• Nghien cu'u - Ky thuat
Nghien cihi bao che vien nen acyclovir noi -
r
ket dinh niem mac dirong tieu hoa
Nguyen H6ng Trang'", Vu Thi Thu Giang^
Pham Thi Minh Hue^ Bui Thi Hong Nhung\ Le Van Thanh ' ' Tnromg Bai hoc Y-Dugc Hue
^ Trucmg Dgi hgc Dugc Hd Ngi
^ Benh vien Chg Rdy, Tp. Hd Chi Minh E-mail: [email protected]
Summary
For gastroretentlve dosage forms, our findings led to the conclusion that the combination of Carbopol 934P and HPMC K100M was the better choice than the use of each polymer separately.
Sodium bicarbonate, as the gas-generating agent, made tablets better float in the gastric fluid. The swelling behavior, bioadhesive strength, in-vitro release of Acyclovir and floating property were investigated. CP934P was the main agent affecting the bioadhesive strength. The chosen optimal formula sustained the release of acyclovir for 12h, lasted the floating time and raised the bioadhesive strength. However, further clinical studies are needed to assess the utility of this system for patients suffering from herpes simplex and varizella zoster.
Keywords: Gastroretentlve Dosage Forms, Acyclovir.
Dat van de
Trong nhu'ng nam gan day, nhieu nghien CU'U vh h§ k^t dinh sinh hoc (KDSH) chira acyclovir (ACV) da d u v c Ihyc hien va dat hi$u qua bu'6'c dau ''•^' ^. Tuy nhien, he KDSH co nhu-Q-c diem la de bi ru-a troi khoi dg day cung
\&p ch^t nhay'^. Vi vgy, vi?c bao ch6 vien n6n acyclovir Iheo hu-wng ket hp'p noi va kel dinh sinh hpc la mpt hu-ang nghien ciru co trien vpng'^. Dgng noi, KDSH cd u'u di^m n6i bat la tang thd'i gian tiep xuc cue thuoc vai niem mac dg ddy, do do keo dai thai gian lu-u cua du'pc chat lgi dg day, giup hSp thu Ihuoc hieu qua h e n , gidm l^n su^l dung thuoc, tang sinh kha di^ng cdc thuoc c6 ciJa so hap thu h^p, 6 phan d^u ruOt non dien hinh n h u A C V ^ .
Myc ti§u cGa nghien CLPU la xay dyng du'pc cfing IhOc bdo che vien n6n acyclovir 200 mg n6i - k^l dinh mem mgc dudng lieu hoa giai ph6ng k6o ddl (GPKD) 12 giin.
NguySn li$u va phu'O'ng phap nghien CLPU
N g u y d n li^u
Acyclovir (Trung Qu6c - USP); lactose (Trung
Quoc - Eur Ph); Avicel PH 101, Aerosil (Trung Quoc USP); Carbopol 934P (CP934P) va Carbopol 940P (CP940P) (My - USP); hydroxy propyl methyl cellulose K4M (HPMC K4M), hydroxy propyl methyl cellulose K100M (HPMC K100M) (My- TCCS), magnesi stearat (Phdp - Eur. Ph. 2000); natri hydrocarbonat (NaHCOa), natri alginat, Talc (Trung Qu6c - BP). Cac nguyen lieu dung cho phan lich kiem nghidm deu dgt tieu chuan TKHH
D o n g vat t h i n g h i e m
Tho trdng tru'O'ng Ihanh, khoe mgnh-, giong dye, trpng lu'ong tit 2,0-2,5 kg, du'pc nuoi du'O'ng Irong dieu kien dinh duang day du, ki^m soat, bo doi qua ngay, d u a c udng n u a c t y do trud'c khi Ihi nghiem.
P h u v n g phap nghien CIFU
Phwong phap bao che vien nen ACV noi - ket dinh sinh hpc
Vien nen ACV dupc bao che bSng phuang phdp dap thang vai cac thanh phan' ACV (200 mg), polyme KDSH (CP934P, HPMC K100M,. ), lactose, Avicel PH 101, natri hydrocarbonat Aerosil, magnesi stearat, laic.
r.\P CHi DirpC HQC - 09/2013 (SO 449 NAM 53)
0 Nghien CIFU - Ky thuat
Phwong phap phan tich Dinh ii^ong
Djnh lupng hogt chat b§ng p h u a n g phdp do quang phfi hap thu 6 b u a c song c y c dai 252 nm (song song li^n hanh vai cdc mau placebo, k4t qua cho Ih^y mat dp quang cua cac m§u ndy luon < 1 % so vai mdu chua acyclovir x u ly Irong cung dieu kien).
