• N g h i e n C L F U — K y t h u a t - Cung co he thong kinh doanh, xuat nhap khau TTBYT. Co chinh sach ho trp ve von va ky thuat cho cac ca sd thanh phan kinh te Nha nude nh§m phat huy vai trd chu dao trong ITnh vyc kinh doanh TTBYT.
S u m m a r y
In Vietnam, medical equipments were produced little, most of them were imported. For more information in this field, we study the subject and gain some results as follows: Nowadays, Vietnam has national completely system for management of medical equipment import. The number of importing company increases per year.
In 2008, there are 650 companies, increase 10,0%compare with 2007. Total import value of
medical equipment is stable. In 2006, the import value are highest in three year, reach 227,1 billions USD. The medical equipments are mostly imported from Asian countries, value is over 90%.
Tai lieu tham khao
1. BO Thuang mai, Trung tam thong tin Thuang mai, Tap chi Thdng tin thuong m$i, chuyen nganh Duoc pham va Trang thiet bj y te. 125, trang 25, 8-2008
2. Bp Y te, Tai lipu hpi nghj nganh Trang thiet bj y te Vi£t Nam sau bin nam thyc hi£n Chinh sach quoc gia ve trang thiet bj y te va chuan bi hpi nhap WTO, Nha XB Y hoc, (2008)
3. WHO, Medical device regulations global overview and guiding principles, Publication of WHO, Geneva- Switzerland, (2008)
N g h i e n c i r u c a i t h i e n d o o n d i n h
pellet omeprazol bao tan trong ruot
Nguyen Nhat Duong, Nguyen Van Long, Nguyen Nam Huong
Trudng dqi hoc Duac Hd Noi Dat vdn d i
Omeprazol la dupe chat thudc nhdm dc che bom proton dupe su dung sdm va rdng r3i nhat trong cac phac do dieu trj viem loet da day ta trang, mang lai hieu qua cao. Do omeprazol rat d i bj phan huy trong mdi trudng acid nen cac chi phim cd chua omeprazol dung dudng ulng chu yiu dupe bao chi dudi dang vien nen hay nang cung chua pellet bao tan trong rudt. Tuy nhien, dam bao dp on djnh cho cac chi phim nay la trd ngai khong nho doi vdi cac nha bao chi, vi omeprazol la mpt dupe chit rit khdng on djnh, nhay cam vdi nhiet, i m va dung mdi la dieu kien thudng xuyen tac dpng trong qua trinh bao chi cung nhu bao quan pellet. Vi v$y nghien cuu dupe tiln hanh vdi muc tieu cai thien dp on djnh cua pellet omeprazol bao tan trong rupt.
Nguyen vat lieu, thiet bj va phuxyng phap nghien cu>u
Nguyen vat lieu
Omeprazol magnesi, Avicel PH 101, lactose, manitol, natri laurylsulfat, Na2HP04, NaCI, Na2C03, PVP K30, HPMC, Eudragit L100, alcol cetylic,
propylen glycol, talc, titan dioxid, dibutyl phtalat, crospovidon, kiim huu co A, kiim huu ca B. Cac nguyen lieu diu dat tieu chuan USP hoSc BP.
Thiit bj nghien cuu
May dun Extruder 65 - LAB, may tao cau Spheriodzer - 250, may bao tang soi UNI - GLATT, he thong thu hoa tan Vankel Varian VK7010, may do quang pho UV - VIS HITACHI, h§ thong sic ky long hi$u nSng cao Spectra SYSTEM Thermo Finnigan, may do khoi lupng rieng biiu kiln ERWEKA SVM, may do toe dd tran chay hat va bdt ERWEKA GWF, may xac djnh dp mai mdn va dp bd Pharmatest PTF - 20E, tu vi khi h|u Climacell...
Phuang phap nghien cuu Bao che pellet omeprazol
Bing phuong phap dun - tao cau. Quy trinh thuc hien qua cac giai doan: trdn hdn hpp bpt kep, them dung mdi d i nhao im, u khoi bdt am trong 30 phut roi dem dun spi va cit doan qua may dun Extruder 65 - LAB (dudng kinh l i sang 1mm, toe Jg dun 30 vdng/phut), spi thu dupe dem tao cau trong may tao ciu Spheriodzer - 250 (tie dp 400
vong/phut trong thdi gian 5 phut), pellet thu dirpc dem say d nhiet dp 40°C trong 4h.
