nghiên cứu bào chế viên trimetazidin phóng thích kéo dài
TRANSCRIPT
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BY T
BO CO KT QUNGHIN CU
TI CP B
Tn ti:NGHIN CU BO CHVIN TRIMETAZIDIN
PHNG THCH KO DI
Chnhim ti:GS. TS. L Quan Nghim
Cquan chtr ti:i hc y dc Tp. HCM (KhoaDc)
TP. HCH MINH
Thng 12/ 2009
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DANH SCH CC CHVIT TT
TVIT TT TNGUYNPTKD Phng thch ko di
TI Therapeutic Index
MR Modifield release
HPMC Hydroxypropylmethylcellulose
TCCS Tiu chun cs
HPLC High performance liquid Chromatography
UV-VIS Ultraviolet
USP United states Pharmacopoeia
IR Infrared
RSD Relative standard deviation
CV Coefficient of variation
ACN Acetonitril
AUC Area Under the Curve
CV Coefficient of Variation
CI Confidence Interval
CPMP Committee for Proprietary Medicinal ProductsFDA United States Food and Drug Administration
GHL Lower Limit of Quantification
GLP Good Laboratory Practice
HPLC High Performance Liquyd Chromatography
SD Standard Deviation
SPE Solid Phase Extraction
TB Trung bnh
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USP United States Pharmacopeia
DANH MC CC BNGS TN BNG SLIU TRANG
2.1. Cc thng sdc ng hc ca Trimetazidin 7
2.2. Nguyn tc loi trtrong xc nh tui thca thuc 16
3.3. Nguyn liu dng trong bo ch 25
3.4. Ha cht dng trong kim nghim 25
3.5. Thit bkim nghim 26
3.6. Thit bbo ch 26
3.7. Phn mm thit k/ti u ha 27
3.8. Thnh phn cng thc 37
3.9 Thiet ke th nghiem tng ng sinh hoc theo mo hnh cheo 42
4.10. Kt qukho st tnh tuyn tnh trong mi trng acid pH 1,2 47
4.11. Kt qukho st nh hng ca t dc trong mi trng acid pH 1,2 48
4.12. Kt qukho st lp li trong mi trng acid pH 1,2 48
4.13. Kt qukho st ng trong mi trng acid pH 1,2 49
4.14. Kt qukho st tnh tuyn tnh trong mi trng m phosphat pH 4,5 49
4.15. Kho st nh hng ca t dc trong mi trng m phosphat pH 4,5 50
4.16. Kt qukho st lp li trong mi trng m phosphat pH 4,5 51
4.17. Kt qukho st ng trong mi trng m phosphat pH 4,5 514.18. Kt qukho st tnh tuyn tnh trong mi trng m phosphat pH 6,8 52
4.19. Kho st nh hng ca t dc trong mi trng m phosphat pH 6,8 53
4.20. Kt qukho st lp li trong mi trng m phosphat pH 6,8 53
4.21. Kt qukho st ng trong mi trng m phosphat pH 6,8 54
4.22. Kho st tnh tng thch trn mu chun Trimetazidin 55
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4.23. Kho st tnh tng thch mu thTrimetazidin 55
4.24. Tng quan gia din tch nh vi nng Trimetazidin chun 56
4.25. Kt qukho st lp li trong phng php HPLC 57
4.26. Kt qukho st ng trong phng php HPLC 57
4.27. So snh 2 phng php nh lng 58
4.28. Thm d cc iu kin phn tch trimetazidin bng phng php HPLC 59
4.29. Cc thng ssc k trong mu chun v mu th 59
4.30. Kt qu kho st s tng quan gia nng trimetazidin trong huyttng v tldin tch nh cht chun trimetazidin v cht chun
Lidocain
61
4.31. Kt qukho st chnh xc trong ngy 63
4.32. Kt qukho st chnh xc lin ngy 63
4.33. phc hi trimetazidin v lidocain trong huyt tng 64
4.34. Kt qukho st n nh ca trimetazidin trong ngy bo qun nhit
phng
65
4.35. Kt qukho st n nh ca trimetazidin sau khi lm lnh v r ng 65
4.36. Thnh phn cng thc vin nhn theo m hnh vung la tinh 66
4.37. Dliu u vo cho phn mm thng minh FormRules 67
4.38. Xu hng v mc lin quan gia nhn v qu 68
4.39. Kt qukho st phng thch hot cht 14 l thc nghim 70
4.40. nh gi cc m hnh lin quan nhn qu 72
4.41. Cc iu kin ti u ha cng thc bng phn mm INForm 72
4.42. Thnh phn cng thc v tnh cht sn phm c don bi INForm 73
4.43. Kt qukim nghim bn thnh phm 3 l thc nghim kim chng 73
4.44. phng thch hot cht ca 3 l kim chng 74
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4.45. phng thch hot cht ca kt qudon bi INForm, trung bnh 3 lkim chng v vin Vastarel MR
75
4.46. Kt qukim nghim vin thnh phm 76
4.47. % hot cht phng thch ca vin thnh phm 76
4.48. So snh cc chtiu gia quy m PTN v pilot 77
4.49. Nng Trimetazidin (ng/ml) trong huyt tng ti cc thi im (gi)sau khi ung vin Vastarel 35 mg MR
80
4.50. Nng Trimetazidin (ng/ml) trong huyt tng ti cc thi i m (gi)sau khi ung vin Trimetazidin 35 mg MR
80
4.51. Tm tc kt qucc thng sdc ng hc ca thuc Trimetazidin MR 83
35 mg v vin Vastarel 35mg MR
4.52. Yu tnh hng da trn gi trAUC0-(ng/ml gi); Cmax(ng/ml) 84
4.53. Trc nghim t da trn gi trAUC0-(ng/ml gi) v Cmax(ng/ml) 85
4.54. Kt quso snh tng ng sinh hc trung bnh 85
4.55. Xc nh Co
884.56. Sthay i hnh thc cm quan iu kin lo ha 89
4.57. Sthay i ha tan iu kin lo ha 91
4.58. Sthay i vcm quan, hm lng trimetazidin trong iu kin tnhinca lZ010209
92
4.59. Sthay i ha tan trong iu kin tnhin ca lZ010209 93
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vi
DANH SCH HNHS TN HNH NH TRANG
2.1 Hthng PTKD c cu trc khung xp 5
2.2. Cng thc cu to ca Trimetazidin 7
2.3. Sn phm Vastarel MR 35 mg 10
2.4. Sn phm Cardimax SR 60 mg 10
2.5. Chu trnh don v ti u ha (INForm) 13
2.6 Skt hp mng thn kinh vi thut ton di truyn 14
4.7. thbiu din tng quan tuyn tnh gia nng v hp thutrong mi trng acid pH 1,2
47
4.8. thbiu din stng quan tuyn tnh gia nng v hpthu trong mi trng m phosphat pH 4,5
50
4.9. thbiu din stng quan tuyn tnh gia nng v hpthu trong mi trng m phosphat pH 6,8
52
4.10. Tng quan tuyn tnh gia nng v din tch nh 56
4.11. Sc k ca mu huyt thanh trng 60
4.12. Sc k ca mu huyt thanh c trimetazidin nng 20 ng/ml 60
4.13. Sc k ca mu huyt thanh c trimetazidin nng 100 ng/ml 61
4.14. thbiu din stuyn tnh gia nng trimetazidin vi dintch nh trimetazidin
62
4.15. Minh ha nh hng ca x1, x2 v x3n y1 69
4.16. Minh ha nh hng ca x1, x2v x3n y2 69
4.17. Minh ha nh hng ca x1v x3ti y3 69
4.18. Minh ha nh hng ca x1,x2v x3n y4 70
4.19. thso snh phng thch hot cht ca 3 l kim chng 74
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4.20. thso snh phng thch hot cht kt qudon ca
INForm, gi trthc nghim v vin chun Vastarel MR 35mg
75
4.21. gii phng hot cht gia vin chun v vin thmi trng
pH 1,2
78
vii
4.22. gii phng hot cht gia vin chun v vin thmi trngpH 4,5
78
4.23. gii phng hot cht gia vin chun v vin thmi trngpH 6,8
79
4.24. Sc k huyt thanh NTN trc khi ung thuc 81
4.25. Sc k huyt thanh NTN sau khi ung thuc 0,5 gi 81
4.26. Sc k huyt thanh NTN sau khi ung thuc 8 gi 82
4.27. Sc k huyt thanh NTN sau khi ung thuc 48 gi 82
4.28. ng biu din nng trimetazidin trung bnh trong huyt thanhNTN sau khi ung ung Trimetazidin v Vastarel
83
4.29. thbiu din nng thuc theo thi gian ca thuc thvthuc i chiu ca NTN 1
86
4.30. thbiu din nng thuc theo thi gian ca thuc thvthuc i chiu ca NTN 2
86
4.31. thbiu din nng thuc theo thi gian ca thuc thvthuc i chiu ca NTN 3
87
4.32. thbiu din nng thuc theo thi gian ca thuc thvthuc i chiu ca NTN 5
87
4.33. thbiu din nng thuc theo thi gian ca thuc thvthuc i chiu ca NTN 4
88
4.34. thbiu din sthay i hm lng caL Z010209 89
4.35. thbiu din sthay i hm lng caL Z020209 90
4.36. thbiu din sthay i hm lng caL Z030209 90
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i
MC LC
Trang
Mc lc i
Danh sch cc chvit tt iii
Danh sch bng iv
Danh sch hnh v
Phn A Bo co tm tt
-Bn tnh gi kt quni bt ca ti
-Tm tt bo co
Phn B Bo co chi tit
1. T VN 1
2. TNG QUAN TI 2
2.1. HTHNG TRLIU PHNG THCH DC CHT KO
DI NG UNG
2
2.2. TRIMETAZIDIN DIHYDROCHLORID 7
2.3. PHT TRIN THUC VI STRGIP CA VI TNH 11
2.4 NGHIN CU N NH CA THUC 14
2.5. XC NH TNG NG HA TAN IN VITRO 17
2.6. PHN TCH HOT CHT TRONG DCH SINH HC 20
2.7. THM NH PHNG PHP NH LNG DC CHT
TRONG DCH SINH HC
20
3. I TNG & PHNG PHP NGHIN CU 24
3.1 I TNG 24
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3.2 NGUYN LIU V THIT BNGHIN CU 25
3.3 PHNG PHP NGHIN CU 27
3.3.1 NH LNG TRIMETAZIDIN NGUYN LIU V TRONG CH
PHM BNG PHNG PHP HPLC V UV-Vis
27
ii
3.3.1.1 PHNG PHP UV-Vis 27
3.3.1.2 PHNG PHP HPLC 30
3.3.1.3 SO SNH 2 PHNG PHP 32
3.3.2 NH LNG TRIMETAZIDIN TRONG DCH SINH HC BNG
PHNG PHP HPLC
32
3.4 PHNG PHP NGHIN CU VBO CH 37
3.5 PHNG PHP NGHIN CU TNG NG IN VITRO 40
3.6 PHNG PHP NGHIEN CU TNG NGIN VIVO 41
3.7 PHNG PHP NGHIN CU N NH V TUI TH 44
3.8 PHNG PHP PHN TCH THNG K 45
4. KT QUNGHIN CU 47
4.1 PHNG PHP NH LNG V THM NH PHNGPHP
47
4.2 NGHIN CU BO CHVIN TRIMETAZIDIN 35 mg PHNG
THCH KO DI
66
4.3 NH GI TNG NGIN VITRO 78
4.4 N NH V C TNH TUI TH 88
5. BN LUN 94
6. KT LUN & KIN NGH 96
7. TI LIU THAM KHO 98
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PHU LC
1. Tiu chun csv phng php thvin bao phng thch ko
di cha trimetazidin 35mg
2. Phiu kim nghim vin theo tiu chun cs
3. Tm tt kt qunghin cu tng ng sinh hc
PHN A
BO CO TM TT
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BN TNH GI
Vtnh hnh thc hin v nhng ng gp mi ca
ti KH&CN cp b
1.Tn ti:Nghin cu bo chvin trimetazidin phng thch ko di2.Thuc chng trnh: Nghin cu nng cao cht lng thuc sn xut
trong nc
3.Chnhim ti:GS. TS. L Quan Nghim
4.Cquan chtr ti:Trng H Y Dc Tp. HCM
5.Thi gian thc hin:t6/2006 n 30/06/2009
6.Tng kinh ph thc hin ti: 500 triu ng
Trong : kinh ph SNKH: 400 triu ng
7.Tnh hnh thc hin so vi cng
7.1.Mc hon thnh khi lng cng vic:
Thc hin ton bkhi lng cng vic so vi cng
7.2.Vcc yu cu khoa hc v chtiu cbn ca cc sn phm KHCN Nghin cu
cng thc v quy trnh bo chvin bao phng thch ko di l dng chphm mi cha
c nghin cu sn xut Vit nam
Quy trnh bo chc nng cp ln quy m 30.000 vin, n nh v c tnh lp
li.
