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

Luận văn

LLI C-M /N

PGS TS Phm Th Minh Hu

GS TS Võ Xuân Minh

thi gian làm lun án v!a qua.

kin thun l=i cho tôi hoàn thành lun án này

nghiên cWu.

thành lun án

/%"D Thu Giang

+ ," )'- &'" /0 12 )+" 345"  " 6" )7u c9a riêng tôi Các s; li<u, k>t qu? nêu trong lu@n án là trung thA)B2) '3D".Ec

ai công b; trong bFt kG công trình nào khác

HI J Thu Giang

BP : [E).^"W" (British Pharmacopoeia)

EDTA : Acid ethylendiamintetraacetic

FDA : }U'"U?"1‚3 U;)– 3 A)ƒ „-†‡Food and Drug

HPMC : Hydroxypropyl methyl cellulose

HQC : $U%^-) 7""{".|cao (high quality control sample)

F-LLOQ : ! Y".J" 1E"#!‡lower limit of quantification)

LQC : $U%^-) 7""{".|3 Fƒ‡low quality control sample)

MEC : {".|3;3 ^U)ˆ3–)#™"‡minimum effective concentration)

MQC : $U%^-) 7""{".|34U"š5" ‡middle quality control sample)

MRT :  '"1U34œ34U"š5" (mean retention time)

MTC : {".|3;3 ^U/0.|)‡minimum toxic concentration)

NaLS : Natri laurylsulfat

NTN : 35" "U0<"

OCC : DL-octanoylcarnitin clorid

PCC : Palmitoyl-DL- carnitin clorid

TEER : <"34¢3 E"š5 (transepithelial electrical resistance)

Tmax :  '".Y3"{".|3 U;)3;.'34&" U0>33}"

VZV : Virus Varicella- zoster

WHO : ©) 7)3>3 >! (World Health Organization)

