:<?c
vA
CONG
NGHl:
UBND
TiNH BiNH
Q|NH
CmfdNG
TRiNH
KHCN CA'p
NHA
Nl/dC
KCIO
BAO CAO
T6NG
H0P
KiT QUA KHOA HQC
C6NG
NGH|
DU
AN
HOAN
THBlN
QUI
TRbfH
C6NG
NGH|
SAN
XUAT
THUdc
TI£M

NHlfdNG
QUY
NHdN
- 2010
BO KHOA HOC VA CONG NGHE UBND TINH BINH DINH
CHUONG TRINH KHCN CAP NHA
Nl/6C
KC 10
BAO CAO TONG HOP
KET QUA KHOA HQC CONG NGHE DE
TAI/DU
AN
HOAN THIEN QUI TRINH CONG NGHE SAN
XUAT
THUOC
TIEM DONG KHO METHYLPREDNISOLON
NATRISUCCINAT
QUY MO CONG NGHIEP
KC10.DA04/06-I0
Chu nhiem du an
•hu
tri du an
;/TdNGGlAMEK5c
'
TdNGOlAMDdC
TS.
LE CONG
NHUONG
Ban chu nhiem chuang trinh
Bo Khoa hoc va Cong nghe

10
2.
Chij
nhiem de tai/dy an:
Hpvdten:
LE CONG
NHUQNG
Ngay, thang, nam sinh: 1963
Nam/Nil:
Nam
Hpc ham, hgc vi: Tien sT Dugc hoc
Chirc vu: Phd Tdng Giam Ddc
Dien thoai:
Td chirc:
056.3646178.
Nha rieng: 056.3824624. Mobile: 0935268568.
Fax: 056.3846846. E-mail:
Ten td chiic dang cdng tac: Cdng ty Dugc - TTBYT Binh Djnh
Dia chi td chuc: 498 Nguyen Thai hgc - Quy Nhon - Binh Djnh
Dia chi nha rieng:
31
Tang Bat Hd - Quy nhan - Binh djnh
3.
Td chirc
chii
tri de tai/dy an:
Ten td chiic chu tri dl tai: CONG TY DUOC - TTBYT BINH DINH
Dien thoai: 056.3847098. Fax: 056.3846846 E-mail:
ctyduocbd(3)dng.vnn.vn
Website: www.bidiphar.com

din
thang 03/ndm
2010
-
Dugc gia han (neu cd):
-
Ldn
1
tir thang
12
nam 2009
din
thang 03 nam
2010
2.
Kinh phi va sir dung kinh phi:
a) Tdng sd kinh phi thuc hien: 7.298,569 tr.d, trong dd:
+ Kinh phi ho trg tir SNKH: 2.200,00 tr.d.
+ Kinh phi tu cac ngudn khac: 5.098,569 tr.d.
+ Ty le va kinh phi thu hdi ddi vdi du an (neu co): 65% so vdi kinh phi ho trg tu
ngan sach SNKH
b) Tinh hinh cap va sir dung kinh phi tu ngudn SNKH:
So
TT
1
2
Theo
ke
hoach
Thdi gian

1
2
3
4
5
6
7
Npidung
cdc khoan
chi
Thiet bj, mdy mdc
mua mdi
Nha xudng xay
dung mdi, cai
tao
Kinh phi
hd trg
cong nghe
Chi phi lao dgng
Nguyen
vat
lifu,
nang lugng
Thue thiet bi,
nha
xudmg
Khac
Tong cong
Theo
ke

vi
tinh: Trieu
ddng
Thuc
te dgt
dupe
Tdng
10.676,141
150,00
1.000,00
337,440
2.734,954
0
727,932
15.626,467
SNKH
700
0
800
131,760
•i'il,lAti
0
176
2.200
Ngudn
khac
9.976,141
150
200
205,601

nam 2007
1540/QD-BKHCN
ngay
31
thdng 07
nam 2007
2733/QDBKHCN
ngay
16
thdng
11
nam 2007
04/2007/HD-DACT-
KC 10.04/06-10
ngay 24 thang 03
nam 2008
784/CTDngay
17
thang 10 ndm 2009
2956/QDBKHCN
ngay 22 thang 12
nam 2009
Ten vdn bdn
Phe duyet Danh muc dy an
san xuat thu nghiem thudc
cac chuong trinh khoa hgc vd
cdng nghe trgng diem cap nha
nudc giai doan
2006-2010
dl

ddng ky theo
Thuyet minh
Khong
Ten to chiec da
tham gia thuc
hien
Khdng
Npi dung
tham gia
chu yeu
Sdn phdm
cha
yeu
dat duac
Ghi
chu*
5. Ca
s6
TT
1
2
3
4
5
6
7
8
nhan tham gia
thi
Ten cd nhan

