NGHIEN CLTU DIEU CHE VA TIEU CHUAN HOA H 6 N DjCH UONG ALBENDAZOLE
Le Hoang Thanh M y \ Vo Thi Tra An', Le Minh Tri^
T O M T A T
Vdi muc tidu bao chd' dang thudc Iting nhu dang hdn dich hay set (kem) dd de dang cung ca'p qua dudng udng cho vat nudi, nghidn eiiu nay da xay dUng dUdc eong thiie hdn dich udng albendazole 6% nhu sau: albendazole 30 g; xanthan gum 1 g; saccharin natri 2,5 g; kali sorbat 2,5 g;
butyl hydroxy toluen 1,25 g; sorbitol 70% 100 ml; nude eat vita dii 500 ml. Chd pham sau khi hoan thanh dupe bao quan trong lp mau, P nhidt dp phdng thi nghiem trong thdi gian 3 thang da dap iing dupe cac yeu clu cha't lupng theo DDVN UI (2002) vaDupc did'n My (2007) v l dp phan tan, mau sic, pH, dinh tinh va dinh ludng.
Tii khda: Albendazole, Hdn dich udng, Dilu chd, Tidu chuan hda
Study and standardization of albendazole oral suspension
Le Hoang Thanh My, Vo Thi Tra An, Le Minh Tri
S U M M A R Y
The goal of this study is to produce a liquid suspension of albendazole which is easily supplied to animal orally. The study has developed the formulas of the mixture of albendazole 6% (albendazole 30 g) with xanthan gum 1 g; sodium saccharin 2,5 g; potassium sorbate 2,5 g;
butylated hydroxytoluene 1,25 g; sorbitol 70% and distilled water. The preparations which were stored in dark botde at room temperature during 3 months had passed the quality requirements of dispersion, color, pH, quantification in the Vietnam Pharmacopeia 2002 and The United States Pharmacopeia - National Formulary 2007.
Key words: Albendazole, Liquid suspension. Preparation, Standardization
I. DAT VAN DE ^ ^ ' '^' '^°^'^ ^^° ™^° ^i?^ cho thu ud'ng thudc vidn khdng thuan tidn va rat khd thao tae, thu Tinh chat eiia albendazole la khdng tan hay dung ludi da'y vidn thude ra ngoai. Dd tirong nude nen hien nay ti-dn thi tirudng luu gi|i quyd't va'n d l nay, mdt yeu clu thuc tiln hanh chii yeu la dang thudc vien hoac thudc Ja ein dang thud'e Icing n h u dang hdn dich bpt. Thud'e chl dupe cap qua dudng mieng, hay set (kem) dd d l dang bPm vao midng gia bang each ti-pn vao thiic an hoac eho ud'ng sue (loai nhai lai) hay de cho chd meo ti^ liem bruc tiep. Ddi vdi eae loai thu ldn nhu loai (thud'e ein cd thdm vi va mUi d i n du).
' B6 mon noi dviac, Khoa chSn nuoi thii y, Dai hoc Nong Lam Tp.HCM - Bo mfin hoa du'dc, Khoa dtfdc, Dai hoc Y duoc Tp.HCM
Hien nay, d a n g thud'e long albendazole rat hid'm tha'y trdn thi trUdng (trong n u d e ehi ed mdt vai san p h a m n h u la Bio-Dewormer d a n h cho thu y va Zentel-Suspension d a n h cho ngudi). Dd dd, nghidn eiiu v l biet d u p e albendazole va t h u n g h i e m dieu chd hdn dich albendazole dd khac p h u c nhifng khd khan khi d u n g thudc bdt, tao d i l u kien t h u a n ldi hdn eho n g u d i chan n u d i trong vide p h d n g benh ki sinh t r u n g la can thidt.
I I . N O I D U N G , V A T L I E U V A P H U O N G P H A P N G H I E N CU'U
2.1. Noi d u n g
- x a y d u n g cdng thiic va d i l u chd'hdn dich albendazole 6 %.
- Theo ddi dp dn dinh cua chd p h a m . - Xay d u n g tidu c h u a n ed sd chd c h d ' p h a m can eii vao DDVN III va USP 30 chuydn luan albendazole suspension.
2.2. Vat lieu
- Hda chat: albendazole (Trung Qudc), kali sorbate (Merck - Diic), saccharine natri (Trung Qud'e), butylhydroxy toluen (Trung Qud'e), sorbitol 70 % siro (OPV - Viet N a m ) , xanthan g u m (Merck - Diie), N u d c ca't.
