• Nghien CIPU - Ky thuat
Hinh 3: Anh hucmg cua noveon AAI din md hinh giii phdng cOa RBM tir vien luu tai dg day;
*) F-NH-4 (10 mg Noveon); m) F-NH-5 (20 mg Noveon); A) F-NH-6 (30 mg Noveon) (n=3, trung binh ± d0 l$ch chuin)
Anh hudng cua lugng noveon tdi mo hinh gidi phdng eua RBM dup'c t h i hign trong hinh 3.
COng thdc s d dyng 10 mg Noveon (F-NH-4) eb xu hudng t h i m nude vdo nhan nhanh hen cdng thdc s d dyng 20,30 mg Noveon (F-NH-5,6) do dd e6 md hinh gidi phbng RBM nhanh hen. RBM gidi phbng theo mo hinh Korsmeyer Pappas t d cdng thdc F-NH-4, vd Weibull t d edng thde F-NH-5, 6.
Nhin ehung md hinh gidi phdng RBM t u vien luu tgi dg ddy s d dyng noveon cd 3 giai dogn. gidi phbng t i l m tdng khodng 1 gid d i u , gidi phbng theo c c e h l an mbn vd bdc 0 t u gid 1 - 8, nhung gid edn Igi d u y e e h l t gidi phdng khfing k i l m sodt do c l u tnJc vien dd bj phd ve.
Ket luan
D l tdi da phdt t r i l n thanh edng dgng vien luu tgi da day mdi ehua rebamipid b i n g each k i t hgp c c c h i noi vd k i t dinh sinh hpc. Hau h i t cdc vidn ddu n l i trong vong 8 gid, va co thdi gian n l i t i l m tang nho hen 20 phut. C c che noi Id ti trgng vien < 1 g/cm^ va s y tham nude han c h i cDa polymer. Vidn bao e h l cd thdi gian bdm dinh toi da khodng 1 gid tren be mat da ddy tho.
RBM gidi phong t d ede vien d i u theo mb hinh an mon vd keo ddi trong khoang 12 gid. Vien iuu tai dg day ed kha nang luu tru lau trong p h i n dau dudng tieu hoa, vd co tiem nang ung dyng cho mpt s l chat cdn duy tri tac dung tai cho hay cdc chat t h i m cao d dg day ta trang nhu acyclovir, metformin, elarithromyein.
Tai lieu tham khao 1. Arakawa T, Htguchi K., Fujiwara Y, Watanabe T, Tominaga K., Sasaki E., Oshitani N., Yoshikawa T.. Tamawski A. S. (2005), "15th anniversary of rebamiplde: Looking ahead to the new mechanisms and new applications", Digestive Diseases and Sciences, pp5.
2. Nagarwal R. C. Ridhurkar D N., Pandit J K.
(2010), 'In vitro release kinetics and bioavailability of gastroretentive cinnanzine hydrochloride tablet", AAPS PharmSciTech. 11, pp 294-303.
3. Tadros M. I. (2010). "Controlled-release effen/escent floating matnx tablets of ciprofloxacin hydrochlonde: Development, optimization and in vitro - in vivo evaluation in healthy human volunteers", European Joumal of Pharmaceutics and Biopharmaceutics. 74, pp 332-339
4. Grabovac V., Guggi D., Bemkop-Schnurch A.
(2005), "Comparison of the mucoadhesive properties of various polymers". Advanced Drug Delivery Reviews, 57. pp 1713-1723.
Nghien cihi bao che vi nang glipizid giai phong Iceo dai bling phu'ong phap dong tu
Nguyen Ng^c Chiln', Nguyen Thj Tbuy Trang
Truang Dai hpc Dupc Ha Npi*E-mail: nguyenngocchien(u,yahoo.com
Summary
The microencapsules of glipizide were made by coacervation-phase separation The suspension consisting of sodium alginate as coating material, glipizide as core material and Aerosil were prepared
T^P CHi DlTpC H p c - 1/2014 {S6 453 NAM 54)
• Nghien CIPU - Ky thuat
by constant agitation with a magnetic mixer at 400-600 rpm for 1.0 hours. The resulting suspension was injected into 10.0% calcium chloride solution by peristaltic pump system, via a nozzle needle of size 25.