Hodng
Npi dung
tham gia
chinh
Chu nhiem
Thuky
Nghien cuu
ky thuat ddng
khd
Hoan chinh
cdng nghe
Danh gid tinh
an loan san
pham
Quy trinh SX
Tham djnh
quy trinh
Theo doi do
dn djnh san
pham d dieu
kien lao hda
Theo doi dp
dn djnh san
pham d dieu
kien thuc
Sdn phdm
chu
yeu dat
duac
Cdng thirc

Sd
TT
1
2
Theo ke hogch
(Not
dung,
thai gian, kinh
phi, dia diem )
Hdi thao gidi thieu san
pham, nam 2009,
20.000.000 vnd
Thuc te dgt dupe
(Ndi
dung,
thai gian,
kinh phi, dia diem )
Tham gia hgi thao:
"Hgp tac khoa hgc cdng
nghe giira Vien ~
Trugng - Doanh nghiep
san xuat va Kinh doanh
dugc pham" thang
8/2008
Tham gia trien lam giai
thieu san pham Hdi nghi
Techmart Viet Nam
ASEAN +3 nam 2009
Ghi
chii*

Theo ke
hoach
12/2007
den
05/2008
12/2007
din
05/2008
12/2007
den
05/2008
03/2008
den
12/2009
03/2008
den
12/2009
06/2009
den
10/2009
Thuc te
dat duoc
05/2007
den
05/2008
05/2007
den
05/2008
05/2007
den

My
Hodng
PGS
Nguyin Van
Long
HI. SAN
PHAM
KH&CN
CUA
DE TAI, DU AN
1.
San pham
KH&CN
da tao ra:
a)
San pham Dang
1:
s6
TT
I
2
Ten sdn phim vd
chi tieu chat lupng
chuyeu
Quy trinh cdng
nghe san xuat
thudc tiem ddng
khd Methyl
prednisolon natri
succinat 40mg/lp

prednisolon natri
succinat
40mg/lg
(SOU MEDON 40)
Yeu cdu khoa hpc
cdn dat
Theo ke
hoach
1.000.000
lg
Thuc te
dat duoc
1.000.000
lg
Ghi
chii
c) San pham Dang
III:
sS
TT
1
2
3
Ten sdn phdm
Bao cao theo doi do dn
dinh san pham
a
dieu
kien lao hoa
Bao cao theo doi do dn

Tap chi
Y
Duac hpc
qudn su, tr.
5-10
(2008)
d) Ket qua dao tao:
s6
TT
I
2
Cap dao tgo, Chuyen
ngdnh ddo tgo
Thac sy
Tien sy
Solupng
Theo ke
hoach
0
0
Thuc te dat
dugc
0
I
Ghi chd
(Thdi gian
ket thiic)
Ndm 2008
d) Tinh hinh dang ky bao hd quyin so
hChi

Thdi gian
Tir 2007
din 2010
Dia diem
(Ghi ro
ten,
dia
chi nai img
dung)
Cdng ty Dugc
- TTBYT Binh
Dinh
Ket qud
sabp
1.000.000
Ip
2.
Danh gia ve
hifu
qua do de tai, dy an mang lai:
a) Hieu qua ve khoa hpc vd cdng nghe:
Hien dai hda ngdnh cdng nghifp dugc Viet Nam: Du an nghien cuu thudc
tiim
ddng khd Methylprednisolone natri succinat
Id
tien de cho su hinh thanh va phdt
trien day chuyen sdn xuat thudc tiem ddng khd tai Cdng ty Dugc - TTBYT
Binh dinh, day la day chuyen san xuat dau tien tren ca nudc ve san xuat cac
dang thudc tiem ddng khd.
Hien day chuyen dang san xuat tren

TT
1
II
III
Ndidung
Bao cdo djnh ky
Lan
1
Lan
2
Kilm tra dinh ky
Lan
1
Lan
2
Nghiem thu co sd
Thdi gian
thuc hien
15/09/2008
30/09/2009
22/11/2008
01/10/2009
20/03/2010
Ghi chu
(Tdm tdt ket qud, ket lugn
chinh,
nguai
chii
tri )
Da hoan thanh cdc ngi