Sn phm t tiu chun cs, n nh v c tui th24 thng
Vin bao tng ng sinh hc vi chphm i chiu l vin Vastarel 35mg
MR
C thng k lu hnh, sn xut cng nghip v thay thc thuc ngoi nhp
7.3.Vtin thc hin:
Tin chm so vi ng k v nhng kh khn trong nh lng trong dch sinh hc
v thtng ng sinh hc
8.Vnhng ng gp mi ca ti:
8.1.Vgii php khoa hc cng ngh:
p dng phng php thit kti u ha trong nghin cu xc nh cng thc
8.2.Vphng php nghin cu:
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Nghin cu bo chvin phng thch ko di bng phng thc sdng dliu thc
nghim v dng phn mm nh gi cc yu tnh hng v ti u ha cng
thc. Kim chng cng thc ti u bng thc nghim.
nh gi cht lng v hiu quso vi thuc i chiu bng thnghim tng ng
ha tan in vitro v tng ng sinh hc in vivo.
8.3.Nhng ng gp mi khc
-Trong khun khca ti o to 03 dc s
-Kt quca ti c dkin cng btrong 02 bi bo trn tp ch chuyn ngnh.
9. ng gi chung
- ti thc hin y cc ni dung v mc tiu theo cng c duyt -
Kinh ph ca ti c cp y theo ph duyt, tuy nhin khng p ng nhu
cu chi tiu thc tdo kinh ph pht sinh t thnghim tng ng sinh hc. -
Thi gian thc hin chm so vi cng
TP.Hch minh, ngy 30 thng 2 nm 2010
Chnhim ti
GS. TS. L Quan Nghim
TM TT BO CO
ti Nghin cu bo chvin Trimetazidin phng thch ko di vi cc mc
tiu nghin cu nhsau:
Mc tiu tng qut
Nghin cu bo chvin nn phng thch ko di cha hot cht Trimetazidin dihydrochlorid 35
mg.
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Cc ni dung nghin cu:
1.Kho st v thm nh cc phng php nh lng ng dng trong in vitro v
in vivo
2.Nghin cu bo chvin phng thch ko di cha Trimetazidin 35 mg qui m
pilot, c thp dng sn xut trong nc
3.Xc nh tng ng sinh hc so vi vin i chiu Vastarel MR 35 mg
4.Nghin cu n nh v don tui thca thuc Kt qu:
1.Kho st v thm nh cc phng php nh lng
1.1. nh lng trimetazidin trong chphm
Phng php quang phUV: nh lng trimetazidin dihydrochlorid bc sng231nm. Phng php c thm nh 3 mi trng pH: 1,2; 4,5; 6,8 v tnh
tuyn tnh, tnh c hiu, lp li, ng, nh hng ca t dc.
Phng php t yu cu c thng dng nh lng trimetazidin dihydrochlorid dng nguyn
liu, trong chphm vin, trong dch thha tan.
Phng php sc k lng hiu nng cao (HPLC)
Xc nh cc iu kin sc k. Phng php nh lng Trimetazidin
dihydrochlorid bng HPLC c thm nh v: Tnh thch hp h thng, lpli, ng v chnh xc: quy trnh phn tch t yu cu c thng dng
nh lng trimetazidin dihydrochlorid.
So snh 2 phng php nh lng UV v HPLC
Kt qucho thy skhc nhau vgi trtrung bnh v phng sai ca 2 phng php l
khng c ngha thng k.
Kt lun: C thnh lng Trimetazidin bng c2 phng php UV v HPLC
1.2. nh lng Trimetazidin trong dch sinh hcThm d cc iu kin phn tch trimetazidin bng phng php HPLC
Phng php sc k lng hiu nng c thm nh v: Tnh thch hp hthng,
c hiu, khong tuyn tnh, gii hn nh lng, ng v chnh xc,
phc hi: quy trnh phn tch trong dch sinh hc t yu cu, c thng dng
trong thtng ng sinh hc in vivo.
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Kho st sn nh ca trimetazidin trong dch sinh hc: Mu trimetazidin
0 tronghuyt tng c thbo qun nhit phng trong 24 gi, -20 C sau khi rng 3 chu k.
2.Nghin cu bo chvin phng thch ko di
2.1.nh gi nh hng ca cc thnh phn: bng m hnh thc nghim vung
la tinh vi 3 mc cho mi yu tc thit kgm 9 cng thc.
2.2.Phn tch lin quan nhn qubng phn mm FormRules
Kt qu: phng thch hot cht cc thi im 0,5 gi, 1 gi, 2 giv 4 gib
nh hng r nt bi thnh phn cc T dc A, HPMC 15cp v Kollidon. Ring
phng thch thi im sau 8 gichbnh hng bi HPMC 15cp vi mc
khng ng k.
2.3.Ti u ha cng thc: M hnh cng thc cho vin nhn Trimetazidin c
thit k bi phn mm Design-Expert theo m hnh D-Optimal gm 14
cng thc. D liu thc nghim c dng lm u vo cho phn mm
thng minh INForm ti u ha cc thng sca thnh phn cng thc.
Thnh phn cng thc v tnh cht sn phm c don bi INForm v c so
snh vi thc nghim cho thy khng c skhc bit.Thnh phn cng thc ti u ca vin nn phng thch ko di cha hot cht Trimetazidindihydrochlorid 35 mg c xc nh l:
Thnh phn Lng(1 vin) mg
Trimetazidin dihydrochlorid35
T dc A19,9
HPMC 15cp31,8
Kollidon29,8
Aerosil2
Magnesium stearat4
Ludipressv 200
2.4.Phng php bo chvin nhn
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Vin nhn Trimetazidin 35 mg PTKD c cu trc khung matrix c bo ch bng
phng php dp thng vi my dp vin xoay trn, sdng chy 8 mm. Quy trnh
gm cc giai an:
- Ry (qua cry 0,5 mm), ring Aerosil ry qua ry 0,8 mm v cn tng nguyn liu.
- Trn ban u trong 8 pht: trMg stearat v Aerosil.
- Trn sau cng trong 2 pht: hn hp, Mg stearat v Aerosil.
- Dp vin vi my dp vin xoay trn
2.5.Nghin cu nng cl tquy m th nghim ln quy m pilot 30.000vin Kt qu
kim nghim sn phm ca 3 l pilot cng c so snh vi sn phm quy m
PTN
So snh cc chtiu gia quy m PTN v pilot
Tnh cht ca vin Trimetazidin MR 35mg
Chtiu Phng th nghim Pilot
cng (N) 84,5 2,45 N 85,8 2,24 N
Khi lng trung bnh (mg)
208,54 13,42 mg (CV 215,64 13,42 mg (CV
= 1,14%) = 1,21%)
nh lng (%)98,53 0,81 % (CV = 97,88 0,81 % (CV =0,55%) 0,71%)
ha tan sau 1 gi(%) 39,12 1,02 40,15 1,32
ha tan sau 4 gi(%) 71,05 0,53 72,12 0,33Nhvy, quy trnh sn xut ca vin Trimetazidin MR 35mg bng phng php dp
thng c nng cp tquy m PTN ln quy m pilot thnh cng. Thnh phm c
p v, mu c cung cp dng cho nghin cu n nh
2.6.Nghin cu quy trnh bao vin nhn
Dch bao phim c iu chdi dng hn dch vi thnh phn l OpadryII 10% (kl/kl)
trong mi trng phn tn cn - nc (tl1:5).
Thnh phn dch bao:
Opadry II 10% Cn 96%
15%
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Nc 75%
Thng skthut bao phim:
Cc thng skthut c thm d v la chn trn thc nghim nhsau:
- My bao phim tng FC 10, 6 cnh o
- u phun: loi IWATA LA 70 B
- Lphun: 1,2 mm
- Cl: 8 kg vin nhn
- Tc ni: 6 7 vng/pht
- Nhit : Kh vo: 65 70 0C
Kh ra: 45 50 0C
Nhit vin: 38 42 0C
- Tc phun dch bao: 12 17 g/pht (tc bm nhu ng: 20)
- p sut kh nn: 2,2 kg/m2
- Brng di phun: Phht brng khi vin
- Khong cch tsung phun n bmt khi vin: 15 17 cm
- Sy sau khi bao: 45 pht 50 oCKim nghim thnh phm: vin bao t tiu chun cs
3.Nghin cu tng ng sinh hc so snh vi thuc i chiu
3.1. Tng ng ha tan in vitro ha tan ca 2 ch phm i chiu (Vastarel MR 35mg) v th nghim
(Trimetazidin MR 35mg) trong 3 mi trng pH 1,2; 4,5 v 6,8 . Kt qutnh ton
gi tryu ttng tf2u > 50 cho thy biu ha tan c trnh by hnh
4.19; 4.20; 4.21. ca 2 chphm trong c3 mi trng l tng tnhau. (f2 ln
lt l 62,32; 99,86,; 99,83).
3.2.Tng ng sinh hc in vivo
nh gi tng ng sinh hc bng phng php nh lng nng thuc trong
huyt tng so snh vi vin i chiu Vastarel MR 35mg.
Tm tc kt qucc thng sdc ng hc ca thuc Trimetazidin MR 35 mg v vinVastarel MR 35mg
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Thng sdcng hc
Vastarel 35 mg MR Trimetazidin 35 mg MR
AUC0-48(g.gi/ ml) 93,0083,306 90,7332,081AUC0-(ng/ ml/h) 1054,5 168,5 1256,5 275,5
Cmax(ng/ ml) 35,74 0,574 32,78 6,89
Tmax(gi) 5,15 2,13 5,34 1,65
T1/2(gi) 6,2 0,782 5,8 1,45
Ke 0,45300,05 0,5100,47
nh gi tng ng sinh hocKt qu trc nghim chng minh c vin Trimetazidin 35 mg MR tng
ng sinh hc so vi vin Vastarel 35 mg MR trong gii hn tng ng v vi
tin cy 90% i vi cc thng sdc ng hc c phn tch.
4.Nghin cu n nh v dan tui th
Theo di n nh ca sn phm iu kin lo ha trong vng 6 thng.
iu kin lo ha: Nhit l 40 oC; m 75%.
Tui thdon ca vin Trimetazidin MR 35mg khong 24 thng.
Kt lun
ti hon thnh tt cmc tiu v ni dung nghin cu. Vin phng thch ko di
chc trimetazidin 35mg c quy trnh bo chn nh, p ng yu cu vcht lng
c thng dng sn xut trong cng nghip.
.III. Cc kt qukhc
3. 1. Trong khun khca ti o to 3 dc si hc
3. 2. Kt quca ti c dkin cng btrn 02 bi bo ( cng b01 bi bo)
IV. Tnhn xt
- ti thc hin y cc ni dung v mc tiu theo cng c duyt -
Kinh ph ca ti c cp y theo ph duyt, tuy nhin khng p ng nhu
cu chi tiu thc tdo kinh ph pht sinh t thnghim tng ng sinh hc. -
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Thi gian thc hin chm so vi cng do nhng kh khn trong qu trnh thc
hin thnghim tng ng invivo
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PHN B
BO CO CHI TIT
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1
1. T VN Trimetazidin l mt hot cht tuy c bit n tlu, nhng vi nhng tc dng
dc l mi pht hin, c nghin cu v a vo phc iu trau tht ngc
n nh. Trimetazidin c khnng bo vtbo ctim theo cchchuyn bit. Mt
khc vic tm kim nhng gii php iu trnhm kim sot tt hn triu chng bnh,
ci thin tnh trnh bnh nhn v nng cao hiu quiu trl mt yu cu cn thit.
Dng thuc ung phng thch ko di (PTKD) vi nhiu u im c s dng
rng ri trong nhng nm gn y v em li nhiu kt quthuyt phc trong iu tr.
Trong bnh au tht ngc n nh, bit dc Vastarel MR 35 mg ca Servier (Php)
vi hot cht Trimetazidin dihydrochlorid c sdng rt phbin v cho kt qu
iu trhtrrt tt.
Ti Vit Nam, cho n thi im ny cha c ch phm dng phng thch ko di
cha hot cht Trimetazidin c sn xut trong nc. Nhm p ng nhu cu iu tr
cng nhgp phn pht trin vic nghin cu dng thuc phng thch ko di, tc gi
chn ti Nghin cu bo chvin Trimetazidin phng thch ko divi cc
mc tiu nghin cu nhsau:
Mc tiu tng qut
Nghin cu bo ch vin nn phng thch ko di cha hot cht Trimetazidin
dihydrochlorid 35 mg.