The prepared microcapsules were cured in the calcium chloride solution for 60 minutes, then dried at room temperature for 12 hours, followed by drying at 50°C for 3-4 hours. The resulted microcapsules were spherical with a smooth surface, and the drug release was up to 7 hours.
Keywords: Microencapsules, glipizide, a method of coacervation-phase separation, sodium alginate, calcium chloride.
D a t v a n d e
Vi nang Id dang bdo c h i eo n h i l u u u diem so vdi vien nen, dac bigt vi nang giai phong d u e c e h l t keo dai d u c c bao e h l vdi polyme t y nhien do CO kha nang k i t dinh niem mac, Idm tang thci gian luu cua d u c c c h i t trong d u d n g tieu hoa, ddn d i n Idm tang sinh kha dung cua nhieu d u e e e h l t . Chinh vi vgy, d l tai nay d u c c t h y c hien vdi mue tieu ddnh gia d u e c dnh hudng mgt s l y l u to v l cdng thue va thong so quy trinh d i n cac chi tieu chat lueng chinh cua vi nang glipizid.
N g u y e n l i e u , t h i e t b j v a p h u ' o n g p h a p n g h i e n CLPU
Nguyen lieu
Glipizid (GL), natri alginat (Al), Aerosil. dat tieu ehuan dug'c dung; cdc hda e h l t khdc: dat tieu chuan phan tieh.
T h i l t bj n g h i e n c u u
May khuay t d IKA RH Basic, b c m nhu dgng Ismatee Eeoline VC 380, kinh h i l n vi dien t u quet FESEM Hitachi S-4800, may t h u do hoa tan ERWEKA DT 60, may do quang p h i UV- VIS Hitachi U-1900, tu say Memmert, edn xac dinh ham am nhanh Preeisa XM 60, mdy sieu dm Ultrasonic LC 60H, may iy tam Hermie Laborteehnik GmbH Z326K, can phdn tich Sartorius TE 241S.
P h u c n g phap bao c h i v i nang glipizid Vl nang glipizid d u e c bao c h i theo p h u c n g phap dong ty hoa muoi. Hdn dieh natri alginat g i m : natri alginat, Aerosil (0,8% so vdi tong e h l t ran) d u e c ngam trong nude khoang 1 gid. Sau db k h u l y t u hoa tan natri alginat, p h i i hep v c i bpt glipizid (dd qua ray 125) theo phueng phap tao hon dich, k h u l y t u 1 g i d d l d i n g n h i t . Lpc hon djeh qua rdy 125. Bern nho gigt h i n djch thu d u e e qua kim tiem s l 25 vdo dung djch calei elorid (4-10%) d l tao vi nang d toe dp 35-45 gipt/
phut. Moi trudng ealei elorid (moi trudng dong
tu) d u g e khuay t u khoang 400-600 vong/phOt. D vi nang tao thanh trong dung djch calei ciorid 60 phOt. Gan ldy vi nang, rua bang nude elt. D l khS vi nang d nhigt do phong trong 12 gid. S l y vi nang bang tu say c 50°C va ray l l y vi nang e6 kich t h u d c 710 - 800 pm.
Phu'O'ng p h d p d a n h gia c h i t i e u chat lug'ng v i n a n g
Hinh dang va kich thwdv
Quan sdt hinh dgng, b l mat vi nang glipizid bang kinh h i l n vl dien t u quet (SEM).
Djnh Iwgng ham Iwoftg glipizid T i l n hanh bang phueng phap do dp h i p thu t u ngoai e bude sdng 223 nm, nong dd khodng 10 pg/ml, dung moi la dem phosphat pH 7,4. Djch t h u d u e e ly tdm d 5000 vong/phut trong 5 phOt, sau do ipc qua mang Ige 0,45 pm.
Hieu suit vi nang hoa (HSVN encapsulation efficiency)
Phdn tram lueng glipizid trong vi nang so vdi t i n g l u c n g glipizid s d dung.
