Nghiên cứu bào chế và đánh giá sinh khả dụng viên nang aciclovir tác dụng kéo dài

1. Cải thiện tính thấm của aciclovir Đã xây dựng được phương pháp đánh giá tính thấm in vitro và chứng tỏ được khả năng ứng dụng của màng nhân tạo trong các nghiên cứu sàng lọc ban đầu về cải thiện tính thấm của aciclovir. Đã lựa chọn được chất cải thiện tính thấm thích hợp đưa vào thành phần công thức viên nang aciclovir giải phóng kéo dài là 3% Tween 80

%Ӝ*,È2'Ө&9¬Ĉ¬27Ҥ2 %Ӝ<7ӂ  **********  1*+,Ç1&Ӭ8%¬2&+ӂ9¬ĈÈ1+*,È 6,1+.+Ҧ'Ө1*VIÊN NANG ACICLOVIR 7È&'Ө1*.e2'¬,  1 %Ӝ*,È2'Ө&9¬Ĉ¬27Ҥ2 %Ӝ<7ӂ  **********  1*+,Ç1&Ӭ8%¬2&+ӂ9¬ĈÈ1+*,È 6,1+.+Ҧ'Ө1*9,Ç11$1*$&,CLOVIR 7È&'Ө1*.e2'¬,    PGS.  GS TS. Võ Xuân Minh 1 i L L  I C  M  N Tôi xin bày t lòng bic: PGS. TS. Phm Th Minh Hu GS. TS. Võ Xuân Minh Nhi thng dn và h tôi trong thi gian làm lun án va qua. xin chân thành c Nguyn Trn Linh cùng toàn th các thy, cô giáo, k thut viên B môn Bào ch, b c lc , tu kin thun li cho tôi hoàn thành lun án này. Trân trng c , tu kin ca TS. Phùng Th Vinh, ThS. Nguyn Th Thanh Tho cùng các kim nghi     c, Vin Kim nghim thu Tôi xin chân thành c      ng, PGS. TS. Nguyn Thanh Bình, TS. Nguy ti h tôi trong quá trình công tác, hc tp và nghiên cu. Cui cùng, tôi xin cn bè       ng viên, to m u kin thun l  tôi hoàn thành lun án. Hà N  Thu Giang ii L   u ca riêng tôi. Các s liu, kt qu nêu trong lun án là trung thc ai công b trong bt k công trình nào khác.  Thu Giang iii DANH MC CÁC KÝ HIU, CH÷ VIÕT T¾T ACV : A ciclovir ACV-KDNM :   AUC :   BAK : B enzalkonium clorid BP :   (British Pharmacopoeia) C-974 : C arbopol 974P NF C max :   CMC : C arboxymethyl cellulose  :   DM : D ung môi DBP : D ibutyl phtalat EBV : V irus Epstein-Barr EC : E thyl cellulose EDTA : A cid ethylendiamintetraacetic FDA :  – Food and Drug Administration) GPDC :   GPKD :   HPCD : 2 -hydroxypropyl E-cyclodextrin HPLC : high performance liquid chromatography) HPMC : H ydroxypropyl methyl cellulose HQC :  cao (high quality control sample) HSV : V irus Herpes simplex HT :   KDNM :   Kl/kl :   Kl/tt :   KSGP :   KT :   KTT :   LLOQ :  lower limit of quantification) LQC :  low quality control sample) iv MEC :  minimum effective concentration) MQC :  middle quality control sample) MRT :   (mean retention time) MTC :  minimum toxic concentration) NaDC : N atri deoxycholat NaGC : N atri glycocholat NaLS : N atri laurylsulfat NTN :   OCC : D L-octanoylcarnitin clorid PCC : P almitoyl-DL- carnitin clorid PEG : P olyoxyethylen glycol PEPT :    P-gp : P -glycoprotein PVA : P olyvinyl alcol PVP : P olyvinyl pyrolidon K30 RSD :  relative standard deviation) SCC : D L-stearoylcarnitin clorid SD :   (standard deviation) SKD :  SMEDDS :   (self-microemulsifying drug delivery system) STT :  T 1/2 :   TBA : 4 -thiobutylamidin TCCS :    :   TEC : T riethyl citrat TEER :   (transepithelial