Nghien
CLFU- Ky thuat
Nghien cmi xay dung cong thuc vien nen venflaxin giai phong lieo dai dang botn tham thau quy u'O'c
Nguyin Van Ha'*, Nguyin Van KhanhS Vu Th| Thu Giang^
Nguyin H6ng UyenS Pham Thj Minh Hue^
' Vien Kiim nghiem Thuoc Trung uang ' Truomg Dai hoc Duac Hd Npi 'E-mail: [email protected] Summary
On the purpose of sustaining drug release, elementary osmotic pump (EOP) tablets of venlafaxin hydrocloride were formulated and evaluated. The formulated EOP tablets composed of an senvipenneabie membrance coated osmotic core with an orifice made on one tablet side by laser drill The fonnulation variables affecting the dmg release were investigated in vitro. The amount of swellable polymers, osmotic agents in the osmotic core and semiipemieabie membrance thickness strongly influenced the dmg release profile. In contrary, the orifice size ranging from 0.5 mm to 1.0 mm proved no significant influence on drug release rate.
The optimized formulation for proposal contained hydroxypropyi methyicellulose K4M as swellable polymer;
and sodium cloride, lactose, manitoi as osmotic agents, with semipermeable membrance thickness 5% and orifice size 0.8 mm. The dmg release profile from the optimized formulation was similar to that from reference drug Effexor XR 75 mg.
Keywords: Venlafaxin hydrocloride, sodium cloride, lactose, manitoi.
Dat van de
Vien nen giai phdng dugc chit (GPDC) theo CO ehe ap suit thim thiu da dugc chirng minh la cd nhiiu uu diem nhu ed kha nang dat duge ddng hpc giai phdng thee bac 0, tie dp giai phdng duge chit khdng bj phu thude vao pH eiia dudng tieu hda, nhu ddng rupt, it bj anh hudng nhit bdi thirc an trpng dudng tieu hda, cd su tuang quan Idn giua kit qua nghien cu'u in vitro va in vivo P-^'.
O Viet Nam hien nay ehua ed nhiiu edng trinh nghien eiru v i dang vien nay dugc cdng bd.
Venlafaxin hydroclorid (VH) la thude chdng trim cam, thudc nhdm eae thudc u'c chi chpn Ipe serotonin va nenepinephrin, ed thdi gian ban thai khoang 5 gid, khi sir dung thudc d dang qui udc thi mdi ngay phai dung tu" 2 din 3 lin '"•'^K De nang eae sinh kha dung, ddng thdi duy tri dn dinh ndng dp thudc treng vung diiu trj, trong bai bae nay chung tdi tiin hanh nghien cuu bae ehi vien nen VH giai phdng keo dai dang bom tham thiu qui udc.
Nguyen lieu va phu'O'ng phap Nguyen lieu
Venlafaxin hydroclorid dat tieu chuin BP (An Dp), hydrpxyprppyl methylcellulpse (HPMC) K100M (My), HPMC K15M (My), HPMC K4M (My), polyethylen oxid (PEO) 5 000 000 (My), natri elerid (Trung Qude), manitoi (Phap), lactose (Trung Qudc), Opadry CA (My), pelyvinylpyrroliden K30
(My), Talc (Trung Qude), magnesi stearat (Phap), Avieel PH 101 (My).
Vien doi chieu Effexor XR chira venlafaxin 75 mg do Wyeth Medica Ireland san xuat.
Thiet bj
May dap vien tam sai Korsch (Dire), may khoan laser Epilog Helix (My), ndi bae truyin thdng, may do dp cirng Erweka (Dire), he thdng thir dp hda tan tu ddng kit ndi may UV-VIS Vankel-Varian VK 7010 (My), can ham i m Sartorius MA30 (Dire), can phan tieh Precisa XB 220 CA.