Danh gia kha n^ng giai phong duuc chit Thiel bj cdnh khuay, loc dp 50 ± 1 vdng/phut;
mdi trud'ng hda tan 900 ml dung djch HCI 0,1 N;
nhiet dp 37 ± 0,5°C; thd'i diem ldy mau 1, 2, 4, 6 vd 8 gid'; djnh lupng bdng phuang phap do quang d" budc song 252 nm.
Danh gid kha nang truxmg no
Vien Ihuoc d u p c cho vdo gid lam bdng thep khong gi cd kich I h u d c mdt ludi 3 8 V m va can xac dinh khoi lupng ban dau (Wo). Sau dd gid thuoc d u p c nhung vdo trong 100 ml n u d c cat a nhi#t dp 25°C. Sau tung khoang thd'i gian nhat djnh gid thu6c d u p c lay ra, dung giay loc tham het phan n u d c thua Iren be mat va can xdc djnh khoi iupng (Wt). Muc dp tniang nd cua vien thuoc dupc xac djnh theo cdng thuc:
Ddnh gi§ kha nSng kSt dinh sinh hoc in vitro tr§n niem mac da day tho
XLP ly niSm mac: bam khdng khi vdo ttnh mach vdnh tai de lam chet tho. Ngay ldp t u c phau thual cat lay dg day thd dem lam sach be mgt niem mac dg day bdng dung dich n u d c muoi sinh ly sao cho khdng lam mat Idp chat nhay tren be mat. Cdt thanh nhij-ng manh niem mac di#n tich 4 cm^ ( 2x2 cm) va lien hdnh thi nghidm ngay.
Thiel bj dung de xdc dinh Iyc KDSH dup'c m d t a Irong hinh 1.
Gdn CO (^nh niem mac dg day thd Idn gia, Idm u d l be mat niem mac bang mot the tich chinh xac 0,1 ml dung djch HCI 0,1 M sau dd dgi vien thuoc len niem mac. Oieu chinh can thdng bdng. Tac ddng len vien thu6c mot Iyc 200 g trong 1 phiit. Cho nud-c tren buret nhd xuong c6c nhya vdi loc dp 3 ml/phul d^n khi vien thuoc bj tach ra khdi b^ mgt niem mac d u d i tac dOng cua Irpng lupng nud'c. Ghi Igi khoi lupng n u d c de xdc dinh Iyc KDSH ciia vl§n thuoc. L y e KDSH linh cho 1 cm^ dien tich b^
mgl vien dup'c tinh theo cong thu-c:
F (N/cm^) = 0,00981 x — Trong do S la dipn lich be mgf vi§n (cm^) ducpc quet hinh anh v d xdc djnh bdng ph^n mem Image J 1.46.
Hinh 1 : Thiet bi danh gid li/c ket dinh sinh hoc che fgo tCr can Roben/al
Danh gia kha nang noi in - vitro Vign thuoc dup'c Iha vao coc chCpa 100 ml dung djch HCI 0,1 M. Thai gian l u khi IhO' din khi vien thu6c bat d i u n6i l§n tren be mgt moi t r u d n g dup'c linh la thdi gian tiem tang (tiag).
Tong Ihdi gian vien thuoc noi tren be mgt m6i trudng la thdi gian n6i (tna,),
Phwong phap thiet kS thi nghipm vi xd' 1^
so Ueu
Phan mem Modde 8.0 dup'c s u dyng de thilt ke thi nghi#m theo mo hinh mat hpp tii' lai tam rut gpn. Anh hudng cua cdc b i l n d i u vdo v^
cdng thiFC toi uu d u p c xac djnh d y a tren mgng than kinh nhdn tgo bang phan m^m INFonn 3.1.