Bao mang pellet omeprazol tan trong ruot Pellet thu dirpc d tren dirpc dem bao nhieu Idp sd dung may bao tang soi UNI GLATT vdi cac thong s i bao:
Nhiet dp khi vao 50-55°C Nhiet dp khi ra 45-50°C T6c dp phun dich 2,4 ml/ phut
Ap suat khi phun 1,25 bar Cac Idp bao glm co:
+ Ldp bao mu6i kiem vo co hoac kiem huu co + Ldp bao bao ve sir dung HPMC E6 + Ldp bao tan trong rupt sir dung Eudragit L100.
Sau khi bao xong, pellet dirpc lam khd trong 24h, nhiet dp 24°C va dp am 30%.
Danh gia mpt sd dac tinh cua pellet - Dinh lupng omeprazol
Phirong phap do quang d budc sdng 301 nm trong dung dich dem phosphat pH 7,4
Phirong phap sac ky long hieu nang cao dya theo Dirpc dien Trung Quoc vdi cac dieu kien:
pha dpng gdm dung dich dem phosphat 0,01 M pH 7,6 va acetonitril ty le 77 : 23; cot C8 (4,6 x 150 mm), kich thudc hat nhdi 5pm; detector td ngoai A = 302 nm; toe dp ddng 1,0 ml/phut; the tich tiem 20 pi.
- Thu dp nda fan dua theo Duoc dien An 06 Thiet bj: canh khuay, toe dp khuay 100 vong/phut.
Dieu kien hoa tan: 2 gid dau trong 900 ml HCI 0,1N va 45 phut tiep theo trong dung dich dem phosphat pH 6,8. Nhiet dp 37 ± 0,5°C.
- Cac dac tinh khac nhir dp am, dp mai mdn, khdi lupng rieng bieu kien, phan bo kich thudc pellet, toe dp tron chay thu theo tieu chuan USP.
Danh gia dp on djnh cua pellet
Pellet dupe ddng gdi trong tiii PE, bupc kin va bao quan trong dieu kien thyc (nhiet dp trung binh 25 - 35°C, dp am tuong doi: 60-85%) va lao hoa cip tic (nhiet dp 40 ± 2°C, dp i m tuong doi: 75 ± 5%). Sau tung khoang thdi gian, danh gia mpt so chi tieu: cam quan, ham lupng omeprazol, dp hoa tan so sanh vdi thdi diem ban diu.
Ket qua t h y c n g h i e m va nhan xet Bao c h i pellet omeprazol
Khao sat anh hudng cua dung mdi va ta duoc kiem den su tao thanh va on djnh pellet
Pellet omeprazol dupe bao chi bing phuang phap dun tao cau vdi thanh phin:
Omeprazol magnesi, manitol, lactose, Avicel PH 101 va dung moi nhao am vua dd.
Kit qua: Khi su dung EtOH hoac isopropanol de nhao am, alcol bay hai nhanh nen khi dim tao ciu, pellet bj kho, hinh tru dai lam giam hi§u suit tao thanh pellet. Su dung dung mdi nude han chi dupe vin de nay nhung sau khi nhao am, khoi bpt am da biln mau chi sau 30 phut u do omeprazol rit kem bin vdi i m . Su dung dung dich Na2HP04 cho kit qua kha quan nhit (pellet diin xong trdn va deu, hieu suit tao thanh pellet cao (75%), pellet on djnh sau 3 thang theo doi d dieu ki$n thuc, (ham lupng cdn lai dat 94,5%) vi Na2HP04 la mpt ta dupe kiim dupe them vao trong cdng thuc 6a lam tang tinh on djnh cua omeprazol [ 2l
Khao sat anh hudng cua chat dien hoat Omeprazol la hoat chit thupc nhdm II theo phan loai SDH (tinh thlm tot, dd tan kem) vl thi tien hanh cho them chit dien hoat de cai thi#n kha nang hoa tan dupe chit. Khao sat vdi hai chit dien hoat la Tween 80 va natri laurylsulfat 5%/ EtOH 96° cho kit qua:
- Vdi Tween 80, sau khi nhao am khoi bdt hoi xam mau. Dun-tao ciu xong theo ddi 7 ngay d dilu kien thudng, pellet sim mau hon.
- Vdi dung djch natri laurylsulfat 5%/EtOH:
pellet tao thanh trdn, deu. Ty le hda tan dupe chit dat 94,5%. Theo ddi on djnh sau 3 thang, pellet bit diu biin mau sang tring xam, ham lupng dupe chit khong giam nhiiu (> 90%).
- Vi thi chiing toi chpn natri laurylsulfat/EtOH d l nhao i m ciing vdi dung djch Na2HP04.
