B Y T

TRNG I HC DC H NI

HONG TH THY HNG

NGHIN CU BO CH VIN PSEUDOEPHEDRIN GII

PHNG KO DI BNG PHNG PHP BAO MNG ZEIN

KHA LUN TT NGHIP DC S

H NI 2013

B Y T TRNG I HC DC H NI

HONG TH THY HNG

NGHIN CU BO CH VIN PSEUDOEPHEDRIN GII

PHNG

KO DI BNG PHNG PHP BAO MNG ZEIN

KHA LUN TT NGHIP DC S

Ngi hng dn:

1. TS. Nguyn Thch Tng

2. ThS. inh Th Hi Bnh

Ni thc hin:

1. B mn Bo ch

H NI 2013

LI CM N

Em xin by t lng cm n chn thnh v su sc ti c gio PGS.TS. Phm

Th Minh Hu - Ph trng b mn Bo Ch, thy gio TS. Nguyn Thch Tng

Ging vin B mn Bo ch v c gio ThS. inh Th Hi Bnh NCS Trng

i hc Dc H Ni lun tn tm hng dn, ng vin v gip em trong

qu trnh hc tp v nghin cu khoa hc.

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

ca B mn Bo ch ht lng quan tm hng dn v to iu kin tt nht

em hon thnh kha lun ny.

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

ngi lun ng vin ng h em 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

Hong Th Thy Hng

DANH MC CC K HIU V CC CH VIT TT

BP

CHD

DBP

DVN IV

LC

EC

EP

GP

GPKD

HPC

HPMC

KLPT

LOR

PAR

PEG

PG

PSE

PSE.HCl

PVP

STT

TB

TCCS

USP

Dc in Anh

Cht ha do

Dibutyl phthalat

Dc in Vit Nam IV

lch chun

Ethyl cellulose

Dc in chu u

Gii phng

Gii phng ko di

Hydroxypropyl cellulose

Hydroxypropyl methyl cellulose

Khi lng phn t

Loratadin

Paracetamol

Polyethylen glycol

Propylen glycol

Pseudoephedrin

Pseudoephedrin hydroclorid

Polyvinyl pyrolidon

S th t

Trung bnh

Tiu chun c s

Dc in M

DANH MC CC BNG

Trang

Bng 1.1. Mt s ch phm cha pseudoephedrin hydroclorid

Bng 1.2. Bng m t t l mt s amino acid c trong cu trc ca zein.

Bng 1.3. Mt s dng bo ch cha pseudoephedrin ..............................

Bng 1.4. Mt s nghin cu v zein ........................................................

Bng 1.5. Mt s nghin cu v dng bo ch cha pseudoephedrin ng

dng zein ...................................................................................................

Bng 2.1. Nguyn liu s dng .

Bng 3.1. cng, mi mn v hm lng trung bnh vin F1 .

Bng 3.2. ng u khi lng vin F1 ..

Bng 3.3. Kt qu hiu sut bao khi thay i tc phun dch

Bng 3.4. Kt qu hiu sut bao khi thay i tc quay ni bao ..

Bng 3.5. Kt qu hiu sut bao khi thay i nhit kh thi vo .

Bng 3.6. Kt qu hiu sut bao khi thay i lu lng kh thi vo ...

Bng 3.7. Tiu chun ha tan d kin cho vin F2 ...

Bng 3.8. Cc cng thc dch bao s dng kho st t l zein v cht

ha do ...

Bng 3.9. Bng kt qu kho st t l cht ha do .

Bng 3.10. Thit k th nghim .....

Bng 3.11. Kt qu th ha tan cho cc cng thc thit k ..

Bng 3.12. Bng kt qu th ha tan vin F3

Bng 3.13. cng v hm lng trung bnh vin F3 .

Bng 3.14. ng u khi lng vin F3

3

7

9

10

12

14

23

23

24

26

26

27

28

29

30

31

32

38

39

40

DANH MC CC HNH V V TH

Trang

Hnh 3.1. th kho st khong tuyn tnh ca php o quang PSE.HCl ..

Hnh 3.2. th th hin mi quan h gia tc phun dch v hiu sut bao

..

Hnh 3.3. th gii phng PSE.HCl ca phn li vin Clarinase pH 6,8

Hnh 3.4. th ha tan vin F2a, F2b v F2c ..........................

Hnh 3.5. Mt p th hin mi quan h gia t l zein v t l PEG 400 vi

s gii phng dc cht ti thi im 1h

Hnh 3.6. Mt p th hin mi quan h gia t l zein v t l DBP vi s

gii phng dc cht ti thi im 3h

Hnh 3.7. th kt qu ca php o nhit vi sai ..

Hnh 3.8. th gii phng vin F2 c cng thc 4 v cng thc 12 ..

Hnh 3.9. th th ha tan vin d kin F3 .

22

25

28

29

33

34

36

37

39

MC LC T VN ............................................................................................................ 1

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

1.1. Pseudoephedrin .............................................................................................. 2

1.1.1. Tnh cht ha l ........................................................................................ 2

1.1.2. Tnh cht dc l ...................................................................................... 2

1.1.3. Mt s ch phm c cha pseudoephedrin .............................................. 3

1.2. Tng quan v dng thuc gii phng ko di .............................................. 3

1.2.1. Khi nim ................................................................................................. 3

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

1.2.2.1. u im ............................................................................................. 4

1.2.2.2. Nhc im ....................................................................................... 4

1.2.3. Mt s dng thuc gii phng ko di in hnh ..................................... 4

1.2.3.1. C ch khuch tn ............................................................................. 4

1.2.3.2. C ch ha tan ................................................................................... 6

1.2.3.3. C ch p sut thm thu .................................................................. 7

1.2.3.4. C ch trao i ion ............................................................................ 7

1.3. Zein .................................................................................................................. 7

1.3.1. Ngun gc, cu to, phn loi .................................................................. 7

1.3.2. Tnh cht vt l ......................................................................................... 8

1.3.3. Tnh cht ha hc ..................................................................................... 8

1.3.4. ng dng .................................................................................................. 8

1.4. Mt s cng trnh nghin cu v cc dng bo ch cha pseudoephedrin

v cc dng bo ch s dng zein ........................................................................ 9

1.4.1. Mt s cng trnh nghin cu v cc dng bo ch cha pseudoephedrin 9

1.4.2. Mt s cng trnh nghin cu v zein v ng dng ca zein ................. 10

1.4.3. Mt s cng trnh nghin cu v cc dng bo ch cha pseudoephedrin

c ng dng zein .............................................................................................. 12

1.5. L do pht trin ti ................................................................................. 13

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

2.1. Nguyn vt liu, thit b ............................................................................... 14

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

2.1.2. Thit b nghin cu ................................................................................. 14

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

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

2.3.1. Phng php bo ch ............................................................................. 15

2.3.1.1. Phng php dp vin ..................................................................... 15

2.3.1.2. Phng php bao vin pseudoephedrin hydroclorid gii phng ko

di ................................................................................................................. 16

2.3.2. Phng php nh gi ............................................................................ 17

2.3.2.1. nh gi vin nhn 60 mg pseudoephedrin hydroclorid ................ 17

2.3.2.2. nh gi nh hng ca cc thng s bao phim ln qu trnh bao 18

2.3.2.3. nh gi cht lng vin bao pseudoephedrin hydroclorid gii

phng ko di ............................................................................................... 19

2.3.2.4. Phng php o nhit chuyn ha thy tinh ca mng bao ...... 20

2.3.2.5. Phng php x l s liu .............................................................. 21

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

3.1. nh gi vin nhn cha 60 mg pseudoephedrin hydroclorid ................ 22

3.1.1. Kho st phng php nh lng pseudoephedrin hydroclorid ........... 22

3.1.2. Kt qu nh gi vin nhn pseudoephedrin hydroclorid ..................... 22

3.2. Kho st nh hng ca cc thng s bao phim....................................... 23

3.2.1. nh hng ca tc phun dch bao ..................................................... 24

3.2.2. nh hng ca tc quay ni bao ....................................................... 26

3.2.3. nh hng ca nhit kh thi vo ..................................................... 26

3.2.4. nh hng ca lu lng kh thi vo .................................................. 27

3.3. Nghin cu xy dng cng thc dch bao.................................................. 27

3.3.1. Xy dng tiu chun th ha tan cho vin bao ...................................... 27

3.3.2. Kho st khong t l zein v cht ha do trong cng thc bao .......... 28

3.3.2.1. Kho st khong t l zein .............................................................. 28

3.3.2.2. Kho st khong t l cht ha do ................................................ 30

3.3.3. Thit k th nghim v ti u ha ........................................................... 31

3.3.3.1. Thit k th nghim ......................................................................... 31

3.3.3.2. Kt qu th ha tan cc cng thc thit k ..................................... 32

3.3.3.3. nh gi nh hng ca zein v cht ha do ln s gii phng

dc cht ...................................................................................................... 33

3.3.3.4. Ti u ha ....................................................................................... 37

3.4. nh gi cht lng vin bao ti u cha pseudoephedrin hydroclorid

gii phng ko di ............................................................................................... 38

3.4.1. nh gi ch tiu th ha tan .................................................................. 38

3.4.2. nh gi mt s ch tiu khc ................................................................ 39

3.5. Bn lun ....................................................................................................... 40

3.5.1. Bn lun nh hng ca cc thng s bao ln hiu sut bao ................. 40

3.5.2. Bn lun nh hng ca zein v cht ha do ln tc gii phng dc

cht ................................................................................................................... 41

3.5.1. Bn lun v phng php bo ch ......................................................... 41

KT LUN V XUT .................................................................................... 43

1

T VN

mt t nc ang pht trin v c nn kh hu nhit i nh Vit Nam, vn

nhim mi trng cng vi tnh hnh kh hu hay thay i l nhng nguyn

nhn c bn khin bnh vim mi d ng v chng cm lnh thng thng tr thnh

nhng bnh l ph bin. Bnh c nhng triu chng nh nght mi, ht hi, chy

nc mi, nga v chy nc mt, gy ra s phin toi cho i sng sinh hot v

hc tp ca bnh nhn. iu tr cc triu chng trn, c nhiu hot cht nhm

cng giao cm cho hiu qu cao, an ton c s dng. Tuy nhin, nhc im

ca chng l c thi gian bn thi ngn, phi s dng thuc nhiu ln trong ngy

khin cho s tun th iu tr ca ngi bnh kh t c. V vy, trn th trng

ngy cng xut hin nhiu ch phm thuc gii phng ko di, gim liu dng v

c tnh, mang li hiu qu iu tr cao v s tin li r rt cho ngi s dng.

Mt trong nhng dng bo ch gii phng ko di ang c y hc quan tm l vin

nn bao phim vi xu hng u tin s dng cc polyme c ngun gc t nhin, an

ton v thn thin vi mi trng.