Mc tiu cth
1.Xy dng cng thc, quy trnh bo chvin phng thch ko di cha Trimetazidin
35 mg qui m pilot, c thp dng sn xut trong nc
2.Xc nh tng ng sinh hc so vi vin i chiu Vastarel MR 35 mg
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2.TNG QUAN TI LIU
2.1. HTHNG TRLIU PHNG THCH DC CHT KO DING UNG
Tcui thp nin 40s n u thp nin 50s, song song vi spht trin cc dng
thuc qui c xut hin xu hng iu ch cc sn phm phng thch ko di
(PTKD) vi nh lm thay i, ci thin hiu qudng thuc bng cch ko di thi
gian tc ng, gim sln cho liu. Tgia n cui thp nin 60s xut hin cc
hthng cung cp thuc c kim sot l hthng trong sphng thch dc cht
c bin i. Htrliu phng thch dc cht ko di to sthun tin gip bnhnhn tun theo phc iu trgip nng cao hiu qutrliu, to mt p ng lm
sng n nh cho php kim sot tnh trng bnh tt hn, gim tc dng ph, c tnh
ca thuc, gip nng cao sinh khdng v c tnh kinh thn.
Tuy nhin, htrliu PTKD i hi dc cht c tnh chn lc, yu cu trnh cng
nghcao, trang thit bhin , hng dn sdng, thng tin thuc phi cht chv
ca ca bnh nhn phi thch ng vi dng thuc PTKD.
2.1.1. c im trliu ca dng thuc PTKD
m bo snhanh chng c hiu lc v duy tr hiu lc iu trtrong mt khong
thi gian di, dng thuc PTKD thng thit kgm hai phn
-Phn phng thch tc thi: cha t l dc cht nht nh, dc cht phng thch
ngay sau khi dng hp thu v t nng trliu trong thi gian ngn nht.
-Phn phng thch dc cht chm: cha tldc cht nhiu hn, sphng thch vhp thu dc cht c tnh ton tng ng vi lng dc cht bchuyn ha
hoc thi trduy tr nng thuc n nh trong khong nng trliu vi thi
gian nh trc.
2.1.2. Tnh cht l ha v sinh hc ca thuc trong hthng PTKD [8]
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2.1.2.1. Cc c tnh l ha
Sha tan trong nc v hng spKa
tan, tc ha tan v hng spKa ca dc cht nh hng n shp thu. Schuyn giao thuc theo cchkhuych tn hoc ha tan phthuc tan ca dc
cht. Dc cht c tan trung bnh hay hi kh tan ph hp thit kh thng
PTKD (tan ph hp khong 0,1 mg/ml).
Hsphn bDu - Nc
Sthm dc cht qua mng phospholipid kp vo mu phthuc hsphn b
du - nc biu kin K.Hsphn bcn nh hng n khnng khuych tn dc cht tbcha hoc
khung xp ra ngoi mi trng.
Sn nh ca dc cht trong htrng v
Sn nh dc cht di tc nhn kim, acid, cc men trong htrng vl mt yu
rt quan trng trong dng thuc ung
Skt hp vi protein huyt tng
S phn b ca dc cht vo m c quyt nh bi sphn gii thuc ra khi
protein. Dc cht c t lkt hp vi protein huyt tng khng cao v thi gian
bn thi khng qu di thch hp cho hthng PTKD.
Kch thc phn tv khnng khuych tn qua mng
S khuych tn dc cht qua mng polymer hoc khi matrix gip kim sot s
phng thch dc cht trong h thng PTKD. Khnng khuych tn c nh gi
bng hskhuych tn, kch thc phn tdc cht, hnh dng v kch thc ng
mao dn trong cu trc xp ca mng polymer.
2.1.2.2. Cc c im sinh hc
c tnh hp thu
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c tnh hp thu ca dc cht nh hng n tnh ph hp hay khng ca dc cht
trong dng PTKD. Tc , mc v sng nht trong hp thu dc cht l cc yu
tquan trng. Mc hp thu phn nh sinh khdng ca dc cht, khng hn ch
khnng thit kthuc trong dng PTKD. Ngc li trong mt vi iu kin, dng tcdng ko di gip ci thin mc hp thu ca dc cht. Tc hp thu rt ln so
vi tc phng thch th hthng skim sot shp thu dc cht. Thuc c tc
hp thu chm khng ph hp thit ktrong dng PTKD. Shp thu dc cht theo
cchchng hoc shp thu chxy mt vng c bit trong htrng vth vic
thit kdng thuc PTKD sgp nhiu kh khn.
Thi gian hp thu ca dc cht phi ph hp c thc phng thch hon ton
khi i qua vng hp thu (dc cht sc hp thu t80 95%).
Sthi trv thi gian bn thi
Mi loi dc cht c tc thi trc trng, tc thi trc xc nh nh
lng bng thi gian bn thi t1/2.Cc dc cht c t1/2 ngn l i tng ph hp
thit kdng PTKD v lm gim sln dng thuc.
Hiu ng phv san tonRt t trng hp dc cht c xc nh nng trliu chnh xc, ngi ta chp
nhn mt khong nng m trn khong ny dc cht c thgy hiu ng ph
v di khong ny dc cht khng thhin c hiu qu. an ton ca dc
cht c nh gi bng chstrliu TI (Therapeutic Index), gi trTI rt thay i,
TI cng ln, thuc cng an ton.
2.1.3. Cu trc v cchphng thch ko di ca khung matrixHin nay, dng thuc ung c quan tm nhiu khi pht trin cc dng PTKD v s
linh ng v tnh a dng ca cu trc trong thit k. Trong cc dng PTKD, hthng
c cu trc kiu khung xp (matrix devices) rt phbin do cch bo chtng i
n gin v t gy sphng thch liu t ngt nn hthng c an ton cao.
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Hnh 2.1.Hthng PTKD c cu trc khung xp
Dng thuc ny c cu trc khung matrix thng bng polymer khng tan. Dc cht
dng ha tan hay tiu phn rn c phn tn ng nht trong khi polymer. Sphn
tn c thc thc hin vi khi polymer nung chy hoc ha tan trong dung mi d
bay hi, sau khi ngui hoc lm bc hi dung mi, khi rn thu c c thxt
ht, dp vin hay ng vo nang.
Sphng thch dc cht phthuc vo tan ca dc cht v skhuych tn dc
cht ra ngoi qua cc ng mao dn trong khung xp. Khi thuc vo cth, bmt
ca thuc bhydrat ha bi dch tiu ha to thnh mt lp gel bao ly vin thuc,
hot cht bmt vin sc khuych tn ra ngoi. Nc cng thm vo su bn
trong, lm tng bdy ca lp gel, dc cht tip tc c khuych tn ra ngoi qua
cc ng mao qun to bi lp gel polymer. Khi ht hot cht, khung khng cha thuc
sc o thi theo phn ra ngoi. Ngoi ra, i vi mt sdc cht khng tan,
khung matrix sc thit k sao cho khung sbbo mn dn di tc dng ca
dch tiu ha phng thch hot cht.
T dc dng to khung matrix trong hthng PTKD
Polymer l mt thnh phn rt quan trng trong hthng PTKD, chng khng chbo
vhot cht trong sut qu trnh di chuyn trong cthm cn kim sot sphng
thch hot cht gip duy tr tc dng ko di ca thuc.
Nhm polymer thn nc (hydrophilic)
Cchhot ng ca cc polymer thn nc l trng n, to gel, lm tng nht
gip hn chtc phng thch ca dc cht hoc to cc khung xp tan dn theo
thi gian. Thuc nhm ny thng l cc dn cht cellulose, polyethylene oxid,
alginat, gmtan c trong nc, trong HPMC c sdng nhiu nht.
Nhm thn du (hydrophobic)
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Nhm thn du c cchhot ng l to khung xp khng tan, dc cht khuych
tn qua cc l, mao qun ca khung xp. Thuc nhm ny thng l sp (sp ong, sp
Carnauba), dn cht glycerid (Compritol 888, Precirol ATO 5), cc nha vinylic,
cc polymer khng tan trong nc nh polymerthacrylates (Eudragit RS/RL 100),polyvinyl acetate (Kollidon SR)
Nhn chung, tc phng thch dc cht c thc iu chnh bng cch phi hp
cc loi polymer khng cng nhm, polymer tan trong cc mi trng khc nhau gip
sphng thch thuc c kim sot bng nhiu cchkhc nhau.
2.1.4. Bao phim cho vin phng thch ko di
Ngoi mc ch che du mi v, mu sc ca hot cht hay bo vhot cht chng li
cc yu tbt li ca mi trng, kthut bao vin m c bit l bao phim cn c
khnng lm thay i sphng thch ca hot cht. Kthut bao phim c nhng u
im rt ln nhlp bao mng, thi gian bao nhanh, hiu quv nng sut cao, c th
sdng cc cng thc bao v qui trnh bao ph hp ci thin sinh khdng ca
thuc v y cng l phng thc thch hp iu chvin tan trong rut, vin tc
dng ko di.Mt s dn cht nhm cellulose c thc dng to mng phim PTKD nh ethyl
cellulose, cellulose acetat, cellulose triacetat, cc cht ny khng tan nhng trng
ntrong nc vi cc mc khc nhau. Tnh thm ca mng phim c thc iu
chnh bng cch phi hp vi cc polymer tan trong nc nhHPMC, PEG, PVP,
hoc phi hp vi cc cht to knh khuych tn dng ht rn khng tan trong nc.
2.2. TRIMETAZIDIN DIHYDROCHLORID
2.2.1. Tn gi [22]
Tn gi: Trimetazidin.
Tn gi khc: Trimetazin.
Tn khoa hc: 1-[(2,3,4-trimethoxyphenyl) methyl] piperazin.
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2.2.2. Cu trc ha hc [22]
Cng thc phn tTrimetazidin: C14H22N2O3= 266.3
Hnh 2.2.Cng thc cu to ca Trimetazidin
2.2.3. Tnh cht l ha [22]
Bt mu trng, tan tt trong nc, t tan trong ethanol 96% v thc tkhng tan trong
diethyl ether.
im chy: 225 228 oC.
2.2.4. Cc thng sdc ng hc [13][19]
Bng 2.1. Cc thng sdc ng hc ca Trimetazidin
Thng sdc ng hc Lng gi
Tc hp thu qua ng ung Nhanh, t nng ti a trong mu trc 2gisau khi dng thuc.
Cmaxtrong huyt tng khi dng liu -Liu 20 mg l 55 ng/ml.duy
nht -Liu 40 mg l 85 ng/ml.Sinh khdng tuyt i Hn 85%.
Khnng thit lp tnh trng cn t c t24 n 36 gisau khi dng ccbng liu lp li
Thtch phn phi 4,8 l/kg.
Gn kt vi protein huyt tng Thp (khong 16%).
o thi Qua nc tiu dng khng bin i.
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Thi gian bn thi trung bnh Khong 5 6 gi.
2.2.5. Tnh cht dc l
Trimetazidin l mt thuc c tc dng chng thiu mu cc b do tc ng ln s
chuyn ha tbo, gicho schuyn ha nng lng ca tbo n nh trc tnh
trng thiu oxy hoc thiu mu, gip ci thin ssdng glucose ca c tim thng
qua skm hm sdng acid bo, hn chsgim ATP trong tbo, khng km theo
tc dng phng kkhi kt hp vi thuc chng au tht ngc truyn thng.
Cc nghin cu c kim sot trn bnh nhn au tht ngc cho thy Trimetazidin c tc dng
lm tng dtrmch vnh, gim nguy ccao huyt p khi gng sc, lm gim ng ktn
sxut hin cn au tht ngc v lm gim liu Nitrat dng trong dphng iu trau tht
ngc.
2.2.5.1. Cchtc ng
Khng thng qua tc dng huyt ng hc nha scc thuc khc dng trong thiu
mu tim cc b, c ch tc dng ca Trimetazidin thun ty trn s chuyn ha.