Phu'O'ng phap nghien cu'u Phircmg phap bao che Bao chi vien nhan
Vien nhan chu'a VH duge bae c h i bang phuang phap xat hat udt, moi cdng thirc bao chi 100 vien. VH va cae ta dugc (tru' ta dugc trgn) duge ray qua ed ray 250 pm, trdn bdt kep, them dung dich PVP 10% vao khdi bdt tren, nhao trdn tap thanh khdi i m . Xat hat qua ray 1000 pm, say hat d nhiet dp 60°C tdi khi dat ham am 2 - 3%.
Sira hat qua ray 800 pm, trdn cdm khd vdi ta dugc tron (Talc, magnesi stearat da dugc ray qua ray 180 pm), dap vien tren may dap vien tam sai vdi bd chay cdi hinh tm trdn cd dudng kinh 10 mm, luc gay vd vien 6 - 8 kP.
Sao mang ban thim Cdng thirc djch bae:
Opadry ® CA (CA: PEG 3350 = 9 : 1): 14 g
64 TAP CHI Oniric nnr . unnit: re A AO-, -.. I . -
• Nghien
CLFU- Ky thuat
Nude: 6,7 g Aceton: 300 ml
Ky thuat bao: Sir dung ky thuat bao truyin thdng (mdi me khoang 30 g gdm 3 mau, 20 vien/
miu va cac vien tro ddn them). Cac thdng sd bao:
Nhiet dp bao 40°C, tie dp phun djeh 3 ml/phiit, toe dp quay ndi bao 20 vdng/phut. Vien sau khi bao, siy hilt chan khdng d 40°C trong 3 gid.
Tao mieng giai phong: Mieng giai phdng dugc chit dupe khoan bang may khoan laser (12 vien/
mau, 36 vien/me).
Bao bao ve: Vien tdi uu se duge bao bao ve vdi thanh phin mang bao:
Hydroxyprepyl methyicellulose E6: 10 g Polyethylen glycol 400: 5 g Talc: 2 g Titan diexid: 1 g Ethanol 70% : 200 ml Ky thuat bae; Sir dung ky thuat bae truyen thong (mdi me kheang 20 g gdm 30 vien thir va cac vien tra ddn them). Cac thdng sd bao: tdc dp quay nil bap 20 vdng/phut, tde dp djch phun: 4 ml/
phut, nhiet dp ndi bao: 60 °C. Bae vien ehe tdi khi khdi lugng vien tang len 3% so vdi khdi lugng vien tnj'de khi bae.
Phirong phap danh gia vien nen Danh gia do hda tan
Sit dung he thdng may thir dp hda tan tu ddng kit ndi may dp quang phd UV-VIS. Cac thdng sd thir: mdi trudng la nudc 900 ml; thiit bj gid quay, tic dp 100 vdng/phut; nhiet dp mdi trudng 37°C
± 0,5; cac thdi diem liy miu 1, 2, 4, 8, 12, 16 va 24 gid. Xac djnh lugng heat chat giai phdng sau eae thdi diem liy miu tai budc sdng 235 nm, miu trang la nude.
Yeu ciu hda tan ciia vien nghien ciru nhu trong bang 1, dua thee yeu ciu hda tan eiia thudc phat minh Effexor XRPi.
Bang 1: Yeu ciu hda tan cda vien nghien ciru
Thdi gian (gid) 2 4 8 12 24
Phan tram hda tan (%)
<30 30-55 55-80 65-90
>80
Dd thj giai phdng dugc chit ciia vien nghien cifu se dugc se sanh vdi vien del ehiiu dua tren chi sd fj.
Danh gia vi mat ham lirgng, luc gay vo vien va do dong deu khoi lugng: Thee tieu chuin DDVN.
Ket qua va ban luan
Khao sat anh hu'O'ng do day mang bao den toe do giai phong du'O'c chat
De khae sat anh hudng ciia dp day mang bao tdi tdc dp GPDC, chiing tdi lua chpn edng thu'c vien nhan nhu trong bang 2.