Xut pht t nhng vn nu trn, ti Nghin cu bo ch vin

pseudoephedrin gii phng ko di bng phng php bao mng zein c tin

hnh vi mc tiu sau:

Xy dng cng thc bo ch vin bao cha 60 mg pseudoephedrin hydroclorid

gii phng ko di 12h.

2

CHNG 1. TNG QUAN

1.1. Pseudoephedrin

Cu to phn t: C10H15NO = 165,2

Tn khoa hc:

(+) (1S,2S) 2 Methylamino 1 phenylpropan 1 ol.

1.1.1. Tnh cht ha l

Ha tnh:

Pseudoephedrin l mt ng phn khng i quang ca ephedrin. N d b kh

thnh methamphetamin v d b oxy ha thnh methcathion.

L tnh:

- Dng bt hoc tinh th mu trng.

- Nhit nng chy: 117 - 118oC (dng mui sulfat: 174 - 179oC, dng mui

clorid: 182 - 186oC).

- tan: 7mg/l nc, dng mui tan t do trong nc hoc ethanol [22].

1.1.2. Tnh cht dc l

Tc dng - ch nh:

Tc dng: co mch, gim sung huyt (c ch cng giao cm).

iu tr vim mi d ng, chng cm lnh thng thng vi cc triu chng:

ngt mi, ht hi, chy mi, chy nc mt.

Dc ng hc:

- D dng hp thu t h tiu ha (SKD: 95 - 98%).

- Bi xut lng ln qua nc tiu dng cn hot tnh, lng nh b chuyn ha

qua gan.

3

- Thi gian bn thi t1/2 = 5 - 8h (gim khi acid ha nc tiu).

- Th tch phn b VD = 2 - 3 l/kg.

- thanh thi Cl = 7,33 ml/pht/kg [7], [22].

1.1.3. Mt s ch phm c cha pseudoephedrin

Pseudoephedrin t khi c bo ch n c trong mt ch phm. Hot cht

ny thng c phi hp vi mt s hot cht khc nh loratadin, cetirizin,

acetaminophen Bng 1.1 sau y trnh by mt s ch phm cha

pseudoephedrin hydroclorid [7], [23].

Bng 1.1. Mt s ch phm cha pseudoephedrin hydroclorid

Hot cht Tn bit

dc

Dng

bo ch Hng sn xut

PSE.HCl Pseudo-Gest Vin nn Major Pharmaceuticals

- M

PSE.HCl

Chlophenamin maleat

Freenos

Junior Siro

PT Ferron Par Pharm -

Indonexia

PSE.HCl

Cetirizin Zyrtec D Vin nn

U.C.B. Farchin S.A -

Thy s

PSE.HCl

Paracetamol

dextromethorphan

hydrobromid

Mixagrip

Cold and

Cough

Vin nn PT Dankos Farma -

Indonexia

PSE.HCl

triprolidin hydrochlorid Actifed Vin nn

Glaxo Wellcome

GmbH & Co - c

PSE.HCl

Loratadin Clarinase Vin nn

Schering - Plough

Labo N.V - B

1.2. Tng quan v dng thuc gii phng ko di

1.2.1. Khi nim

Thuc gii phng ko di (GPKD) l nhng ch phm c kh nng ko di

qu trnh gii phng v hp thu dc cht t dng thuc nhm duy tr nng dc

cht trong mu trong vng iu tr mt thi gian di, vi mc ch ko di thi gian

tc dng, gim s ln dng thuc, gim tc dng khng mong mun, nng cao hiu

4

qu iu tr ca thuc [1].

1.2.2. u nhc im

1.2.2.1. u im

So vi thuc quy c, thuc GPKD c mt s li im sau:

- Duy tr nng dc cht trong mu trong vng iu tr (trnh hin tng nh -

y), do gim tc dng khng mong mun ca thuc.

- Gim c s ln dng thuc cho ngi bnh, trnh qun thuc, b thuc, thc

dy gia m ung thuc...V vy, m bo c s tun th iu tr ca ngi

bnh nht l vi nhng ngi b bnh mn tnh kinh nin phi iu tr di ngy (nh

bnh cao huyt p, i tho ng...).

- Tng sinh kh dng do thuc c hp thu u n v trit hn.

- Gim c lng thuc dng cng nh gi thnh cho c t iu tr.

1.2.2.2. Nhc im

- Kh thi tr ngay thuc khi c th c nu xy ra hin tng ng c v tc

dng khng mong mun.

- K thut bo ch phc tp.

- Phm vi ng dng hp, ng dng cho mt s t dc cht [1].

1.2.3. Mt s dng thuc gii phng ko di in hnh

Cc sn phm c bo ch thnh cng di dng thuc gii phng ko di

hu ht c pht trin trn c s mt s c ch sau:

- C ch khuch tn.

- C ch ho tan.

- C ch p sut thm thu.

- C ch trao i ion.

Trong kha lun ny, chng ti nghin cu h mng bao gii phng dc cht

theo c ch khuch tn dng k thut bao mng mng (bao phim).

1.2.3.1. C ch khuch tn

H mng bao khuch tn

Nguyn tc cu to: bao dc cht bi mt mng polyme khng tan

5

trong dch tiu ha, ng vai tr l hng ro khuch tn kim sot tc gii phng

dc cht.

u nhc im:

u im l d t c s gii phng dc cht hng nh theo ng hc bc

0, duy tr nng mu trong vng iu tr. Tc gii phng dc cht c th

thay i bng cch thay i thnh phn v dy mng bao.

Tuy nhin, dng thuc ny c nhc im:

- i hi k thut bo ch cao, c th gy c hi nhim mi trng (nu dng

dung mi hu c).

- Polyme thng t tin.

- Bt k sai st no dn n khim khuyt mng bao u dn n s gii phng

nhanh dc cht, thay i thit k ban u. Khng thun li cho dc cht tc dng

mnh, vng iu tr hp, dc cht phn t lng ln, t tan.

Cng thc bao phim thng c cc thnh phn sau:

- Cht to phim: l cc polyme c ngun gc khc nhau.

+ Polyme tng hp: HPMC, EC, Eudragit... u im: kh bn vng, tinh khit

ha hc, c nghin cu y , d s dng. Tuy nhin, qu trnh sn xut

polyme tim n nhiu nguy c gy nhim mi trng.

+ Polyme chit xut t thin nhin: zein, collagen, gelatin... u im: thn thin

vi mi trng, gi r, d chit xut v s dng. Tuy nhin, loi polyme ny kh

nhy cm nhit , d tng tc vi cc ha cht khc v cha c nghin cu y

.

- Cht ha do: c chia lm 2 loi da vo tan.

+ Thn nc: glycerin, PG, PEG, sorbitol ...

+ Thn du: dibutyl phthalat, du thu du, acid oleic, triacetin ...

- Cht chng dnh: talc, aerosil, titan dioxyd ...

- Cht mu: titan dioxyd, carmin, chlorophyl ...

- Dung mi: nc, cc alcol, ester, ceton ...

6

ng hc gii phng theo phng trnh ca nh lut Fick:

dQ

dt =

D

e S (C1 C2)

Trong : Q l lng dc cht khuch tn qua mng trong thi gian t,

D l h s khuch tn ca dc cht qua mng,

e l b dy mng,

S l din tch b mt khuch tn,

C1 l nng dc cht pha trong mng,

C2 l nng dc cht pha ngoi mng.

Vi mt h xc nh, nu cc yu t D, e v S khng i th tc gii phng

dc cht ch yu ph thuc vo C. Khi tc ha tan ca dc cht ln hn tc

khuch tn nhiu ln, trong h s to nn dung dch bo ha v nu C2 coi nh

khng ng k th tc gii phng s t mc hng nh theo ng hc bc 0 cho

n lc gii phng c 80 - 90% dc cht.

Ngoi c ch khuch tn, h mng bao cn kim sot gii phng dc cht

theo mt s c ch khc nh c ch n mn v c ch thm thu.

H ct tr khuch tn

Nguyn tc cu to: dc cht c phn tn vo mt ct tr xp, khng tan

trong ng tiu ha, ct ny ng vai tr nh mt b khung mang thuc. Sau khi

ung, thuc gii phng khi ct bng cch khuch tn t ct ra dch tiu ha v ct

c o thi nguyn vn ra ngoi.

1.2.3.2. C ch ha tan

Mng bao ha tan

Nguyn tc cu to: dc cht c bao bi mt mng ha tan chm hoc n

mn dn trong ng tiu ha, ng vai tr l cc hng ro lm chm s gii phng

dc cht ra khi dng thuc.

Ct thn nc v ct s nc n mn

Nguyn tc cu to: phi hp dc cht vi mt polyme thn nc hoc vi

sp hay cht bo, ng vai tr nh mt ct mang thuc. Sau khi ung, ct s ha tan

7

hoc n mn t t trong ng tiu ha ko di s gii phng dc cht.

1.2.3.3. C ch p sut thm thu

Nguyn tc cu to: dc cht d tan trong nc c dp thnh vin, sau

bao bn ngoi vin mt mng bn thm c ming gii phng dc cht. Sau khi

ung, nc i qua ha tan dc cht to nn mt p sut thm thu cao hn p sut

ngoi mng, y dung dch dc cht i qua ming ra mi trng bn ngoi.

1.2.3.4. C ch trao i ion

L mt dng ca ct khng tan, trong nha trao i ion ng vai tr cht

mang thuc. Khi bo ch, cc dc cht ion ha c gn vi nha trao i. Sau

khi ung, thuc s c gii phng khi ct bng cch trao i vi cc ion c trong

dch tiu ha. Nh vy s gii phng dc cht t l thun vi nng ion trong

dch tiu ha [1], [6], [14].

1.3. Zein

1.3.1. Ngun gc, cu to, phn loi

- Tn khoa hc: zein.

- Cu to: zein l mt protein khng cha lysin v tryptophan, c khi lng phn

t khong 38000 [20].

Bng 1.2. Bng m t t l mt s amino acid c trong cu trc ca zein

STT Thnh phn T l % STT Thnh phn T l %

1 Alanin 8,3 % 10 Leucin 19,3 %

2 Arginin 1,8 % 11 Methionin 2,0 %

3 Asparagin 4,5 % 12 Phenylalanin 6,8 %

4 Cystin 0,8 % 13 Prolin 9,0 %

5 Acid glutamic 1,5 % 14 Serin 5,7 %

6 Glutamin 21,4 % 15 Threonin 2,7 %

7 Glycin 0,7 % 16 Tyrosin 5,1 %

8 Histidin 1,1 % 17 Valin 3,1 %

9 Isoleucin 6,2 %

8

- Ngun gc: chit xut t ng (dng ht nguyn, bt th hoc mm ng).

- V mt cu trc, zein c th c chia thnh 4 loi khc nhau: , , v [21].

Trong , -zein l ph bin nht, chim ~ 70% ca tng s [25]. -zein c th

c chit xut bng cch s dng dung mi ethanol, trong khi cc zein khc cn

thm mt tc nhn kh trong dung mi th mi chit c. Zein thng mi c

to thnh t -zein [17].

