Nghien cihi - Ky thuat

Xay dung cong thuc thuoc bot cefuroxim pha hon djch uong
Nguyen Ngoc Nha Thao, Trinh Thi Thu Loan Khoa Dwac, DH Y Duoc TP.HCM

Dat van de
Cefuroxim la mdt khang sinh diet khuan thupc nhdm cephalosporin the he thir hai, khdng bj tac ddng va mat hoat tinh bdi hau het cae betalactamase. Cefuroxim dupe ehi dinh trong dieu tri nhieu benh nhiem triing do cd phd khang khuan rdng[2]. Mdt trong nhung dang thudc chira cefuroxim la bdt pha hdn djch udng, day la dang thudc thich hpp eho tre em. Tuy nhien, viec khac phuc vj ding cua cefuroxim la mdt thach thire Idn ddi vdi nha bao che vi cefuroxim ed vj rat dang va keo dai, vj dang nay khdng the che dupe bang nhung tinh bdt bien tinh tao vj ngpt va tao mill thdng thudng. Hon nira, cefuroxim rat it tan trong nude, viec ap dung cae ky thuat che vj dang cang anh hudng den tinh tan eiia eefuroximl^. ^j. Trong phan I, cdng thirc thudc bdt cefuroxim dUdc xay dung vdi ta dupe che vj B, thanh pham cd vi ngon, gan nhu khdng dang nhung dd hda tan ehi dat mire yeu cau (63,43%, yeu eau khdng nhd hon 60%), dc dd, trong phan II nay, edng thire thudc bdt cefuroxim dupe xay dung vdi ta dupe che vj S. Mue tieu cua de tai la xay dung cdng thirc thude bdt cefuroxim pha hdn djch ud'ng it dang va dat yeu cau kiem nghiem, dac biet la ve dp hda tan.

b) Hdn hpp d budc a) va tinh bdt bien tinh dupe ray qua ray 0,5 mm va trdn trong 20 phiit. e) Acid citric, nath eitrat, aerosil, ta dupe C, aspartam, tinh bdt bien tinh, ta dupe tao miii, natn benzoat, dudng saeearose dupe ray qua ray 0,5 mm vao may trdn; hdn hop d bude b) dupe them vao va trdn trong 10 phiit. Thiet ke va tdi uu hda edng thire: Md hinh thue nghiem duoe thiet ke bang phan mem Design Expert V.7.0 va tdi uu hda edng thire bang phan mem INform V3, 6 f.s] Phuong phap djnh lugng: Che pham dupe djnh lupng bang phuong phap UV, mdi trudng dem phosphat pH 7, bude sdng 280 nm. Phuong phap dinh lupng da dupe tham djnh ve dd tuyen tinh, dp ehinh xac, dd diing theo nguyen tac chung H. Phuang phap danh gia do hda tan: Thiet bj canh khuay; mdi trudng 900 ml dung djch dem phosphat pH 7; toe dp 50 vdng/ phiit; nhiet dp 37 0,5C. Sau 30 phiit, lpc mdi trudng thir. Hilt ehinh xac 5 ml dich Ipc cho vao binh dinh mire 50 ml, bd sung dung djch dem phosphat pH 7 vua du. Lac deu, lpc, do hap thu UV d bude sdng 280nm[6. 7]. Phuong phap danh gia do dang: Tien hanh vdi nhdm thir nghiem gdm 10 ngudi tinh nguyen. Trudc thu nghiem 10 phiit, ngudi tinh nguyen khdng dupe an va ud'ng bat cir gi ngoai trir nudc Ipc. Hda mdt gdi thudc bpt cefuroxim vdi khoang 5 ml nudc, ngudi tinh nguyen udng va ngam trong mieng 10 giay rdi nha ra, siie mieng va udng khoang 50 ml nude Ipc, giua 2 lan thir tren mpt ngudi tinh nguyen each nhau it nhat 5 gid. Op dang dupe ghi nhan ngay sau khi siie mieng va sau khi siie mieng, udng nude. Op dang eiia thudc dupe danh gia bang 4 mire cam nhan: Khdng dang hoac gan nhu khdng dang (-), dang it (+), dang vira (++), rat dang (+++). Ket qua dupe ghi nhan la mire dd dang dupe nhieu thanh vien trong nhdm cam nhan nhat.