- Can didn tii, may k h u a y tii khdng gia nhidt, may do p H , m a y ttdng hda Erweka, edi chay bang sU.
2.3. P h u o n g p h a p n g h i e n ciiu
- Xay t i u n g c d n g thtic e h o chd p h a m h d n dich u d n g g o m eae t h a n h p h i n sau:
albentlazole ( d u p e c h a t r a n ) , n u d e eat ( d u n g mdi), x a n t h a n g u m (ta d u p e treo), saccharine n a t r i (ta d u p e g a y n g p t ) , BHT (chat c h d n g oxy h d a ) , kali s o r b a t (chat bao q u a n ) .
- D i l u chd' h d n dich albendazole bang p h u d n g p h a p p h a n tan cd hpc .
- Theo ddi d p dn d i n h ciia c h d ' p h a m dUa trdn cac chi tidu n h u : d d l i n g , m a u s i c c a m
q u a n , d p p H , m u i , vi, h a m l u p n g a l b e n d a z o l e ciia chd' p h a m sau khi m d i bao chd' va so sanh v d i chd' p h a m da bao q u a n d u p e 3 t h a n g P 2 d i l u kien n h i e t dp: trdn 32''C va 28°C - 32"C.
- Xay d u n g tidu ehuan eho thanh pha'm d u a trdn nhiing tidu ehuan ctia DDVN III (2002) chuyen luan h d n dich va USP 30 chuyen luan albentlazole suspension.
I I I . K E T Q U A V A T H A O L U A N 3.1. D i e u che h o n dich a l b e n d a z o l e
N u d e eat d u p c chpn lam d u n g mdi bdi vi n u d c de ud'ng nha't, re, dd san xua't. Cac ta d u p e d u p e chpn phai tan trong nudc va khdng t u d n g ki vdi albendazole.
Kali sorbate d u d e chpn lam chat bao quan vi day la 1 cha't tan trong n u d e lanh, khdng gay ra vi khd chiu cho che p h a m va khdng gay dde eho ed the (ttudc Bd Y te'eho p h e p sii tiung trong thue pham). Ndng dp sti d u n g la 0,5-1%.
Ve chat chdng oxy hda, butylhvdroxy toluen (BHT) tlude ehpn lua, dd la chai chdng oxy hda tdng h d p , ed che tac tiung n h u vitamine E (6). Ndng dp su d u n g la 0,25%.
C h u n g tdi cho them chai gay ngpt dd lam giam bdt vi d a n g eiia albendazole. Saccharine natii la d u d n g hda hpe, ngpt gap 400 lan d u d n g saccharose. N d n g dp su d u n g khoang 0,5-1%.
T r o n g thii n g h i e m d i u tien, che' p h a m d u p c d i e u chd' b a n g each p h a n tan dUdc chat e h i n h v a o d u n g m d i . Kd't q u a la h d n dich ra't k e m b i n . Sau 6 gid, c h u n g tdi tha'y cd h i e n t u p n g tach t h a n h 3 l d p : d u p e chat P d u d i d a y va trdn b l m a t cdn d u n g mdi d g i u a . Do dd, d e h d n dich h i n h t h a n h va b i n v u n g b i t b u d e p h a i sti d u n g ta d u p e gay t r e o . T r o n g n g h i e n cifu n a y , x a n t h a n g u m d u p e sii d u n g lam ta d u p e treo cho chd'
pha'm vi cha't nay khdng tUdng ki vdi cd Uu die'm la khdng tao bpt khi lie va albendazole, ed gia thanh tha'p, d'n dinh khdng lam cho chd'pham ed vi khd chiu khi trong mdt khoang p H rdng, ed dp nhdt eao, ud'ng. Kd't qua thii nghiem d i l u chd' eae che tan trong nude. Bdn canh vide khdng gay pham cd nong dp xanthan gum khac nhau dde dd'i vdi ed the' ngudi, xanthan gum edn dupe ghi nhan P bang 1.
Bang 1 Thi nghiem nong do xanthan gum anh huong din dp nhdt ciia chi pham
Lo 1
2
3
4
5
Nong do xanthan gum 0,1 %
0 , 1 5 %
0,2 %
0,4 %
1 %
Hien tUdng ghi nhan
Che pham tach thanh 2 Idp sau 3 gid. Che pham loang nhU nUdc.
De' lau hdn thi thay cd Idp mau trang due no'i len tren. Khi lac che pham trd lai trang thai phan tan deu.
Che pham khdng tach Idp sau 24 gid. Nhung de lau hdn thi thay cd Idp mau trang due ndi len tren. Hdi set. Khi lac che pham trd lai trang thai phan tan deu.