1.3.2. Tnh cht vt l

- Bt mu vng rm hoc vng nht, dng v nh hnh hoc l cc mnh nh, c

mi c trng v v nht.

- T trng: 1,23 g/cm3.

- im nng chy: zein kh khi un nng ln 200oC khng thy s phn hy.

- Phn b kch thc tiu phn: 100% kch thc nh hn 840 m.

- ha tan: thc t khng tan trong aceton, ethanol, nc; tan trong hn hp dung

mi alcol v nc, aceton v nc (nng 60 - 80% (tt/tt)), glycol, dung dch

kim trong nc c pH 11,5 [20].

1.3.3. Tnh cht ha hc

Zein mang y tnh cht ha hc ca mt protein.

1.3.4. ng dng

Trong dc phm, zein c s dng lm nguyn liu bao phim hoc bao kh

nhm mc ch kim sot gii phng dc cht cho vin nn, che giu mi v

cc dng thuc dng ng ung. Mng bao c tnh thm km vi O2 v CO2,

thch hp ng dng bao dc cht nhy cm, d phn hy hoc d b oxy ha.

Trong thc phm, zein c s dng to:

- Mng ph bo v trong bao b nha, mng bao trng trn bao b giy ng n,

mng ph ln c chua, v trng,... vi mc ch bo v, trnh oxy ha, tng bn

c hc.

- L thnh phn trong ko cao su tng do dai cho ko khi nhai hoc to

mng c v ngt bao ngoi ko cao su [17].

9

1.4. Mt s cng trnh nghin cu v cc dng bo ch cha pseudoephedrin v

cc dng bo ch s dng zein

1.4.1. Mt s cng trnh nghin cu v cc dng bo ch cha pseudoephedrin

Mt s nghin cu trn th gii v cc dng bo ch c cha PSE c tm tt

trong bng 1.3 sau y.

Bng 1.3. Mt s dng bo ch cha pseudoephedrin

Dc

cht Polyme

Phng

php

bo ch

Mt s kt qu Ti

liu

PSE HPMC;

EC

- Bo ch

vin nn:

to ht

t.

- Bao

phim kim

sot gii

phng.

- ng

nang

HPMC

- Vin GP nhanh c cha PSE v HPC (t l thay

i) c bao HPMC. Vin GP chm ch cha

PSE c bao phi hp HPMC v EC.

- Kt qu: HPC khng nh hng n tc gii

phng PSE. HPMC cn tr gii phng PSE km.

Vin GP chm c tc GP dc cht ph thuc

vo b dy mng bao, th ha tan c lag time.

c bit, lag time tng khi tng t l EC.

- Bo ch c h vin nang cha 2 vin mini GP

nhanh (gii phng PSE hon ton trong 1h) v 3

vin mini GPKD (gii phng PSE trong 8 - 10h)

t yu cu t ra.

[16]

PSE

Acid

stearic;

Eudragit

NE30D

- Bo ch

pellet

bng n -

to cu.

- Bao

phim kim

sot gii

phng.

- Lp bao nn nng chy c tc dng nh hng ro

ngn gia pellet nhn cha PSE v mng bao

phim. Lp bao phim th hin kh nng kim sot

GP dc cht hiu qu.

- Kt qu, pellet c bao vi t l bao nn 10%

v bao phim 5% cho m hnh GP ph hp vi

USP29 v c kh nng kim sot gii phng PSE

tt hn so vi pellet ch bao phim vi t l 10%.

[26]

PSE

LOR

Kollicoat

SR-30D;

- Bo ch

pellet

- Pellet khng bao GP nhanh cha PSE (c hoc

khng LOR). Pellet bao GP chm ch cha PSE. [27]

10

HPMC

bng n-

to cu

- Dp vin

nn t

pellet

- Bao

phim kim

sot gii

phng.

Hn hp 2 loi pellet trn c ng nang hoc

dp vin khi c thm Ceolus KG-801.

- c vin nn v vin nang, kt qu th ha tan

tng ng nhau. LOR gii phng hon ton

trong 2h, PSE trong pellet khng bao GP hon

ton sau 10 pht.

- Bo ch c vin nn c dp t hn hp 2

loi pellet trn theo m hnh la chn vi PSE

trong pellet bao GPKD n 12h theo ng hc bc

0.

Cc dng bo ch cha PSE gii phng ko di trn ng dng bao phim

bng cc loi polyme tng hp. Tuy nhin, t tc gii phng mong mun,

phi phi hp t nht 2 loi polyme khc nhau trong mt hay nhiu lp bao, qu

trnh bao tn km v phc tp.

1.4.2. Mt s cng trnh nghin cu v zein v ng dng ca zein

Cc nghin cu v ngun gc, tnh cht cng nh nhng ng dng c th ca

zein trong dc phm cng nh i sng c tm tt trong bng 1.4.

Bng 1.4. Mt s nghin cu v zein

Dc cht Polyme Tm tt kt qu Ti

liu

- Zein;

EC

- Tnh cht th tch, tnh thm nc v tnh ngn kh ca

mng zein tng ng EC vi h s thay th 1,1 - 1,4.

Tg ca mng zein thp v ph thuc nhiu vo m

mi trng.

- Cc cht ha do tng hp vi zein cn c phn

cc ph hp, to lin kt hydro vi zein. Nhng CHD c

KLPT ln kh trn ln vi zein nn ch c s dng

t l gii hn. Nu chn CHD l ester ca acid tartaric v

lactic th chng li di tr hoc bay hi khi mng bao.

- So vi cc polyme bn cht polyacrylat, mng zein

[10]

11

kim sot gii phng km hn.

5 -

fluorouracil Zein

- Thit k c m hnh gii phng bc 0 cho vin nn

bao kh s dng zein (dng bt tinh khit, dng ht v

hn hp) nh nguyn liu bao vi t l khc nhau.

- C ch kim sot GP ca zein: zein nhanh chng to

thnh mng li dng keo, cho php dc cht khuch

tn t t qua mng.

- Qu trnh GP gm cc giai on: dung mi thm nhp

vo trong vin, ha tan v khuch tn thuc ra bn ngoi

qua 1 nh chnh gia mt vin. nh ny hot ng

nh 1 h thng thm lc v GP thuc theo m hnh bc

0.

[15]

- Zein

- Tm tt ngun gc, cch chit xut, tnh cht, ng

dng trong i sng cng nh trong y hc ca zein t

mt s nghin cu trn th gii v zein.

- Tm lc v dung mi bao, cht ha do cho zein.

- Trnh by mt s iu kin bao v tnh cht mng bao

khi s dng zein lm nguyn liu bao.

[17]

Thymol Zein

- Bo ch v so snh h mng phim zein n v a lp,

cha 35% (kl/kl) thymol v tinh bt m.

- Tc GP thymol gim khi tng dy mng bao

hoc gim lng tinh bt trong c 2 h n hay a lp.

Kt qu: h n lp v t l tinh bt cao nht th GP

nhanh nht, h a lp v khng c tinh bt th GP chm

nht.

[18]

Paracetamol

Zein;

Eudragit

L30 D-55

- Zein dng pseudolatex vi t l zein 6% (kl/tt) c

dng bao phim cho vin nn v pellet cha PAR. Sau

12h, ch c 35% PAR gii phng trong mi trng nc

khi bao mng c t l zein l 5% (kl/kl) so vi nhn.

- Vin nn v pellet c ha tan trong cc mi trng:

dung dch gi d dy, dung dch HCl 0,1N, m

[19]

12

phosphat pH 6,0, 6,8 v 7,4. Kt qu cho thy: c s lin

quan gia pH v tnh thm ca mng zein. Ngoi ra, mi

trng gi d dy c cha pepsin lm thuc GP nhanh

nht do pepsin phn hy zein. V vy, cn bao thm lp

Eudragit L30 D-55 bao tan ti rut, bo v zein.

- Php phn tch nhit lng v nhiu x tia X cho thy

paraben l CHD thch hp cho mng zein.

Cc nghin cu trn cho thy zein c nghin cu kh y v c ng

dng trong nhiu phng php bo ch khc nhau: bao phim v bao kh. Nh vy,

zein l mt polyme t nhin tim nng trong cng nghip dc phm.

1.4.3. Mt s cng trnh nghin cu v cc dng bo ch cha pseudoephedrin c

ng dng zein

Mt s nghin cu c thc hin ti nc ta v vin nn cha PSE gii

phng ko di bng phng php bao mng zein. Bng 1.5 tm tt li ni dung cc

nghin cu ny.

Bng 1.5. Mt s nghin cu v dng bo ch cha pseudoephedrin ng dng zein

Dc

cht Polyme

Phng

php bo

ch

Tm tt kt qu Ti

liu

PSE zein

- Bo ch

vin nn:

dp thng.

- Bao phim

kim sot

GP.

- La chn c phng php chit xut zein

t ng bng dung mi ethanol, zein t tiu

chun dc in M.

- Xc nh c vin bao mng zein vi t l

zein 9,6% so vi nhn v t l PG 20% so vi

zein c c tnh ha tan tng t vin i chiu

(Clarinase) mi trng pH 6,8.

[8]

PSE

LOR

Zein;

HPMC

E6

- Bo ch

vin nn:

xt ht t.

- Bao phim

- M hnh gii phng vin i chiu

(Clarinase): 2h u, phn v cha 5 mg LOR

v 60 mg PSE GP nhanh v hon ton trong d

dy; 10h sau, phn li cha 60 mg PSE GPKD

[9]

13

kim sot

GP.

trong mi trng pH 6,8.

- Bo ch c vin PSE GPKD bng cch bao

mng zein vi t l zein so vi nhn 10% v t

l PG so vi zein 20%.

- Bo ch vin phi hp 2 dc cht c m

hnh gii phng tng t vin Clarinase.

Hai ti trn cha sng lc thng s bao phim thch hp cho qu trnh bao

trn my bao Vanguard, loi CHD tng hp vi zein. Vic a ra cng thc dch

bao cho vin PSE gii phng ko di mang tnh cht d on, cha c nghin

cu su v c h thng. V vy, ti ny nghin cu cc vn cn thiu trn.

1.5. L do pht trin ti

Pseudoephedrin l mt trong nhng alcaloid t nhin ca ephedra, c thi

gian bn thi ca PSE ngn (5h 8h). V vy, yu cu t ra l nghin cu phng

php duy tr nng PSE trong huyt tng di (10 12h), tng ng liu dng

2 ln/ngy. Mt trong nhng phng php n gin v thng dng nht hin nay l

bo ch vin bao phim GPKD. M hnh i chiu c chn l li vin Clarinase

ca hng Schering Plough lu hnh rng ri trn th trng, cht lng

c kim duyt bi B y t Hoa K. Theo ti liu sn xut c cng b, li vin

l 1 vin nn bao phim bng zein cha 60 mg PSE.HCl gii phng ko di.