Nguyen lieu va phuong phap

Nguyen lieu Cefuroxim axetil chuan (Vien Kiem Nghiem Thudc TP.HCM); cefuroxim axetil (ASC - Y); ta duoc S (Phap); eac ta dupe khac dat tieu chuan dupe dung; cac dung mdi hda chat dat tieu chuan dimg trong phan tieh kiem nghiem. Xay dung cong thirc Thanh phan cdng thuc: Thanh phan thudc bdt cefuroxim bao gdm: cefuroxim axetil, ta dupe che vi chinh S, tinh bdt bien tinh, ta dupe tao vj C, aerosil, aspartam, nath benzoat, acid cithe, nath eitrat, huong trai cay, dudng saeearose. Qui trinh dieu che thudc bgt cefuroxim a) Cefuroxim axetil va ta dupe S dupe trdn trong 10 phiit, tiep tue trdn trong 5 phiit dudi dieu kien dae biet.

Ket qua va ban luan

vdi thanh phan cdng thirc dupe chpn, ta dupe S va tinh bdt bien tinh dupe khao sat d 3 mire ndng

TAP CHI DUOC HOC - 2/2010 (SO 406 NAM 50)

21

Nghien cuu - Ky thuat

dd, ta dupe C d 2 mi/e ndng dp, nhirng ta dupe khac dupe giu ed djnh ngoai trir dudng saeearose. Md hinh thue nghiem 14 edng thirc dupe thiet ke bang phan mem Design Expert v7.0. Nhirng cdng thirc theo md hinh dupe dieu che, dupe danh gia ve dp hda tan va dd d i n g theo cae phUPng phap nhu da neu. Ket qua thue nghiem dupe trinh bay d Bang 1. Bang 1 : Du lieu ve bao che va ket qua nghiem theo mo hinh CT 1 2 3 4 5 6 7 8 g 10 11 12 13 14 kiem Bang 2 : Gia tn R^ thit va R^ luyen ciia mo hinh chon loc Gia tri ff Luyen Thu-

y,
99,9815 99,9404

y.
99,7198 99,1579

X,

*.
300 300 150 450 150 450 450 300 450 300 150 300 150 150

*.
20 40 40 40 20 20 40 20 40 20 40 40 20 20

y,
1 1 1 0 0 1 0 0 1 1 0 0 1 1

y.
77,23 83,56 82,89 76,98 63,12 77,98 63,68 62,91 83,22 83,41 61,48 78,15 77,63 81,87

Ket qua danh gia cheo giua gia trj R^ luyen va R 2 thir cho thay cd mdi lien quan nhan qua giua thanh phan cdng thirc thudc bdt va cac tinh chat dupe xet (dd dang va dp hda tan). Kha nang du doan ciia md hinh nay tdt (gia tri R2 luyen > 99% va gia trj R2 thir > 99%). Dieu kien tdi uu hoa: - Rang budc ddi vdi x,: x^ > 312 - Trpng sd dd'i vdi yj: mac nhien - Ham muc tieu dd'i vdi yj: Op dang cua che pham: min <=> y-| = Down Op hda tan: max cc y2 = Up Cac thdng sd tdi uu va tinh chat d u doan dupe eho bdi phan mem INForm: Thdng so tdi uu: Xi (Lupng ta dupe S) = 312,75 mg X2 (Lupng tinh bdt bieji tinh) = 450 mg X3 (Lupng ta dupe C ) := 39,95 mg . ..<. ^-

312 234 234 312 468 312 468 468 234 234 468 312 312 234

Tinh chat du doan: yi (Od dang) = 0,00 y2 (Op hda tan) = 78,05% Vay thanh phan cdng thuc td'i uu nhuf sau: 1 gdi (mg) 125 312,75 30 450 39,95 20 22 40 6 60 3000 11d labo (ri) 37,5 93,83 9 135 11,9 6 6,6 It 1,8 18 vd900

Ghi chu: xf. Lugng ta dugc S (mg); x^.' Luang tinh bgt bien tinh (mg); x^: Lugng ta dugc C (mg) y-;: Dg dang, trong do: y-f = 0 (khi muc khong dang () hoac it ding (+) chiem da sd trong thu nghiem) yi = 1 (khi mdc dang vda (++) hoac rat dang (-I-++) chiem da so) y2. Do hoa tan sau 30 phut (%) Toi uu hda cdng thuc Dir lieu thue nghiem ve bao che va kiem nghiem trong Bang 1 dupe diing lam dau vap cho phan mem INForm v3.6 de luyen mang va thuc hien cae budc tiep thep. Ket qua luyen mang vdi thuat toan lan truyen ngupc Asymmetric Sigmoid, ham truyen Idp an Linear, ham truyen Idp ra RPROP, md hinh lien quan nhan qua da dupe thiet lap vdi gia trj R2 luyen va R^ thu ciia thir nghiem danh gia cheo duc(c trinh bay trong Bang 2.