Thw do hda tan
T h i l t bi canh khuay, toe dd khuly: 50 ± 1 vong/phut, nhidt do: 37 ± 0,5"C. Moi tnTdng: 900 ml dung djeh dgm phosphat pH 7,4. Sau nhung khoang thdi gian djnh trudc, hut m l u , Ipc qua giay Ipc 0,45 pm va do quang pho hap thy 6 b u d c sdng 223 nm, so sanh vdi mSu e h u l n . Cdc k i t qua d u e e b i l u thj d u d i dang gtd tri tmng binh (n = 3, ± SD). T i l n hanh vdi k h l i lugng vi nang t u c n g dng 10 mg glipizid.
K i t q u a v a b a n l u a n
Ket q u a k h a o sat a n h h u ^ n g c u a cdc thdnh p h a n c d n g thiFC b a o c h e
D l khao sdt dnh h u d n g eua cdc yeu t l cfing thuc, t i l n hdnh bdo e h l vi nang glipizid theo cdc cong thue (CT) d bang 1.
T^P CHI DirpC HQC - 1/2014 (S6 453 NAM 54)
• Nghien ciru - Ky thugt
Bdng 1 ; t^ng thuc vi m^t
CT 1 2 3 5 6 7 8 9 11 12 13 14 15 16
Tyli Al: DC
1 : 1 2 : 1 5 ' 1 9 : 1 9 : 1
9 : 1 9 : 1 9 : 1 5 : 1
N6nB <r$
alginat
2.5%
2%
3%
3.5%
4%
4%
3%
3.5%
SO ket quA bio che Dung moi
sirdiJng
Nui/c
Nipdc
Nu'dc Dem D#m Nuac 0#m
vi nang glipizid (ca mSu 3,3 g N6ng do
calei ciorid
10%
10%
10%
6%
4%
10%
10%
10%
Ham loang DC
(•/,)
chat rSn) Hieu suit vi nang hoa
(%)
Khong thLTC hien din^c 16.27 59,25 7.96 60.51 4.47 63.89 4.43
5.55 5.57 5.80 5.58 5.26 6.56 6.05 10.46 11.41
60.23 68.38 67.13 68,44 65.79 62.13 77.51 75.02 75.35 82.16 ChO thich: D$m = dung djch dpm phosphat pH 7,4; DC = dupc chit; Al = alginat
Bdng 1 eho t h i y khi ty lg alginat:DC tang t d 2:1 (CT2) d i n 9:1 (CT5). HSVN tang. Khi ty le DC qud eao (CT1), sau 1 gid khuly, h i n djch con vdng dye ehua d i n g n h i t , ndn khfing t i l n hdnh ddnh gid t i l p . Khi n i n g d | alginat trong dung djeh tdng t u 2% (CT6) d i n 2,5% (CT5) vd 3% (CT7), HSVN hda tdng d i n , nhung t i l p tgc tdng n i n g dfi alginat d i n 3,5% (CT8) vd 4 % (CT9), HSVN thay
d l i khong y nghTa. Tucng t y nhu vgy khi tdng n i n g d | calei ciorid t u 4 % (CT12) len 6% (CT11) vd 10% (CT9) thi HSVN hoa tdng. HSVN hda tang mgnh d ede CT s u dyng dgm phosphat pH 7,4 Idm dung moi hda tan alginat khi so sdnh vdi cde CT s d dyng nude d eCing dieu kign (so sdnh CT 15 va 16; 9 va 13, CT7 vd CT14, bdng 1). Do vgy, ddm pH 7,4 dugc lya chgn d l nghidn edu t i l p .
...
1"
1"
1 «a
0 1
A ^f - * - i m IMlirHI J%|
/ i » ' -^CTB (llglrut J.Sitl
l^^ -•-CT9UI|l'Ut4K)
1 Z 3 4 5 6 7 S
TMFlElinlh) Hinh 1 : Di thi di? hda tan DC tir vi nang
glipizid cd ty 1$ AI:DC khdc nhau
Vi nang thu d u g c t u t i t cd cdc cdng thuc trdn t u c n g d l i c l u d i u , ngogi t r d CT6 (nong dp alginat trong dung djch = 2%) va cdc cdng thue t h u nghidm khdc cd n i n g dfi alginat nho hon 2%, vl nang b| xgp sau khi s l y Khi n i n g d | alginat £ 4 % , dO nhdt dung djch alginat eao, gdy khd khdn cho qud trinh nhd gigt, vi nang bj kdo dufii, khfing
clu diu.