electrical resistance) T max :   TT :   Tt/tt :   USP :   (United States Pharmacopeia) VA : V iên nén Vacrax ® 200 mg VKNTTW :   VZV : V irus Varicella- zoster WHO :   (World Health Organization) v   1 CHNG NG QUAN 3 1.1. ACICLOVIR 3 aciclovir 3 aciclovir  7  20  20   21  22 aciclovir  24 T 28  28 1.3.2 28  31 aciclovir 35 CH    VÀ PHNG PHÁP NGHIÊN  39  39  39  40   41  41 2.2. PH 41 2.2.1. Ph 41 2.2.2. Ph 44 2.2.3. Ph 47 2.2.4. Phin vivo  50 2.2.5. Ph 53 2.2.6. Ph 54 CH 55 CLOVIR 55 vi aciclovir 55  60  62 . 68 aciclovir  68 aciclovir 200 mg GPKD 87   89 g ph  89   94  103  104 3.4.1. Theo dõi hàm l 104 3. 107  110 3.5.1. ng 110  121 CH 130 NGHIÊN CLOVIR 130 CLOVIR GPKD 134   138  141  141  146  . 147  148  156 vii    aciclovir  o  4   aciclovir -2 4 1.3. aciclovir 7            aciclovir 37 5.  39 6.  45 7.    app ) 56 8.   57 .   58 .   59 11.    61 .   63 .                64 .    66 .  67 .    69 .  70 .    70 .  71 .    72 .  73 viii . màng bao GPKD  74 .   74 .  GPKD  khác nhau 75  3.25.  77 6.  77 7. T 78 8.   bao GPKD 79 29.   GPKD 80  3.30.   81 1.   86 2.  86 3.    87 4.   GPKD 88 3.35.  ACV   90 6.    91 7.    92   94 .    95 .   khí vào khác nhau 97 .   khí phun khác nhau 98 3.42.                 99 .    100 [...]... Val-valaciclovir Q QK WW Yj Fy WDQ WURQJ QF FDR KQ $&9 0W V tỏF JL m FKQJ PLQK F 99$&9 OjP WQJ 6.' QJ XQJ FD $&9 OrQ NKRQJ  OQ [54], [70] Cỏc WLQ GF FKW dipeptid L-Valin-L-valin -aciclovir, L-valin-D-valinaciclovir v D-valin-L-valin -aciclovir F 7DOOXUL 56 Yj FQJ V [71] FKQJ minh X Fy iL OF YL 3(37 nờn WQJ WKP $&9 TXD PjQJ W EjR &DFR-2 theo WK W L-valin-D-valin -aciclovir > L-Valin-L-valin -aciclovir. .. BjR FK F viờn nang aciclovir 200 mg GPKD  JL 2 iQK JLi 6.' FD YLrQ QDQJ aciclovir GP.' EjR FK WUrQ QJ YW WKt QJKLP WKF KLQ PF WLrX UD OXQ iQ EDR JP FiF QL GXQJ VDX 1 &L WKLQ WtQK WKP FD $&9 2 ;k\ GQJ F{QJ WKF EjR FK YLrQ QDQJ $&9  PJ *3.' 3 ;k\ GQJ TXL WUuQK EjR FK YLrQ QDQJ $&9  PJ *3.' TXL P{  YLrQ Yj [XW WLrX FKXQ FKW OQJ 4 iQK JLi Q QK 5 iQK JLi VLQK NK GQJ viờn nang ACV 200... Q QK 5 iQK JLi VLQK NK GQJ viờn nang ACV 200 mg GPKD trờn chú 3 CH1* , 71* 48$1 1.1 ACICLOVIR 1.1 L FQJ Y aciclovir  &{QJ WKF KRi KF &{QJ WKF SKkQ W & 18 H 11 N 5 0 3 KL OQJ SKkQ W  7rQ NKRD KF -amino-9[(2-hydroxy ethoxy)-methyl]-1,9-dihydro-6H-purin-6on [69], [1]  7tQK FKW Oờ KyD Aciclovir Fy FiF WtQK FKW Oờ KyD VDX [1], [69], [13]: - DQJ EW NW WLQK PjX WUQJ, tW WDQ... 1KLW QyQJ FK\ NKRQJ  o& VDX y E SKkQ K\ - Aciclovir Fy  KQJ V SKkQ O\ pKa 1 = 2,41 0,27 pKa 2 = 9,06 0,88 - 7KHR SKkQ ORL VLQK GF KF $&9 WKXF QKyP  [13] Fy WtQK WKP NpP 4 %QJ  WDQ FD aciclovir  o& WURQJ FiF P{L WUQJ S+ NKiF QKDX [13] STT pH WDQ PJPO 1 1,2 > 3,5 2 4,5 ~ 2,6 3 5,8 ~ 2,3 4 6,8 ~ 2,4 5 7,4 ~ 2,5 %QJ 1.2 H V WKP ELX NLQ FD aciclovir TXD PjQJ W EjR &DFR-2 [13] STT pH... EBV, Cytomegalo [3], [69] - Fy