Bang 2: Cdng thirc vien nhan (CTO) VH
HPMC K100 Avieel PH101 NaCI PVPK30
86,1 mg 50 mg 75 mg 10 mg 16 mg
Manitoi Lactose Mg stearat Tale
50 mg 75 mg 2mg 2mg
Tiin hanh bae c h i vien nhan va bae mang ban thim vdi khoi lugng mang bae tang len so vdi vien nhan tuong u'ng la 5% (CTI), 7% (CT2) va 10%
(CTS) va cd cung kich thudc mieng GPDC 0,8 mm. Kit qua thir dp hda tan duge trinh bay thee h i n h l .
90 So
| 7 0 l
°-6o 3 SO
• 5 d o
^ 3 0 Q
# 20 10
o 1
O /J 8 12 TTierJalaoiBi*)
—•—CT1 - • - c r 2 - * - c r 3 16 ?o M
Hinh 1: Dd thi giai phdng duvc chit tu vien ed do day mang bao khae nhau
Kit qua nghien eiru eho thiy khi tang do day mang bao thi tde dp GPDC giam va thdi gian tiim tang tang. Nguyen nhan la de khi mang bao day han, kha nang hut nude vao ben trong vien nhan eham han, din din thdi gian hda tan, truong nd eae thanh phin treng vien nhan tang len, de dd duge ehit bi diy ra mdi trudng hda tan cham ban.
Tde dp GPDC tir miu vien CTI (mang bap 5%) che thiy la phu hgp nhit vdi yeu ciu giai phdng cua vien nghien ciru vi vay miu CT1 duge sir dung trong cac nghien eiru tiip theo.
Khao sat anh hu'O'ng kich thu'O'c mieng giai phong den tdc dp giai phong du'O'c chit
De nghien eiru anh hudng eiia kich thudc mieng giai phdng din qua trinh GPDC, tiin hanh bae c h i miu vien nhan theo cdng thire CTO, khdi lugng mang bae ban thim tang len 5% so vdi vien nhan, kieh thudc mieng giai phdng 0,5 mm (CT5), 0,8 mm (CTI) va 1,0 mm (CT4). Tien hanh thir dp hda tan cac miu vien, kit qua thir dp hda tan nhu dugc trinh bay treng hinh 2.
TAP CHI Dl/OC HOC - 6/2016 (SO 482 NAM 56) 65
• Nghien
CIFU- Ky thuat
90 1 80 J S7o\
^ 6 0 -'
£ " 5 0 -
§ • 3 0 - Q 1
10 - .
0 tur
o A 8
Thor 1 2 gian (ei^')
- • - C T d
- * - C T i
16 20 24
Hinh 2: Do thj giai phdng duge ehit tu cac mau vien cd kich thuac mieng giai phdng khae nhau Ca 3 mau vien nghien eiru deu cd thdi gian lag - time tuong tu nhau, khoang 1 gid. Kich thudc mieng giai phdng it anh hudng din tdc dp GPDC, diiu nay cung phu hgp vdi mdt sd nghien ciru trudc day v i anh hudng ciia kich thudc mieng gial phdng tdi tie dp GPDC '''•^. Thuc t i khap sat, cdng thire CTI cd kieh thudc mieng giai phdng 0,8 mm che thiy la phu hgp de lua chpn de cho cac nghien eiru tiip theo.
Xay dyng cong thiFC vien nhan venlafaxin hydroclorid
Danh gia firong tac dirg/c chat-fa dugv Tiin hanh nghien ciru tuong tac dugc chit, ta dugc dua tren kit qua do phd hdng ngoai ciia dugc chit VH, hdn hgp VH - HPMC K4M, hdn hgp VH - lactose va hdn hgp VH - manitoi. Kit qua khao sat duge chi ra treng hinh 3. Dai hip thu dae trung eiia dugc chit la tuong tu dai hip thu dac trung cua hdn hgp duge ehit va ta dugc khae sat, vi vay khdng cd su tuong tae giO'a duge chit va ta duoe.
2 '"
20
3 50
1
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1 40
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Hinh 3: Phd hong rigoai ciia VH (D), VH-laetose (A), VH-HPMC K4M (C), VH-manitol (B).