Kit qua bao chi pellet omeprazol:
Bang 1: Phan bd kich thudc cua pellet Kich thw&c pellet Khoi Iwong (g) Tyi?(%)
< 0,8 mm 10,7 2,6
0,8-1 mm 88,6 21,9
1-1,25 mm 250,2 61,8
> 1,25 mm 55,6 13,7 Tong cong 405,1 100,0
TAP CHI DUQC HQC - 10/2010 (SO 414 NAM 50) 13
• N g h i e n C L F U - K y t h u a t Bang 2: Cic thdng sd chit luong
Cac thong so Kit qua Hieu suit tao thanh pellet 83,6 % Kh6i luang rieng bieu kien 0,76 g/ml
Dp mai mon 0,04 % Dp am 2,43 % Op tron chay 3,85 g/s Ham lupng omeprazol 99,1 %
% omeprazol hoa tan trong dung dich 94,5%
Bang 3: Kit qui thu hoa tan
Alcol cetylic HPMC (9) (9) M1 2 10 M2 3 10
Nhu vay, pellet thu dupe co cac dac tinh thich hpp de bao mang tan trong ru6t.
Khao sat mang bao bao ve va bao tan trong rupt
Pellet thu dupe d tren dupe bao 2 ldp: mang bao bao ve (HPMC, alcol cetylic, DPB, Tween 80, Span 80, PG, EtOH 96 %, nude) va mang bao tan d rupt (Eudragit L100, alcol cetylic, Tween 80, Span 80, PG, Talc, titan dioxyd, EtOH 96%), sau do tien hanh thu hoa tan.
Eudragit L100 % hoa tan % hoa tan (g) trong pha acid trong dem pH 6,8
15 - 737 _ _ _ _ M3 4 10 15 - 71,2 M4 4 11 15 39,5 69,9
~M5 4 12 15 37A 67/T
~M6 4 15 15 32,6 62^5
~M7 4 15 18 26^3 62^8
~M8 4 15 ~21 21^8 62/T
~M9 4 15 24 17^5 63^0 M10 4 15 27 13^9 62^5 Nhin xef:
Alcol cetylic la chat than dau, dupe su dung de tao thanh Idp mang bao so nude bao quanh pellet, han che omeprazol tham qua mang bao ra ngoai moi trudng acid, tuy nhien khi tang lupng alcol cetylic, du kha nang khang acid cua pellet t§ng nhung vin chua dat yeu ciu (khi thu so bd, sau 2h pellet da bj biin mau), d§ hoa tan omeprazol trong moi trudng dem phosphat pH 6,8 sau 45 phut giam.
HPMC dupe su dung de bao bao ve. Khao sat cho thiy khi tang lupng HPMC trong cong thuc mang bao bao ve, kha nang khang acid tang len nhung dong thdi cung lam giam dp hoa tan dupe chit trong moi trudng pH 6,8.
Eudragit L100 la polyme cd dp tan phu thupc pH dupe su dung lam mang bao tan trong rupt.
Tang Eudragit L100, dp hoa tan dupe chat trong pha acid giam ro r#t, dp hoa tan trong moi trudng dem pH 6,8 c6 dao d6ng nhung khong dang ke.
Cdng thuc me bao M10 da giam dupe lupng omeprazol hoa tan trong moi trudng acid con 13,9% dat so vdi yeu ciu cua DDVN IV va Dupe dien An Op (yeu cau dudi 15%) nhung chua dat so vdi USP 32 va BP 2009 (yeu ciu dudi 10%).
Khao sat anh hudng cua ta dupe sieu ra trong cdng thuc pellet
Do dp hoa tan dupe chit tu pellet trong moi trudng pH 6,8 con tuong doi thlp so vdi yeu ciu cua cac Dupe dien (> 75% theo DDVN IV, Dupe dien An Op va > 80% theo USP 32, BP 2009) nen chung toi su dung ta dupe sieu ra la crospovidon (khoang 2%) vao thanh phin pellet d tren.
Bang 4: Kit qui thu hda tan su dung ti duoc sieu ra
Ta dwov % DC hda tan % DC hda tan sieu ra trong pha acid trong dem pH 6,8
Khong co 13,9 62,5
Co 14,5 81,7
Nhin xef; Khi them ta dupe sieu ra, dp hoa tan cua omeprazol trong moi trudng acid tang khong dang ke, trong khi trong mdi trudng dSm pH 6,8 lai tang manh. Pellet sau khi them ta dupe sieu ra c6 dp hoa tan dat yeu cau cua DDVN IV va Dupe diin An Op (dp hda tan trong moi trudng acid phai < 15%, trong moi trudng pH 6,8 phai > 80%) nhung chua dat yeu ciu cua USP 32 va BP 2009 (dp hoa tan trong m6i trudng acid phai < 10%).