So sdnh hai do thj GPDC:
/ 2 = 50 X
yH^'-
«100Trong 66:
f2.' Chi^ bleu hi6n cho sir giong nhau;
t: so th& tie diem lay m§u; n: s6 diim iiy miu;
Rl vi Tt: % ACV giai ph6ng t?i thai diem t cOa wSn doi chieu va vi4n bio che. Giii trj fz trong khoing ti/
50-100 thi hai do thf dugc coi la giong nhau.
Cac thi nghigm dup'c lap lai 3 l l n vd l l y kit qua trung binh.
K e t q u a v a b a n l u $ n
Khao sat p h u v n g phap bao che v i i n n^n ACV KDSH
Tien hanh bao ch6 vien nen 700 mg khdng chua dup'c chat v 6 i l u n g polymer KDSH (CP934P, CP940P, HPMC K100M, HPMC K4M,
12
TAP CHi D i r o c HOC - 09/2013 fS6 449 NAM 53)
• Nghien CIFU - Ky thuat
natri alginat) d t^ 1$ 20%, lactose 20%, magnesi stearat 2%, Aerosil 1 % , laic 1 % , Avicel vi>a du 100%. Cdc m l u vi§n d u p c bdo che song song bdng 2 p h u a n g phdp dgp t h i n g va tgo hat ucrt.
Vai phuang phap Igo hgt uat, cac ta d u p c dinh khan n u a c nhu isopropanol, ethanol tuyet doi d u g c chpn de nghien cuu. Tuy nhien, CP934P va CP940P cd the hoa tan trong cac td d u p c dinh ndy Idm bOl bet dinh va vdn cue do dd khdng xat iiat qua ray dupc. Natri alginat tgo d u p c hat nhung khdng chdc, sau khi sdy hat bj bd, khd lien ket. Cdc td d u a c HPMC K100IVI vd HPMC K4M tao d u p c hgi nhung vien nen bao che cd b^ mdlxCi xi, khdng nhan bdng. Khi ddnh gid khd ndng Irupng n d , vien ra nhanh chdng sau 10 phul vi vay kho cd the dap ung d u p c yeu cau giai phdng ACV keo ddi.
Vdl phuang phdp dap t h i n g , mac du Carbopol vd nalri alginnat d i hut am, dnh hud'ng den khd nang trpn chay cua khoi bpt kep, vien khdng bdng dgp, d§ bong mat, khd Bang 1 : Cdng thuc cua vien ACV bao chS v&i
dam bdo dp ben c a hpc nhung khi ket hpp vdi cdc Id d u a c ddp t h i n g HPMC K100M va 4M d ty lp thich hpp lai khdc phuc d u p c nhiing nhugc diem ke tren. Carbopol 934P cho vien cd kha nang KDSH va tnj'ang n d tot han cd. Kdt qua nghien ciru cho thdy viec s u dung hon hgp cdc polymer v d cdc fd d u g c dap t h i n g , tran chay d ty lp thich hpp cd the dam bao dp tran chay ciia khoi bdt kep khi dap Ihang, vien dong deu khoi lupng cd be mat nhdn bdng va dp ben ca hpc Idt.
TCF ket qua khao sat, phuang phdp dap Ihang dupc lya chpn de bao chd vien nen ACV KDSH.
Nghien cuu ket hap polymer KDSH Tren ca s d kdt qua nghien ciru muc khdo sdt phuang phap bao che, polymer KDSH gdm CP934P kel hgp vdi HPMC K100M, HPMC K4M d u p c chpn t i l p tuc nghien ciru. De khao sat sa bp ly lp polymer, cac m l u vien vdi cac thanh p h i n the hien trong bang 1 d u p c lien hanh bao che theo phuang phdp dap thang.
CP va HPMC CT vien
M1 y 2 M3 M4 M5
CP 934P (mg)
50 50 80 80 60
HPMC K100M (mg)
50 20 50 20
HPimC K4M (mg)
50
Lactose (mg)
100 100 100 100 100
Avicel (mg) 272 272 272 242 292
ACV (mg) 200 200 200 200 200
Ta du^ tron (mg)
28 28 28 28 28
TliM olnn IpliAt)
Hinh 2: Khd nSng trwang na cua cac miu vi&n theo thai gian
Hinh 3: /.(/c KDSH cua ciic miu vien b^o chS v&i luv^g polymer khic nhau
TAP CHI Dlf0C HQC - 09/2013 (S6 449 NAM S3)
— » - M s « M l - • - M a i l M 2 - • - M a i l M 3
— 1 — M a u M ?