Che pham khdng tach Idp sau 24 gid. Che pham set, hoan toan khdng tach Idp sau 3 thang theo ddi.
Che pham khdng tach Idp sau 24 gid. Che' pham rat set, hoan toan khdng tach Idp sau 3 thang theo ddi.
Che pham rai dSc, rai khd rdt ra khoi chai.
Qui trinh dieu che:
Xanthan ?uni
y
Khuay
Hon hgp A
'
Phoi hoi)
Saccharine natri (leu cho tan hoan t(
+ Kali Sorbat
)an
Albendazole + niro'c cSt
•
Ban thanh pham
Nu
'
ph
Hon hop B ac, khuay dei
an tan deu
J trong 30'
Sado 1. Qui trinh bao che hon dich ud'ng albendazole
3.2. Ket qua k i e m n g h i e m
- Kha n a n g tach ldp: kdt q u a kidm tra d u p e ghi n h a n d bang 2
Bang2 Kit qua kiem ngiem kha ning tach ldp ciia cac che pham mdi dieu chi So che
pham 01 01
01
27
Xanthan gum sir dung Khdng 0,1 %
0 , 1 5 %
0,2 % trd len
Hien tUcfng ghi nhan
Che pham tach thanh 3 ldp
Che' pham tach thanh 2 Idp nhung khi l i e thi phan tan deu trd lai. DUdc chat ran ndi len tren be mat
Khdng tach Idp. DUdc chai ran ndi len tren be mat
Khdng tach ldp.
Ket luan
Khdng dat Khdng dat
Khdng dat
Dat
- Sau 3 thang bao q u a n , 2 7 / 2 7 chd p h a m su d u n g xanthan g u m tU 0,2 % trd len d i u k h d n g ed hidn t u p n g tach ldp.
- C a m q u a n : Sau khi m d i d i l u chd, ngoai trU chd p h a m k h d n g sU d t i n g ta d u p e rat k e m b i n , 29 chd p h a m cd sU d u n g x a n t h a n g u m sau d i u cd m a u t r a n g d u e , the chat gid'ng sUa, m u i t h d m , vi n g p t . 2 / 3 0 chd p h a m cd hidn t u d n g d u p e cha't r a n ndi ldn trdn b l mat. 2 chd p h a m n a y k h d n g d a t tidu e h u a n ndn k h d n g d u p e tidp tue theo ddi.
N h u vay, cd 27 chd p h a m edn lai d u p e tidp tuc theo ddi.
- Sau 3 t h a n g t h e o d d i , cd 1 6 / 2 7 chd' p h a m bi bid'n ddi m a u sac va m u i so vdi ban d a u . Mau sac k h d n g cdn t r a n g n h u sua nUa ma chuydn s a n g hdi s a m . Xuat hien m u i la, ra't n d n g . 1 1 / 2 7 chd' p h a m v a n giU d u p e mau s i c t r i n g d u e , thd c h a t gid'ng siia, cd m u i thdm, vi n g p t . N h u v a y , ehi ed 1 1 / 2 7 sau 3 t h a n g t h e o d d i d a t tidu e h u a n v l m a t cam quan.
- pH: tat ea cae chd' p h a m d i u dat ehi tidu p H la hi 4,5-5,5
- Dd dn d i n h : Cd 16 chd' p h a m hi bidn
ddi m a u sac va m u i t r o n g q u a t r i n h b a o q u a n k h d n g cd d p dn d i n h can thidt, n g u y d n n h a n ed t h e d o a l b e n d a z o l e t1a hi oxy h d a . Do dd, 6.e khac p h u e tinh t r a n g trdn chai lp b a o q u a n che p h a m ttudc t h a y d d i n h u sau: chai t h u y tinh m a u c h a n s a n g d u p e su d u n g t h a y eho chai thiiy tinh t r o n g sudt, d d n g t h d i c h a t c h d n g oxy hda la BHT d u p c bd s u n g v a o chd' p h a m (16 chd' p h a m bi h u k h d n g su t i u n g BHT). Kei qua la 11 chd p h a m su t i u n g thdm BHT va bao q u a n t r o n g chai m a u c h a n s a n g v a n g i u d u p e d p set, m a u t r a n g , p H , m u i n h u luc d a u d u d u p e d e h nhidt d p n a o di nUa.