Lira chgn fa dugc truvmg n& cho cong thin vien nhan venlafaxin hydroclorid
Cac ta dugc HPMC K100M, HPMC K15M, HPMC K4M v i PEO da duge lua chpn de khao sat anh hudng ciia ta duge trugng nd d i n tie dp giai phdng eua duge chit.
Tien hanh bao c h i eae miu vien cd cdng thu'c nhu trong bang 3 va thir hda tan. K i t qua thir dp hda tan dugc trinh bay trong hinh 4.
uo
g
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20 24
Hinh 4: Dd thi giai phdng duuc chat tir cac miu cd ta duge truang na khae nhau
Cd the thiy, ty le ta dugc truang nd da khao sat cd anh hudng rd ret den tde dp GPDC. Ta duge HPMC cd dd nhdt cao thi cang lam cham tde do GPDC. Nguyen nhan la do HPMC cd dp nhdt cae khi hut nudc truang nd tae Idp gel dac gay can trd su thim hut ciia mdi trudng vao sau ben trong vien, ddng thdi vdi Idp gel dac nay se khd bj day ra ngoai mdi trudng hda tan ban. Hai miu vien CT7 (chua HPMC K4M) va CTI 6 (chira PEO) cho thiy phin tram GPDC la phu hgp vdi yeu ciu va tuong tu nhu vien ddi ehiiu, chi sd f^ cua CT7 va CTI 6 se vdi vien doi ehiiu lin lugt la 67,0 va 79,9.
HPMC duge sir dung nhiiu do tinh an tean, sin cd va thieh hgp vdi nhiiu leai dugc chit, vi vay ehung tdi lua chpn mau vien CT7 chu'a HPMC K4M de sir dung chp cac nghien ciru tiip theo.
Bang 3: Cdng thirc vien thim thiu chu-a cac loai ta duge truang na khae nhau
66
Thanh phan vien VH
HPMCK100M HPMCK15M HPMC K4M PEO 5 NaCI Manitoi Lactose Avieel PH 101 PVP K30 Magnesi stearat Talc
(mg) CT1 86,1
50 0 0 0 10 50 75 75 16 2 2
Cong thire CT6 86,1
0 50 0 0 10 50 75 75 16 2 2
C77 86,1 0 0 50 0 10 50 75 75 16 2 2
CT16 86,1
0 0 0 50 10 50 75 75 16 2 2
TAP CHI DlTOC HOC - 6/2016 lah dn-) M * «.. , , -
• Nghien
CIPU- Ky thuat
Nghien cu'u anh hirong cua ty le HPMC K4M den toe do giai phong dirge chat
De lua chpn dugc ty le HPMC K4M tdi uu, tiin hanh bap c h i cac miu vien cd ham lugng HPMC K4M khac nhau nhu treng bang 4, tiin hanh thir dp hda tan. Kit qua thu dugc nhu trong hinh 5.
Bang 4: Cdng thirc wen tiiim thiu vdi ty le HPMC K4M khae nhau
Thanh phan 1 vien (mg) VH HPMC K4M Avieel PH 101 NaCI Manitoi Lactose PVP K30 Magnesi stearat Talc
CTT 86,1
50 75 10 50 75 16 2 2
Cong thirc CT8 86,1
30 95 10 50 75 16 2 2
CT9 86,1
70 55 10 50 75 16 2 2
120 100 - S 80 - D.