14
1.1.4.3.Bien
phap khac phuc su thdy phan
ciia
MPN trang
16
1.2.
Tham dinh quy trinh san xuat trang 19
1.2.1. Khai niem, djnh nghla tham dinh trang
19
1.2.2.
Ddi tugng tham dinh trang 20
1.2.3. Thdng so tham dinh trang
21
1.2.4.
Loai hinh tham djnh quy trinh san xuat trang 22
1.2.4.1.
Tham dinh trudc trang 23
1.2.4.2.
Tham dinh tiep trang 23
1.2.4.3. Tham dinh lai trang 24
1.2.4.4.
Tham dinh lui trang 24
1.2.5.
Ngi dung tham dinh quy trinh san xuat trang 24
1.2.5.1.
Ngi dung ciia ke hoach tham dinh trang 24
1.2.5.2.
Ngi dung
ciia

MPN va thudc tiem dong kho MPN trang 38
1.4.1.
Cau tnic hda hpc trang 38
1.4.2.
Tinh chdt vat ly trang 38
1.4.3.
Tinh dn dinh hoa hgc trang
38
1.4.4.
Dac tinh dugc dong hgc trang 40
1.4.5.
Tac dung dugc ly trang 40
1.4.6.
Chi dinh trang 41
1.4.7.
Chong chi dinh trang 41
1.4.8.
Lieu lugng,
each
diing trang
41
1.4.9.
Che pham trang 41
1.4.10.
Thudc tiem dong kho MPN trang 41
Chuong 2.
NOI
DUNG VA PHUONG
PHAP HOAN
THIEN trang 43

2.3.2.4. Khao sat nhiet do ddng lanh trang 54
2.3.2.5.
Nhiet do ddng khd trang 55
2.3.2.6. Khao sat nhiet do say khd trang 55
2.3.2.7. Ap sudt thdi ky dong lanh trang 55
2.3.2.8.
Khao sat dp suat thdi ky ddng khd trang 55
2.3.2.9. Ap suat thdi ky say khd trang 56
2.3.3.
Tdi uu hda cong thirc va thdng so ky thuat ddng
khd bang phan mem thong minh INFORM
v3.5.
trang 56
2.3.3.1.
Tucmg quan giira nghien ciru thi nghiem va qui
md san xuat cdng
nghiep.
trang 56
2.3.3.2. Thiet ke md hinh thyc nghiem. trang 58
2.3.3.3.
Phuong phap phan tich nhan qua trang 61
2.3.3.4. Phuong phap toi uu hda cdng thiic/ quy trinh trang 61
2.3.4. Tham dinh quy trinh san xuat trang 62
2.3.4.1.
Tham dinh md phong trang 62
2.3.4.2. Tham dinh theo phugng phap truyen thdng trang 66
2.3.5.
Phuomg phap danh gia chat lugng san pham va
xay dung tieu chuan cho che pham trang 67
2.3.5.1.

2.4.4. Dgng vat
thii
nghiem trang 77
Chuong
3.
KET QUA DAT DUOC trang 78
3.1.
Khao sat lua chgn thanh phan cdng thirc trang 78
3.1.1.
Khao sat chgn he dung moi trang 78
3.1.2. Chgn he dem trang 78
3.1.3.
Chgn ta dugc dgn tao khung trang 82
3.1.4.
Chat bao quan trang 83
3.1.5.
Ket qua khao sat thyc nghiem xac djnh pH trang 84
3.1.6. Ket qua khao sat anh hudng bao bi len che pham trang 86
3.2. Khao sat thuc nghiem xac
djiih
thdng so ky thuat dong khd trang 88
3.2.1.
Thdi gian dong lanh trang 88
3.2.2. Thdi gian dong kho trang 89
3.2.3.
Kit
qua khao sat thdi gian
sdy
khd trang 90
3.2.4. Nhiet do ddng lanh trang 92

3.4.4. Tdi
uu
hda trang
111
3.3.4.1.
Diiu
kien toi
uu
hoa trang
111
3.3.4.2.
Kit
qua tdi uu hda trang
111
3.3.4.3.
Diiu
chinh thdng sd may ddng khd GZL-6 trang
112
3.5.
Tham dinh quy trinh san xuat trang
116
3.5.1.
Thim
dinh cac thdng so trgng yeu trong qua trinh trang
116
3.5.2.
Thim dinh
md phdng trang 118
3.6. Theo doi do on djnh san pham trang
118