- Dinh tinh va dinlr lupng: chpn n g a u nhidn 2 / 1 1 che' p h a m d ti'dn, 2 che' p h a m nay d i u d u p c bao q u a n d 28°C - 32''C va cd eung cdng thifc pha chd. 1 m a u mdi d i l u chd va 1 m a u da dieu che d u p e 3 thang. 2 m a u chd' p h a m d u p c gui ddn Vidn kidm nghiem thud'e (so 200 Cd B I C ) dd tid'n h a n h dinh tinh va dinh lupng, phifdng p h a p d u p e sii d u n g la HPLC.
Ket qua la ea 2 m a u d i u dat tidu ehuan dinh tinh. M a u m d i pha chd' cd h a m lupng albendazole 5,65%. Dat 94,16% so vdi h a m l u p n g albendazole ghi tien n h a n (6%). Mau
n a y dat tidu e h u a n . C d n m a u d a d i l u chd d u p e 3 t h i n g thi h a m l u p n g a l b e n d a z o l e hdi giam (chl cdn 5,63%, d a t 93,83%) n h u n g v l n n a m trdng tidu c h u a n chd p h e p la tU 90 -110%.
Chd ndn, ca hai m a u d i u d a t ehi tidu dinh ti'nh va dinh lUdng.
3.3. Tieu chuan thanh p h a m
T i d u c h u a n ciia chd' p h a m h d n dich n g h i d n c i i u d u p c x a y d U n g d u a v a o USP 30 c h u y d n l u a n a l b e n d a z o l e s u s p e n s i o n v a D D V N III t d m t i t t r o n g B a n g 3 n h u s a u :
Bang 3 Tieu chuan thanh pham
Chi tieu Cam quan
Kha nang tach Idp Ojnh tinh
pH
Ham lUdng albendazole
Tieu chuan
Che pham mau trang, the chai gid'ng sCfa, mui thdm, vi ngpt Khdng dupc tach Idp
Cd mat albendazole trong che pham 4,5-5,5
Khdng nho hdn 90% va khdng qua 110% ham lUdng ghi tren nhan.
III. K E T L U A N
Thanh p h a m h d n dich ud'ng albendazole 6%, su d u n g x a n t h a n g u m lam ta d u p c treo vdi n d n g dd 0,2%, kali sorbate lam chat bao q u a n vdi n d n g d d 0,5%, saccharine natri 0,5%
dd tao vi ngpt, BHT 0,25% dd n g a n can su oxy hda va 20% sorbitol 70.
P h u d n g p h a p d u p c s u d u n g dd d i l u chd' hdn dich albendazole la p h u d n g p h a p p h a n tan cd hpc vdi d u n g eu la edi chay b a n g sii.
Nghidn eiiu sP bd d p dn dinh eiia chd' p h a m trong 3 t h a n g . Ket q u a cho tha'y chd' p h a m dn d i n h v l m a t thd chat la: h o a n toan k h d n g tach ldp, m a u sac, m u i , vi k h d n g thay ddi eiing n h u h a m l u d n g d u p e chat chinh cdn ra't td't. N h u vay, vdi dieu kien n h i e t d p 28°C- 32''C va d u n g trong chai m a u c h i n sang, chd' p h a m ed thd bao q u a n tdi thidu la 3 t h a n g m a van dat cac tidu c h u a n d l ra.
TAI L I E U T H A M K H A O
1. Bo Y te, 2002. Dudc die'n Viet Nam III. NXB Y hoc. Ha Ndi.
2. 56 Y te, 1998. Quyet dinh sd 867/1998/QD- BYT V/v ban hanh danh muc tieu chuan ve sinh ddi vdi ludng thifc, thuc pham.
3. Bo Y te, 2001. Quyet dinh sd 3742/2001/QD- BYT V/v ban hanh qui dinh danh muc cac chat phu gia dudc phep sii dung trong thuc pham.
4. Bo Y te, 2002. Dudc thu qud'e gia Viet Nam.
Lln xuat ban thU 1. NXB Y hpc, U. 112-113.
5. Le Quan Nghiem va Huynh Van Hoa, 2007.
Bao che'va sinh dudc hpc (Dung cho dao tao dupc sr dai hoc). Tap 2. NXB Giao due Ha Noi.
6. Ludng Due Pha'm, 2000. Vi sinh vat va an toan ve sinh thifc pha'm. NXB Nong nghiep.
7. Nguyen Duy Thinh, 2004. Cac chit phu gia dung trong san xuS't thifc p h i m (Bai giang cho hpc vien cao hpc nganh cdng nghifp thuc pha'm). Trudng dai hpc Bach Khoa Ha Noi.
8. The United States Pharmacopeia - National Formulary (USP 30-NF25), 2007. The United States Pharmacopeia and the National Formulary, USA.