Trimetazidin c kh nng c chmen 3-ketoacyl Coenzyme A Thiolase (3-Kat), lmt enzyme xc tc qu trnh oxy ha acid bo, gy tiu tn ATP v sdng rt nhiu
oxy. Trimetazidin to iu kin cho soxy ha glucose, qua duy tr c lng
ATP cn thit cho tbo bthiu mu cc b. Khi lng oxy cung cp bgim, lng
ccht cng gim th lng ATP vn dng duy tr chc nng ca ctim. Thuc
m bo chc nng bm knh Na+- K+, gip lung Na+, K+qua mng tbo n nh
v duy tr tnh hng nh ni mi trong tbo, ci thin schuyn ha nng lng c
tim, khng lm chm nhp tim v gim tnh co c, y l iu c bit hu ch trongvic iu trbnh tim khng thit lp c trng thi cn bng bng nhng liu php
thng thng. Trimetazidin lm ng bha qu trnh phn gii glucose v oxy ha
glucose, v vy ion lactate v H+sinh ra do sphn gii glucose kkh c a vo
chu trnh Kreb lm gim nng acid trong cc tbo thiu mu cc b, snhim
toan trong tbo do thiu mu cc bgim ng kv nhanh chng trli gn nh
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bnh thng. Trimetazidin lm gim c tnh ca cc gc tdo c oxy ha trong
tnh trng thiu mu cc btbo.
2.2.5.2. Chnh-Trong tim mch: iu trcc chng au tht ngc, suy mch vnh (phng cn au
tht ngc, dng sau nhi mu ctim cp).
-Khoa mt: Tn thng mch mu vng mc
-Khoa tai: chng mt Mniere hoc do nguyn nhn vn mch, gim thnh lc.
2.2.5.3. Tc dng ngoi
Him khi gy mt sri lon tiu ha nh(bun nn, ma).
2.2.5.4. Sdng thuc cho phnc thai v phncho con b
Cc nghin cu trn th vt cho thy thuc khng c tc dng gy qui thai, do thiu
cc sliu lm sng, khng thloi trnguy cgy ddng. Do , nn thn trng
trnh k toa cho phnang mang thai. Do thiu sliu vsbi tit qua sa m,
khng nn cho con b trong qu trnh iu tr.
2.2.5.5. Tng tc thuc
Cho n nay khng c tng tc no c ghi nhn c thvi cc thuc chn beta,
thuc c chCalci, Nitrate, Heparin, thuc hlipid huyt hoc Digitalis
2.2.5.6. Liu dng
Trimetazidin thng c dng 40 60 mg/24 gi, chia lm 2 hoc 3 ln trong ccba n.
-Suy mch vnh: ngy 3 ln, mi ln 1 vin hoc 10 git. Sau c thgim ngy 2 ln,
mi ln 20 mg.
-Khoa mt v tai: ngy 2 - 3 vin hoc 40 - 60 git chia 2-3 ln vo ba n.
2.2.6. Cc chphm cha Trimetazidin PTKD trn thtrng Vit Nam
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Vastarel MR 35 mg (Servier Php)
Hnh 2.3.Sn phm Vastarel MR 35 mg
Cardimax SR 60mg (n)
Hnh 2.4.Sn phm Cardimax SR 60 mg
2.2.7. Cng trnh nghin cu thc nghim vhot cht Trimetazidin
Hot cht Trimetazidin vi cch tc ng c bit, cho hiu qucao trong iu tr
bnh au tht ngc n nh thu ht squan tm nghin cu ca cc nh khoa hc.Vmt bo ch, ngoi nhng nghin cu iu chdng khung matrix, c nghin
cu thit kvin ba lp phng thch ko di sdng gm Guar lm cht mang cho
hot cht Trimetazidin vn c khnng kim sot sphng thch hot cht theo yu
cu [14][15]. Vmt kim nghim, c nhiu phng php c nghnh lng
hot cht Trimetazidin ch phm cng nh trong huyt tng khi th tng ng
sinh hc, t cc phng php n gin nh phng php to phc vi iron (III)
chlorid, phng php o quang UV-Vis [11], hay nhng phng php hin i v tintin nhHPLC [21], kt hp LC/ESI-MS [24] c khnng nh lng rt chnh xc
mu sinh hc, tp cht, hay sn phn hy (nu c). Vmt lm sng, c rt nhiu
nghin cu vhiu lc, an ton, nhng tc ng c li khi dng chung vi nhng
thuc khc cng nhhiu qulm sng ca hot cht trong hthng PTKD cha au
tht ngc [23]. Hot cht Trimetazidin vn cn c tip tc nghin cu nhm tng
cng hiu qutrliu ca thuc trong iu tr.
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2.3. PHT TRIN THUC VI STRGIP VI TNH
Pht trin thuc vi strgip ca vi tnh (Computer Aided Drug Development) lmt lnh vc mi xut hin trong ngnh Dc trn thgii vo thp nin va qua, nh
ng dng thnh tu nghin cu ny em li nhiu thun li trong vic nghin cu
v pht trin thuc. Ni bt nht l sp dng cc phn mm thng minh trong vic
thit kv ti u ha cng thc.
2.3.1. Nghin cu v pht trin thuc
Giai on nghin cu v pht trin thuc c lin quan n hai ni dung chnh l
nghin cu cng thc v xy dng qui trnh sn xut. Do cht lng ca sn phm c
thbnh hng bi nhiu yu t, vic thnh lp cng thc cn phi c sxem xt v
cc thnh phn nguyn liu cng nhnhng iu kin pha ch. Ni cch khc, cng
thc nn c thit kv ti u.
2.3.2. Thit kcng thc
Nh bo chcn c m hnh thc nghim (m hnh cng thc, m hnh quy trnh)
nh hng cho vic chit xut v thu thp d liu. Mi lin quan nhn qu c th
c minh ha theo biu xng c hay biu nhn qu. Vmt ton thng k,
nhn c xem l bin sc lp (xi): thnh phn cng thc v/ hoc iu kin sn
xut; quc gi l bin sphthuc (yj): tnh cht sn phm.
Mt m hnh thc nghim c F yu tvi L mc i hi sth nghim l LF. M hnh
yu ty c u im l cho php kho st snh hng ca cc yu tcng nh
tng tc ca chng, tuy nhin m hnh ny cn c sth nghim rt ln khi syu t
tng ln. M hnh gin lc cho php gim bt rt nhiu s th nghim nhng vn
kho st c s nh hng ca cc yu t (th d: m hnh D-Optimal, Taguchi
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OA...). Ngy nay, vic thit kcc m hnh thc nghim c thc thc hin nhanh
chng v chnh xc nhphn mm chuyn dng (Design-Expert).
2.3.3. Nghin cu mi lin quan nhn qu
Cng ngh thng minh c tn l logic m - thn kinh (vi mng thn kinh nhhp
xm c gi l mng bnhlin hp), th d: phn mm thng minh FormRules, c
khnng nghin cu mi lin quan gia thnh phn cng thc v/ hoc iu kin sn
xut vi tnh cht sn phm vcc mt nhxu hng, mc v quy lut lin quan
nhn qu. Quy lut nhn quc xem l tri thc nng, c thcho nh bo chbit
nu thnh phn cng thc v/ hoc iu kin sn xut nh thno th tnh cht snphm sra sao.
Qua kt qunghin cu lin quan nhn qu, nh nghin cu c thchn yu tc nh
hng quan trng yu tin ti giai on ti u ha, bqua cc nh hng khng
ng k. Nh vic xy dng cng thc bo chc nhmong mun m tit kim
thi gian v cng sc.
2.3.4. Ti u ha cng thc
Khi ti u ha, cc bin c lp (x1, x2...) c thc chn sao cho bin phthuc
(y1, y2...) c ti a hoc ti thiu. i vi thuc, mi sn phm thng c nhiu tnh
cht (yj) nn phi c sdung ha cho cc gi try1, y2.. t c ti u thay v cc
bin (y) ti thiu hoc ti a.
Skt hp hai cng nghthng minh gm mng thn kinh (vi mng thn kinh nh
hp en hay gp l mng thn kinh a lp) vi thut ton di truyn, l cng crt hiu
quti u ha cc thng s, th dphn mm thng minh INForm:
-Mng thn kinh c cng dng xc lp mi lin quan nhn qu; don chnh cc
tnh cht sn phm tgia thnh phn cng thc v/ hoc iu kin sn xut.
-Thut ton di truyn c khnng ti u ha cc thng sda trn m hnh lin quan
nhn qunu trn.
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Hnh 2.5. Chu trnh don v ti u ha (INForm)
Ngoi skt hp hai cng nghnu trn, logic mcng c p dng tng cng nn
mng thn kinh hiu quhn trong vic thit lp m hnh lin quan nhn qui vi
cc dliu phc tp v thut ton di truyn thun tin hn trong sti u ha nhcc
hm mc tiu trc quan. Nh, phng php ti u ha thng minh c nhiu u
im hn cc phng php ti u ha truyn thng:
-Khng gii hn vsbin x1, x2,... xk: p ng yu cu nghin cu vi nhiu bin v
thnh phn cng thc v/ hoc iu kin sn xut.
-C thti u ng thi nhiu bin y1, y2,... yk: ph hp vi thc tkt quchit xut
cn p ng nhiu mt nhchtiu kim nghim, tc dng in vitro/ in vivo, gi thnh
sn phm...
-Khng ph thuc m hnh ton hc m da vo kh nng luyn mng vi s la
chn nhiu thng sph hp.
-Ph hp vi nhiu loi d liu phc tp, phi tuyn, khng dng s, nh tnh hay
thiu trs(missing values).
-p dng mt cch ddng nhcc hm ti u ha trc quan: Tent, Up, Down, Flat
hay Flat-Tent.
Cng thc Sn phm
Ti u ha
Thit lpm hnh
Don
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Hnh 2.6.Skt hp mng thn kinh vi thut ton di truyn
2.4. NGHIN CU N NH CA THUC
2.4.1.Phng php theo di n nh di hn (tham kho)
2.4.2.Phng php lo ha cp tcKho st cht lng thuc da trn slo ha cp tc l v nu theo di hm lng
thuc theo thi gian nhit thng th cn phi theo di mt khong thi gian kh
lu hng nm, ti thiu l 12 thng, c thkhng p ng c vmt thi gian
a vo sn xut.
Do vy, sdng stng nhit , m tng tc phn hy rt ra kt lun
mt cch nhanh chng vtui thca thuc.
Nguyn tc chn nhit
-Nhit kho st ln hn nhit thng t10 oC, 20 oC, 30 oC hay hn.
-Nn chn cc nhit sao cho khi cng vi nhit tuyt i (273 oC) th cc nhit
tng ng l mt cp scng.
Ch : khng nn chn nhit qu cao, kt quskhng ph hp khi quy trv
nhit bnh thng.
u vo (dliu thc nghim)
M hnh lin quan nhn qu
Tiuha
u ra (cng thc ti u)
Cha Thuttonditruy n
Logicm
Mngthnkinh Hiu quhn
Thun tin hn
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Nguyn tc chn thi gian xc nh hm lng
-Sau nhng khong thi gian nht nh ly mu ra nhn xt v tin hnh nh lng
xc nh hm lng trn 3 l sn xut th.
-Nn cn cvo tnh cht ca chphm m chn chu kthch hp. Trong thc t, haychn khong thi gian thc nghim trong 6 thng.
2.4.3. c tnh tui thca thuc
Quy tc Vant Hoff
-Khi tng 10 oC th tc phn ng ha hc c thtng 2 4 ln.
-Quy tc ny chng vi khong chnh lch vnhit khng ln.-
Tui th ca thuc = K tui th iu kin lo haPhng php tnh theo quy tc Vant Hoff:
Phng trnh Vant Hoff xc nh gi tr ca hng scn bng (hng s tc )
theo sthay i nhit .
So: entropy chun ca phn ng
Ho: enthalpy chun ca phn ng.
R: hng skh l tng (1,987 calo/ oK mol). T: nhit tuyt i (273 + t oC).
Phng trnh Vant Hoff c thc p dng tnh tui thca thuc nhit T1
bng phng php lo ha cp tc mt nhit cao T2vi cng m.
R = 8,314 J/ mol K.Cng thc :
C = K.C*
t90 (t2) = K t90 (t1)
-Xc nh hm lng theo thi gian.
-Vng ln [D] = f(t) tnh c k1.
-Tnh tui thnhit t1= t90 (t1).
-Sdng cng thc Vnt Hoff suy ra tui thnhit cn bo qun t2(K : h
stra theo bng ca Vant Hoff).
Trong :
C* = tui thnhit gi ha cp tc.
= t90(t1) = 0,1053/ k.
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C = tui thnhit bo qun = t90(t2).
t2: nhit gi ha cp tc.
K : hsVant Hoff = 2t/ 10.
Mc chnh lch nhit , t = t1 t2.
Mt snguyn tc loi tr:
Tui thca thuc c xc nh bng thc nghim cc nhit khc nhau nh35o o o
C, 45 C, 55 C v cho cc kt qukhc nhau.
Bng 2.2.Nguyn tc loi trtrong xc nh tui thca thuc
Tui ththc nghim chnh nhau Tnh tui th
Trn 180 ngy
Nhhn 60 ngy
Trn 60 ngy
Loi b gi tr tui th tm c
nhit cao
Tnh tui th theo gi tr trung bnh
thng thng
Ly gi trnhnht tnh ton.
