• Nghien ciru - Ky thuat
Nghien cihi xay dmig cong thirc vien nen giai phong keo dai chu*a acid valproic va natri valproat
Phung Ch§tS Huynh Thanh Phong' Trtf<mg Phan Ngoc My^ Le Hau^'
' Cong ly Co phdn Duac Danapha
^ Dai hoc YDuac Thanh phd Ho ChiMinh
* E-mail: [email protected]
Summary
Formulation of hydrophilic matrix tablets containing valproic acid and sodium valproate was established. Aerosil was found to be an effective ingredient to produce a dry mixture with acid valproic (in liquid form). Experimental findings proved that mixture of hydrophilic polymers could sustain the release of drugs up to 12 hours. The dissolution proves of the resultant tablets were similar to those of Depakine Chrono 500 (Sanofi-Aventis) with similarity factor (f^ of 79.6.
Keywords: Valproic acid, sodium valproate, hydrophilic matnx.
Dat v i n de
Acid valproic (AV) va natri valproat (NV) la thuoc d i u tay trj bgnh dgng kinh toan the va co giOf^i. T h u l c cd khoSng n i n g dd trj lidu hgp, t u 50-100 \iglrr\\ h u y l t t u a n g . thdi gian ban thai t u a n g doi n g i n , cd t h i gay ra cdc tdc di^ng phg trdn gan, hd tidu hda vd mgt so c a quan khac eua c a t h i do s y dao dOng cilia n i n g dd t h u l c trong mdu. AV vd NV d u g c dung pho b i l n d u d i dgng vidn bao tan trong ruOt vd vidn gidi phdng kdo ddi (GPKD). Vidn GPKD eho higu qua dieu trj I n dinh, (t tdc dyng phy. liOu trinh dan gidn (1-2 lln/ngdy)'^'. Dgng vidn GPKD p h i i hgp AV va NV da dug'c nghidn edu bdi mgt s l tdc gid tren the g i d i i ' * ' . € ) l tdi d u g c thyc hiOn n h l m xdy dyng cdng thuc bdo c h i vidn nen GPKD va danh gia dnh hudng ciia cdc y l u to cdng thue d i n dd giai phdng AV vd NV t u vidn.
N g u y S n l i $ u v a p h v c n g p h a p n g h i e n c i j u
Nguyen li$u, thiet bj nghien c(ru Nguyen ll^u
Acid valproic (Id VA/12/002, India, dgt tidu e h u l n USP); natri valproat (Id SV/12/045, India), Aerosil 200, dicalci phosphat dlhydrat (Calipharm D). microcrystalline cellulose 102, povidon K30, lactose, acid stearic, talc, magnesi stearat. eae polymer tgo khung (HPMC K 15M, HPMC 615;
PEG 6000).
77j/e(b/
May trdn sidu toe (HLSG 10P, cdng s u i t 1-5 kg/me); may trgn Igp phuang (cdng s u i t 1 - 5 kg/me); may do dg cung vien (Copley TBF 1000);
mdy do do mai mdn (Copley FR1000); may thu dg hda tan (Hanson Research); may sdc ky long higu nang cao (SKLHNC) (Ultimate 3000 -Dionex).
Phuang phap bao che vien GPKD Aerorsil va NV d u g c trgn d i u va xay mjn. ray qua ray 0,8 mm; them AV, trgn deu. say khd, xay mjn; 1dm I m va tgo hgt hon hgp tren vdi polymer tgo khung, dicalci phosphat dihydrat bdng dung djch polyvinyl pyrrolidon (PVP) K30 15 % trong isopropanol; sua hgt qua ray 1,2 mm, say den dO am S 1,5 %; thdm hon hgp magnesi stearat-talc, trdn d i u va nen thanh vidn cd khoi lugng trung binh 700 mg, lye gay v d vien tnjng binh 140 + 10 Newton. Cac thdng so khao sat gom logi vd tl 10 cdc polymer dung tao khung kiem scat giai phdng d u g c chat (GPDC).
PhiFcng phap danh gia cac thong s o ky thuat cua vien nhan
Phu-ong phap danh gia do cung Do dO cung ridng biOt 20 vien trdn may do dd cdng, tinh do cung trung binh va dg Igch e h u l n .