"cb 5 0
" 4 0 O 20
-20
3 A 8 Ther
12 giar
- • - 0 7 -HH-CTS - * - c r 9
16 (gi^)
2 0 2 4
Hinh 5: Dd thi giai phdng dugc chit tir eae miu ed ty ie hydroxypropyi methyicellulose K4M khac nhau
Kit qua thir dp hda tan cho thiy khi lugng HPMC K4M tang din den tdc dp GPDC giam tde dp GPDC, dac biet d nhiing gid diu. Miu vien CTS ed lugng HPMC K4M thip (30 mg/vien) cd tdc dp GPDC nhanh ban miu vien CT7 va CT9 cd lugng HPMC K4M eae, sau 10 gid da giai phdng duge 91,3% dugc chat. Nguyen nhan ed the do miu vien chira lugng HPMC k4M thip khi gap nude truang nd va ehi tao ra Idp gel mdng, nudc d l dang thim sau vae ben trong vien va hda tan dugc ehit nhanh ban. Lugng HPMC 4M thip cung tao ra hdn hgp dugc chit - ta dugc ed dp nhdt thip ban nen d i dang bj diy qua mieng giai phdng ra ngpai mdi trudng hda tan ban. Miu vien CT9 ed phin tram giai phdng duge ehit d nhu'ng gid dau tuong ddi thip va ehi sd f^ se vdi vien ddi ehiiu khdng cae. Vi vay ehung tdi lya chpn mau vien CT7, cd phin tram GPDC phu hgp vdi yeu ciu eho nhtrng nghien ciru tiip thee.
Nghien ciru anh hirong cua ta dirge tao ASTT den foe do GPDC
Ap suit thim thiu trong vien nhan cd vai trd rat quan trpng de keo nudc qua mang ban thim, do dd quyit dinh tdc dd GPDC. De nghien eiru anh hudng ciia ta dugc tao ASTT d i n tdc dp GPDC, cac miu vien ed ty ie eae ta duge tao ASTT khac nhau duge tien hanh bao c h i vdi cdng thirc nhu trong bang 5.
Bang 5: Cdng thire vien thim thiu vdi ty le ta duge tao ASTT khac rihau (n = 3)
Thanh phan vien (mg) VH HPMC K4M Avieel PH 101 NaCI Manitoi Lactose PVP K30 Magnesi stearat Tale
CT7 86,1
50 75 10 50 75 16 2 2
CT10 86,1
50 65 20 50 75 16 2 2
Cong thirc CT11 86,1
50 85 0 50 75 16 2 2
CT12 86,1
50 45 10 80 75 16 2 2
CT13 86,1
50 105
10 20 75 16 2 2
CTU 86,1
50 25 10 50 125 16
2 2
cr/5
86,1 50 125 10 50 25 16 2 2 Tiin hanh thir dp hda tan cac miu vien, kit qua thu dugc trinh bay treng hinh 6, 7 va 8.
a''°° 1
0. 80
a
D
•S 60 - 6- 4 0 -
a
-e 1
0 i 8 12
Thcrt gian (gio*) -^-cry
• CTio
16 20
I
24
Hinh 6: Od thi giai phdng duge ehit tu eae mau ed ty le natri clorid khac nhau
120
100
•o
•& 80
1>
• ^ 60
Jj
§" 4 0
20
.
0 4 8
JhOl 12 giar (ei&)
- ^ C T 7 - • - C T 1 2 - « r - C T l 3
16 20 24
Hinh 7: Dd thi giai phdng duge chit tu cac miu cd ty le manitoi khae nhau
TAP CHI DLTOC HOC - 6/2016 (SO 482 NAM 56) 67
• Nghien cCru - Ky thuat
120 cnlOO o- 80 S 60
> 40 Q
* 20
0 4 8 12 16 Thdi gian (gio)
- • - c n
~9-cn
20 24
Hinh 8: Sd thj giai phdng duge chit tu cac miu cd ty ie lactose khae nhau
Tif kit qua thir dp hda tan che thiy: khi lugng ta dugc tae ASTT treng vien tang thi tde dp GPDC tang va nguge lai. Nguyen nhan la de khi tang ta dugc tae ASTT trong vien din din chenh lech ap suit trong va ngeai mang bao Idn, nude dugc hut vao trong vien nhanh ban, hda tan dugc chit, lam truong nd ta dugc va day dugc ehit ra ngoai nhanh ban.
Phan tram giai phdng duge chit tir mau vien CT7 eho thiy la phu hgp vdi yeu ciu giai phdng dat ra cho vien nghien cu'u, ehi sd f^ so vdi vien ddi ehiiu cao 67,0. Do dd mau vien CT7 duge chgn la mau vien phu hgp vdi nghien ciru.