80
^
.AO
SO -
60 - SO 1
30 -j
^° 1 ^ 10 j^T
'
2 1 6 S- ^ M a u M l - • - M i i i M 2 1 -*-MauM3
— M « i M 4
10 Hinh 4: Do thi giai phong di/ac chat theo thai gian cua cac miu vien
Kel qua the hien trong hinh 2-4 cho thay CP934P ket hgp vdi HPMC K100M cho vien cd khd ndng truang n d va KDSH tot han ( m l u M l ) so vdl HPMC K4M (mdu M2). Khi tang ty le CP934P, Iyc KDSH vd mirc do truang nd cua vien nen bao che tang theo nhung toe dp GPDC gidm xu6ng (mdu M4) Ket qua tuang t y cung xdy ra doi vdi HPMC K4M ( m l u M3 vd M4).
Chung to cd s y tuang quan Ihugn giua kha ndng truang n d , KSDH vd t u a n g quan nghjch vdi toe dp GPDC.
Nghien CLPU - Ky thuat
Tr§n ca s d kel qua thu d u g c , hdn hgp CP934P va HPMC K100M d u g c chpn de tiep tyc khao sdt va toi u u hda cdng thCrc vien nen ACV KDSH.
L i r a c h p n ta d u ^ c tao k h i
Oe dam bao chdc chan han kha nang ket
dinh luu gii> thu6c d' dg day, cac mau vifin n6n ACV 200 mg d u g c bdo che v d i ty le NaHCOa khac nhau, lactose 20%, magnesi stearat 2%, Aerosil 1 % , talc 1 % , Avicel v u a du 100%. Ddnh gia mpt so chi tieu chat l u g n g mau vidn bdo che, kel qua I h i hien trong bang 2 va hinh 5.
Bang 2: Mot s6 chi tieu chat luxyng cua cic miu vien bao che vol NaHCOs
m
M6 M7
NaHCOl (mg)
0 70 100
Kha ning noi t i „ (phijt) u (gia) 21,67±3,51 >12 13,33±4,28 >12
Lire KDSH (N/cm') 0,38±0,09 0,40±0,08 0,41±0,06
Afire do tnrong n& theo thoi gian (%) lOph 20ph
27,64 41,85 29,12 44,28 33,45 46,75
30ph 53,72 55,62 59,31
40ph 63,98 67,31 71,14
50ph 60ph 72,81 80,92 78,02 86,14 82,56 88,52 (Dau "-"bieu thi vten khong noi)
Hinh 5: Dd thi gial phong du^c chat theo thai gian ciJa cac miu vi§n
K i t qua cho I h l y NaHCOs ddng vai trd la ta d u g c Igo khi CO2 trong mdi Inpdng add giiip v\en n6i. Lugng NaHCOa tang Ihi mipc dp Iruang nd' va KDSH tang, kha nang GPDC giam nhung khdng dang ke. Nguyen nhan cd the do NaHCOa da trung hda lam lang dd nhdt cua CP934P.
Xay d y n g c o n g thii'c bdo che vidn nen ACV noi - ket d i n h s i n h hpc
Bang 3: Cac bien doc l$p
STT BiSn dgc lap G'^ fjf" Gioipan IVIwc
^ • ^ dwoi tren co- lyan Carbopd^934P ^ 3^, ^^
2 HPMC^KIOOM - - — Natri
hydrocarbonat (mg)
Bang 4: Cac bien phg thugc
Bien phu thugc Ky hipu Yeu cau Phan tram acyclovir giai
phdng sau 1'' (%) 15-25
Phin tram acyclovir giai phdng sau 2'' (%)
Bien phu thupc Phan tram acyclovir giSi phong sau 4'' (%) Phan tram acyclovir giai phong sau 6^ (%) Phan tram acyclovir giai phdng sau 8^ (%) Lye KDSH (N/cm')
Ky hieu Y4 Ye Vs KDSH
yeu ciu 4 5 - 6 0 6 5 - 8 0
>85
>0,30 Cac thdng so giO co 6\nh bao gom: Acyclovir 200 mg; lactose: 100 mg; magnesi stearat 14 mg; Aerosil 7 mg; laic 7 mg; khoi lupng vign:
700 mg; Iyc gdy vd' vien: 11 - 13 kp.