Zein l mt polyme c ngun gc thin nhin, biu hin nhiu c tnh ha l

thun li cho qu trnh bao mng phim. Cc c im v th tch, hp th nc

v kh nng ngn kh tng t nh ethyl cellulose. Tuy nhin, zein th hin mt s

tnh cht u vit hn nh nhit chuyn ha thy tinh ca zein thp hn ethyl

cellulose cng iu kin. V vy, mng bao zein do dai hn. Mng bao zein cn c

tnh thm km i vi oxy v carbon dioxyd [10]. Tnh thm oxy ca mng zein

thp hn so vi polyethylene v polyvinyl clorua [17].

Sau khi la chn c dng bo ch, m hnh mu i chiu v nguyn liu

nghin cu, chng ti xc nh mc tiu cho ti l: xy dng cng thc bo ch

vin bao cha 60 mg pseudoephedrin hydroclorid gii phng ko di 12h.

14

CHNG 2. I TNG V PHNG PHP NGHIN CU

2.1. Nguyn vt liu, thit b

2.1.1. Nguyn vt liu

Bng 2.1. Nguyn liu s dng

STT Nguyn vt liu Ngun gc Tiu chun

1 Pseudoephedrin HCl Trung Quc USP

2 Lactose monohydrat M USP

3 Tinh bt m Php EP

4 PVP K30 Trung Quc USP

5 Zein Trung Quc USP

6 Polyethylen glycol 400 Trung Quc BP

7 Dibutyl phthalat Trung Quc BP

8 Titan dioxyd Trung Quc BP

9 Talc Trung Quc BP

10 Aerosil Trung Quc BP

11 Magnesi stearat Trung Quc BP

12 Isopropanol Trung Quc Tinh khit ha hc

13 Ethanol 96% Vit Nam DVN IV

14 Dinatri hydrophosphat Trung Quc Tinh khit ha hc

15 Kali dihydrophosphat Trung Quc Tinh khit ha hc

16 Natri hydroxyd Trung Quc Tinh khit ha hc

17 Nc ct Vit Nam DVN IV

18

Vin nn Clarinase

(s l OFE20245OAF,

hn dng 9/11/2014)

Schering Plough TCCS

2.1.2. Thit b nghin cu

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

- My o cng Pharmatest

15

- My th ha tan Vankel 7010

- Cn phn tch Sartorius BP 121S

- Cn k thut Sartorius TE3102S

- My o quang Hitachi U-1800

- Cn xc nh m nhanh Precisa

- My bao phim Vanguard

- B siu m WiseClean

- My khuy t IKA RH basic 1

- My phn tch nhit Mettler Toledo

- My o b Pharmatest typ PTF20E

- T sy BINDER

- Ni cch thy BUCHI 461 water bath.

2.2. Ni dung nghin cu

- nh gi vin nhn cha 60 mg pseudoephedrin hydroclorid.

- Kho st nh hng ca cc thng s bao phim.

- Nghin cu xy dng cng thc dch bao phim.

- nh gi cht lng vin bao ti u cha 60 mg pseudoephedrin hydroclorid gii

phng ko di.

2.3. Phng php thc nghim

2.3.1. Phng php bo ch

2.3.1.1. Phng php dp vin

Cng thc vin nhn cha PSE.HCl (k hiu vin F1):

Psedoephedrin hydroclorid

Lactose

Tinh bt m

PVP K30

Ethanol 70%

Magnesi stearat

Aerosil

60 mg

190 mg

30 mg

10 mg

50 mg

1,3 mg

6,8 mg

16

Bo ch vin F1 vi quy m 2000 vin, theo phng php xt ht t:

- Cn nguyn liu. Nghin bt n cc nguyn liu, trn bt kp (PSE.HCl, lactose

v tinh bt m) theo nguyn tc ng lng.

- Nho m vi dung dch t dc dnh (PVP K30 ha tan trong ethanol 70%). Xt

ht qua ry 1 mm.

- Sy ht nhit 50 - 55oC n khi m t 3 - 4%.

- Sa ht qua ry 1 mm.

- Nghin t dc trn (magnesi stearat, aerosil), ry qua ry 180 m, trn vi ht.

- Dp vin bng my dp vin tm sai vi b chy ci c ng knh 9 mm, khi

lng vin trung bnh 300 mg, cng 8 12 Kp.

2.3.1.2. Phng php bao vin pseudoephedrin hydroclorid gii phng ko di

Vin F1 c bao mng kim sot gii phng vi thnh phn chnh (polyme)

l zein, trong thit b ni bao c l.

Chun b dch bao:

Thnh phn dch bao gm:

Zein

PEG 400 hoc DBP

Talc

Titan dioxyd

Isopropanol : nc (8:2)

Thay i

Thay i

10% zein (kl/kl)

20% zein (kl/kl)

va dch bao cha 6% zein (kl/tt).

Quy trnh pha dch bao:

- Ha tan hon ton zein vo khong 70% lng hn hp dung mi (isopropanol :

nc) (1).

- Nghin bt n titan dioxyd v talc, ry qua ry 180 m, trn bt kp (2).

- Thm ng lng dung dch (1) vo (2), nh thnh bt nho. Sau , dng lng

hn hp dung mi (isopropanol : nc) cn li ko bt nho ny vo dung dch (1).

- Thm cht ha do.

- Khuy lin tc 12h bng my khuy t. Lc qua ry 180 m.

- B sung hn hp dung mi isopropanol : nc va .

17

Tin hnh bao phim:

Cn mt lng vin nhn khong 300g. em bao bng my bao Vanguard (h

ni bao c l) vi cc thng s ph hp. Tin hnh bao n khi khi lng vin

bao t yu cu, thu c vin F2. Vin F2 c n nh ti thiu 72h iu

kin phng trc khi em i nh gi cc ch tiu.

2.3.2. Phng php nh gi

2.3.2.1. nh gi vin nhn 60 mg pseudoephedrin hydroclorid

cng: o 10 vin bng my o lc gy v vin, ly kt qu trung bnh.

Yu cu: cng > 5Kp, vin nhn mi ph hp bao phim.

mi mn: cn chnh xc mt lng vin loi b bt (khi lng m1),

khong 6,5 g, cho vo my quay 100 vng, lm sch bi v cn khi lng cn

li (m2). mi mn c tnh theo cng thc:

X = (m1 m2)/m1 100% [24].

Yu cu: mi mn < 1%, vin nhn mi ph hp bao phim.

ng u khi lng: ly 20 vin, cn khi lng tng vin, cn khi lng

c 20 vin, tnh khi lng trung bnh. Tnh % chnh lch khi lng ca tng

vin so vi khi lng trung bnh.

Vin t yu cu v ng u khi lng nu khng c qu 2 n v nm

ngoi gii hn chnh lch 5% v khng c n v no chnh lch trn 10% so vi

khi lng trung bnh [3].

nh lng:

- Kho st phng php nh lng:

+ Tin hnh qut ph trn my quang ph Hitachi U-1800, xc nh v la chn

bc sng ph hp l 217 nm.

+ Xc nh khong nng tuyn tnh ti bc sng 217 nm theo cc bc: cn

chnh xc khong 100 mg PSE.HCl, ha tan hon ton vo mi trng m

phosphat pH 6,8. Cho vo bnh nh mc 100 ml, lc u. T dung dch gc ny,

tip tc pha long bng m phosphat pH 6,8 c cc dung dch chun c nng

18

PSE.HCl xp x: 10-20-40-60-80-100 g/ml. o quang bc sng 217 nm.

Ghi kt qu v nhn xt.

- Tin hnh nh lng:

Cn khi lng 20 vin, nghin mn trong ci s. Cn chnh xc khi lng

bt bng khi lng trung bnh vin (300 mg), ha vo mi trng m phosphat

pH 6,8 v cho vo bnh nh mc 100 ml. Thm mi trng. Siu m 15 pht,

ngui, lc u. Lc qua giy lc th, b 20 ml dch lc u. Pha long 10 ln. Dung

dch thu c em o quang bc sng 217 nm, so snh vi dung dch chun

c pha vi nng tng t (khong 60 g/ml).

Cng thc tnh hm lng

Hm lng (%) =

100%

Trong :

l nng dung dch chun pseudoephedrin hydroclorid,

l mt quang ca dung dch chun v dung dch th,

60 l hm lng (mg) pseudoephedrin hydroclorid trn nhn.

Hm lng vin nhn phi nm trong khong 90 110% so vi hm lng ghi

trn nhn (60 mg) [24].

2.3.2.2. nh gi nh hng ca cc thng s bao phim ln qu trnh bao

Vi mc tiu la chn cc thng s bao phim ti u, gim hao ph nguyn liu

ng thi thun tin trong qu trnh bao, tin hnh kho st nh hng ca cc

thng s bao ln qu trnh bao thng qua s thay i ca hiu sut bao phim.

Trn c s cng thc dch bao mc 2.3.1.2, tin hnh kho st cc thng s

ca thit b ni bao Vanguard theo quy trnh sau y:

Tin hnh bao 300,08 g vin nhn (tng ng 1000 vin) trong ni bao

Vanguard vi cc thng s c thay i trong khong xc nh: tc quay ni

bao (8 10 vng/pht ), tc phun dch bao (3 5,5 ml/pht), nhit kh thi

vo (55 65oC) v lu lng kh thi vo (8 10 m3/h). Tnh chnh lch khi

lng khi vin trc v sau mi ln thay i thng s bao phim.

19

Hiu sut bao c tnh theo cng thc:

H% =

100%

Trong :

Mt v MS ln lt l khi lng khi vin trc v sau mi ln thay i thng

s bao (g),

v l tc phun dch bao (ml/pht),

15 l thi gian phun dch cho mi ln thay i thng s bao (pht),

0,084 l khi lng cht rn theo l thuyt ca 1 ml dch bao (g).

2.3.2.3. nh gi cht lng vin bao pseudoephedrin hydroclorid gii phng ko

di

ng u khi lng v nh lng: tin hnh nh i vi vin F1 (mc

2.3.2.1).

Th ha tan vin F2:

Th ha tan vin F2 trong mi trng m phosphat pH 6,8. S dng my th

ha tan Vankel 7010 kiu cnh khuy, vi cc thng s:

Tc khuy: 50 vng/pht.

Th tch mi trng: 900 ml m phosphat pH 6,8.

Nhit : 37oC 0,5oC.

Thi gian th: 8h [24].

Ly mu: ht 10 ml dung dch ti cc thi im 1h, 2h, 3h, 4h, 6h, 8h. Lc qua

giy lc th, b 5 ml dch lc u tin. o quang ti bc sng 217 nm, so snh vi

dung dch chun c pha nng ~ 60 g/ml.

Th ha tan vin Clarinase

Cc mi trng dng th ha tan vin Clarinase gm: dung dch HCl 0,1N

(pH 1,2) v dung dch m phosphat pH 6,8. Thit b, iu kin th ha tan v qu

trnh ly mu nh gi tng t nh th ha tan vin F2 (mc 2.3.2.3).