(22

56 7 1

CH/NG "8NG QUAN 3

1.1 ACICLOVIR 3

Y)}"B«aciclovir 3

|3•;" 6")7U)?3 <" Fƒ3 Uaciclovir U'."36U ˆ' 7

’ –"<-B«3 U;)?ƒ ˆ"%‰&#2 20

|3•;#Y"3 U;)?ƒ ˆ" %‰&#2#±"3 ž&."U;" 21

+ 5" š2&) >3 U;)?ƒ ˆ"%‰&#2#Y"-2"š'& 22

²|3•; <?ƒ ˆ"%‰&#2) 7'aciclovir #±") &."U;" 24

’ –"<-•" % ?#™"B23}".}"•"  () 28

1.3.2–" –•" % ?#™")9'3 U;) 28

·U0.J" B«.–" –•" % ?#™"B23}".}"•"  () 31

²|3•;" 6")7U•" % ?#™"."U;")9'aciclovir 35

CH/ " :; 3<   = VÀ PH/NG PHÁP NGHIÊN > 39

U06"1<U 39

 >3šJ 40

 U;) ;) >U 41

²|"B@33 X" <- 41

2.2 PH§´ —¼— ¬» 41

2.2.1 Ph}"ƒ –ƒ" 6")7U3X" 3 F- 41

2.2.2 Ph}"ƒ –ƒš2&) > 44

2.2.3 Ph}"ƒ –ƒ.–" –36U) U„") F31E" 47

2.2.4 Ph}"ƒ –ƒ.–" –•" % ?#™"in vivo 346".|"B@33 X" <- 50

2.2.5 Ph}"ƒ –ƒ3 >3%>3 X" <-B23;U &–)+"3 7) 53

2.2.6 Ph}"ƒ –ƒ" 6")7U.|©".J" 54

CH/@"BE- ;> 55

­¬¬º¾¿ÀWW¬CLOVIR 55

Á/0#A"-+ 5" -2"" /"3Y&.–" –3X" 3 F-)9'aciclovir 55

 6")7U)?3 <"3X" 3 F-)9'WHU'-2"" /"3Y& 60

 6")7U)?3 <"3X" 3 F-)9'WHU'-2"•"  () 62

 6")7Uš2&) > Y3aciclovir ?ƒ ˆ"%‰&#2 68

 6")7Uš2&) >B6""'"aciclovir 200 mg GPKD 87

’ ?&•–3)–)3 +"•;)9'U–345" 3Y& Y3šË"g ph}"ƒ –ƒ3Y& Y3 !3B2#A%>"36U) U„" Y3WH 89

’ ?&•–3)–)3 +"•;)9'U–345" š'&B2#A%>"36U) U„" Y3WH ?ƒ ˆ"%‰&#2 94

«,UF3-|3•;) Ì36U) F31E") &B6""'"WH —’[ 103

²¼ ¬¼ÍÎÏ 104

3.4.1 Theo dõi hàm lE" 104

3.² ž&#Ð.| Ñ'3'" 107

¼ ¬¼¬’­[³ 110

3.5.1  „-.J" ƒ }"ƒ –ƒ.J" 1E"WH34&" U0>33}ng 110

–" –•" % ?#™"B6""'"WH —’[ 121

CH/"= 130

²HÈNGHIÊN »­¬¬º¾¿ÀWW¬CLOVIR 130

¿¹§Ê H¬W WH- —’[ 138

²²Hȼ ¬¼ÍÎÏ 141

²Hȼ ¬¼¬’­[³ 141

B 7O6 146

 (2YZ  [Y=\ ;E  147 3 (B -0 148

# 22 156

 (2=-<=_

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100

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105

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120 121

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100 101

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50 £34" Eƒ•" "&")ˆ16"U'.>"B4U•"20 ž&3©) 7)03>3 >!

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Aciclovir 12-|3#$") F33©" Eƒ)9'')d nucleosid - guanosin có tác

#™" -Y"  B2 ) (" 1() 346" )–) B4U• /0 š<"  ¢ " š'& {- Herpes simplex 1&YB21&YÓ Varicella- zoster,Epstein-Barr và Cytomegalo Ngoài ra

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aciclovir ƒ ? E) #±" 3  '" #2Ó BX #™ «U 34J ^ -×" #J)  % +" 3–

ƒ –3ž4ƒž••-ƒ1ž,ƒ ?#±"3 U;)3 –" &Ô)#2 }"H5B@0B<)" 6")7U35-4'#Y"3 U;)U;"GPKD có SKD ca&Ó)ˆ3 ^7"#™"B2&3 A)3×"

•?",UF312BF".«)Fƒ3 >3Ó)ˆ‚" ã'34&"1ã" BA)" 6")7UB2•?",UF3

#E)ƒ „-

ÁUF3ƒ –33D3 A)3>346"Ó) œ"3+3>" 2" bc$)d*ef+gjke$lvà

mo*$c)op)*$q$rst*cviên nang aciclovir }oest*cq~ksj) B!các -™)

tiêu sau:

^3 A) <"-™)36U.«4'Ó1U@"–"š'&{-)–)"|#U"•'U

1 ‚& „'$C6–‚/+

- RFt b«n vÞ"Ó34&"-+34ng ki«m ©".J"  }"34&"-+34ng acid.

-  <3.|"ˆ") ?0% &?"oÓ•'U.ˆšJƒ /" 90

- Aciclovir )ˆ Ë"•;ƒ /"10

pKa1= 2,41 ± 0,27pKa2= 9,06 ± 0,88

-  ž&ƒ /"1&Y•" #E) ()ÓWH3 U|)" ˆ-[13] )ˆ3X" 3 F-%‰-

- SKD 3 ž& " U;" 3 Fƒ B2 % +" ©" J" Ó % &?" 20%  7) "

% +"12-?"  ¢".>" Fƒ3 U3 U;) [3], [69]WH.E) Fƒ3 U) 90>U

3 ž&)}) >% U>) 3–"3 ™.|"Ó Fƒ3 U) @- và không hoàn toàn [13]

-  '".Y3max •'U% U;"12Ó– [69]