Bang 5: Bang thiet ke thi nghiem va khi nSng noi ciJa cac miu vien
CT CTI CT2 CT3 CT4 CT5 CT6 CT7 CTS CT9 CTIO C T I I CTI 2 CTI 3 CTI 4 CTI 5 CTI 6 CTI 7
HPMC K100M (mg)
10 10 40 40 10 10 40 40 25 25 10 40 25 25 25 25 25
CP934P (mg)
50 90 50 90 50 90 50 90 50 90 70 70 70 70 70 70 70
NaHCO, (mg)
85 85 85 85 115 115 115 115 100 100 100 100 85 115 100 100 100 (Dau "-"bieu ihi vi§n khdng ndi)
Kha nang n6l
tlag tnSi
(phiit) (gitiL 15 22
-
10
.
40 18 17 43 28 35 30 25 27 25 29
>12
>12
>12
>12
>12
>12
>12
>12
>12
>12
>12
>12
> 1 2 ,
>J2j
A
TAP CHI Diroc HOC - 09/2013 (SO 449 NAM 53)
» Nghien ci>u - Ky thuat
Xi> ly cac s6 lipu thu d u g c bang p h i n mem INForm 3.1 d l xdc djnh anh h u d n g cua bien dOc l$p Id'i cdc bien phg fhuOc. Ket qud thu dugc nhu sau;
C P 9 3 4 P " oo , , , ™ ( ™ B )
Hinh 6: Anh hir&ng cua Carbopol 934P va natri hydrocarbonat t&i Yg (Khoi luvmg HPMC KWOMIa 10 mg)
H P M C K I O O M (rag)
Hinh 7: Anh hwang cua CP934P va HPMC K100Mt&iYe(Kh6Uux?ngNaHCO3la 115mg)
TSng ly lp CP934P, HPMC K100M Ihi l6c dO GPDC gidm ddng ke. Do hai polymer cd dp n h d i cao, tnrang nir mgnh tgo ra I6p hdng rdo gel bao xung quanh be mgt vien k h i l n cdc kenh d i n bj bit kin, hgn c h l s y t h i m cOa mdi tnj'd'ng vao vidn khd ndng hod tan vd khuedi tdn d u g c chat ra ngodi d i | m . Trong phgm vi khdo sat, mirc dp dnh hudng cOa HPMC K100M tdi khd nang GPDC n h i l u han so vdi CP934P. Tdng NaHCOs cung Idm gidm l6c dd gidi phdng d u g c ehll, tuy nhiSn mi>c dO dnh hirdng il han cdc potymer(hinh6,7).
Cdc m l u vidn bdo c h l deu cd Iyc KDSH t6l.
Tdng lugng CP934P thi kha nang KDSH tdng rd r$t, d$c bi$t khi t^ 1$ CP934P trong vien t h i p . Khi lugng CP934P tdng cao thi Iyc KDSH tdng ch$m Igi cd I h l do Idp gel hinh Ihdnh d vung nfing dO bdo hda. CP934P cd dnh hudng chu y i u a I n Kfc KDSH (hinh 8,9).
TAP CHi DlTQC H p c - 09/2013 (S6 449 NAM 53)
L i ^ K D S M <N'
Hinh 8: Anh hud'ng cue Carbopol 934P va NaHCOl t&i Iwc KDSH (Khoi lwang HPMC K100M la 25 mg)
Luc KDSH OJ/(
HPMCKIOOM
Hinh 9: Anh hwdng cua Carbopol 934P vi HPMC K100M t&i Igv KDSH (Khdi lux^g NaHCOa li 100 mg)
Toi u u hda cdng thuc bdng p h i n m i m INForm 3,1 va I i l n hdnh bdo c h l 3 md, mS md 100 vien n^n theo cdng thirc t l i uu. Sau dd ddnh gid khd ndng GPDC, KDSH vd ndi. K i t qud nhu sau:
Hinh 10: Do thi GPDC cua mau vien bao che theo cong thirc toi wu va dw doan
Hinh 1 1 : Kha nSng noi cua viin n^n bio chS (A: 0 gi&. B: Sau 30 phut: C:Sau 12 gid)
• Nghien cu'u - Ky thuat
Vien nen ACV bao che theo cdng thu'c tdi u u CO kha nang GPDC keo dai giong vdi md hinh d y dodn, sau 8 gid gidi phdng > 85% d u g c c h i t .