Khao sat anh hudng cua Idp mang bao mu6i kiim
Theo doi on djnh cua pellet dupe bao hai ldp mang bao tren nhan thiy pellet bj hong nhanh hon so vdi pellet chua bao (chi sau 2 tuin bao quan trong dilu kien thudng, pellet co hien tupng biln mau sau do nhanh chong chuyln sang mau tim). Cd thi do nhiet dp, ham Im, dung moi trong qua trinh bao da lam anh hudng den omeprazol hoac c6 su tuong tac giua omeprazol vdi thanh phin mang bao.
Theo cac tai lieu v i bao mang film cho vien chua omeprazol, nhiet dp bao 50-55°C trong khoang thdi gian ngln (khoang 6-7 tilng) gay anh hudng khong dang k i din ham lupng omeprazol. Hon nua nlu ha nhiet dp xulng 40- 45°C thi dung moi khong bay hoi kjp nen pellet bi dinh vao nhau gay kho khan cho qua trinh bao. Nhu vay nguyen nhan gay hong pellet co the do co tuong tac giua dupe chit-vdi thanh phin cua mang bao, cu thi la mang bao HPMC
[3'. Do do, pellet dupe bao them mpt Idp mang bao on dinh su dung cac muoi kiim trudc khi bao mang HPMC va Eudragit L100.
Doi vdi mang bao on djnh su dung cac muli vo co (thanh phin: natri clorid, dinatri hydrophosphat, PVP K30, natri carbonat, aerosil, EtOH 96% va dung djch NaOH 0,01 N).
Kit qua cho thiy sau khi l£o hoa cip toe 2 tuin, v l cam quan pellet bao them muoi kiim on djnh hon khi khong bao. Ldp bao muoi hiu nhu khong anh hudng din kha nang hoa tan dupe chit. Tuy nhien, pellet vin chua dat dp on djnh mong muln (lao hoa cip toe sau 3 tuin, pellet da co anh tim).
Dii vdi mang bao on djnh su dung cac muoi kiim hCru co (thanh phin nhu tren co them kiim huu co (KHC) A hoac KHC B ty le 1%), kit qua cho thiy them KHC A hoac KHC B hiu nhu khong anh hudng din kha nang hoa tan dupe chit trong dung djch dem phosphat pH 6,8 do KHC A va B deu tan tot trong nude va dupe su dung vdi lupng nho nen khdng lam thay doi dac tinh hoa tan cua pellet. Theo doi on djnh trong dilu kien lao hoa cip toe, pellet on djnh hon do hai ta dupe kiim nay tao ra vi moi trudng c6 pH kiim xung quanh tilu phan dupe chit nen c6 vai trd bao v& dupe chat. V l cam quan va kit qua dinh lupng omeprazol trong pellet, KHC A co tac dung on dinh dupe chit tot hon so vdi KHC B.
Bang 5: Kit qui danh gii pellet khi c6 th§m ta duac kiim huu ca
Pellet
% DC hoa
tan trong Sau 2 tuan Sau 4 tuan Pellet
moi trw&ng pH6JB Cam
quan HLDC
% Cam
quan HLDC
% Khong
them 81,7 Trang
xam 91,2 tim 80,5 Them
KHC A 81,2 Trang 98,3 trang xam 93,1 Them
KHC B 82,1 Trang
xam 95,1 anh tim 87,2 Tilp tuc khao sat ty le cua KHC A trong cdng thuc mang bao on djnh, kit qua cho thiy cac ty le khac nhau cua KHC A hiu nhu khdng anh hudng din kha nang hoa tan cua omeprazol trong ca moi trudng acid va dem phosphat pH 6,8. Theo doi dp on djnh pellet da bao trong 2 tuin d diiu kien lao hoa cip toe: vdi ty le KHC A tang din trong cdng thuc, dp dn djnh cua omeprazol trong pellet cung tang len.
Bang 6: Kit qua khao sat pellet v&i cac ty 1$
KHC A khic nhau Ty/?
hoa tan %DC %DC
hoa tan Sau 2 tuan LHCT (%) trong pha
acid trong dem
pH6,8 Cam HLDC
quan % 0 13,9 80,7 tring xam 91,2
1 14,1 81,2 trang 98,3
1,5 13,8 80,5 tring 98,7
2 13,9 81,6 trang 98,9
Ket luan
Pellet omeprazol dupe bao chi bing phuong phap dun - tao ciu vdi thanh phan:
omeprazol magnesi, Avicel PH 101, manitol, lactose, natri laurylsulfat/ EtOH 96°, dung djch Na2HP0415%. Hieu suit tao pellet cao (83,6%), pellet thu dupe cd cac dac tinh thich hpp de bao mang tan trong rudt. Pellet chua bao on dinh sau 3 thang bao quan d diiu kien thudng va lao hoa cip too
Ty l$ alcol cetylic, HPMC, Eudragit L100 trong cong thuc mang bao anh hudng din dd h6a tan dupe chit trong 2 mdi trudng HCI 0,1N va dem pH 6,8. Khi them ta dupe sieu ra crospovidon, %omeprazol hoa tan dat yeu cau DDVN IV va Dupe diin An Dp.
