CT4.7 cc iu kin thng, 40oC,

60oC, 80oC khng c xu hng r rng.

Vai tr ca nc trong qu trnh cn c xem xt.

3.3.2. nh hng ca thi gian

Vin bao CT4.7 60oC trong cc thi gian khc nhau l 0 gi, 15 gi v 24 gi.

Kt qu nh trong bng 3.15.

42

Bng 3.15. Phn trm TPL gii phng t vin bao 60oC trong cc thi gian khc nhau

T

(gi) % TPL gii phng

0 gi 15 gi 24 gi

2 0,69 0,41 0,41

4 2,10 1,13 1,79

6 4,80 3,94 6,53

7 29,11 34,74 95,26

8 101,3 99,57 103,38

Hnh 3.13. Phn trm TPL gii phng t vin bao 60oC trong cc thi gian

khc nhau

- Nhn xt:

o Thi gian khng nh hng nhiu ti gii phng dc cht t vin bao

CT4.7: tlag vn gi mc 6-7 gi.

o Tuy nhin vi cc thi gian khc nhau, tlag nh hng mnh ti gii phng

trong gi u tin sau pha tim tng.

- Gii thch:

o 60oC nh hn rt nhiu nhit chuyn ha thy tinh ca HPMC

K4M, cn tng thi gian nhn bit s nh hng ca thi gian r

rng hn.

o Xem xt vai tr ca nc nh trong th nghim cc iu kin nhit

khc nhau

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

h

ng

Thi gian (gi)

24 gi

15 gi

0 gi

43

3.3.3. nh hng ca thi gian sau

La chn CT4.7, nhit l 60 oC v thi gian l 24 gi, nh gi nh hng

ca khong thi gian sau l 1 ngy, 7 ngy v 30 ngy ti gii phng dc cht

nh gi s b n nh v kim sot gii phng dc cht ca lp v bao.

Kt qu thu c nh sau:

Bng 3.16. Phn trm TPL gii phng t vin bao 60oC trong 24 gi

sau cc khong thi gian khc nhau

T

(gi)

% TPL gii phng

1 ngy 7 ngy 30 ngy

2 0,41 0,34 0,39

4 1,79 1,37 1,50

6 6,53 4,72 5,64

7 95,26 8,61 79,12

8 103,38 77,14 103,82

Hnh 3.14. Phn trm TPL gii phng t vin bao 60oC trong 24 gi

sau cc khong thi gian khc nhau

Nhn xt:

Thi gian sau l 1 ngy, 7 ngy v 30 ngy khng c nhiu s khc bit

trong kt qu th ha tan

Tlag ca vin sau 7 ngy c tng nhng c 3 vin 8 gi u cho kt qu gii

phng dc cht tng i cao.

0

30

60

90

120

0 2 4 6 8 10

% T

PL

gi

i p

hn

g

Thi gian (gi)

1 ngy

7 ngy

30 ngy

44

- Gii thch:

Qu trnh cha t c lp v bao n nh nht, tip tc iu kin

thng, lp v bao vn tip tc bin i.

ng thi trong qu trnh bo qun, m mi trng vo vin lm lp v bao

km bn, kim sot gii phng li gim.

Kt lun:

Vi cc iu kin nhit , thi gian v thi gian sau nh gi, trong

khun kh ti, chng ti cha lm r c vai tr ca cc yu t ny ln qu

trnh gpdc t vin bao.

=> Cn tip tc kho st cc mc nhit v thi gian lu hn lm r

vai tr ca cc yu t qui trnh .

45

KT LUN V XUT

1. Kt lun

Qua thi gian tin hnh nghin cu ti t c mt s kt qu nh sau:

1. xy dng c cng thc vin nhn theophylin gii phng ngay, sau 30 pht

trn 85% dc cht c gii phng.

2. s b nh gi nh hng ca yu t cng thc v qui trnh ti gii phng

dc cht t vin bao.

3. nh gi nh hng ca nhit v cht ha do ti nhit chuyn ha thy

tinh HPMC K4M v kh nng kim sot gii phng dc cht c th ng dng

trong la chn thng s qu trnh .

2. xut

Do ln u tin p dng phng php bao bt kh vo bo ch vin gii phng

theo nhp Vit Nam v thi gian nghin cu ti c gii hn nn vn cn mt s

vn nhm nghin cu cha nh gi c. V vy, chng ti c mt s xut

cho nghin cu tip theo l:

- Tip tc hon thin cng thc v qui trnh bo ch vin theophylin gii phng

theo nhp bng phng php bao bt kh.

- nh gi n nh v sinh kh dng ca theophylin t vin gii phng theo

nhp

TI LIU THAM KHO

Ting Vit

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2. B Y T (2009), Dc in Vit Nam IV, tr.605-606.

3. B Y T (2009), Dc th quc gia Vit Nam, tr.1079-1081 .

Ting Anh

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performance", Pharmaceutical development and technology, 11(1), pp.47-53

PH LC 1

Sy 600 trong 30 pht

Sa ht ry 1000 m

Hm m 3-4%

Nho m

Xt ht ry 800 m

10% PVP/ethanol 70o

Nghin, ry qua ry 250

m

Trn bt kp

Dp vin

TPL, avicel, lactose

mt phn t dc r

Sy 600 - 700

Trn cm

Magnesi

stearat, talc,

TD r ngoi : 7 mm, m = 180

7,5% (mg),

Lcgyvvin: 6-8

kP

Hnh PL1. S bo ch vin nhn theophylin 100 mg

PH LC 2

Ry 125 m HPMC K4M,

HPMC E6, talc

TLMB:120% Bao bt

Trn u

Vin nhn

Lc (ry

180m)

Bao lt TLMB:5-6%

Lm mn

trong ni bao

Ha tan

Phn tn Dibutyl phtalat

Siu m

HPMC E6, nc

Khuy t

60o/24 gi

Bao lt: va phun dch, va

thi kh nng

Bao bt: phun dch, rc bt,

thi kh nng.lp li n khi

mng bao t khi lng

Hnh PL2. S bao vin bng phng php bao bt kh