WiF GQJ aciclovir SKL F SKRVSKRU\O KyD OQ  GR WK\PLGLQN\QDVH F KLX FD +69 WR WKjQK GQ [XW PRQRSKRVSKDW, OQ WK  Yj WK  GR FiF HQ]\P FD W EjR YW FK WR WKjQK GQ [XW GLSKRVSKDW Yj WULSKRVSKDW ẩL OF FD WK\PLGLQN\QDVH +69 PQK NKRQJ KQ  OQ VR YL HQ]\P FD W EjR YW FK nờn aciclovir F KRW KyD KX QK FKQ OF WURQJ FiF W EjR QKLP +69 Aciclovir WULSKRVSKDW F FK WQJ KS $'1 YLUXV... GF WKQJ SKL LX WU EQJ $&9 WURQJ PW WKL JLDQ GjL [27] 7  0W V ELW GF FKD aciclovir &iF GQJ EjR FK FD $&9 NKi D GQJ QKQJ Fy PW WUrQ WK WUQJ F WURQJ QF FQJ QK WUrQ WK JLL KX KW YQ Oj FiF GQJ EjR FK TXL F %QJ 1.3 0W V ELW GF FKD aciclovir STT %LW GF 'QJ EjR FK 1 Herpevir 2 Vitrazolin LL Kem 3 Zovirax 4 Zoraxin 5 Aciclovir Stada Viờn nộn +jP OQJ 1Kj VQ [XW 200 mg Sanofi Synthelabo VN 5 %, tuýp... $&9 7LQ GF FKW D,E-poly(N-2-hydroxyethyl) - DL- aspartamid -Osuccinyl aciclovir F *LDPPRQD * Yj FiF FQJ V [41] WQJ KS Fy NK QQJ WDQ W GR WURQJ QF QKLW SKzQJ Yj Q QK KQ $&9 7URQJ FiF P{L WUQJ P S+   Yj  WLQ GF FKW E WK\ SKkQ JLL SKyQJ 2succinylaciclovir v ACV DL WiF QJ FD FiF HQ]\P WURQJ F WK, OLrQ NW HVWH FD 2-succinylaciclovir E WK\ SKkQ WUF WLrQ JLL SKyQJ $&9 Cỏc tỏc JL m FKQJ PLQK F... WURQJ QKLX WUQJ KS 2 aciclovir SKL F GQJ WKL JLDQ GjL Yt G LX WU PLQ GFK NK{QJ WiL SKiW +HUSHV VLPSOH[ SKL GQJ WKXF  WKiQJ KRF GjL KQ 9u Y\ YLF QJKLrQ FX WuP UD GQJ WKXF XQJ GPKD cú SKD caR Fy WK QJ GQJ YjR WKF WLQ VQ [XW Oj YQ FS WKLW Fy ờ QJKD WURQJ OQK YF QJKLrQ FX Yj VQ [XW GF SKP ;XW SKiW W WKF W WUrQ FK~QJ W{L WLQ KjQK 1JKLrQ FX EjR FK v iQK JLi VLQK NK GQJ viờn nang aciclovir WiF GQJ... GL GQJ NK{QJ ELQ L 9carboxy methoxy methyl guanin Oj FKW FKX\Q KyD iQJ N FD aciclovir, FKLP NKRQJ  WQJ OQJ WKXF WK\ WURQJ QF WLX [69]  7KL JLDQ EiQ WKL EQK QKkQ Fy FKF QQJ WKQ EuQK WKQJ WKL JLDQ EiQ WKL FD $&9 NKRQJ 2- JL WU V VLQK Oj  JL FzQ EQK QKkQ VX\ WKn mn t 1/2  JL [3], [69]  7iF GQJ GF Oờ - Aciclovir Oj PW FKW WQJ W QXFOHRVLG Fy WiF GQJ FKQ OF WUrQ W EjR QKLP YLUXV... Kem 200 mg 5 %, tuýp 5g 7 Hutevir Viờn nộn 200 mg Glaxo SmithKline Valor Pharmaceuticals Hutecs Korea 8 Aciclovir Viờn nộn 200 mg Pharmaceutical Sinil Pharmaceuticals 9 Herpex Viờn nộn 200 mg Torrent Pharmaceuticals 10 Genvir Viờn GPKD 600 mg Flamel Technologies 1.1 0W V QJKLrQ FX FL WKLQ KS WKX aciclovir TXD QJ WLrX KyD ACV Fy WtQK WKP NpP WKkQ GX Yj Fy NKL OQJ SKkQ W WKS   QrQ F KS WKX FK .  viên nang aciclovir  các  tiêu sau: 1. B  viên nang aciclovir 200 mg GPKD . 2.  aciclovir GP. tuýp 5g 7 Hutevir Viên nén 200 mg Hutecs Korea Pharmaceutical 8 Aciclovir Viên nén 200 mg Sinil Pharmaceuticals 9 Herpex Viên nén 200 mg Torrent Pharmaceuticals 10 Genvir Viên GPKD 600 mg Flamel. 200 mg/5ml 4 Zoraxin Viên nén 200, 400 và 800 mg Valor Pharmaceuticals Kem 5 %, tuýp 2g và 10g 5 Aciclovir Stada Viên nén 200 và 800 mg Stada –VN Kem 5 %, tuýp 2g, 5g 6 Vacrax Viên nén 200 mg Samchully