Phuvng phap danh gia dg mai mon Cdn 10 vidn b i t ky (da d u g c 1am sgch bgi trude dd) cho vdo t r l n g quay cua may t h u dO mai mdn, vOn hdnh mdy trong 4 phut vdi t i c dO quay 20 vdng/phut. Sau dd vien d u g c l l y ra, Idm
T^P CHi DirpC HQC - 2/2014 (S6 454 NAM 54)
• Nghien CIJU - Ky thuat
sgch bui trdn b l mat, cdn lai va tinh do mai mdn, bieu thj bang t! Id p h i n tram khdi l u a n g m i t di sau Oiu nghidm.
Danh gia dong deu khoi lutmg vien Theo DDVN IV, Phu luc 11.3
Can ridng biet 20 vien, tinh khdi lug'ng trung binh. Khdng d u g c qua 2 vidn ed k h l i lugng chdnh lOch qua 5 % so vdi k h l i lugng trung binh va khdng dug-c cd vidn nao cd k h l i lug'ng chenh lech qua 10 % so vdi khdi lugng trung binh.
Phuxmg phap djnh fuwig duvfc chit Can 20 vien, xac djnh khdi lugng trung bjnh vidn, nghien thdnh bdt mm. Can chinh xac mdt lugng bdt vidn tuang dng vdi 100 mg c h u i n natn valproat cho vao binh djnh muc 50 ml, them khoang 5 ml aeetonitrll, l i e mgnh, sieu am 2 phut, them methanol v u a du den vach. l i e ddu. Lgc qua mang Igc 0,45 pm, dug'c dung djch t h u de tidm vao may.
Djnh lugng dong thdi AV va NV bang phuang phap SKLHNC vdi cac didu kiOn sau: cdt Acclaim RP8 (100 X 4,6 mm, 3 pm), pha ddng gom h i n hgp aeetonitrll : dem phosphat pH 2,7 (55:45), t h i tich tiem m l u 10 ^1, toe do ddng 1 ml/phOt, phat hign b i n g detector quang pho t u ngoai dat d b u d c sdng 210 nm. CH dieu kign pH 2,7 eua pha ddng, NV d u g c c h u y i n thanh AV, k i t qua djnh lugng d u g c qui ve AV.
PhiFcng phap danh gia GPDC'^
T h u nghidm GPDC d u g c thyc hien vdi t h i l t bi canh khuly, toe dg 100 vong/phut trong 02 giai doan:
- Giai doan 1:500 ml acid HCI 0,1 N, nhiOt dg 37 ± 0,5''C, mau t h u d u g c l l y tai thdi diem 45 phut.
- Giai doan 2: 900 ml dem pH 5,5 (cd 0,05 % natri lauryl sunfat) d u g c duy tri d 37°C. cac mSu t h u d u g c l l y vao cac thdi d i l m 1, 2, 4, 6, 8, 10 va 12 gid.
Lugng AV va NV giai phdng d u g c xac djnh bang phuang phap SKLHNC nhu phdn dinh lugng Kha nang GPDC cua vidn nghien c u u d u a c so sanh vdi vien ddi chieu Depakine Chrono 500 (Sanofi Aventis) trdn c a s d he s612. dugc tfnh theo cdng thuc:
/,=50xig{[I + -!-x£(/ir-7>)^]-
xIOO}Trong d d : n: s6 diem lay miu
Rt trung binh phan trBm hoat chat phong thich tir thuoc ddi chiiu tai thai diim t
Tt: trung binh phin tram hoat chit phong thich t^
thudc thCt- tai th&i diim t t: thdi diim iiy mau
Kha nang GPDC giua thuoc doi chllu vd t h u l c t h u nghiem dyg-e xem la t u a n g t y khi f^
dat gia trj Idn hoac bang 50.
K e t q u a v a b a n l u a n
Anh h u d n g cOa hydroxy propylmethyl cellulose (HPMC) K15M den do GPDC
Qua cac nghidn c u u sang Igc, 03 cdng thiic vien nhan vdi ti 10 HPMC K15M khac nhau lln l u a t dug'c thiet k l n h u trinh bay trong bang 1.
B a n g 1 : Cac cong thu-c vien nhan trong nghien cuv sang loc
Khoi limng cho mgt vien (mg)
CT1 CT2 CT3
Acid valproic 145 145 145 Natri valproat 333 333 333 Aerosil 46.8 46,8 46,8 Dicalci phosphat dihydrat 80 45 10 HPMCK15M 70 105 140 PVPK30 8 8 8 Talc 6.8 6,8 6,8 Magnesi stearat 10.4 10,4 10,4 Tong 700 700 700 HPMC K l 5M la td d u g c chinh tao khung kiem soat t i e do GPDC. Aerosil vd dicalci phosphat dihydrat ed vai trd lam ta d u g c hut va ta dugc don. V d i eCing ^ l u kidn bao che da chgn, cic cdng thue deu cho cac vidn nhan dat ydu c l u v l thdng sd c a ly (bang 2). V l do GPDC so vdi vien d l i chidu (hinh 1), chi cd cdng thue 2 va 3 dgt ydu cau {f>^ 50).