Trong trng hp thuc mi sn xut ra cha kp lm gi ha cp tc, thi gian tlc
mi sn xut cho n khi lm thc nghim l Co, ta sc:
C = K.C* + Co
2.5. XC NH TNG NG HA TAN INVITRO
2.5.1. Khi nim vtng ng dc hc
Hai dc phm l tng ng dc hc khi chng tng ng dc hc hoc
thay thdc hc c sinh khdng khng khc nhau c ngha thng k. c th
thay th trong tr liu, hai ch phm tng ng v dc hc cha m phi
tng ng vsinh hc. Nhng c thxc nh tnh tng ng sinh hc ca
chphm mt cch y , chnh xc, hiu qu nht th vic xc nh tnh tng
ng dc hc l mt bc u khng ththiu.
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Hai chphm tng ng dc hc (tng ng bo ch) khi:
-Cng dng thuc.
-Cha cng loi v cng lng dc cht.
-Cng ng sdng.
-Cng t cc tiu chun cht lng quy nh vhm lng v tc phng thch
dc cht (in vitro). c th tin hnh nghin cu tng ng sinh hc th
trc tin hai chphm phi c hm lng khc nhau khng qu 5% v tc
phng thch hot cht ca 2 chphm phi tng ng.
2.5.2. Thnghim ha tan
Thnghim ha tan trthnh phng tin chun kim sot cht lng dc
phm rn trong nhiu Dc in, l cng c rt quan trng trong nghin cu pht
trin, cng nhkim sot cht lng thuc trong sn xut.
Mc ch ca thnghim nhm nh gi khnng ha tan v sn sng hp thu ca
thuc trong ng tiu ha, do iu kin thnghim ha tan in vitro cn tng
t vi tnh trng in vivo (quy nh v kim sot cht chiu kin nhit , mi
trng, tc khuy,) cc thay i nu cn phi trn csc lin quan n th
hin ca thuc in vivo.
Tiu ch xc nh ha tan l tlphn trm dc cht ha tan vo mi trng th
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nghim so vi hm lng ghi trn nhn, c xc nh mt thi im i vi thuc
phng thch tc thi. i vi dng phng thch ko di tldc cht ha tan
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19c kim sot ti thiu 3 thi im.[3] Quy nh ny cho php kim sot nguy c
phng thch t thi im u tin, nh gi tc phng thch ca thuc thi
im thhai v khnng phng thch ti a thi im cui cng.
Trong nghin cu pht trin thuc, thnghim ha tan in vitro c p dngrng ri trong ccbc:
-Nghin cu la chn t dc xy dng cng thc bo ch(giai on sng lc).
-Theo di sn nh vcht lng thuc (so snh vi mu ng k).
-nh gi sng nht gia cc l mu (so snh vi mu ng k).
-nh gi sbcc dng chphm khc nhau (so snh cc chphm).
-Xc nh nh hng ca cc yu tl ha ca dc cht.
Ngoi ra cn l bc thnghim u tin khi kho st sinh khdng v nh gi tng
ng sinh hc.
2.5.3. Thit lp tng ng in vitro bng thnghim ha tanThnghim ha tan c dng nhthnghim thay ththit lp tng ng sinh
hc i vi mt sthuc rn dng ung khi p ng mt siu kin quy nh.
Vi mc ch xc nh tng ng sinh hc in vitro, thnghim ha tan c
thc hin 3 mi trng c pH 1,2; 4,5 v 6,8 cho cdng thv dng i chiu. S
liu ha tan theo thi gian ca hai dng c xc ng bng trc nghim xc nh s
tng tf2.. Khi gi trf250, hai dng thuc c kt lun l tng tvha tan
hoc tng ng in vitro.
2.5.4. nh gi tng ng in vitro
nh gi ha tan c thdng phng php yu tng dng kiu c lp. Sdng yu tkhc bit(f1) v yu tng dng(f2) so snh hatan.
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20Yu tkhc bit (f1) l phn trm khc nhau gia hai ng cong mi thi im v l
thc o sai sgia hai ng cong:
n
Rt Ttf1 = t n 100
Rtt
Yu tng dng (f2) l php bin i hm logarit ca nghch o cn bc hai
ca tng sai lch v gi tro ca sng dng tnh bng phn trm (%) ha tan gia hai ng cong:
f 2 = 50lg
Trong
n: sthi im
Rt: gi trha tan ca l thuc thi im t
Tt: gi trha tan ca l thuc thnghim thi im t
Cch xc nh yu tkhc bit (f1) v yu tng dng (f2) nhsau
Tin hnh thha tan ca thuc thnghim v thuc gc (12 n v/ mi loi
thuc) trong cng iu kin vmi trng ha tan, thtch ha tan, cc thi im ly
mu, nhit , thit b.
-Da vo gi trha tan tng cong mi thi im tnh f1 v f2.
2
100t=n
(Rt Tt )1+
t=
1
n
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21
-i vi nhng ng cong ging nhau, gi trf1 nn gn v0 v gi trf2 nn gn
n 100. Ni chung gi trf1 c thln n 15 (t0 15) v gi trf2 ln hn 50 (t
50 100) sm bo sging nhau hay stng ng ca hai ng cong thc
hin trn thuc thnghim v thuc gc.nh gi kt qu:
-Nu f1 < 15 th ha tan ca thuc thnghim v thuc gc khng khc nhau.
-Nu f2 > 50 th ha tan ca thuc th nghim v thuc gc tng t
nhau.Phng php ny thch hp nht cho vic so snh ha tan ti ba ti bn
thi im hoc nhiu hn.
2.6. PHN TCH HOT CHT TRONG DCH SINH HC
2.6.1.Mu sinh hc
Dch sinh hc trong cthgm mu (huyt thanh, huyt tng), nc tiu, dch no ty,
dch mng phi, cht cha trong ddy, dch mng i,
Huyt tng (plasma) l phn lng ca mu, c mu vng nht, hi kim. Thnh
phn ca huyt tng gm c mui, nc, v cc cht hu c nh protid, glucid,
lipid, cc phn ha t, sinh t, hormon, cc khng thv cc yu tng mu.
2.6.2.Phng php xl mu
Vic xl mu huyt tng nhm mc ch chit tch c ti a lng hot cht v
loi bhon ton protein c trong huyt tng. y l vic rt cn thit v lng hot
cht trong mu sinh hc thng rt nh, trong khi protein c khuynh hng ta bm
trn bmt cht mang sc k, gy tng p sut trong sc k lng, protein lm tt ct,
dn n hct v lm ngng trhon ton vic phn tch. C rt nhiu phng php
x l mu nh: phng php to ta protein (Protein precipitation), Phng php
chit lng-lng (Liquid-liquid extraction), Phng php chit qua pha rn (Solid
phase extraction).
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22
2.7. THM NH PHNG PHP NH LNG DC CHTTRONGDCH SINH HC
Qu trnh nghin cu v ng dng phng php nh lng dc cht trong dch sinhhc gm 3 giai on: nghin cu phng php nh lng, thm nh phng php
nh lng v theo di qu trnh nh lng trong nghin cu.
Nng dc cht trong dch sinh hc c gi trrt nh, do c thnh lng ngi
ta phi p dng cc phng php hin i. Csxy dng v thm nh phng php
nh lng hot cht trong dch sinh hc da vo cc ch tiu gm c hiu, tuyn
tnh, gii hn nh lng, chnh xc, ng, hi phc v n nh ca dc cht
trong dch sinh hc.
2.7.1.c hiu
c hiu ca mt phng php phn tch l khnng cho php xc nh mtcch chnh xc shin din ca cc thnh phn trong mu phntch.
Tin hnh phn tch t nht 6 mu trng ca dch sinh hc tng ng ca mu th.
Mi mu trng c kim tra vnhiu v chn lc xc nh chc chn giihn di nh lng.
Cht c khnng gy nhiu trong dch sinh hc gm: thnh phn ni sinh trong
dch sinh hc, cht chuyn ha, sn phm phn hy, c thtthuc ung km.
2.7.2.ng
ng ca mt phng php l mc st gn ca cc gi trtm thy so vi gitr thc t (v nng ) ca cht phntch.
ng c xc nh bng cch lp li qu trnh phn tch mu bit hm lng
cht phn tch. Thc hin t nht trn 5 mu cho mi nng v ti thiu 3 nng
trong khong nng dnh o sau ny.
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23Gi trtrung bnh nm trong khong 15% so vi gi trthc, ring ti gii hn di
ca nh lng (LLOQ) cho php 20%. lch ca gi trthc so vi gi trtrung
bnh dng nh gi ng
2.5.3. chnh xc
chnh xc ca mt phng php phn tch l mc st gn gia cc kt quth
nghim ring lo c ca mt cht phn tch khi phng php c p dng c
tnh lp li vi nhiu mu sinh hc c cng thtch.
chnh xc c thc hin t nht ti 3 nng trong phm vi nh lng, vi
mi nng tin hnh t nht trn 5 mu thkhc nhau.
chnh xc mi mc nng khng c vt qu 15% hsphn tn, ring ti gii
hn di nh lng th khng c vt qu 20% hsphn tn.
chnh xc bao gm lp li gia cc ln thnghim, chnh xc trung gian v
sao chp li.
2.7.4.phc hi (hiu sut chit)
phc hi ca mt cht phn tch trong nh lng l p ng ghi nhn c t
mt lng cht phn tch thm vo v chit ra tdch sinh hc, c so snh vi p
ng tnng thc ca cht phn tch.
phc hi l hiu sut chit ca phng php phn tch trong mt gii hn nht nh.
phc hi thc nghim c xc nh ti 3 nng .
phc hi ca cht chit khng nht thit phi l 100% nhng phi n nh, chnh
xc v lp li.
2.7.5.ng cong chun v khong tuyn tnh
Cc mu th nn c chun b trn cng mt dch sinh hc nh mu th trong
nghin cu bng cch cho cht i chiu bit trc nng vo dch sinh hc.
Nng ca cht i chiu dng xy dng ng chun phi da vo phm vi nh
lng c don trong nghin cu thc t.
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24Gii hn di ca nh lng: im thp nht ca ng chun sc xem nh
gii hn di ca nh lng nu nhp ng ca n so vi p ng ca mu trng
t nht bng 5 ln (tsS/N 5), v c thxc nh vi lp li trong khong
20%, ng t80 120%.
ng chun bao gm 6 8 im trim 0 nm trong phm vi cn nh lng, c
cgii hn di ca nh lng, yu cu lch khng qu 20% ti gii hn di
ca nh lng v khng qu 15% cc nng khc.
2.7.6. n nhn nh sau khi lm lnh v r ng
n nh ca cht phn tch c xc nh sau 3 chu klm lnh v r ng. Thc hin t
nht 3 mu mi nng cao v thp, lm lnh nhit bo qun dkin trong 24 giv
r ng nhit phng, khi r ng hon ton mu c lm lnh trli trong vng 12
24 giging ln u, sau 3 chu knhth, mu c em i phn tch. Nu phn tch khng
n nh nhit dkin th phi lm lnh nhit -700
C.
n nh ngn hn
Thc hin trn 3 mu khc nhau mi nng cao v thp, sau khi r ng nhit
phng v ginhit ny t4 24 gi, sau em phn tch.
n nh di hn
Thi gian bo qun trong nh gi n nh di hn nn ln hn khong thi gian t lc
ly mu n ngy phn tch mu cui cng.
n nh di hn c xc nh bng cch bo qun t nht 3 mu mi nng thp v
cao nhit bo qun d kin. Th tch mu phi cho phn tch 3 ln khc nhau.
Nng ca mu sau mi ln xc nh c so snh vi gi tr trung bnh ca nng
tng ng ngy bt u thnghim n nh di hn.
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3.I TNG V PHNG PHP NGHIN CU
3.1. I TNG
Sn phm th(sn phm nghin cu )
-Tn sn phm: vin bao phim Trimetazidin 35 mg MR
-Ngun gc: sn phm nghin cu ca Khoa Dc, HYD TP HCM, sn xut
ti X nghip Dc phm 3-2.
-Hot cht: Trimetazidin Hm lng: 35 mg
-L sn xut: 010109 Hn dng: 01/2011
-Sn phm thnghim c ly mu tl pilot vi cl 30.000 vin. Sn phm
t tiu chun cht lng theo tiu chun cs(Phiu kim nghim c Phn
vin kim nghim TP HCM cp ngy 12/03/2009).-Hm lng thuc thnghim: 99,5%
Sn phm i chiu
-Tn sn phm: Vastarel 35 mg MR
-Ngun gc: Servier (Php)
-Hot cht: Trimetazidin Hm lng: 35 mg
-L sn xut: 816892 Hn dng: 05/2011
-Hm lng thuc i chiu: 99,8%
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3.1.2. Cht chun lm vic
Cht chun lm vic Trimetazidin do Vin Kim nghim TP HCh Minh cungcp.