126
3.7.2.1.
Anh hudng
ciia
Soli - Medon tren sy tang trgng
lugng tho thi nghiem khi diing dai ngay trang
126
3.7.2.2. Anh hudng ciia Soli - Medon ddi vdi dien tim
thd thi nghiem khi dimg dai ngay trang
127
3.7.2.3 Anh hudng cda Soli - Medon ddi vdi mdt so
chi tieu ve huyet hgc thd thi nghiem khi dimg
dai ngay trang
129
3.7.2.4 Anh huong ciia Soli - Medon doi vdi mgt so
chi tieu ve chirc nang gan, than thd thi nghiem
dung dai ngay trang
132
3.7.2.5. Anh hudng cua Soli-Medon tren mo benh hgc
tang gan, lach, than, da day thd thi nghiem khi
diing dai ngay trang
136
3.7.3.
Ket qua nghien cim so sanh tac dung chdng viem giam
dau
ciia
Soli-Medon trang 139
3.7.3.1.
Ket qua nghien
ciiu

trang
155
PHU
LUC
Phu luc
1.
Dir lieu tham dinh quy trinh san xuat ve khdi lugng trang
161
Phu luc 2.
Biiu
dd Shewhart R va XTB trang
164
Phu luc 3. Bieu dd cusum trang
167
Phu luc 4. Cac chi bao hieu nang trang
168
Phu luc 5. Sd lg khdng dat trong qua trinh ddng djch vao lg trang
169
Phu luc 6. Bieu dd Shewhart p trang
170
Phu luc 7. Dir lieu tham dinh trang
171
DANH MUC HINH VE, BANG,
BIEU,
SO DO
Hinh I.I. Gian do pha cua nudc trang 5
Hinh
1.2.
So dd ciia lg trong giai doan lam khd so cap trang 6
Hinh

X4
va
X5
tren
yi
trang
106
Hinh
3.4.
Cac xu hudng anh hudng cua
Xi,
X3,
X4
va
X5
tren
y2
trang 107
Hinh 3.5. Cac xu hudng anh hudng cua X|,
X2,
X3
va
X4
tren
y4
trang 107
Hinh 3.6. Cac xu
hudmg
anh hudng cua
X|

110
Hinh 3.10. Anh huong cua thudc nghien
cCm
tdi ty le % tang the tich
ban chan chugt d cac thdi diem sau gay viem trang
141
Hinh
3.11.
Anh hudng
ciia
thudc nghien ciru tdi ty le
lic
che
phii
(%) trang
142
Sff
do
1.1.
Cac doi tugng tham dinh trong quy trinh san xuat trang
21
So do 1.2. Cac loai thong sd tham dinh trang 22
Sff do 1.3. Cac giai doan trong tham djnh mgt QTSX thudc mdi trang 27
So'
do 1.4. Tdm tat quy trinh thiet lap md hinh nhan qua va tdi uu hda trang 37
Sff do
2.1.
Trinh ty cac giai doan
xii:
ly nap nhdm trang 44

Bang
2.11.
Md hinh tham dinh trudc QTSX theo truyen thong trang 66
Bang 2.12. Nguyen lieu sii dung trong san xuat, nghien curu trang 75
Bang 2.13. Thiet bi diing kiem nghiem trang 76
Bang
3.1.
Anh hudng cua dung moi den do tan va do trong
ciia
dung
dich pha lai tir bgt ddng kho trang 78
Bang 3.2. Do mat khdi lugng do say kho cua cong thirc khao sat A5,
A6 va A7 trang 79
Bang 3.3. Ket qua khao sat do ddng deu khdi lugng cua cdng thirc A6
va A7 trang 80
Bang 3.4. Ket qua khao sat pH cua cong thiic A6 va A7 trang 80
Bang 3.5. Ket qua dinh lugng tren 2 cdng thirc A6 va A7 trang
81
Bang 3.6. Bang ket qua khao sat chi tieu hinh thu'c, ham lugng va do
am, pH trang 82
Bang 3.7. Ket qua anh hudng cua pH tdi ham lugng MPN trang 85
Bang 3.8. Ket qua xac dinh % mat khdi lugng do say khd trang 87
Bang 3.9. % mat khdi lugng do say khd va ham lugng MPN cdn lai
cua ciing mdt cdng thirc
(B18)
trang 88
Bang 3.10 Thdi gian ddng lanh cda
3
mau nghien cim
CI,