Cefuroxim axetil (*) Ta dupe S Aerosil Tinh bdt bien tinh Ta duoc C Acid citric Nath eitrat Aspartam Nath benzoat Ta dU(?e tao mui Oudnq saeearose vd
(*) duac tinh theo

cefuroxim

Kiem chung cdng thuc td'i uu: Cdng thire thudc bdt cefuroxim dupe dieu che lap lai 2 lan vdi cimg dieu kien va qui trinh. San pham dupe kiem nghiem tueng t u giai doan thiet ke de so sanh vdi ket qua d u doan bdi phan mem INForm.

22

TAP CHI DUOC HOC - 2/2010 (SO 406 NAM 50)

 Nghien ciru - Ky thuat

Bang 3: Ket qua thuc nghiem va du doan bdi phan mem Thuc nghiem Tinh chai san pham Dp dang (y,) Dp hoa tan (y^ %) Lo 1 0 77,56 Lo 2 0 77,85 Trung binh 0 77,73 0 77,71 INForm

Ket qua thue nghiem cho thay cae tinh chat san pha'm theo thiet ke cd tinh lap lai. Ket qua thue nghiem (trung binh) va ket qua du doan tuong tu

nhau. Cdng thire va qui trinh dieu che thudc bdt cefuroxim ed tinh on dinh.

Bang 4: Ket qua kiem nghiem 2 16 thudc bgt vdi ta dugc S tu cong thuc tdi uu Chi tieu Mdc chai lugng Ldl Cam quan Djnh tinh Do min
Dinh luong Op hda tan Nudc

Kei qua Ld2 Oat Oung Oat (99,60%)

Oat (100,77%) Oat (77,45%) Dat (4,68%)

Bpt trang hoac tring nga, kho toi, vj ngpt dang nhG, mill tham Thdi gian luu dinh ciia miu thir phai tuong duong vdi dinh cua mau chuan. > 97% qua ray 500
90,0-110,0% C,eH,3N,08S ^ 6 0 % C,,HN,0,S < 6%

Oat Dung Oat (99,40%)

Oat (99,99%) Oat (78,16%) Oat (4,35%)

pH

3,5-7,0

Oat (5,12)

Oat (5,32)

Thudc bdt cefuroxim dupe dieu che vdi ta dupe che vj S dat ta't ea nhu'ng ehi tieu de ra. Op hda tan cao hon nhieu so vdi thudc bdt dupe dieu che vdi ta dupe B (78,16% so vdi 63,84%). Vay thudc bdt

cefuroxim vdi ta dupe che vj S dupe chpn de nghien ciru nang cap cd Id phuc vu cho thir nghiem tuong duong sinh hpc va dp dn djnh eua thudc.

Bang 5: Ket qua so sanh do dang giua thanh pham vdi ta dugc B, vdi ta dugc S va hon hgp bgt ddi chung
Mirc dp dang Nguai tinh nguyen Thanh pham vai ta duac B Thanh pham vdi ta dugc S Bot doi chirng vdi ta dugc B Bgt doi chung vai ta dugc S 1 2 3 4 5 + 6 7 + 8 g 10

+ +++ +++

+++ +++

+++ +++

+ +++ +++

+ +++ ++-1-

+++ +++

+++ +++

+++ +++

+++ +++

+ +++ +++

Neu cefuroxim axeWchi dUpc trdn don gian vdi nhung ta dupe khac trong cdng thire (bdt ddi chirng) vj ding eua thudc khdng dupe khic phuc. Trong trudng hpp nay, tat ca 10 ngudi tinh nguyen tham gia thir nghiem deu nha thudc ra ngay khi ud'ng, khdng the giu thudc trong mieng 10 giay. Dd'i vdi thude vdi ta dupe B va S, sau khi dupe xir ly bang nhu'ng ky thuat che vi, dp dang cua thudc giam TAP CHI DUOC HOC - 2/2010 (SO 406 NAM 50)

dang ke ddng thdi cung dam bao ve ehi tieu dd hda tan.