Hinh 2: Do thi dg hda tan DC tir vl nang glipizid cd ndng dg alginat khac nhau
Dg hda tan eOa dugc chat bj anh hudng bdi ty Id alginat:DC vd nong dp alginat trong dung djeh. Khi ty lg alginat:DC tdng t u 2:1 d i n 9:1 (hinh 1) h o l e n i n g dg alginat trong dung djeh tang t u 2 d i n 4 % (hinh 2) thi khd ndng gidi phdng DC gidm. K i t qud ndy cung phiJ hgp vdi nghidn cdu eua Yaswanth Allamneni >^i. N i n g d | calei ciorid (4, 6 vd 10%, hinh 3) vd dung mdi hda tan alginat
T ^ CHi DU'OC HQC - 1/2014 (S6 453 NAM 54)
• Nghien CLFU - Ky thuat
it anh hudng ddn s y giai phong glipizid t u vi nang (hinh 4). Trong cac cong thue tren, CT6 co kha nang kdo dai giai phdng DC kem nhdt (sau 2 gid
hoa tan 95,05% DC), CT9 d i o kha nang kiem soat giai phdng DC eao n h i t (sau 7 gid hoa tan 96,28%
DC). CT9 phu hep cho giai phdng DC keo dai.
I M
1 M J ""
.
^//y ^ ^ -•-CT14{aem) U ^ Jf -•-CT7(iliTOC|
/ J ^ * ^ ' -ft-CT13{aem) a^^ -&-CT16{aem)
^ ^ -*-CT15(nuw:)
' .«J.,.,
«
Hinh 3: Do thi do hda tan DC tu vi nang glipizid su dung ndng do CaCI^ khac nhau
Be thu d u e c HSVN hoa eao, thdi gian giai phbng DC keo dai, va thuan lei eho qua trinh bao c h i , cong thdc cd ty le alginat: DC= 9 ' 1 , n i n g dp alginat trong dung djch la 4 % , n i n g dp calei ciorid bdng 10% va dem phosphat 7,4 lam dung mdi hoa tan alginat d u e c lya ehon d l khao sat t i l p (CT22).
Bang 2: Cdngf thuv va kit qua bao che vi nang GL cd thdng s6 quy trinh khac nhau
Hinh 4: Dd thi do hoa tan DC tir vi nang glipizid su dung dung mdi khac nhau
Kit qua Ithao sat anh h u d n g cua cdc thdng s l quy trinh
Cong thue bao e h l vi nang giipizid e bang 2 dung de khao sat anh h u d n g cua cae thong so q u y t r i n h .
CT 22 22b 22c 22d 20a 20b 20c 20cl 21a 21b 21c
CT vl nang CT22 CT22 CT22 CT22 CT9 CT9 CT9 CT9 CT9 CT9 CT9
Nhiet do 30°C 30»C 30»C SO'C SO'C 30»C 30»C 30"C 10°C 30"C 40''C
Toe do khuay Mirca Md'c 3 Mi>c3 Miic3 Mljc 0 Ml>c2 MLi'c3 y u ' c 4 MircS Mi>c3 Mi>c3
Thai gian u 60 phut 30 phut 15 phut Ophut 60 phut 60 phut 60 phut 60 phut 60 phut 60 phut 60 phiit
Hiiu suat vi nang hoa 74,44 76.25 75.44 75.45 64,05 66,58 66,85 Khong tinh
70.68 68.44 60,85
Hinh thiec Cau. deu Cau. deu Cau. fleu ,?