Trimetazidin: hm lng 98,66%, hm m 1,43%3.2. NGUYN LIU V THIT B
3.2.1.Nguyn liu, ha cht v dung mi
Cc nguyn phliu, ha cht v dung mi sdng trong qu trnh nghin cu
bo ch cng nh kim nghim vin thnh phm c tm tt ln lt trong
Bng 3.3vBng 3.4.
Bng 3.3. Nguyn liu dng trong bo ch
Tn nguyn liu Tiu chun Ngun gc Hn dung
Trimetazidin dihydrochlorid USP XIX n 11/2009
HPMC K100M TCCS M 05/2010
HPMC 15cp TCCS c 03/2010
Kollidon TCCS M 02/2009
Aerosil BP 2001 Trung Quc 07/2010
Magnesium stearat BP 2001 Trung Quc 02/2009
Ludipress TCCS c 09/2009
OpadryII Pink TCCS M 01/2009
Bng 3.4.Ha cht dng trong kim nghim
Tn ha cht Tiu chun Ngun gc
Acid hydrochloric Tinh khit Trung Quc
Acetonitril HPLC Merk
Natri trihydrophosphat Tinh khit Trung Quc
Orthophosphoric acid 85% PA Prolabo
Potassium dihydrophosphat Tinh khit Trung Quc
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Nc ct DVN III Trung Quc
Triethylamin PA MerckHuyt tng Y t Bnh vin Truyn mu &
Huyt hc
3.2.2.Trang thit bv phn mm
3.2.2.1.Trang thit bbo chv kim nghimCc trang thit bbo chv kim nghim phc vcho qu trnh nghin cu bo
chv thc nghim c trnh by trongBng 3.5 v Bng 3.6.
Bng 3.5.Thit bkim nghim
Tn thit b M s Ngun gc
Cn in tSartorius TE412 c
Cn phn tch Precisa XB220A c
My thcng Erweka TBA 30 c
My thmi mn Erweka TYPE TAP c
My thha tan Pharmatest PTWSIII-SI2-
D6-PTS3C
c
My o quang phhp thu UV-Vis Hitachi U2010 M
My o quang phhng ngoi Shimadzu FTIR 120PC Nht
My sc k lng hiu nng cao Shimadzu LV2010 Nht
My o pH Meter Toledo MP220 Thy S
Cn xc nh m Shimadzu Libror EB 340 MOC Nht
My o thtch cm Erweka SVM 102 c
My o thi gian v tc chy ca ht Erweka TYPE GTL c
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Bng 3.6. Thit bbo ch
Tn thit b M s Ngun gc
My trn kh Erweka AR420 c
My dp vin xoay trn CJB 3B 27 n
My bao phim tng FC 10 Vit Nam
Cc thit bkhc
3.2.2.2.Phn mm thng minh chuyn dng
Bng 3.7.Phn mm thit k/ti u ha
Tn phn mm ng dng Nh cung cp
Design-Expert v7.0 Thit kcng thc Stat-Ease INC., USA
FormRules v3.2 Nghin cu lin quan nhn qu Intelligentsys Ltd., UK
INForm v3.7 Ti u ha cng thc/qui trnh Intelligentsys Ltd., UK
3.3. PHNG PHP NGHIN CU
3.3.1. NH LNG TRIMETAZIDIN NGUYN LIU V TRONG CH
PHM BNG PHNG PHP HPLC V UV-Vis
3.3.1.1. Phng php UV-Vis
Trimetazidin c kho st nh lng bng phng php quang phUV-VIS,
nhm ng dng nh lng Trimetazidin trong th nghim ha tan, trong
nguyn liu cng nh thnh phm. Phng php c thm nh c 3 mitrng: pH 1,2; 4,5 v 6,8. Phng php: quang phtngoi hp thu UV-Vis.
Nguyn tc: Qut phUV cho mu chun v mu thcha Trimetazidin xc
nh bc sng hp thu cc i. Kt quchn bc sng l 231nm
Qui trnh chun bmu
Chun bdung dch i chiu
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Cn chnh xc khong 35 mg Trimetazidin dihydrochlorid chun cho vo bnh
nh mc 100 ml. Ha tan v iu chnh n vch bng dung dch acid HCl 0,1N. Ht chnh xc 3 ml dung dch trn chuyn vo bnh nh mc 50 ml, pha long
v iu chnh n vch bng dung dch HCl 0,1 N c dung dch c nng 21
mcg/ml.
Chun bdung dch th
Cn 20 vin thuc bt k, tnh khi lng trung bnh ca mt vin. Nghin trn
klng vin trn trong ci sn khi thu c hn hp bt ng nht. Mu thc chun bnhsau: cn chnh xc khong mt lng bt tng ng vi khi
lng trung bnh ca mt vin. Chuyn vo bnh nh mc 100 ml, ha tan v
iu chnh n vch bng dung dch acid HCl 0,1 N. Siu m mu thtrong 15
pht. Lc qua mng lc, b 10 ml dch lc u. Ht chnh xc 3 ml dch lc
chuyn vo bnh nh mc 50 ml, pha long v iu chnh n vch bng dung
dch acid HCl 0,1 N.
Mu trng l dung dch acid HCl 0,1 N.nh lng: tin hnh o hp thu ca mu i chiu v mu thbc sng
231 nm vi cc o 1 cm.
Hm lng phn trm Trimetazidin dihydrochlorid c tnh theo cng thc:At m
X% = Cc d 100
Ac p H
Trong : X%: hm lng phn trm Trimetazidin trong mu.
At, Ac: hp thu ca mu thv mu i chiu.Cc: nng ca mu i chiu (mcg/ml). m: khilng trung bnh ca mt vin (mg). p: lngbt thuc cn cho mu th(mg). H: hm lngTrimetazidin trong mt vin (mg).
d: hspha long.
Thm nh quy trnh
Tnh tuyn tnh
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Nguyn tc
Khong tuyn tnh c xc nh bng cch o hp thu nhng mu i chiuc nng khc nhau bng phng php o quang phUV-Vis bc sng 231
nm. Phng trnh hi quy tuyn tnh c xc nh bng phng php bnh
phng cc tiu (sdng cng cRegression trong MS-Excel).
Tin hnh
Dung dch gc (100mcg/ml): Cn chnh xc khong 10 mg Trimetazidin
dihydrochlorid chun cho vo bnh nh mc 100 ml. Ha tan v iu chnh n
vch bng mi trng ha tan. Pha long Dung dch ra thnh cc nng o t
(8 32 mcg/ml)
o hp thu dy chun, xc nh phng trnh hi quy, kim tra tnh tng
thch ca phng trnh hi quy v ngha thng k ca cc hsb v bo.
Tnh c hiu
Nguyn tc
m bo kt qunh lng hm lng cht cn phn tch l chnh xc, trnh s
nhiu ca cc thnh phn khc c trong mu.
Tin hnh
-Chun bmu: mu chun, mu trng (thnh phn ging mu thnhng khng
cha hot cht cn th) v mu ginh (mu trng thm chun).
-Xc nh nng mu chun v mu gi nh cng nng (24 mcg/ml)
bng phng php UV-Vis, tin hnh 6 ln.Dng kt qutrc nghim F-test v t-test kt lun nh hng ca t dc n kt
qunh lng hot cht.
lp li
Nguyn tc
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Ch phm c lm ng nht v c chun b thnh 6 mu th khc nhau.
Tin hnh nh lng xc nh lch chun tng i.Yu cu: phng php phi c lch chun tng i RSD < 2%.
Tin hnh
Cn 20 vin thuc bt k, tnh khi lng trung bnh ca mt vin. Nghin trn
k20 vin trong ci sn khi thu c hn hp bt ng nht. Vi cng mu
bt ng nht ny, chun b trong cng iu kin (vngi, phng th nghim,
dng cv thi gian) 6 mu thtng tMc 3.3.1.1.trong tng mi trng ha
tan tng ng.
Xc nh hm lng hot cht tmi mu th, xc nh hm lng trung bnh,
lch chun, lch chun tng i (RSD%).
ng
Nguyn tc
ng ca phng php c thc hin bng phng php thm chun vo
mu thvi lng bng 85%, 100%, 115% so vi lng mu th. Thc hin 3
mu mi mc, tnh tlphc hi.
Yu cu: tlhi phc cht chun phi nm trong khong 100 2%.
Tin hnh
Dung dch chun gc v dung dch thgc: thc hin tng tMc 3.4.1.trong
tng mi trng ha tan tng ng.Pha mu ththm chun
3.3.1.2. Phng php sc k lng hiu nng cao (HPLC)
Dung dch th: cho 10 vin thvo bnh nn thy tinh. Thm dung mi l pha
ng khuy u bng my khuy t, lc qua giy lc, ly mt thtch chnh xc
v pha long vi dung mil pha ng c dung dch th c nng
100g/ml Dung dch chun: cn chnh xc cht chun i chiu, tng tnh
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cch pha trn, dung dung mi l pha ng pha dung dch c nng 100
g/ml iu kin sc k:Ct: bng thp khng r, kch thc (15cmx4,6mm)
Pha tnh: Nucleosil 100-C18, ng knh tiu phn 5
Pha ng: nc:methanol:acetonitril:dd SHS(60:40:10:3 thtch)
(dd SHS: Sodium heptane sulphonate monohydrate)
Tc dng: 1,3ml/pht;
Bphn pht hin: UV 230nm;
Thtch tim mu: 10 l
Thm nh qui trnh nh lng bng phng php HPLC
Kho st tnh tng thch ca hthng
Tnh tng thch h thng l mt phn tnh ton cn thit khi tin hnh cc
phng php phn tch bng sc k, nhm xc nh phn gii v lp li ca
h thng phn tch sc k thch hp vi phng php phn tch ang thc hin.
Tnh tng thch ca quy trnh phn tch c xc nh da trn gi trv lp
li ca cc thng skthut ca hthng khi tin hnh thc hin quy trnh trn
mu chun v mu thvi 6 ln tim mu lin tip.
Cc thng ssc k: thi gian lu Rt, din tch nh S, chiu cao nh H, hsbt i T, sa l thuyt N, hsdung lng k. Xl thng k sliu cc gitrthu cGi trtrung bnh lch chun lch chun tng i
n
i=1X i RSD = SD 100X = SD=X
n
Chun bmu chun v mu th, dung dch c nng 35 g/ml.
tuyn tnh
)
( )11
2
=
n
X Xn
ii
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Cn chnh xc khong 35 mg Trimetazidin dihydrochlorid chun cho vo bnh
nh mc 100 ml. Ha tan v iu chnh n vch bng nc ct. Pha long dungdch trn thnh 8 dung dch c nng tng dn u t20-200 mcg/ml. Cc mu
c xc nh nng bng phng php HPLC.
Phng trnh hi quy tuyn tnh c xc nh bng phng php bnh phng
cc tiu (sdng cng cRegression trong MS-Excel).
lp li
Cn 20 vin thuc bt k, tnh khi lng trung bnh ca mt vin. Nghin trnk trong ci n khi thu c mt hn hp bt ng nht. Vi cng mu bt
ng nht ny, chun btrong cng iu kin (vngi, phng th nghim, dng
c v thi gian) 6 mu th, mi mu c chun b nh sau: cn chnh xc
khong mt lng bt tng ng vi khi lng trung bnh ca mt vin. Cho
vo bnh nh mc 100 ml, ha tan v iu chnh n vch bng dung mi. Siu
m mu th trong 15 pht. Lc qua giy lc, b10 ml dch lc u. Ht chnh
xc 5 ml dch lc cho vo bnh nh mc 50 ml, ha tan v iu chnh n vchbng dung mi. Xc nh nng trong 6 mu th bng phng php HPLC.
Da trn kt quthu c, tnh lch RSD. Phng php gi l chnh xc khi
RSD 2%.
ng
nh lng hm lng ca mu th
Chun b mu th: cn 20 vin thuc bt k, tnh khi lng vin trung bnh.Nghin v trn kkhi bt trong ci n khi thu c hn hp ng nht. Cn
lng bt tng ng vi mt vin, cho vo bnh nh mc 100 ml, iu chnh n
vch bng nc ct v lc Siu m mu thtrong 15 pht. Ht 5 ml dch lc cho
vo bnh nh mc 50 ml. Ha long v iu chnh n vch bng nc ct lc
u.
v lc qua mng lc millipore 0,45 m.