B a n g 2: Cac thong so ky thu$t cua vien nhin chu'a acid valproic va natri valproat
Thong s6 Dp Cljng (Newton) D6 mai mon {%) Khoi lijong vi§n (mg) Ham iu-t^ng (%, tinli tlieo NV)
VN1 136 0,017
VN2 VN3 141 144 0,014 0.022 702 ± 18,6 698 ± 28,48 701 ± 26,36
99,89 100.52 99,65
T4P CHi D i r p c HQC - 2/2014 (S6 454 N A M 54)
Nghien ciru - Ky thuat
Hinh 1 : Anh hudng cOa ti le HPMC K15M den kha nSng GPDC cua vien
So v d i thuoc doi e h i l u , vidn t u cdng thuc 1 khdng dat t u a n g duang hda tan (f^ = 48,80), ty 10 polyme chua phu hg'p d l tao khung kiem soat kha nang GPDC, vidn t u cdng thuc 3 GPDC nhanh trong giai dogn d i u (1-5 gid), nhung cham t u thdi d i l m 6 gid, v d i he so f^ = 56,52 so v d i thuoc d l i c h i i u . Vien t u cdng thue 2 ed vdi he so fj = 61,27 so vdi thuoc doi e h i l u .
A n h h u ' d n g cua s y p h o i hg'p cdc polymer d i n khd ndng GPDC
O l thj GPDC (hinh 1) cho thay hogt ehlt gial phdng cGa vidn t d cdng thuc 2 nhanh han so vdi vidn d l i chiiu tgi cdc thdi diem dau (2-6 gid), nen d n thilt phdi k i l m sodt s y GPDC trong cac thdi d i l m d i u . Hai polymer g i m HPMC K4M va HPMC 615 d u y c ddng k i t hgp vdi HPMC K15M d hai n i n g dO khdo sdt Id 5,0 % va 2,5 %. Thdnh p h i n cy t h i cCia ede cdng thdc dugc llgt kd trong bang 3.
Bang 3: Thdnh phin ciic cdng thuc nghien cuu siJ" di^ng 2 polymer phii h<?p
Acid valproic Natri vaiproat Aerosii
Dicalci phosphat dihydrat HPMC K15M HPMC K4M HPMC SIS PVP K30 Talc Magnesi stearat
Ting
Khoi Iwgng cho mgt vien (mg) CT4
145 333 46.8 10 105 35
8 6.8 10,4 700
CT5 145 333 46,8 27,6 105 17,S
8 6.8 10.4 700
CT6 145 333 46,8 10 105 35
8 6,8 10,4 700
CT7 145 333 46.8 27,5 105 17,5 8 6,8 10,4 700
Ket qua kiem nghidm eae thdng so e a ly eua 04 cdng thuc deu dgt ydu cau t h i l t ke. Ket qua t h u dg GPDC d u g c trinh bdy d hinh 2 va 3.
{ S ) I O O -
Hinh 2: Kha nang GPDC cua vien tu cong thCec 4 va cong thuc 5 so v&i thudc ddi chieu
Hinh 3; Kha nSng GPDC cua vidn tir cdng thuc 6 vd cong thiic 7 so vdi thuoc doi chiiu
S y phoi hgp thdm cdc HPMC K4M vd HPMC 615 vdi HPMC K15M trong cdng thuc deu lam gidm dp GPDC d cac g i d dau. Tuy nhien.
HPMC K4M (CT4 va CT5) do cd do nhdt cao.
ndn khi p h i i hgp vdi HPMC K15M da tao khung truang n d manh vd ben vung trong mdi trudng thu nghiOm. Do dd. khong nhiing lam giam dg GPDC d 6 g i d dau, ma edn lam giam mgnh d nhung gid sau.