Ket luan
Cdng thire tdi uu ciia thudc bdt cefuroxim vdi ta dupe che vj S da dupe thiet lap. Thanh pham tir cdng thire tdi uu dat tat ca nhirnq chi tieu de ra. Op dang eua thudc giam dang ke, gan nhu khdng dang; dp hda tan ciia thudc cao hon nhieu so vdi 23

Nghien ciru - Ky thuat

thudc dupe dieu che vdi ta dupe che vj B (77,80% so vdi 63,43%). Vi vay, viec xay dung tieu ehuan san pham, nang cap cd Id se duac thuc hien tren thanh phan edng thire tdi Uu vdi ta dupe S.

Tai lieu tham khao

1. Oang Van Giap (2002), Thiet ke & tdi uu hda cong thuc va quy tnnh, NXB Y hgc, TPHCM, tr. 1-97. 2. American Society of Health, Drug Information (2006), pp. 140, 230. 3. H.J. Robson, D.Q.M. Ciaig, D. Deutsh (2000), An investigation into the release of cefuroxim axetil from taste-masked steahc acid microspheres. Part 2: The effects of buffet composition on drug release, Int. J. Pharm. 195, 137-145. 4. K. Gowthamarajan, Gihraj T. Kulkarni and M. NarendranKumar (2004), "Pop the pills without bitterness-Taste-masking technologies for bitter drugs", Resonace, pp. 25-32. 5. Plumb A. P., Rowe R. C, York P. and Brown M. (2005), Optimisation of the predictive ability of artificial neural network (ANN) models: A comparison of three ANN programs and four classes of training algorithm, Eur J. Pharm. Sci., 25: 395-405. 6. British Pharmacopeia (2007), 5**^ edition, volume 1, p. 400. 7. The United States Pharmacopeia (2007), 30*''^ edition, pp. 378, 1694.

Summary
Previously (Part I), polyme B and the other excipients were used to mask the extremely bitter taste of acetyl-cefuromime, an optimal formula for cefuroxim oral powder was chosen. The product was complied with the properties of cefuroxim for oral suspension by USP 30 and almost without bitterness. However, the dissolution of the drug was just met the minimal requirement (63.43% vesus not less than 60% as required). In this report (part II), taste-masking S excipient was used to develop formulae for cefuroxime powder to improve the drug dissolution. An optimal formula for cefuroxim powder with S excipient was established. The bitterness was reduced remarkably, the dissolution was much higher than that of the products with B excipient (77.80% vesus 63.43%). Key words: Cefuroxim suspension, dissolution, bitter. powder for oral

Khao sat chat luang tinh dau duong cam ciic theo mua, each sa che, bao quan va ky thuat trong
Tran Anh Vu l Le Thi Hanh2 ^ Khoa Dugc, Trwdng dgi hgc Y Dwac TP. HCM 2 Trung tam trong che bien cay thuoc Da Lat ^

Dat van de
Duong cam ciic la mdt cay dupe lieu cd nhieu dac tinh quy, hoat chat tinh dau cd. tinh khang khuan, khang viem, khang di irng, v.v... Duong cam ciie ed ngudn gdc tir chau Au va da dupe di thue vao Viet Nam. Cay td ra thich hpp vdi khi hau mat lanh nen Da Lat la npi trdng nhieu nhatHi. Trudng Dai Hpc Y Dupe TP. HCM da ed de tai nghien ciru ve dupng cam ciie nham tao ra cac dupe pham, my pham ed ngudn gdc tir thien nhien, it tac dung phu, cd hieu qua dieu tri cac cd kha nang dan thay the hang ngoai nhap. De nang cao chat lupng thudc tir dupe lieu san 24

xuat trong nudc, mdt van de dat ra la phai cd ngudn nguyen lieu dn djnh va dat tieu chuan. Vi vay Trudng dai hpc Y Dupe TP. HCM da ket hop vdi Trung tam trdng che bien cay thudc Oa Lat khao sat chat lupng tinh dau duong cam ciie theo miia, each so che, bao quan va chuan hoa qui trinh chpn gidng trdng trpt, thu hai, nham tao ra ngudn nguyen lieu chil ddng, tranh nham lan khi thu gom dupe lieu trong mdi trudng tu nhien, thuc hien theo md hinh GAP de cung cap nguyen lieu dat chat lupng che san pham t^l

Nguyen lieu va phuang phap nghien cuu

Nguyen lieu

TAP CHI DUOC HOC - 2/2010 (SO 406 NAM 50)