Bang 3.19. Do mat khdi lugng do say khd ciia
3
QT chay may
CI6,
C17vaC18 trang 99
Bang 3.20.
Kit
qua dinh lugng tren
3QTC16,C17vaC18.
trang
100
Bang
3.21.
DO
lieu thyc nghiem (dau vao cda phan mem FormRules) trang
105
Bang 3.22. Cac xu hudmg va muc do lien quan giii'a
Xi
va
y,
trang
106
Bang 3.23. Cac thdng sd cd dinh cho quy trinh chay may trang
112
Bang 3.24. Cac thdng sd thay ddi cho chuong trinh chay may trang
113
Bang 3.25. Danh gia so bg chat lugng 2 mau
QTl
va QT2 trang
114

dung djch
pha trang 125
Bang 3.37. Ket qua nghien ciru dgc tinh cap ciia Soli - Medon tren
chugt nhat trang trang
125
Bang 3.38. Anh hudng ciia Soli - Medon ddi vdi TLCT thd trang
126
Bang 3.39. Anh hudng cua Soli - Medon ddi vdi dien tim ciia thd d
dao trinh D,| (n
=/O)
trang 128
Bang 3.40. Anh hudng cua Soli - Medon ddi vdi sd lugng
HC
tho trang
129
Bang
3.41.
Anh huong cua
SoU
- Medon ddi vdi HST thd trang 130
Bang
3.42.
Anh hudng cda Soli - Medon ddi vdi sd lugng
BC
tho trang
131
Bang
3.43.
Anh hudng cua Soli - Medon ddi vdi sd lugng
TC

Bang 3.53. Tac dung giam trgng lugng u hat
(mg/lOO
g)
ciia
Soli -
Medon trang
143
Bang 3.54. Anh hudng
ciia
thuoc nghien cira tdi nguong dau ciia td
chiic trang
144
Bang 3.55. Anh hudng
ciia
thudc nghien ciru tdi so con dau quan cua
chugt nhat trang trang
145
Bang 3.56. Anh hudng cua thudc nghien
ciiu
tdi thdi gian dap ling dau
ciia
chugt nhat trang trang
146
Bieu do
3.1.
Su bien thien dien trd theo nhiet do
ciia
dung djch Methyl
prednisolon natri succinat trong
I ml

Dugc chat
Dugc dien Viet Nam lan xuat ban thir 3
Thuc hanh tdt san xuat theo tieu chuan cua To chirc Y te the
gioi
Huyet sac td
Hdng cau
Sac ky long hieu nang cao
Lieu chet 50% dgng vat thi nghiem
Methylprednisolon natri succinat
Mat khdi lugng do say khd
Nghien
ciiu
cua Nguyen Van Long va cgng su ve thudc tiem
ddng khd Methylprednisolon natri succinat
Phu luc
Quy trinh san xuat
Quy trinh
Relative standard deviation (Do lech chuan tuong ddi)
Serum
glutamo-oxalo
transaminase
Serum glutamo-pyruvic transaminase
Tieu cau
Trgng lugng co the
Thong so dong kho
Dugc dien My
MdoAu
Dong khd la qua trinh lam kho cac thudc va che pham sinh hgc d nhiet do
thap,
dudi cac dieu kien thich hgp, de loai

ITnh
vuc y te du phdng tdi trg.
Nam 2004 trudng Dai hgc dugc Ha Ngi da cd nhirng nghien cuu ky thuat
ddng khd d qui md phdng thi nghiem [8]. Trong khi dd, nhu cau ve cac che
pham thuoc dong khd ndi chung, thudc tiem ddng khd ndi rieng, ngay mgt
tang ddi hdi phai san xuat d quy md cdng nghiep.
Thudc tiem Methylprednisolon natri succinat la mgt thuoc chong viem
steroid dugc sir dung kha rgng rai tren lam sang, dac biet trong cac ca benh
cap
cim.
Methylprednisolon natri succinat rat de bi thiiy phan, khdng ben d
d^ng
dung dich nen thuoc dugc bao che dudi dang thuoc tiem dong khd va chi
-
dugc pha lai thanh dung djch trudc khi tiem [8],
[51].
Nham dap irng nhu cau
dieu trj trong nudc thay the dan thudc nhap ngoai cho che pham chira hoat
chat nay, tren nen tang de tai nghien cim cua PGS.TS. Nguyen Van Long
nhung dugc hoan thien va img dung vao san xuat quy
ind
cdng nghiep, nang
cao chat lugng va han diing phuc vu tdt hon cho cgng ddng chiing tdi thuc
hien dy
an:
"Hoan thien quy trinh san xuat thudc tiem ddng khd
Methylprednisolon natri succinat quy md cong nghiep" vdi ba muc tieu:
1.
Hoan thien quy trinh cdng nghe san xuat thudc tiem ddng kho Methyl
prednisolon natri succinat 40mg/lg quy md cdng nghiep