Cdng thuc 6 cho vien cd he so f^ dgt 68.55;
dudng b i l u dien GPDC g i n sat vdi dudng b i l u dien GPDC cua vien d l i chieu. Tren ea s d ndy.
ty 10 HPMC K15M vd HPMC 615 t i l p tyc dugc d i l u ehinh d l cai thign hg so f^. Ket qua cdc thye nghiOm da xac djnh d u g c cong thuc F eho dO GPDC g i n g i l n g n h i t (fj=79,6) so vdi t h u l c d l i e h i l u Depakine Chnsno 500.
(Xem tiip trang 25)
T^pCHt DU<;K: H Q C - 2/2014 ( s 6 454 NAM 54)
• Nghien ciru - Ky thuat
and membrane purification process in isolation of steviosides with improved organoleptic acWvity", Advances in Bioscience and Bhtechnology, 3, pp.
327-335
3. Erkucuk A „ Akgun I. H.. Yesil-Celiktas O. (2009),
"Supercntical CO^ extraction of glycosides from Stevia rebaudiana leaves: Identification and optimization", The Joumal of Supercritical Fluids, 51, pp. 29-35.
4. Goyal S.K. et al. (2010), "Stevia {Stevia rebaudiana) a bio-sweetener: a review", Intemational Joumal of Food and Nutrition, 61(1), pp. 1-10.
5. Munish Purl, Deepika Shanma, Colin J. Barrow, A. K. Tiwary (2012), "Optimisation of novel method for the extraction of Steviosides from Stevia rebaudiana leaves". Food Chemistry, 132, pp. 1113-1120.
{Ngay nhan bai: 07/12/2013 - Ngay
6. Venkata Sai Prakash Chaturvedula, Indra Prakash (2011), "A new diterpene glycoside from Stevia rebaudiana'. Molecules. 16, 2937-2943
7 Venkata Sai Prakash Chaturvedula, Indra Prakash (2013), 'Stmctural characteri-zation and hydrolysis studies of Rebaudioside E, a minor sweet component of Stevia rebaudiana", Eur. Chem. Bull., 2(5), pp. 298-302
8. Xin-Yi Huang, Jun-Fang Fu, Duo-Long Di (2010), "Preparative isolation and purification of stevlol glycosides from Stevia rebaudiana Bertoni using high- speed counter-current chromatography". Separation and Purification Technology. 71. pp. 220-224.
thdng qua phan bien: 08/01/2014)
Nghien cmi xay dung...
(Tiep theo trang 11)Bang 4: Thdnh phin cdng thCec vi6n cdng
thucF
Thdnh phin Acid valproic Natn valpnsat HPIV1CK15IVI HPMC 615 PVP K30
Dicalci phosphat dihydrat Aerosil
Talc Magnesi stearat Ting
1 vien (mg) 145,0 333,0 115,0 25,0 15,0 10,0 39,8 6,8 10,4 700
20,71 47,57 16,43 3,57 2,14 1,43 5,69 0,97 1,49 100
Hinh 4: D6 thj GPDC cOa vi§n tie cdng thuc F vd Depakin Chrono 500 (Sanofi Aventis)
Ket luan
Cdc k i t qua cua nghien cuu da chdng minh bdng cdch s u dung cdc polymer vdi ky thudt xdt hgt udt tao khung matrix than nude, cd the t h i l t k l duge vidn nen ehua AV va NV dgng GPKD, cd t i c do GPDC tuang duang vdi san p h i m Depakine Chrono 500. Vdi dg GPDC da dgt duge, cdng thue F cd t h i duge s d dgng d l t i l p tyc thyc hidn cdc nghien cdu tiep theo gom bao mang chong am, nang d p c d 16 va hoan thign qui trinh san xuat san p h i m .
Tai lieu tham khao 1. Bg Yte (2009), Dugv: thu quoc gia, Nha xult ban Y hpc Ha Ngi, 127-130.
2. VA Ptiarmacy Benefits Management Strategic Healthcare Group and Medical Advisory Panel (2006), Depakote EC versus Depakote ER.
3. Phaechamud T, Mueannoom W., Tuntarawongsa S., Chitrattha S. (2010), "Preparation of coated valproic acid and sodium valproate sustained-release matrix tablets', Ind. J. Pharm. Sci. 72 (2), 173-183.
4. Chakraborty S., Pandit J. K.. Snnatha A. (2009).
"Development of extended release divalproex sodium tablets containing hypdrophobic and hydrophilic matnx", Cun^. Drug Deliv., 6 (3), 291-296.
5. United States Pharmacopoeia 34.
(Ngiy nh$n bdi: 22/09/2013 - Ngay thdng qua phan bi$n: 28/01/2014)