L y e KDSH =0,41± 0,05 N / c m l
Kha nang noi: tag =25 ± 2,82 phut, ^>^2 gid.
Kit luan
Viec ket hgp Carbopol 934P, HPMC K100M va NaHCOs giiip k i l m scat qud trinh GPDC tdt han, ddng thdi vien bao c h l cd Iyc KDSH cao, thdi gian noi keo dai.
Da xay dyng d u g c cdng thiPC bao che vien nen ACV 200 mg noi - KDSH niem mgc da day vd giai phdng keo dai 12 gid. Tuy nhien, de khang djnh chdc chdn k i t qua Ihu d u g c c i n tiep tuc t h y c hi#n cdc nghien ciru in vivo.
T a i l i e u t h a m k h a o 1. Bhosale U. V„ Kusum Devi V. (2011),
"Formulation and optimization of mucoadhesive nano drug delivery system of acyclovir". Int J. Cur Biomed.
P/jarm. Res., 1(3), pp. 113-121.
2. Dhaliwal S., Jam S et al. (2008),
"Ivlucoadhesive microspheres for gastroretentlve
delivery of acyclovir In vitro and in vivo evaluation".
AAPS J. 10(2), pp. 322-330.
3. Dias R, Sakhare 8. et al (2010), "/n-vffro absorption studies of mucoadhesive tablets of acydovir", Indian J. Pharm. Educ. Res., 44(2), pp. 183 -188.
4. Panigrahy R. N. , Mahale A. M. (2011).
"Fonnulation and in-vitro evaluation of bioadhesive controlled acyclovir matrix tablet". Inter. J. pharm.
/nnov.,1(2), pp. 2 8 - 4 0 .
5. Shadab M. D., Alka Ahuja A. ef al. (2011),
"Acyclovir-loaded chilosan microspheres for gastroretention: Development and evaluation", J.
Disper. Sci. Tech., 32, pp. 1318-1324,.
6. Shaikh R., Raj Singh T. R. e( a/. (2011),
"Mucoadhesive drug delivery systems", J. Pharm.
Bballied Sci., 3(1), pp. 89-100.
7. Sweetman 8. C. ef al. (2009), Martindale 36.
Pharmaceutical Press, pp. 862-864, 911.
8 Tavakoli N.. Varshosaz J. et al. (2012).
"Development and evaluation of a monolithic floating drug delivery system for acyclovir". Chem. Pharm.
eu//..60(2), p. 172-177.
9. Yadav S., Jain S ef al (2011), "Fonnulation and in vitro and In vivo characterization of acydovir loaded mucoadhesive microspheres". J. Pharm. Sci.
Tech. Z(^), pp. 44^-447.
r
Nghien cu'u bao che
pellet gliclazid giai phong keo dai
Nguyen Hanh Thuy*, Nguyen Ngoc Chiln Truang Dgi hgc Dugc Hd Ngi E-mail, [email protected]
S u m m a r yGliclazide pellets were prepared by extrusion-spheronization using manitol, potassium chloride and alkaline excipients to enhance the dissolution of gliclazid from the pellets. Then, pellets were coated with methylmethacrylate polymers to control the drug release. The relationship between independent factors (including type of polymers, ratio of talcum, DBP, weight gain of coating membrance) and response factors (percentage of drug release at 2hr, 4hr and 6hr) was analyzed and optimized by FormRules and InForm softwares. The obtained pellets were able to sustain the drug release up to 8 hours, and in addition, the dissolution profile of optimal formulation was similar to that of the reference product (Diamcron MR 30mg).
Keywords: Pellet, gliclazid, enhance the dissolution, controlled-release, Eudragit RS. Eudrag'tt RL.
D a t v a n d i dung d ca 2 dgng bao c h l gidi phdng nggy vd Gliclazid la mpt sulfonyl ure it lan va cd dp giai^phdng keo ddi, chu yeu la vi&n ndn'''Wd vi tan phu thupc vao pH cua mdi Irudng^^'^', d u p c ^at^^l Pellet la m p l trong cdc dgng bao che hi^n
16