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nh lng mu ththm chun
Thm vo mu th (c chun b nh trn) mt lng Trimetazidin
dihydrochlorid chun c hm lng bng 80%, 100%, 120% hm lng trung
bnh ca mu th.
Chun b3 mu mi mc. Tin hnh xc nh hm lng vi phng php
xut. Phng php t ng khi tlhi phc c gi trtrong khong 100%
2%.
3.3.1.3. So snh 2 phng php nh lngHm lng Trimetazidin trong vin Vastarel MR 35mg v vin thnghim c
nh lng bng 2 phng php: quang phUV-Vis v HPLC, so snh 2 gi tr
trung bnh v phng sai hai dy th nghim
3.3.2. NH LNG TRIMETAZIDIN TRONG DCH SINH HC
BNG PHNG PHP HPLC
Thm d tlpha ng
Acetonitril:dung dch kali dihydrophosphat 0,025M:triethylamin ln lt vi cc
t l:( 25:75:0,1); ( 5:95:0,1); (35:65:0,1); ( 15:85:0,1); chnh pH bng acid
orthophosphoric n pH 3,3.
Tin hnh: ln lt tin hnh sc k dung dch mu chun, mu thv mu huyt
tng c cha cht chun vi cc iu kin trn chn pha ng ti u. Mimu tim 3 ln.
3.3.2.1. Thm d iu kin sc k
iu kin sc k
Ct sc k : Varian Pursuit C 18 ( 150 x 4.6 mm; 5 m )
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Bc sng pht hin: 231 nm; 270 nm
Tc dng : 1 ml/phtThtch tim mu : 10 l; 50 l
Nhit ct : 28 0C
3.3.2.2. Cch pha mu
Dunh dch m: 3,4g KH2PO4pha trong 1000ml nc ct 2 ln, iu chnh pH
3,3 bng acid orthophosphoric
Dung dch mu chun gc: cn chnh xc khong 10 mg trimetazidin chun chovo bnh nh mc 100 ml, ha tan trong 60 ml dung dch kali dihydrophosphat
chnh pH 3,3, siu m 10 pht, tip tc thm dung dch kali dihydrophosphat
pH 3,3 va thtch, lc u. Ht chnh xc 1ml dung dch trn cho vo bnh
nh mc 100 ml, thm dung dch kali dihydrophosphat pH 3,3 va thtch,
lc u.
Dung dich mu chun: ht chnh xc 5 ml dung dch mu chun gc cho vo bnhnh mc 100 ml, thm dung dch kali dihydrophosphat pH 3,3 va thtch,
lc u, lc qua mng lc 0,45 m. Dung dch thu c cha 50 ng/ ml.
Dung dch mu thgc: cn chnh xc mt lng bt thuc cha khong 10 mg
trimetazidin cho vo bnh nh mc 100 ml, ha tan trong 60 ml dung dch kali
dihydrophosphat pH 3,3, siu m 10 pht, tip tc thm dung dch kali
dihydrophosphat pH 3,3 va thtch, lc u, lc. Ht chnh xc 5 ml dch lc
trn cho vo bnh nh mc 100 ml, thm dung dch kali dihydrophosphat pH 3,3va thtch, lc u.Ly dch trong lc qua mng lc 0,45 m
Dung dch mu th :Ht chnh xc 5 ml dung dch trn cho vo bnh nh mc
100 ml, thm dung dch kali dihydrophosphat pH 3,3 va thtch, lc u, lc
qua mng lc 0,45 m. Dung dch thu c cha 50 ng/ml.
Dung dch Lidocain: pha tng tdung dch mu chun
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Mu huyt tng c cha chun: Ht chnh xc 50 l dung dch mu chun gc,
v 50 l dung dch Lidocain, sau cho vo 400 l huyt tng, lc kbng mylc trong 30 giy, thm vo 500 l Acetonitril ly tm vi tc 13000 vng/pht
trong vng 1 pht. Ly dch trong lc qua mng lc 0,45 m.
Mu huyt tng c cha th: tng t, thay bng 50 l dung dch mu thgc.
3.3.2.3.Thm nh phng php
Xc nh tnh tng thch hthng
Tnh tng thch hthng nhm xc nh phn gii v lp li ca hthng
phn tch sc k thch hp vi phng php phn tch ang thc hin.
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Tin hnh: Sc k 6 ln cho mi mu thv mi mu chun.
Xl thng k sliu cc gi trthu c.
Qui trnh t tnh tng thch hthng khi cc thng ssc k trong chai mu mu
i chiu v mu thtto phi t theo yu cu quy nh trong nh lng v c
RSD 15%. Ring ti gii hn di ca nh lng th RSD 20%.
Khong tuyn tnh-Gii hn nh lng
*Khong tuyn tnhChunbmu:
T dung dch mu chun m, pha long thnh cc dung dch c nng trong
khong 20 100 ng/ml. Tin hnh sc k 2 ln cho mi dung dch.
Xc nh stng quan gia nng v tldin tch nh ca cc dung dch mu
chun vi dung dch lidocain. Vng biu din stng quan gia nng v t
ldin tch nh.
Sdng phn tch hi quy vi trc nghim t kim tra ngha cc h s trong
phng trnh hi quy v trc nghim F kim tra tnh thch hp ca phng trnh
hi quy.
*Gii hn di ca nhlng ( LLOQ )
im thp nht ca ng chun sc xem nhgii hn di ca nh lng nu
nhp ng ca n so vi p ng ca mu trng t nht bng 5 ln (tsS/N
5), v c thxc nh vi lp li trong khong 20% , ng t80 120%.
Xc nh LLOQ theo cch sau
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Da vo tstn hiu trn nhiu (S/N): p dng i vi cc phng php c nhiu
ng nn. Xc nh bng cch o tn hiu thu c tmu c cha cht phn tch
vi nng thp bit v tn hiu thu c tmu trng. Xc nh nng cht
phn tch m tstn hiu trn nhiu (S/N) t nht l 5:1.
ng v chnh xc
ng v chnh xc trong ngy c xc nh trn 3 nng khc nhau ca
trimetazidin trong huyt tng (20 ng/ml, 30 ng/ml, 50 ng/ml), mi nng c
thc hin 5 mu. Xl mu nhtrn. Tin hnh sc k 1 ln cho mi mu th.
Yu cu :
Phng php t ng khi gi trtrung bnh ca % lch nm trong khong
15% so vi gi trthc, ring ti LLOQ cho php 20%.
Phng php t chnh xc khi tnh gi trthng k hm lng thu c trn 5
mu mi nng c RSD 15%, ring ti LLOQ th khng c vt qu 20%.
phc hi
Ln lt chun bdung dch mu chun m, pha long thnh cc cc dung dch mu
chun gc 3 nng 20 ng/ml, 50 ng/ml, 100 ng/ml. Tcc dung dch mu chun
gc ny pha thnh cc dung dch mu chun v mu thnhsau:
Tin hnh sc k cc mu trn, mi mu tim 6 ln, xc nh tldin tch nh, sau
tnh hiu sut chit: din tch nh trung bnh ca trimetazidin trong dung dch
mu th.
n nh
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Chun bcc mu trimetazidin trong huyt tng hai nng 20 ng/ml; 50 ng/ml,
mi nng thc hin 3 mu. Tin hnh xl mu theo mc 3.5.2.1.
* n nh ngn hn: bo qun -20 0C trong 24 gi, sau r ng nhit
phng, ginhit ny trong 24 gi. Tin hnh sc k 2 ln trn mi mu.
* n nh ng v r ng: bo qun -20 0C trong 24 gi, sau r ng
nhit phng, sau khi r ng hon ton cc mu c lm lnh trli trong
vng 12 24 ginhln u, sau 3 chu knhth, mu c mang ra phn tch.
Nu mu phn tch khng n nh nhit dkin th phi lm lnh nhit
-70 0C
* n nh trong ngy: pha cc mu trimetazidin trong huyt tng cc
nng 20 ng/ml; 50 ng/ml. Mi nng lm 3 mu. Cc mu r ng tnhin v
nhit phng. Cc mu c phn tch sau 6 gi
* n nh cch ngy: pha cc mu c nng nhtrn. Mi nng lm 3
mu. Cc mu c bo qun trong cng iu kin nhiu kin nghin cu. Phn
tch mu sau 7 ngy, 15 ngy v 30 ngy v so snh vi nng ca ngy u tin
lu mu.
3.4. PHNG PHP NGHIN CU KTHUT BO CH
3.4.1. Xy dng cng thc v quy trnh sn xut vin nhnDa trn nhng kt qunghin cu thm d thnh phn cng thc vi nhiu nhm
t dc khc nhau, thnh phn cng thc vin nhn c nghnhsau:
Bng 3.8. Thnh phn cng thc
Thnh phn Lng(1 vin) mg
Trimetazidin dihydrochlorid35
T dc AX1
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HPMC 15cpX2
Kollidon X3Aerosil
2Magnesium stearat
4Ludipress
V200Opadry II Pink
M hnh thc nghim vung la tinh vi 3 mc cho mi yu tc thit k(gm 9
cng thc) c trnh by trong bng 3.32. kho st s nh hng ca cc
polymer n phng thch hot cht tng thi im. Kt quthc nghim c
dng lm u vo cho phn mm FormRules c trnh by trong bng 3.33, nhm
nh gi quy lut nhn qugia cc thnh phn t dc.
Kt quthc nghim tm hnh vung la tinh c sdng lm nn tng cho vic
thit km hnh cng thc cho vin nhn Trimetazidin c thit kbi phn mm
Design-Expert theo m hnh D-Optimal gm 14 cng thc.
3.4.2. Quy trnh iu chvin Trimetazidin
3.4.2.1. Quy m phng th nghim
Vin nhn Trimetazidin 35 mg PTKD c cu trc khung matrix c bo chbng
phng php dp thng vi my dp vin xoay trn, sdng chy 8 mm Tt ccc
cng thc c iu chcng mt iu kin:
- Ry (qua cry 0,5 mm), ring Aerosil ry qua ry 0,3 mm v cn tng nguynliu. - Trn ban u trong 8 pht: trMg stearat v Aerosil.
- Trn sau cng trong 2 pht: hn hp, Mg stearat v Aerosil.
- Dp vin vi my dp vin xoay trn.
Chtiu vin nhn
- Khi lng trung bnh ca vin nhn: 200mg
- cng vin: 80 100 N
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3.4.2.2. Quy m pilot
Quy trnh sn xut vin Trimetazidin MR 35mg quy m pilot (30.000 vin)
c xy dng vi 3 l lin tip nhm nh gi khnng nng cp cl (c thc
hin ti nh my F.T Pharma). Sn phm ca 3 l c nh gi mc lp li v
ng u khi lng v ha tan trc khi tin hnh theo di n nh v
nh gi tng ng sinh hc
3.4.2.3. Bao phim vin nhn
Vin nhn Trimetazidin c tin hnh bao phim nhm mc ch bo vvin trnh
tc ng ca mi trng nhnh sng v m, gip hot cht n nh ng thi
to mt gi trthm mcho vin.
Chun bdch bao
Dch bao phim c iu chdi dng hn dch vi thnh phn l OpadryII 10%
(kl/kl) trong mi trng phn tn cn - nc (tl1:5).
Cch iu ch
-Lng dch bao:
Opadry II 10% Cn 96%
15%
Nc 75%
iu ch: phn tn lng bt Opadry IItrong nc. Khuy u hn dch bng cnh
khuy chn vt , cho ht lng cn vo hn dch ang khuy, khuy u hn dch
trong 5 pht. Tin hnh bao phim vin nhn, hn dch c khuy lin tc trong
sut qu trnh bao gip trnh hin tng lng cc tiu phn.
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Thng skthut bao phim
Cc thng skthut c thm d v la chn trn thc nghim nhsau:
-My bao phim tng FC 10, 6 cnh o
-u phun: loi IWATA LA 70 B
-Lphun: 1,2 mm
-Cl: 8 kg vin nhn-Tc ni: 6 7 vng/pht
-Nhit : Kh vo: 65 700
CKh ra: 45 50 0C
Nhit vin: 38 42 0C
-Tc phun dch bao: 12 17 g/pht (tc bm nhu ng: 20)
-p sut kh nn: 2,2 kg/m2
-Brng di phun: Phht brng khi vin
-Khong cch tsung phun n bmt khi vin: 15 17 cm-Sy sau khi bao: 45 pht 50 oC
3.5. PHNG PHP NGHIN CU TNG NG HA TAN
IN VITRO
Th nghim ha tan c dng nh th nghim thay th thit lp tng
ng sinh hc i vi mt sthuc rn dng ung khi p ng mt syu cu quy
nh
i tng: Tin hnh thnghim ha tan trn vin thv vin i chiu Mi
trng thnghim: Mi trng acid pH 1,2, m pH 4,5, m pH 6,8.