20

Trong 2h u tin, th ha tan vin Clarinase trong 900 ml dung dch HCl

0,1N, khng ht mu. Sau , chuyn vin Clarinase trn vo 900 ml m phosphat

pH 6,8, tip tc th ha tan 8h tip theo, c ht mu nh gi.

Kt qu th ha tan ca vin i chiu Clarinase c coi l c s xy dng

tiu chun ha tan cho vin F2.

2.3.2.4. Phng php o nhit chuyn ha thy tinh ca mng bao

Mt trong nhng yu cu c bn ca cht ha do l tnh tng hp vi

polyme. Tnh tng hp ny thng c nh gi thng qua mc gim nhit

chuyn ha thy tinh (Tg) ca mng bao. Th nghim sau nhm xc nh Tg ca

mng bao c cha ng lng cc loi cht ha do khc nhau.

Quy trnh bo ch mu th:

- Chun b 2 l thy tinh sch dung tch 100 ml.

- Thm vo mi l 50 ml hn hp dung mi isopropanol : nc (8:2) v 3 g zein

to dung dch zein 6% (kl/tt). Sau , thm vo mi l cc cht ha do khc nhau

(DBP v PEG 400) vi lng tng ng 12% (kl/kl) so vi zein.

- Khuy u dung dch trong mi l lin tc 12h bng my khuy t.

- Bc hi trn ni cch thy 70oC, m np l bc hi hon ton dung mi cho

n khi thu c cn kh. Bo qun cn kh trong l kn, iu kin thng t nht

72h trc khi em i phn tch nhit vi sai.

Tin hnh phn tch nhit vi sai:

- Tin hnh phn tch mu chun (zein nguyn liu) v 2 mu th trn.

- Cn mt lng mu tng ng khong 7 mg zein, p mu trong chn ng mu

bng nhm dung tch 40 l. Mu trng l chn ng mu 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 qua 2 giai on:

+ Giai on 1: tng nhit t 30oC n 180oC vi tc 10oC/pht, sau h

nhit xung 30oC vi tc 10oC/pht.

+ Giai on 2: tng nhit ln 200oC vi tc 5oC/pht.

- Phn tch ph bng phn mm c ci t sn, ghi li Tg.

21

2.3.2.5. Phng php x l s liu

a. Phng php thit k th nghim v ti u ha

S dng phn mm Modde 8.0 thit k th nghim theo m hnh hp t ti

tm vi mt bin nh tnh (loi cht ha do: DBP v PEG 400), 2 bin nh lng

(t l zein so vi nhn, t l cht ha do so vi zein).

S dng phn mm Inform demo v3.1 x l s liu nh mng thn kinh

nhn to, ti u ha cng thc dch bao phim.

b. Phng php x l cc s liu khc

a s th nghim c tin hnh t nht 3 ln. S liu c x l, a ra gi tr

trung bnh, lch chun nh phn mm Microsoft Excel 2010.

H s tng ng f2 th hin s ging nhau gia 2 th gii phng dc cht

c tnh theo cng thc:

f2 = 50 lg {

( )

100}.

Trong :

v l % dc cht gii phng ti thi im t ca mu i chiu v mu

th,

n l s im ly mu.

Hai th c coi l tng t nhau khi f2 trong khong 50 100.

- Khi f2 = 100: hai th ha tan hon ton ging nhau.

- Khi f2 = 50: s sai khc trung bnh ti mi thi im l 10% [12].

22

CHNG 3. THC NGHIM, KT QU V BN LUN

3.1. nh gi vin nhn cha 60 mg pseudoephedrin hydroclorid

3.1.1. Kho st phng php nh lng pseudoephedrin hydroclorid

Kt qu qut ph hp th dung dch chun nng 100 g/ml cho thy:

khng c bc sng cc i no m ti mt quang nm trong khong (0,2

0,8). Sau khi sng lc kt qu, bc sng vi hp th ph hp c la chn l

217 nm.

Kt qu kho st khong tuyn tnh php o quang PSE.HCl ti bc sng

217 nm trong mi trng m phosphat pH 6,8 c th hin trong hnh 3.1.

Hnh 3.1. th kho st khong tuyn tnh ca php o quang PSE.HCl.

H s tng quan R2 = 0,9945 cho thy hp th ca dung dch PSE.HCl

trong mi trng m phosphat pH 6,8 ti bc sng 217 nm t l tuyn tnh vi

nng dung dch trong khong 10 - 100 g/ml.

3.1.2. Kt qu nh gi vin nhn pseudoephedrin hydroclorid

Bo ch vin nhn F1 vi quy m 2000 vin. Tin hnh nh gi mt s ch

tiu cht lng v thu c kt qu trong bng 3.1 v 3.2.

y = 0.0068x + 0.0756 R = 0.9945

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0 20 40 60 80 100 120

Mt

q

uan

g

Nng dung dch chun (g/ml)

23

Bng 3.1. cng, mi mn v hm lng trung bnh vin F1

Ch tiu Kt qu

cng trung bnh (Kp) (TB LC, n = 10) 12,77 2,57

mi mn (%) (TB LC, n = 3) 0,14 0,03

Hm lng trung bnh (%) (TB LC, n = 5) 102,59 2,27

Bng 3.2. ng u khi lng vin F1

STT Khi lng (mg) % chnh lch

khi lng STT Khi lng (mg)

% chnh lch

khi lng

1 302,1 2,50 11 323,7 4,47

2 296,1 4,43 12 303,2 2,14

3 288,8 6,79 13 318,9 2,92

4 328,8 4,12 14 311,4 0,50

5 310,6 0,25 15 328,6 4,05

6 320,1 3,31 16 308,5 0,43

7 307,0 0,92 17 322,4 4,05

8 302,4 2,40 18 287,4 7,24

9 309,9 0,02 19 312,4 0,83

10 311,7 0,60 20 302,7 2,30

Hm lng trung bnh vin F1 l 102,59 2,27% (so vi yu cu 60 mg), vin

c hm lng nm trong gii hn cho php (90 110%). Vin F1 c cng tt (>

9 Kp), mi mn thp (< 1%), ph hp cho vic bo ch vin bao GPKD. Cc

vin u c % chnh lch khi lng so vi khi lng trung bnh (309,8 mg) nm

trong gii hn cho php (5%), t ch tiu v ng u khi lng.

Nh vy, vin F1 t y cc ch tiu yu cu cht lng v hon ton

thch hp cho vic nghin cu bo ch vin bao F2.

3.2. Kho st nh hng ca cc thng s bao phim i vi hiu sut bao

kho nh hng ca tng thng s bao phim i vi hiu sut bao, cn la

chn trc mt tp hp cc thng s gc lm c s ban u. Tin hnh bao mng

vi cng thc dch bao sau:

24

Zein

DBP

Talc

Titan dioxyd

Isopropanol : nc (8:2)

60 g

6 g (10% zein)

6 g (10% zein)

12 g (20% zein)

va 1000 ml.

Cc thng s ca thit b c thay i trn c s thng s gc nh sau:

Nhit kh thi vo: 55oC.

Nhit kh ht ra: 50oC.

Tc quay ni bao: 9 vng/pht.

Lu lng kh thi vo: 10 m3/h.

Lu lng kh ht ra: 12 m3/h.

p sut phun dch: 1,8 atm.

Tc phun dch bao: 5 ml/pht.

3.2.1. nh hng ca tc phun dch bao

Tin hnh phun dch bao vi cc tc khc nhau: 3, 3,5, 4, 5 v 5,5 ml/pht,

ng thi gi nguyn cc thng s khc.

Hiu sut bao c tnh ton v th hin trong bng 3.3 v hnh 3.2.

Bng 3.3. Kt qu hiu sut bao khi thay i tc phun dch

Tc phun dch (ml/pht) 3 3,5 4 5 5,5

Hiu sut (%) 30,95 32,65 49,70 62,86 73,02

25

Hnh 3.2. th th hin mi quan h gia tc phun dch v hiu sut bao

H s tng quan R2 = 0,9696 cho thy: hiu sut bao phim t l tuyn tnh

vi tc phun dch bao trong khong tc 3 - 5,5 ml/pht. Khi tng tc phun

dch bao, hiu sut bao cng tng. Nguyn nhn c th do khi tng tc phun dch

bao, mt git phun tng lm gim xc sut git phun b pht tn, bm vo ni

bao bi lung gi thi trong ni bao. ng thi, vi cng p sut phun, khi tng tc

phun th tc chuyn ng ca cc git phun cng tng, gim thiu kh nng

git phun b ha rn nhanh di tc dng ca nhit sy trn qung ng i, v

vy hiu sut phun tng.

Qu trnh kho st trn s dng cng thc dch bao c cha DBP vi t l

10% so vi zein. Qu trnh bao din ra thun li. Tuy nhin, ngoi DBP, PEG 400

cng c la chn lm cht ha do nghin cu. V vy, tip tc bao vin F1

vi cc tc phun dch khc nhau, s dng cng thc c cht ha do l PEG 400.

Trn thc t, vi tc phun dch bao 3,5 ml/pht, khi bao nhng cng thc

c t l PEG 400 cao ( 12%), hin tng dnh vin d xy ra. V vy, tc phun

dch c la chn cho thc nghim l 3 ml/pht.

y = 17.504x - 23.679 R = 0.9696

0

20

40

60

80

100

2 3 4 5 6

Hi

u s

ut

(%)

Tc phun dch (ml/pht)

26

3.2.2. nh hng ca tc quay ni bao

Vi tc quay 11 vng/pht, vin b bn ra ngoi. Tin hnh bao phim vi

cc tc quay ni bao: 8, 9 v 10 vng/pht. Hiu sut bao trong cc ln bao c

th hin trong bng 3.4.

Bng 3.4. Kt qu hiu sut bao khi thay i tc quay ni bao

Tc quay ni bao (vng/pht) 8 9 10

Hiu sut (%) 47,62 62,86 38,10

Theo bng 3.4, vi tc quay ni bao 9 vng/pht, hiu sut bao phim ln

nht. Vi tc quay 8 vng/pht, vin khng c o trn lin tc, tn ti

khong thi gian khi vin trt trn b mt ni bao, v vy, lm gim lng git

phun tip xc vi khi vin trong mi chu k o trn. Vi tc quay 10

vng/pht, c th vin c o trn qu mnh, lc bm dnh ca git phun khng

thng c lc ma st gia cc b mt vin, git b kh v to bi nn hiu sut bao

nh.

Nh vy, la chn tc quay ni bao l 9 vng/pht.

3.2.3. nh hng ca nhit kh thi vo

Gi nguyn khong chnh lch nhit thi vo v ht ra l 5oC, tin hnh

bao phim vi cc iu kin nhit kh thi vo l 55oC v 65oC. Kt qu hiu sut

bao ca 2 iu kin trn c th hin trong bng 3.5.