Miu vien CT7 dugc bao bao ve vdi thanh phin nhu trinh bay trong muc 2, tiin hanh thir dp hda tan, kit qua dugc trinh bay treng bang 6 va hinh 9.
Bang 6: Phin tram dugc chat giai phdng tu vien bao bao ve va vien khdng bao bao ve (n = 12)
Thdi gian (g/6')
1 2 3 4 6 8 10 12 16 24
Vien khdng bao bao ve (CU)
1,8 11,1 23,9 36,0 57,2 70,0 77,1 82,9 89,8 98,7
Vien bao baove
2,7 12,7 27,2 43,0 60,0 70,9 78,1 84,4 92,8 100,9
Effexor XR 3,4 16,4 30,3 41,7 57,2 67,0 74,9 78,8 876 106,4
Chi so f. 670 70,1
Hinh 9: 0d thi giai phdng duge ehit tu vien bao bao ve, vien khdng bao bao ve (CT7) va vien doi ehiiu
EffexorXR
Kit qua thir dp hda tan cho thiy dugc chat giai phdng tir vien bao bao ve va vien khdng bao bao ve khac nhau khdng dang ke va d i u phu hgp vdi vien ddi ehiiu.
Sir dung phin m i m S-PLUS 8.0 de phan tieh ddng hpc giai phdng ciia vien nghien ciru va vien ddi chieu trong khoang thai gian tu-1- 24 gid. Kit qua dugc trinh bay trong bang 7.
Bang 7: Kit qua phan tieh ddrig hoc giai phdng eua mau vien nghien eiru va vien ddi ehiiu
Gia trj AlC Mau vien
BacO
^'^" 5999
nghien CLPU
^'?" . 5545 46i chieu
6act
39,04
35,55 Higuehi
49,57
41,48
,,,., „ Hixson- '*«'""'' Crowell
29,71 33,95
34,15 32,77 Korsmeyer-
Peppas 52,48
45,96
Tif kit qua phan tich cho thiy md hinh ddng hpc Weibull la phii hgp nhit eho qua trinh GPDC eiia vien nghien ciru, gia trj AlC nhd nhit (29,71) cdn vien ddi ehiiu giai phdng theo ddng hpc Hixsen - Crowell (AlC = 32,77). Vien nghien cu'u giai phdng theo ddng hge bae 0: y = 8,7575x - 2,9507, he sd R^ = 0,9676 treng khoang 1 -10 gid.
Diiu nay cung phu hgp vdi nhan djnh cua Gregory A. McClelland va CS. '^i, khi dua ra rang ddi vdi eae ehit rit de tan treng nudc thi chi mdt lugng nhd dugc chit ban d i u giai phdng tuan theo ddng hpc giai phdng bac 0.
Kit qua khao sat met sd ehi tieu chit lugng vien thim thiu khoan lo
Do ma/ 00 cmg Kfcht/iiroc Khoi tuvng Ham/uong
mon vien vien nhan mieng giai phong trung binh vien duvc chit nhan(%) (kP) (mm) sau bao baove (%)
W
0,51 7,2t0,4 0,827510,0072 387,9 + 5,1 mg 100,3t1,4
Kit luan
Trong nghien ciru nay, vien nen venlafaxin hydroclorid giai phdng kee dai dang bom tham thiu qui udc da duge khao sat va danh gia. Kit qua cho thiy khi tang ty le ta dugc truong nd thi tdc dp GPDC giam, treng khi dd ty le ta dugc tao ap suit thim thiu tang thi tdc dp GPDC cung tang, dp day mang ban thim tang d i n d i n giam tdc dp GPDC, kich thudc mieng giai phdng thay ddi tif 0,5 din 1,0 mm ehe thay khdng cd su khae biet dang ke tde dp GPDC. Phin tram GPDC tir cdng thirc lua chpn phu hgp vdi vien ddi ehiiu va phii hgp vdi yeu ciu GPDC dua ra ehe vien nghien ciru.
68 TAP CHID' .ifrTf/"* XI/^/^ /:/'»«•«