Dp on djnh cua pellet dupe tang cudng bing each bao them Idp muoi kiim su dung ta dupe
TAP CHI DUQC HQC - 10/2010 (SO 414 NAM 50) 15
• N g h i e n C L F U - K y t h u a t kiem huu ca A ho§c B trudc khi bao Idp bao ve va bao tan d rupt. KHC A cho ket qua dp on djnh tot hon KHC B nen tiep tuc khao sat ty le KHC A cho vao thanh phan pellet.
Lop Eudragit LI00 Lop HPMC Lop bao muoi kiem Pellet chiia omeprazol Ciu true cua pellet bao nhiiu lap
S u m m a r y
Omeprazole pellets containing omeprazole, mannitol, lactose, Avicel PH 101 were prepared by extrusion-spheronization method, then pellets were coated with three-layer film using multifunctional fluid-bed system to form enteric- coated omeprazole pellets. The film includes a layer of alkali salts, a protecting layer using HPMC and an enteric-coated layer using Eudragit L 100.
The results of dissolution test conducted according to Indian Pharmacopoeia indicate that pellets have the ability to resist against gastric conditions (no more than 15% drug release
occur after 2 hours in 0. 1N HCI solution) and percentage of omeprazole release from pellets in phosphate buffer pH 6.8 after 45 minutes is at least 80%.
Stability studies were carried out in a stability chamber at 40°C ± 2°C and 75 ± 5% relative humidity show the remaining omeprazole decreased insignificantly.
Tai lieu t h a m khao
1. M. Turkoglu et al., Tableting and stability evaluation of enteric-coated omeprazole pellets, Eur.
J. Pharm. Biopharm., (2004) 57, p. 279 - 286.
2. A. Ekpe et al., Effects of various salts on the stability of lansoprazole, omeprazole, and pantoprazole as determined by high performance liquid chromatography, Drug Dev. Ind. Pharm., (1999) 25, 9, p. 1057-1065.
3. Wei He et al., Design and in vitro/ in vivo eluvation of multi-layer film coated pellets for omeprazole, Chem. Pharm. Bull. (2009), 57, 2, p.
122-128.
4. C. Holvoet et al., Development of an omeprazole parenteral formulation with hydroxypropyl -B- cyclodextrin, Pharm. Dev. Tech. (2007), 12, p.
327-336.
N g h i e n c u u b a o c h e v i e n n e n p a r a c e t a m o l 650 mg giai phong keo dai chira pellet
Nguyln Thi Trinh Lan, Nguyen Ngoc Chien, Vu Van Tuan Truong dai hoc Duoc Ha Noi Dat v i n d i
Hien nay, pellet ngay cang dupe cac nha bao che quan tam, dac biet trong dang bao che giai phong keo dai (GPKD) dung theo dudng uong. So vdi vien nen, pellet co nhieu uu diem nhu thdi gian luu trong dudng tieu hoa hing djnh hon, tranh dupe su bung lieu, don lieu va dao dpng sinh kha dung it hon. Tuy nhien, pellet chi la mpt che pham trung gian va thudng dupe dua ra thj trudng dudi dang vien nang do vien nen giai phong keo dai chua pellet thudng kho giu dupe nhung uu diem cua pellet. Cd rat nhieu tac gia tap trung vao nghien cuu vien nen giai phong keo dai chua pellet, nhung thuc te tren thi trudng rat hiem che pham nhu vay. Vi
vay, chung toi dat van de: "Nghien cuu bao che vien nen paracetamol 650 mg giai phong keo dai chua pellet".
Nguyen lieu va p h i r o n g phap nghien c i r u
Nguyen lieu
Paracetamol, ethylcellulose (EC), hydroxypropyl methylcellulose (HPMC E6), Avicel PH 101 (Avicel), lactose, talc, Aerosil, magnesi stearat, starch glycolat natri (SSG): dat tieu chuan dupe dung.
Opadry®clear (trong thanh phan cd chua HPMC), Surelease® (trong thanh phan c6 chua EC) dat tieu chuan nha san xuat. Cac hoa chat khac dat tieu chuan hoa chat phan tich.