Bng 3.5. Kt qu hiu sut bao khi thay i nhit kh thi vo

Nhit kh thi vo (oC) 55 65

Hiu sut (%) 62,86 61,11

Theo bng 3.5, khng c s khc bit r nt v hiu sut bao trong 2 trng

hp ny. C th do trong khong nhit 55 65oC, nhit kh thi vo nh

hng ln hiu sut bao khng ng k. Do iu kin thc t, nhit mi trng

t 15 25oC, trnh hin tng dnh vin, ta la chn nhit kh thi vo v ht

ra ln lt l 65oC v 60oC.

27

3.2.4. nh hng ca lu lng kh thi vo

Gi nguyn khong chnh lch lu lng kh thi vo v ht ra l 2 m3/h, tin

hnh bao phim vi cc iu kin lu lng kh thi vo l 8, 9 v 10 m3/h. Kt qu

hiu sut bao c trnh by trong bng 3.6.

Bng 3.6. Kt qu hiu sut bao khi thay i lu lng kh thi vo

Lu lng kh thi vo (m3/h) 8 9 10

Hiu sut (%) 78,57 71,59 62,86

Theo bng 3.6, c th thy: khi tng lu lng kh th hiu sut bao gim.

Nguyn nhn c th do khi tng lu lng kh thi, lm tng kh nng git phun b

cun theo lung kh thi trc khi tip xc vi b mt vin, do lm gim hiu

sut bao. Tuy nhin, khi gim lu lng kh, nguy c dnh vin cng tng.V vy,

lu lng kh thi vo v ht ra c la chn ln lt l 10 m3/h v 12 m3/h.

Nh vy, sau qu trnh kho st, cc thng s bao phim c la chn nh

sau:

Nhit kh thi vo: 65oC.

Tc quay ni bao: 9 vng/pht.

Lu lng kh thi vo: 10 m3/h.

p sut phun: 1,8 atm.

Nhit kh ht ra: 60oC.

Tc phun dch bao: 3 ml/pht.

Lu lng kh ht ra: 12 m3/h.

Cc thng s ny s c s dng trong nhng phn nghin cu tip theo v

xy dng cng thc bao cho vin PSE gii phng ko di.

3.3. Nghin cu xy dng cng thc bao

3.3.1. Th ha tan cho vin i chiu

Vin i chiu Clarinase s l OFE20245OAF, hn dng 9/11/2014 c

chn lm vin i chiu cho vin F2 v c th ha tan theo phng php ghi

trong mc 2.3.2.3. Kt qu th ha tan vin Clarinase c th hin hnh 3.3.

28

Hnh 3.3. th gii phng PSE.HCl ca phn li vin Clarinase pH 6,8

(TB LC, n = 4)

Da trn kt qu th ha tan ca phn li vin Clarinase cha 60 mg PSE.HCl

gii phng ko di, d kin % dc cht gii phng ca vin F2 theo bng 3.7.

Bng 3.7. Tiu chun ha tan d kin cho vin F2

Thi gian % PSE.HCl gii phng

1 h 5 - 15

3 h 15 - 25

6 h 40 - 60

8 h Trn 60%

3.3.2. Kho st khong t l zein v cht ha do trong cng thc bao

tm khong t l zein v cht ha do ph hp cho bc thit k th nghim

tip theo, tin hnh xy dng cc cng thc bao theo bng 3.8, bo ch v nh gi

da trn mt s tiu ch xc nh.

0

20

40

60

80

100

0 2 4 6 8 10

% P

SE

gi

i p

hn

g

Thi gian (h)

29

Bng 3.8. Cc cng thc dch bao s dng kho st t l zein v cht ha do

Tiu ch Cng thc

F2a F2b F2c F2d F2e F2f F2g F2h

Zein (%) (so vi nhn) 4 8 10 8 8 8 8 8

DBP (%) (so vi zein) 4 4 4 12 - - - -

PEG 400 (%) (so vi zein) - - - - 10 12 15 20

Talc (%) (so vi zein) 10 10 10 10 10 10 10 10

Titan dioxyd (%) (so vi zein) 20 20 20 20 20 20 20 20

Isopropanol : nc (8:2) va dch bao cha 6% zein (kl/tt)

3.3.2.1. Kho st khong t l zein

Kho st khong t l % (kl/kl) ca zein so vi nhn da trn tiu ch v tc

gii phng dc cht ca vin bao.

Tin hnh bao phim vi cng thc bao c t l DBP l 4% so vi zein. Ly

vin ra khi ni bao ti cc thi im khc nhau, thu c vin F2a, F2b, F2c tng

ng c t l zein l 4, 8 v 10%. Kt qu th ha tan vin F2a, F2b, F2c c th

hin trong hnh 3.4.

Hnh 3.4. th ha tan vin F2a, F2b v F2c (TB LC, n = 3)

0

20

40

60

80

100

0 2 4 6 8 10

% P

SE

gi

i p

hn

g

Thi gian (h)

Vin F2a - 4% zein Vin F2b - 8% zein

Vin F2c- 10% zein Vin Clarinase

30

T th trn, c th thy:

- Vin F2a (t l zein 4%) r rng c tc ha tan nhanh hn so vi vin

Clarinase, trong khi s khc bit ny gia vin F2b (t l zein 8%) v vin i chiu

l khng r rng. Do , la chn gii hn di ca t l zein so vi nhn l 4%.

- Vin F2c (t l zein 10%), trong 4h u tin, r rng tc ha tan chm hn so

vi Clarinse. V vy, s b la chn gii hn trn ca t l zein so vi nhn l 10%.

Nh vy, khong t l % (kl/kl) zein so vi nhn c la chn l 4 10 %.

3.3.2.2. Kho st khong t l cht ha do

Kho st gii hn trn ca t l % (kl/kl) cht ha do so vi zein da trn cc

tiu ch v hnh thc vin v mc thun tin khi bao.

Tin hnh bao vin vi cc cng thc dch bao F2e, F2f, F2g, F2h tng ng

c t l cht ha do (PEG 400) l 10, 12, 15 v 20%. Ghi li nhn xt v mc

tha mn cc tiu ch trn ca m bao. Kt qu kho st c trnh by ti bng 3.9.

Bng 3.9. Bng kt qu kho st t l cht ha do

Cng

thc

T l %

PEG 400

so vi zein

Nhn xt

F2h 20 B mt do dnh ngay c sau khi lm kh, qu trnh sy ko di.

Rt kh bao vin ngay c khi tc phun dch l 3 ml/pht.

F2g 15

Dnh vin tc phun 5 ml/pht. B mt x x, c nhng vt

git phun trn trn b mt khi phun vi tc 3 ml/pht. Qu

trnh bao rt d dnh. Phi gim tc phun < 3 ml/pht ng

thi tng nhit bao.

F2f 12 B mt kh x x, tc bm khng qu 3,5 ml/pht.

F2e 10 B mt nhn, hnh thc p, qu trnh bao thun tin.

Theo bng 3.9, c th thy: gii hn trn ca t l PEG 400 l 12% (kl/kl) so

vi zein. Tip tc kho st cng thc F2d s dng DBP lm cht ha do vi t l

12%. Kt qu: b mt vin nhn, qu trnh bao thun tin. Nh vy, gii hn trn

thch hp ca t l CHD l 12% (kl/kl) so vi zein.

31

m bo bn v do dai cho mng bao, s b la chn gii hn di

ca t l CHD l 4% (kl/kl) so vi zein.

Nh vy, khong t l % (kl/kl) CHD so vi zein c la chn l 4 12%.

3.3.3. Thit k th nghim v ti u ha

3.3.3.1. Thit k th nghim

S dng phn mm Modde 8.0 thit k th nghim theo m hnh hp t ti

tm. Kt qu thu c c trnh by bng 3.10 gm 20 cng thc, trong c 4

cng thc ti tm.

Bng 3.10. Thit k th nghim

STT % zein so vi nhn Loi CHD % CHD so vi zein

1 4 DBP 4

2 10 DBP 4

3 4 DBP 12

4 10 DBP 12

5 4 DBP 6,6667

6 10 DBP 9,3333

7 8 DBP 4

8 6 DBP 12

9 4 PEG 400 4

10 10 PEG 400 4

11 4 PEG 400 12

12 10 PEG 400 12

13 4 PEG 400 9,3333

14 10 PEG 400 6,6667

15 6 PEG 400 4

16 8 PEG 400 12

17 7 PEG 400 8

18 7 PEG 400 8

19 7 PEG 400 8

20 7 PEG 400 8

32

3.3.3.2. Kt qu th ha tan cc cng thc thit k

Tin hnh bo ch cc cng thc c thit k bng 3.10. Tin hnh th

ha tan theo phng php th ha tan c trnh by trong mc 2.3.2.3. Kt qu th

ha tan 20 cng thc trn c trnh by ti bng 3.11.

Bng 3.11. Kt qu th ha tan cho cc cng thc thit k (TB LC, n = 3)