Tu'ong doi cau ' Khdng deu
Cau, d i u Cau, deu •' Vi nang l<h6ng thanh Vi nang dinh nhau
C l u . deu C l u , d i u Chil thich: Mire 0 ~ tdc do khuay 0 vong/phut, mire 2: •
mire 4. -800 - 1000 vong/phut
K i t qua d bang 2 cho t h i y thdi gian Ci t u 15 den 60 phut khong anh h u d n g den HSVN hoa hay hinh dang vi nang. Khi khong u (CT22d), vi nang tao ra co do e l u kem. K i t qua thu d u c e cung phu hep vdi k i t qua nghien c u u cua Polona Smrdei ciing cpng sy^^. N g u e c lai, t i e do k h u l y trong moi trudng dong tu anh h u d n g mgnh den dg e l u va HSVN hoa. Khi khong k h u l y (CT20a), hat calei alginat tao ra noi tren b l mgt moi t r u d n g
-100 - 200 vdng/phut, mire 3: -400 - 600 vong/philt,
dong tu, sau mpt thci gian chim xuong day Khi tang t i c dp k h u l y len m d c 2 va m d c 3, eae hat ealei alginat lien tue dugc k h u l y trfin tao dilu kien cho ion Ca^* xdm nhap vdo mang ludi lidn k i t , ddn den HSVN hoa tang va vi nang cau diu h e n . Khi t i e do khuay qua eao (mue 4), vi nang khong d u e c tao thdnh do moi t r u d n g b| khuly trgn manh, gay ddng xoay Idn cuon va hoa tan cac thanh p h i n cOa vi nang.
T^P CHI DirqC HQC - 1/2014 (S6 453 NAM 54)j
Nghien ciru - Ky thuat
Khi tdng nhidt dp eua moi trudng dong ty, HSVN hoa gidm nhung nhiet do moi trucng t h i p qud (CT21a), vi nang ktiong eau, bj keo dufii vd dinh vdi nhau. Dya vdo cdc k i t qua trdn, cae ttiong s l phueng phdp d u e c lya chgn la: Nhiet dg mdi trudng ddng ty 30°C, ttidi gian u 60 phut vd t i c do k h u l y frong moi tn/dng dfing tu d muc 3.
Ket qua khao sat dnh h u v n g cua A e r o s i l den h i n h d a n g cua v i nang glipizid
Tien hdnh bao che cde vi nang theo CT22 vdi eae thong so da lya chgn, chf thay d l i ty le Aerosil t u 0 d i n 1 % . K i t qua chup SEM b l mat vi nang d u c c the hien e hinh 5.
Hinh 5c: Miu vl nang 0,8%Aerosil Hinh 5d: Mau vi nang 1% Aerosil Hinh 5: Anh chi^p SEM cua cdc miu vi nang glipizid cd ty /g Aerosil khdc nhau Khi khfing s d dyng Aerosil, vi nang glipizid
thu d u g c sau khi s l y khd meo, be mgt cd n h i l u l6 x i p , kich thudc khfing dong n h i t . eo n h i l u vi nang dinh nhau. Vdi ty lg Aerosil 0,5%, dg c l u cOa vJ nang da d u g c cdi thidn, tuy nhien n h i l u vi nang cd hinh dgng chua c l u d i u Khi s u dyng Aerosil d ty 1$ 0,8% vd 1 % thi thu d u g c vi nang c l u , d i u . Tuy vdy khi ty 1$ Aerosil = 1 % , h i n djeh ed dO nhdt cao gdy khb khdn cho qud trinh e l t gigt tgo vi nang. Vi v$y fr? Id Aerosil 0,8% Id phu hgp.
B a n l u a n
Tren t h i gidi da co mgt s l nghidn euu bao e h l vi nang glipizid bdng phucng phdp dong ty hoa m u l l s d dung alginat mgt minh hodc p h i i hgp vdi cac polyme k i t dinh sinh hpc khdc. Yaswanth Allamneni chi ra vdi nong dg alginat 5% thu d u g c VI nang glipizid HSVN cao, k i l m sodt gidi phdng DC d i n 8 gid '^'. Tuy nhien, trong nghidn cdu ndy khi nong dg alginat trdn 4 % thi r l t khd nhd gigt hon djch DC vd alginat. Cde nghidn cuu
TAP CHi DlTQC HQC - 1/2014 (S6 453 NAM 54)
• Nghien ciru - Ky thuat
khae eho t h i y khi p h l l hgp alginat vdi Carbopol 934P 1^, Carbopol 974P '^i, polycarbophil'"' hoac gom Kondagogu '^', eho vi nang cd kha nang giai phfing DC keo dai va tinh bdm dinh tot. Ngodi phuong phap dong tu hda muoi, Sai Krishna Putta vd cgng s y (cs) cdn dung phueng phap gel hda nhu t u c n g de bao e h l vi nang glipizid. 0 phuong phap nay tac gia nho hfin dich cua DC trong dung djeh alginat va gom Kondagogu vao dung djch ddu parafin trong d i l u kien k h u l y trgn n h l m tgo eae gigt nhu hba, sau do nho mgt lugng dung djch CaCI^ vao va eung t i l p tue k h u l y trfin lien tuc trong 15 phut d l tao thanh cac vi nang ^^.