Slng: tin hnh trn 12 vin thv 12 vin i chiu mi mi trng. nh
gi kt qu: Da vo hstng ng f2nh gi kt quthnghim ha tan
ca vin thv vin i chiu.
Khi f2c gi tr50 < f2< 100, hai ng biu din ha tan l tng tnhau.
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1 t 2 0,5
f2 = 50 x log 1 + n
i=1 (Rt Tt)
x 100
Trong :
N : sthi im
Rt : gi trha tan ca l thuc gc thi im t
Tt : gi trha tan ca l thuc thnghim thi im t.
3.6. PHNG PHAP NGHIEN CU TNG NGIN VIVO
3.6.1. THIT KNGHIN CU THTNG NGIN VIVO3.6.1. 1. Chn ngi tnh nguyn
Chon ngi tnh nguyen trong o tuoi 18-55, can nang va chieu cao can oi, ch so
BMI at trong khoang 18-25 (kg/m2). Mot tuan trc khi tien hanh nghien cu,
NTN c kiem tra lam sang, xem xet tien s benh va cac xet nghiem toan dien
ve cac ch tieu: tuoi, can nang, chieu cao, Hct, Hb, WBC, Tieu cau, AST, ALT,
total bilirubin, direct bilirubin, BUN, creatinin, FBS
Ngi tnh nguyen phai co kha nang hieu cac thong tin ve nghien cu va viet n
xin tnh nguyen tham gia nghien cu, co ban cam ket, phai c thong bao ve tat
ca cac thong tin ve san pham cung nh c biet cac nguy c se co the xay ra khi
tham gia vao nghien cu trc khi tien hanh nghien cu. Nghien cu phai c s
thong qua va chap nhan cua Hoi ong y c.
3.6.1.2. Tieu chuan chap nhan
NTN tnh nguyen (NTN) phai co ch so tng quan gia can nang va chieu cao
(BMI) t 18-25 (kg/m2), khong b cac benh man tnh, khong nhiem HIV/AIDS,
HBV, khong d ng vi cac thanh phan cua thuoc nghien cu, khong hut thuoc la,
khong nghien ru, khong s dung cac chat gay nghien, chc nang gan than bnh
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thng. Trong vong 2 tuan trc khi tham gia cac th nghiem, cac NTN khong
c s dung bat ky thuoc nao.
3.6.1.3. Tieu ch loai tr
- Khong chap hanh che o an uong, sinh hoat a quy nh.
- Khong am bao nh ky lay mau va so lng mau c lay.
- Phai s dung thuoc khac trong qua trnh tham gia th nghiem
3.6.1.4. Rut khoi nghien cu
NTN c quyen t y rut khinghien cu bat ky luc nao ma khong can phai bien
ho cho quyet nh cua mnh Ly do rut khoi nghien cu:
Khong ong y tham gia
Phan ng bat li
Vi pham qui nh
Khong lien lcc3.6.1.5. Cmau nghien cu
So lng ngi tnh nguyen tham gia th nghiem thuoc la 12 (C mau n = 12).
3.6.2. Mohnh th nghiem
Ap dung mo hnh nghien cu cheo, ngau nhien, n lieu, hai giai oan, hai trnh
t, co nhn oi qua em.
Benh nhan c la chon ngau nhien vao trong 2 nhom. Moi benh nhan se nhanhai lan ieu tr thuoc nh sau:
Bang 3.9. Thiet ke th nghiem tng ng sinh hoc theo mo hnh cheo
Giai oan 1
Thi gian ngh
(07 ngay)
Giai oan 2
Trnh t1 Thuoc th Thuoc oi chieu
Trnh t2 Thuoc oi chieu Thuoc th
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Sau moi giai oan, co mot thi gian ngh gia hai lan dung thuoc la 07 ngay
(thng c chon gap 5 lan tcua thuoc), e nham cham dt hoan toan cac tacong cua ieu tr thuoc giai oan au, neu khong se xay ra hieu ng carry-over
(hieu ng ma trong giai oan 2, cac nhom ieu tr van con chu anh hng cua
thuoc ieu tr giai oan 1).
Trong thi gian ngh, NTN c cho phep tr ve nha va sinh hoat bnh thng.
3.6.3. Quy trnh thnghiemSau thi gian nhn oi qua em t nhat 10 gi, NTN se c cho uong 1 lieu duy
nhat thuoc oi chieu hoac thuoc th nghiem vi 150 ml nc. 2 gi sau khi dung
thuoc, NTN se c phuc vu ba an a chuan hoa va se dung cung loai thc an
trong ca hai giai oan th nghiem.
Benh nhan co the uong nc theo nhu cau nhng khong c uong trong vong 1
gi trc va sau khi dung thuoc, khong c uong ru, thc uong co xanthin Moisinh hoat, van ong c quan ly e tranh anh hng tao s khac biet trong hoa
tan va hap thu thuoc.
3.6.4. Xc nh cc thng ssinh khdng
Cc thng ssinh khdng Cmax v Tmax c ghi nhn trc tip tkt quphn
tch.
AUC0tc tnh theo cng thc:
n Ci +Ci+1
AUC0t = (ti+1 ti )i=1 2
Trong :
AUC0-t (g.h/ ml): Din tch di ng cong nng trimetazidin trong huyt
thanh tnh ti thi im 0 n thi im t.
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Ci(g/ ml) : Nng trimetazidin trong huyt thanh ti thi im ly mu mu
thi
Ci+1(g/ ml) :Nng trimetazidin trong huyt thanh ti thi im ly mu mu th
i+1
ti(h) : Thi im ly mu mu ln thi ti+1(h) : Thi im
ly mu mu ln thi + 1 i = 1 : Tng ng vi thi im
ly mu mu ln 1 (0 gi) i = n : Tng ng vi thi im
ly mu mu cui cng
AUC0-c tnh theo cng thc:
AUC0-= AUC0-t+ Cn/KeTrong
:
Cn(g/ ml): nng trimetazidin trong huyt thanh ti thi im ly mu mu cui
cng
Ke: hng sthi tr(dc ca ng thng biu din logarit nng trimetazidin
theo thi gian trong pha thi tr)
Tnh ton nhng thng s Cmax; AUC; Tmax. nh gi tng ng sinh hc in vivo
bng phng php trc nghim mt bn kp (Phn mm Phasolpro BE).
3.7. NGHIN CU N NH V TUI TH
Tin hnh nghin cu n nh trn 3 l lin tip
Theo di sn phm iu kin tnhin v iu kin lo ha.
nh gi cc chtiu
Hnh thc cm quan
Hm lng hot cht
ha tan sau 2, 6 v 12 gi
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iu kin tnhin
-Nhit 30
o
C, m 75% trong 24 thng.-nh kly mu vo cc thi im 0, 3, 6, 9, 12, 18 v 24 thng
iu kin lo ha-Nhit 40 oC, m 75% trong 6 thng.
-nh kly mu vo cc thi im 0, 1, 2, 3, 4, 5, 6 thng
Da trn sthay i vhm lng hot cht theo thi gian bo qun, c tnh tui
thca 3 l sn phm theo phng php Vant Hoff iu kin mt nhit .
t(90)= -ln (0,90)/ k = C*
Tui thca thuc iu kin bo qun ng yu cu l
C = K x C*+ C0 Trong
:
C* = tui thnhit lo ha cp tc.
= t90 (t1) = 0,1053/ k.
C = tui thnhit bo qun = t90 (t2).
Co : sngy ktngy sn xut n ngy em lo ha. t2
: nhit gi ha cp tc.
K : hsVant Hoff = 2. t/ 10.
Mc chnh lch nhit , t = t1 t2.
3.8. PHN TCH THNG K
3.8.1. nh gi cho
Khi luyn mng, m hnh c thit lp tnhm luyn sc dng don cc
tnh cht ca nhng cng thc trong nhm th. Hai gi trR2luyn v R2thc
tnh bi phn mm INForm.
n 2
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2 ESS ( yi yi )
R =1 100 =1 100
TSS ( yi yi ) 1
Trong : y: gi trthc nghim.
y: gi trdon ni (R2luyn) hoc gi trdon ngoi (R2th).
Thng thng gi trR2luyn > 95% v R2th> 70% th m hnh c chp nhn.
Gi trR2thcng tin ti 100 th khnng don ca m hnh cng tt.
3.8.2. Phn tch phng sai (ANOVA)
Phng php phn tch phng sai ANOVA dng so snh gi trtrung bnh ca
tnh cht sn phm (phng thch hot cht) -Gia cc l tcng thc ti u.
-Gia gi trdon ca INForm vi gi trthc nghim (trung bnh).
-Gia cc l ca vin nhn v vin bao.
Trong kt quphn tch phng sai ANOVA, nu F< F0,05th gi trtrung bnh ca
tnh cht sn phm trong cc trng hp trn khc nhau khng c ngha.
1
2n
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4.KT QUNGHIN CU
4.1.PHNG PHP NH LNG & THM NH PHNG PHP
4.1.1.nh lng hot cht trong chphm
4.1.1.1. Phng php quang phUV
Thm nh phng php quang phUV mi trng acid pH 1,2
Tnh tuyn tnh
Sbin thin hp thu theo nng ca Trimetazidin chun pH 1,2 c trnh by
trong bng 4.10.
Bng 4.10. Kt qukho st tnh tuyn tnh trong mi trng acid pH 1,2
Nng (mcg/ml)
8 12 16 20 24 28 32
hp thu 0,2079 0,3228 0,4325 0,5409 0,6538 0,7673 0,8745
0 5 10 15 20 25 30 35
Nng (mcg/ml)
Hnh 4.7.thbiu din tng quan tuyn tnh gia nng v hp thu trong mitrng
acid pH 1,2
Dng cng cRegression (MS-Excel) ta c kt qunhsau:
y = 0.0278x 0.0126
R2
= 0.9999
0
0.2
0.4
0.6
0.8
1
h
pth
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F = 88618,62 > F0,05 = 4,876. Vy phng trnh hi qui c tnh tng thch.
|t0| = 6,25 > t0,05= 2,57. Vy hsb0c ngha.
|t| = 297,69 > t0,05= 2,57. Vy hsb c ngha.Phng trnh hi qui tuyn tnh gia hp thu v nng Trimetazidin
dihydrochlorid chun trong mi trng acid c phng trnhy = 0,0278x0,0126
v h
stng quan R2= 0,9999.
Kt lun: c s tng quan tuyn tnh gia nng v hp thu ca Trimetazidin
dihydrochlorid chun khong nng 8 32 mcg/ml trong mi trng acid pH 1,2.
Tnh c hiu
Bng 4.11.Kt qukho st nh hng ca t dc trong mi trng acid pH 1,2
N X chun(mg) X ginh (mg)
Kt qu
X ginh = 35,05 mg F
= 1,85 < F0,05= 5,05 t
= 1,32 < t0,05 =
2,23
6 34,98 34,84
Trc nghim t-test cho dy sc phng sai khng khc nhau cho kt quhm lng
ca hai mu chun v ginh khc nhau khng c ngha (chp nhn githuyt Ho).
Vy t dc khng nh hng n kt qunh lng trong mi trng acid pH 1,2
lp li
Bng 4.12.Kt qukho st lp li trong mi trng acid pH 1,2
2 35,23 35,16
3 35,28 34,96
4 35,53 35,29
5 35,26 35,35
1 35,06 34,69 Xchun= 35,22 mg
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N X l thuyt(mg) X thc(mg) Hm lng TMZ(%) Kt qu
1 35,02 34,95 99,79
RSD = 0,795% < 2% e =
0,825 (n - 1 = 5; P =
0,95; t = 2,57)
= 98,915 0,825%
6 35,11 34,41 98,00
lch chun tng i RSD = 0,795% < 2%. Vy phng php xut t yu cu
vlp li trong mi trng acid pH 1,2.
ng
Bng 4.13. Kt qukho st ng trong mi trng acid
Mc
kho st
Lng thm vo
(mg)
Lng tm thy
(mg)
Tlphc hi
(%)
lch chun
(CV%)
29,32 29,28 100,14
85% 29,75 29,78 99,90 0,34
29,40 29,23 100,58
35,06 34,68 101,10
100% 35,12 35,18 99,83 0,93
35,08 35,33 99,29
40,54 40,73 99,53
115% 40,25 39,88 100,93 0,71
40,05 39,85 100,50
2 35,07 34,58 98,60
3 35,04 35,03 99,98
4 35,09 34,60 98,53
5 35,00 34,51 98,59
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Trung bnh 100,2 0,62
Kt quthm nh ng c trnh by trong bng 4.13.Tlphc hi trung bnh
i vi dliu l 100,2%, hsphn tn ca dli