STT

% zein

so vi

nhn

Loi CHD

% CHD

so vi

zein

% PSE gii phng

1h 2h 3h 4h 6h 8h

1 4,67 DBP 4 17,64

0,98

36,36

1,03

60,58

2,03

72,08

9,00

88,17

6,50

100,00

0,99

2 9,89 DBP 4 7,12

0,68

8,08

1,06

11,53

2,23

17,63

1,60

48,95

4,52

72,98

3,74

3 3,98 DBP 12 11,18

3,50

20,67

2,62

48,40

1,55

65,64

3,13

83,63

3,41

97,94

7,79

4 9,78 DBP 12 15,58

1,08

16,77

0,55

16,02

1,33

19,94

2,43

49,74

7,26

68,02

2,46

5 4,08 DBP 6,67 19,33

0,41

36,29

5,09

64,99

7,46

78,86

6,65

91,02

3,05

98,85

1,33

6 10,86 DBP 9,33 8,78

0,41

6,47

2,09

7,39

3,46

6,61

2,65

15,87

3,05

34,50

1,33

7 8,04 DBP 4 8,75

1,67

8,88

1,05

20,93

2,14

39,01

4,38

65,67

6,86

91,52

7,94

8 5,72 DBP 12 21,31

1,76

19,42

1,40

21,90

2,68

40,53

6,18

80,71

7,41

93,98

8,53

9 3,98 PEG 400 4 28,92

4,66

41,22

2,18

57,56

8,22

76,02

5,01

92,64

7,19

100,59

4,36

10 9,99 PEG 400 4 20,33

3,39

17,54

2,93

21,91

4,98

47,47

3,65

75,93

3,43

88,01

4,28

11 4,42 PEG 400 12 22,97

1,14

42,64

1,32

60,62

2,35

70,82

4,09

90,93

7,44

101,52

2,25

12 10,77 PEG 400 12 6,85

0,66

8,73

0,87

23,38

4,99

33,78

9,68

60,43

9,83

75,64

8,90

13 4,19 PEG 400 9,33 19,39

1,09

19,77

1,82

22,85

0,98

40,34

2,14

72,57

5,58

84,53

3,98

14 10,10 PEG 400 6,67 9,25

0,50

12,30

3,43

15,87

1,57

17,40

2,39

53,97

10,00

67,50

4,54

15 6,09 PEG 400 4 13,88

2,67

19,15

0,78

45,56

4,84

62,35

1,55

77,65

1,08

89,01

3,41

33

16 7,90 PEG 400 12 20,43

4,42

23,82

4,56

39,27

3,51

53,08

8,89

68,30

9,99

80,60

6,99

17 6,66 PEG 400 8 17,48

1,77

34,66

8,91

58,19

0,59

69,22

2,23

85,35

4,28

93,99

7,03

18 7,70 PEG 400 8 17,76

2,25

25,56

4,54

49,14

8,29

65,78

7,57

80,22

4,53

91,63

3,83

19 6,64 PEG 400 8 17,96

3,70

34,44

5,33

56,79

5,22

73,00

4,84

86,17

2,03

97,69

5,14

20 6,77 PEG 400 8 20,71

6,03

26,36

1,04

34,56

7,78

57,35

1,78

79,08

5,50

90,21

6,26

3.3.3.3. nh gi nh hng ca zein v cht ha do ln s gii phng dc cht

X l s liu bng phn mm Inform demo v3.1, c nh bin loi cht ha

do, thu c mt s mt p th hin nh hng ca cc bin cn li n s gii

phng dc cht. Cc mt p ny c th hin trong hnh 3.5 v 3.6 (tng ng

c nh loi cht ha do l PEG 400 v DBP).

a. nh hng ca zein

Zein l polyme ca mng bao. nh hng ca zein i vi s gii phng

dc cht c th hin rt r 2 mt p hnh 3.5 v 3.6.

Hnh 3.5. Mt p th hin mi quan h gia t l zein v t l PEG 400 vi s gii

phng dc cht ti thi im 1h

34

T hnh 3.5 v hnh 3.6, c th thy: nhn chung, khi t l zein tng t 4 -12% th

% PSE gii phng c xu hng gim. iu ny c th gii thch rng: khi t l

zein tng, tng ng l dy mng bao tng, dn n s tng kh nng cn tr

dung mi thm qua mng, xm nhp vo nhn ha tan dc cht. V vy, lm

% PSE gii phng gim.

Hnh 3.6. Mt p th hin mi quan h gia t l zein v t l DBP vi s gii

phng dc cht ti thi im 3h

Tuy nhin, ta thy:

Trong hnh 3.5, khi t l zein tng t 4 7,2 %, ng thi t l PEG 400

trong khong 8,8 12%, % PSE gii phng ti thi im 1h gn nh khng

thay i. Nguyn nhn c th do tn ti mt ngng gii hn m PEG 400

lin kt cht nht vi zein trong cu trc mng bao. Khi b dy mng bao

mng (tng ng t l zein 7,2%), ng thi t l PEG 400 cao ( 8,8%)

vt ngng gii hn, kh nng cn tr gii phng PSE ca mng t mt

gi tr cc i v khng cn ph thuc vo b dy mng bao. V vy, % PSE

gii phng gn nh hng nh.

Trong hnh 3.6, khi t l zein so vi nhn tng t 8,8 12%, % PSE gii

phng ti thi im 3h khng thay i. C th khi s dng DBP lm cht ha

do, t l 8,8% l t l ti hn ca zein. Ti t l ny, d t l zein tng, kh

35

nng cn tr s thm dung mi khng i v t gi tr ti a.

b. nh hng ca cht ha do

Cht ha do l thnh phn rt quan trng trong thnh phn mng bao, tng

tnh mm do, ci thin kh nng bm dnh ca mng vo nhn v ci thin tnh

thm ca mng. nh hng ca 2 loi cht ha do: DBP v PEG 400 ln s gii

phng dc cht c th hin kh r trong hnh 3.5 v 3.6 trn.

Nhn chung, i vi c 2 cht ha do l DBP v PEG 400, khi t l cht ha do

tng th % PSE gii phng c xu hng gim. Nguyn nhn l do phn t CHD

lin kt vi phn t zein to thnh cu trc mng li vng chc, ngn cn

dung mi thm qua, ha tan v gii phng dc cht. Khi lng CHD tng lm

s lng v kch thc khe h trong mng li trn gim, v vy, lng PSE gii

phng cng gim (*). iu ny s c th hin r hn qua php o nhit vi sai

(hnh 3.7).

Tuy nhin, c mt s trng hp khng tun theo quy lut trn.

Hnh 3.5 th hin nh hng ca PEG 400 ln s gii phng PSE thi im

1h. Vi t l zein t 8,5% n di 12%, khi t l PEG 400 so vi zein tng

t 6,5 12%, % PSE gii phng c xu hng tng, ngc li vi quy lut

(*). C th do mt nguyn nhn no m khi lng PEG 400 trong mng

tng ln, cu trc mng tr nn lng lo hn, dung mi d dng i vo nhn,

ha tan v gii phng PSE ra ngoi mng.

Hnh 3.6 th hin nh hng ca DBP ln s gii phng PSE ti thi im

3h. Vi t l zein so vi nhn trong khong 8,8 12%, khi t l DBP so vi

zein tng, % PSE gii phng khng i. Nh vy, trong trng hp ny, c

th ch c zein ng vai tr quan trng trong vic hnh thnh kh nng kim

sot gii phng dc cht cho mng bao, s nh hng ca DBP l khng

ng k. Do t l zein cao (> 8,8%) nn kh nng kim sot trn t gi tr

ti a v hng nh.

nh gi thm v tng tc gia zein vi cc cht ha do, tin hnh o

nhit chuyn ha thy tinh (Tg) ca mng bao phim vi cng t l DBP v PEG

36

400 so vi zein trong mng (12%).

c. Tng tc zein vi cht ha do

Hnh 3.7. th kt qu ca php o nhit vi sai

Theo hnh 3.7, Tg ca zein nguyn liu l 172,16oC. Khi phi hp zein vi

DBP (12% (kl/kl) so vi zein), Tg mng bao l 155,68oC, tc l gim 16,48oC.

Tng t khi phi hp zein vi PEG 400 (cng t l DBP), Tg mng bao l

130,50oC, tc l gim 41,66oC.

Nh vy, khi phi hp zein vi DBP hay PEG 400 th Tg ca mng u gim.

Mc gim Tg ca mng cha PEG 400 mnh hn so vi mng cha DBP.

Nguyn nhn c th do, yu cu ca mt cht ha do tng hp vi zein l cn c

phn cc thch hp v to cu ni lin kt hydro vi zein [17]. PEG 400 l mt

dng polyme ca ethylen glycol, trong cu trc c cc nhm chc OH, trong khi

cu trc DBP khng c nhm chc ny. Zein l mt prolamin, cu trc zein cha

cc nhm chc OH v NH2 t do nn d dng to lin kt hydro vi PEG 400,

nh mng li zein tr nn bn v do dai hn. Do vy, PEG 400 tng hp vi

zein hn DBP, t , mng cha PEG 400 do dai v c bn c hc cao hn.

nh gi nh hng ca tng tc gia zein v CHD n tc gii

phng dc cht, th ha tan cng thc 4 v cng thc 12 (trong bng 3.10) c

cng t l CHD l 12%. Kt qu th ha tan c th hin trong hnh 3.8 sau y.

37

Hnh 3.8. th gii phng vin F2 c cng thc 4 v cng thc 12

Vi cng t l zein so vi nhn l 10%, r rng:

- Trong 2h u tin, PSE trong vin bao cng thc 12 gii phng chm hn so vi

vin bao cng thc 4. Nguyn nhn l: PEG 400 lm mng zein do dai hn so vi

DBP nn ng thi lm tng kh nng kim sot gii phng dc cht cho mng.

- Tuy nhin, trong 6h tip theo, tc gii phng PSE ca vin bao cng thc 12

nhanh hn. Nguyn nhn c th l: PEG 400 d tan trong nc, nn trong qu trnh

ha tan, PEG 400 b dung mi ko mt phn ra ngoi mng bao. Ngoi ra, do DBP

c tnh s nc, v vy n cng khin cho mng bao s nc hn v thm mi

trng km hn so vi mng cha PEG 400.

Nh vy, mc d PEG 400 lm mng bao do dai, bm dnh nhn tt hn v

kim sot gii phng dc cht hiu qu hn trong 2h u tin nhng DBP li lm

gim tnh thm dung mi ca mng bao hiu qu hn trong 6h cui.

3.3.3.4. Ti u ha

Xy dng cng thc d kin

S dng phn mm Inform ti u ha cng thc mng bao theo tiu chun

0

20

40

60

80

100

0 2 4 6 8 10

% P

SE

gi

i p

hn

g

Thi gian (h)

Cng thc 4 (12% DBP) Cng thc 12 (12% PEG 400)

38

trong bng 3.7 thu c cng thc vin F3 sau:

Zein

DBP

Talc

Titan dioxyd

Isopropanol : nc (8:2)

8,24% so vi nhn (kl/kl)

4% zein (kl/kl)

10% zein (kl/kl)

20% zein (kl/kl)

va pha dch bao cha 6% zein (kl/tt).

Qu trnh gii phng dc cht theo thi gian c d on bng phn mm

Inform nh sau:

Thi gian % PSE gii phng

1 h 8,33

3 h 19,48

6 h 57,63

8 h 82,37

Vin F3 c bo ch v nh gi theo cc phng php trnh by mc

2.3.2.3.

3.4. nh gi cht lng vin bao ti u cha pseudoephedrin hydroclorid gii

phng ko di

3.4.1. nh gi ch tiu th ha tan

Kt qu th ha tan cng thc d kin F3 c trnh by ti bng 3.12 v

hnh 3.9.

Bng 3.12. Bng kt qu th ha tan vin F3 (TB LC, n = 3)

Thi gian % PSE gii phng

1h 9,89 1,16

2h 13,132,49

3h 17,911,94

4h 33,211,27

6h 59,591,81

8h 76,292,59

39

Hnh 3.9. th th ha tan vin d kin F3 ( LC, n = 3)

Tnh gi tr f2 ca vin F3 so vi vin Clarinase. Kt qu f2 = 59,30 nm

trong khong (50 - 100). Nh vy, c th khng nh m hnh gii phng ca vin

F3 ging vi m hnh gii phng vin i chiu Clarinase.

Tnh gi tr f2 ca vin F3 so vi m hnh gii phng d on t phn mm

Inform. Kt qu f2 = 72,64. Nh vy, c th khng nh m hnh gii phng ca

vin F3 ging vi m hnh gii phng d on.

3.4.2. nh gi mt s ch tiu khc ca vin bao ti u

Tnh cht vin F3: vin bao nhn, khng nt cnh, khng dnh tay, kh, mu

vng ng nht. Nhn trong ca vin bao c mu trng.