Ngoai aiginat, Kavitha Chindanooru vd cs nghien cdu bdo c h i vi e l u bam dinh glipizid s u dung \ovj methoxyl pectin (LMP) vd cdc poiyme khdc (HPMC K15, gom guar, gom karaya) vdi tae nhdn tao lien ket chdo id calei ciorid. Nghidn c d u chung minh viec k i t hep giua LMP vd gom guar eho HSVN eao, t r u c n g ne tot, giai phong keo dai, bdm dinh tot i^'.
K i t luan
Da nghien euu d u g c anh h u d n g cua cac yeu to eong thuc va quy trinh d i n higu s u i t vi nang hoa va dp hoa tan glipizid t u vi nang bao c h i bdng p h u c n g phap dong tu hoa m u l i . Cdng thue d u c c lya ehpn eo hieu s u i t vi nang
hda trdn 7 5 % va keo dai giai phong d u c c chit tren 7 g i d .
Tai lieu tham khao 1. Allamneni Y. et al. (2012), "Perfomiance evaluation of mucoadhesive potential of sodium alginate on microspheres containing an anti-diabetic dmg: Glipizide", IntemationalJournal of Pharmaceutical Sciences and Dmg Research. 4(2), pp. 115-122.
2. Chowdary K. P. R., Rao Y. S. (2003), "Design and in vitro and in vivo evaluation of mucoadhesive microcapsules of glipizide for oral controlled release:
a technical note", AAPS PharmSciTech, 4(3), pp. 1-6.
3. Gajanan S. et al. (2009), "Formulation and evaluation of mucoadhesive beads of glipizide using 2^ factorial design", Joumal of Pharmacy Research, 2(5), pp. 934-938.
4.HosmaniA.H etal (2009), "Study of formulation variables on properties of glipizide mucoadhesive microspheres by factorial design", DARU, 17(4), pp.
236-244.
5. Kavitha C , Rajendra A. (2012), "IVlucoadhesive multiparticulate drug delivery systems for antidiabetic drug glipizide: effect of formulation variables on drug release", Journal of Pharmacy Research, 5(5), pp.
2883-2887.
6. Putta S. K. et al. (2010), "Formulation and m vitro evaluation of mucoadhesive microcapsules of glipizide with gum kondagogu". Journal of Chemical and Pharmaceutical Research, 2(5), pp. 356-364.
7. Smrdei P. etal. (2008), "The influence of selected parameters on the size and shape of alginate beads prepared by ionotropic gelation", Sci. Pharm., 76, pp.
77-89.
r
Tac dung ciia phan doan chiet than y di tren chuot tang glucose huyet thwc nghiem
boi streptozocin
Phung Thanh Hmrag'*, Nguyen Thi Dong^
' Truang Dgi hpc Du(rc Ha Npi
^ Truang Cao dang Dupc Trung uang Hai Duang ' E-mail: i
Summary
As the ethanol stem extracts of Coix tachryma-jobi exhibited hypoglycemic effects in mice, of which the chloroform fractions were the most potent, in this study, the chloroform fractions were tested on streptozocin (STZ) injected mice. The fractions exerted hypoglycemic effects same as the reference drug metformin on hyperglycemic mice induced by both doses of STZ. Meanwhile, the standard
TAP CHi DlTQC HQC - 1/2014 (S6 453 NAM 5