Vin ti u F3 c bo ch v nh gi mt s ch tiu vi kt qu thu c

trong bng 3.13 v 3.14.

Bng 3.13. cng v hm lng trung bnh vin F3

Ch tiu Kt qu

cng trung bnh (Kp) (TB LC, n = 10) 12,3 2,05

Hm lng trung bnh (%) (TB LC, n = 3) 102,37 2,33

0

20

40

60

80

100

0 2 4 6 8 10

% P

SE

gi

i p

hn

g

Thi gian (h)

Li vin Clarinase Vin F3

40

Bng 3.14. ng u khi lng vin F3

STT Khi lng

(mg) % chnh lch STT

Khi lng

(mg)

% chnh lch

1 335,1 0,74 11 334,4 0,53

2 331,2 0,43 12 334,0 0,41

3 335,0 0,98 13 320,5 3,65

4 331,2 0,43 14 337,4 1,43

5 332,8 0,05 15 338,2 1,67

6 333,0 0,11 16 332,7 0,02

7 318,7 4,19 17 339,0 1,91

8 340,2 2,27 18 331,3 0,40

9 337,3 1,40 19 333,3 0,20

10 316,9 4,73 20 339,6 2,09

Hm lng trung bnh vin F3 l 102,372,33 (so vi yu cu 60 mg), nm

trong gii hn cho php (90 110%). Vin F3 c cng gn st vin F1, chng

t mng bao khng lm gim cng ca vin. Cc vin u c % chnh lch

khi lng so vi khi lng trung bnh (332,6 mg) nm trong gii hn cho php

(5%), t ch tiu v ng u khi lng.

Kt lun: Vy vin F3 t cc ch tiu cht lng, c m hnh gii phng ng

theo d on v ging vi m hnh gii phng vin i chiu Clarinase.

3.5. Bn lun

3.5.1. Bn lun nh hng ca cc thng s bao ln hiu sut bao

Trn thc t, qu trnh bao mng zein rt d xy ra hin tng dnh vin. c

bit khi s dng cht ha do l PEG 400 t l cao ( 12%), Tg ca mng gim

mnh (41,66oC) nn mng bao cng d dnh hn. trnh hin tng ny, dung

mi c s dng phi bay hi nhanh, hn ch s dng nc. Tuy nhin, hu qu l

dch bao c phun ra nhy cm vi nhit, nhanh kh, d bin thnh bi rn, lm

41

gim hiu sut bao. Kt qu nghin cu cho thy: cc thng s v tc phun dch,

tc quay ni bao v nhit l nhng thng s c nh hng r nt i vi hiu

sut bao. Hiu sut bao tng khi tc phun dch tng, nhit gim v tc

quay ni t gi tr ti u. Vic sng lc tt c cc thng s bao gip qu trnh

bao thun tin hn v em li hiu sut cao, gim thiu chi ph sn xut.

3.5.2. Bn lun nh hng ca zein v cht ha do ln tc gii phng dc

cht

Nghin cu cho thy c mi quan h gia t l zein v t l cht ha do vi

tc gii phng gii phng dc cht. Nhn chung, tc gii phng dc cht

gim khi tng ng thi hoc ring l t l zein so vi nhn v t l CHD so vi

zein.

Trong cu trc mng, PEG 400 c kh nng lin kt cht vi zein hn DBP.

Nhng nh hng ca lin kt gia zein v PEG 400 ln qu trnh gii phng dc

cht kh l gii v cn c nghin cu thm. Do c tnh s nc, DBP lm gim

tnh thm dung mi ca mng hiu qu hn, bi vy, lm gim tc gii phng

PSE tt hn PEG 400. Tuy nhin, khng th nhn ra c nh hng ng thi ca

t l zein v DBP i vi tc gii phng dc cht.

3.5.1. Bn lun v phng php bo ch

c rt nhiu nghin cu trong v ngoi nc v cc dng bo ch cha PSE

gii phng ko di s dng nhiu loi polyme tng hp. Nghin cu y cho thy

bao mng zein c nhiu u im vt tri. Trong cc nghin cu trc y, t

c m hnh gii phng PSE mong mun, cn phi phi hp hai hay nhiu polyme

khc nhau trong mt hay nhiu lp trong khi y ch cn s dng zein trong mt

lp mng. Khi s dng EC - mt polyme thng dng kim sot gii phng -

th gii phng xut hin thi gian tim tng (lag time), trong khi s dng zein,

khng tn ti lag time ny [16], [26], [27].

Zein c dng bao kh hoc bao phim. ng dng trong phng php bao

kh, tc gii phng dc cht ph thuc vo kch thc tiu phn ca zein cng

nh tng tc gia zein vi cc thnh phn trong mng bao [15]. Vi zein dng

42

pseudolatex, qu trnh bo ch tri qua nhiu bc, phc tp [19]. Trong khi ,

y phng php bao mng xut pht t dung dch zein kh n gin. c bit, khi

phi hp zein vi cht ha do thch hp m khng cn phi hp thm loi polyme

khc, kt qu thu c vin bao cha PSE gii phng ko di vn tun theo m hnh

gii phng mong mun. Nh vy, phng php bo ch c nghin cu y u

vit hn so vi mt s phng php bo ch c nghin cu trc .

43

KT LUN V XUT

Kt lun

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

1. Kho st c nh hng ca mt s thng s bao phim ln hiu sut bao, vi

thit b l my bao Vanguard (h ni bao c l), quy m bao khong 300g vin.

La chn c cc thng s ti u cho qu trnh bao:

Nhit kh thi vo: 65oC.

Nhit kh ht ra: 60oC.

Tc quay ni bao: 9 vng/pht.

Tc phun dch bao: 3 ml/pht.

Lu lng kh thi vo: 10 m3/h.

Lu lng kh ht ra: 12 m3/h.

p sut phun: 1,8 atm.

2. nh gi c nh hng ca zein v cht ha do (DBP v PEG 400) ln tc

gii phng PSE v s b nh gi c tng tc gia zein v cht ha do

trong mng bao.

3. Bo ch thnh cng vin cha 60 mg pseudoephedrin hydroclorid gii phng

ko di 12h vi m hnh gii phng dc cht tng ng vin i chiu

Clarinase (f2 = 59,30). Cng thc dch bao ti u thu c nh sau:

Zein

DBP

Talc

Titan dioxyd

Isopropanol : nc (8:2)

8,24% nhn (kl/kl)

4% zein (kl/kl)

10% zein (kl/kl)

20% zein (kl/kl)

va pha dch bao cha 6% zein (kl/tt).

xut

T kt qu thu c, chng ti c mt s xut nh sau:

1. Nghin cu c ch tng tc ca zein v cht ha do trong mng bao.

2. Tip tc pht trin phng php bo ch vin gii phng c kim sot phi

hp hai thnh phn pseudoephedrin v loratadin da trn vin cha 60 mg

pseudoephedrin hydroclorid gii phng ko di 12h nghin cu trn.

TI LIU THAM KHO

Ting Vit

1. B mn Bo ch (2005), Mt s chuyn v bo ch hin i, Nh xut bn Y hc, tr.132-156, tr.91-113.

2. B mn Dc Lm sng (2009), Bi ging bnh hc, Trng i hc Dc H Ni, tr.42-43.

3. B Y T (2009), Dc in Vit Nam IV, PL 220-230.

4. B Y T (2009), Dc th quc gia Vit Nam, tr.748-750.

5. B Y T (2008), K thut bo ch v sinh dc hc cc dng thuc, Nh xut bn Y hc, 2, tr.192-193.

6. B Y T (2009), K thut sn xut dc phm, Nh xut bn Y hc, 3, tr.138-158.

7. B Y t (2008), Thuc bit dc v cch s dng, Nh xut bn Y hc, tr.606.

8. o Th Ngc Hn (2011), Nghin cu iu ch v ng dng zein l t dc bo ch thuc gii phng ko di, Kha lun tt nghip dc s, Trng i hc Dc H Ni.

9. Quang Huy (2012), Nghin cu bo ch vin gii phng c kim sot cha pseudoephedrin v loratadin, Kha lun tt nghip dc s, Trng i hc Dc H Ni.

Ting Anh

10. Beck M.I et al. (1996), Physico-chemical characterization of zein as a film coating polymer, a direct comparison with ethyl cellulose, International Journal of Pharmaceutics, 141, pp.137-150.

11. British Pharmacopoeia (2007), Monograph 0478.

12. Costa P et al. (2001), An alternative method to the evaluation of similarity factor in dissolution testing, International Journal of Pharmaceutics, 200, pp.77-83.

13. Elzoghby A.O (2012), Protein-based nanocarriers as promising drug and gene delivery systems, Journal of Controlled Release,161, pp.38-49.

14. Gilbert S.B (2002), Modern Pharmaceutics, Marcel Dekker Inc., New York, pp.503-525.

15. Guo H.X, Shi Y.P (2009), A novel zein-based dry coating tablet design for zero-order release, International Journal of Pharmaceutics, 370, pp.81-86.

16. Ishida M et al. (2008), A novel approach to sustained pseudoephedrine release: Differentially coated mini-tablets in HPMC capsules, International Journal of Pharmaceutics, 359, pp.46-52.

17. Lawton J.W (2002), Review zein: a history of processing and use, American Association of Cereal Chem, 79(1), pp.1-18.

18. Mastromatteo M et al. (2009), Controlled release of thymol from zein based film, Innovative Food Science and Emerging Technologies, 10, pp.222-227.

19. ODonnell P.B et at. (1997), Aqueous pseudolatex of zein for film coating of solid dosage forms, European Journal of Pharmaceutics and Biopharmaceutics 43, pp.83-89.

20. Rowe R.C et al. (2009), Handbook of Pharmaceutical Excipients 6th, Pharmaceutical Press and American Pharmacists Association, pp.790-791.

21. Shewry P.R, Casey R. (1999), Seed protein, Kluwer Academic Publishers, pp.109-139.

22. Sweetman S.C (2009), Martindale 36th, Pharmaceutical Press, pp.1571.

23. Sweetman S.C (2009), Martindale The Complete Drug Reference 36th, 2, pp.3011.

24. The United Stated Pharmacopoeia 29 (2005), 2, pp.3046-3047, pp.1858-1860.

25. Thompson G.A et al. (1989), Structural elements regulating zein gene expression, BioEssays, 10, pp.108-113.

26. Yang Z.Y et al. (2008), Pseudoephedrin hydrochloride sustained-release pellets prepared by a combination of hot-melt subcoating and polymer

coating, Drug Development and Industrial Pharmacy, 34, pp.1323-1330.

27. Zeeshan F, Bukhari N.I (2010), Development and evaluation of a novel modified-release pellet-based tablet system for the delivery of loratadin and

pseudoephedrine hydrochloride as model drug, American Association of Pharmaceutical Scientists, 11(2).