- — /"š;aciclovir ƒ /"š;34&"#J) )}3 ^B2)–))}U'"" "Ú&Ó

3 @"Óƒ ©Ó4U|3Ó'"Ó1–) Ó)}Ó3Û)U"Ó"6--Y)Ó#J) /-.Y&Ó"!)-3Ó3 903" #J) Ó#J) "Ú&390{".|34&"#J) "Ú&390.Y33!i 50 £"{".| U0>33}" ¹6" %>3 ƒ4&3ž" 3 FƒÓ % &?" % (9 - 33 £Ù  U;) U' E) nhau

3 'B2ƒ /"š;34&"•Þ'-ëFƒ3 UWHU'#'•'U% š+3 "4F3X3,3U0" 6"% ?"" Fƒ3 U#E)) F3)ˆ3 ^3"16"% 3 '0.©3 2" ƒ S")+"3 7)3 U;)[1], [3], [69]

-  U0^" ˆ'B23 ?34D

î— S"1!"3 U;).E).2&3 ?U'3 @"#!#Y"% carboxy methoxy methyl guanin 12 ) F3 ) U0^" ˆ' –" %^ )9' aciclovir,) >-% &?"² £3©"1E"3 U;)3 F034&""!)3^U[69]

- ^ )ˆ 3–) #™"Ó aciclovir ƒ ? E) ƒ &•ƒ &401 ˆ'Ó 1S"  #&

3 0-#"%0"'•ž.Ô) <U)9'H3Y&3 2" #$",UF3-&"&ƒ &•ƒ '3, 1S"3 7B23 7#&)–)ž"ò0-)9'3>š2&B@3) 9.^3Y&3 2" #$",UF3#ƒ &•ƒ '3B234ƒ &•ƒ '3¼1A))9'3 0-#"%0"'•ž¢H-Y" % &?" }"1S"•&B!

ž"ò0-)9'3>š2&B@3) 9nên aciclovir E) &Y3 ˆ' SU" ) ("1()34&")–)3>š2&" ×-HAciclovir 34ƒ &•ƒ '37)) >3©" EƒW[B4U•B2•A

" /" 16" )9' B4U• -2 % +" ?"  ¢" 5 >" ) U0^" ˆ' )9' 3> š2& š5" 

3 " [3], [69]

Aciclovir E)) Ì.J" .«U34J34&")–)34" Eƒ•'U

- «U34J% ¢.SUB2#Aƒ Ñ"" ×-H30ƒB230ƒ¢#'Ó"6--Y)Ó3 S" %" B2•" #™)ÓB6-"Ú&#&H [3], [69]

- «U34J" ×-ž4ƒž•ò&•3ž4)Fƒ3X" ¢-3Óƒ ©, 3 S"%" [3], [69]

- «U34J% ¢.SUB23–ƒ –3 ž4ƒž••" #™) [3], [69]

- [A ƒ Ñ" B2 «U 34J " ×- B4U• ¢ " •U0 ?- -×" #J) Ó )F0

 ‰ƒ)}U'"Óš<" 3 90.@U [3], [69]

-  ;") Ì.J" ) &" Þ"š<" " /"-$")?-B!3 U;) [3], [69]

- Th@n tr(ng v!i b<nh nhân suy th@n, ph™ nÞ có thai và cho con bú [3], [69]

- Tiêm truy«"3ã" -Ych ch@-.^ tránh k>t t9a aciclovir trong th@n [3], [69]

Aciclovir có th^ gây ra m|t s; tác d™ng ph™ sau:

- Có th^ gÔp bu{n nôn, tiêu ch?0Ó"+"Ó.'Uš™ng, n©i ban, các ph?n 7ng v«thS"%" " ) ˆ"-Ôt, ?o giác, bu{n ng9 [3], [69]

- ng tiêm truy«"3ã" -Ych có th^ gÔp các ph?n 7"" B6-ÓB6-3ã" -Ych ¢ vJ trí tiêm [3], [69]

- Kem bôi: Có khi gÔp c?m giác nóng bŽng hay nhói nhë ¢ vJ trí bôi kèm

Tuy nhiên, •Û#™"WH34&".«U34Jԃ-|3•; Y") >"  Fƒ3 UWH U' " 36U ˆ' ) @-Ó ƒ ™ 3 U|) B2& 1«UÓ % +" ©" J"  B2 hoàn 3&2"’ &?"¥£1«UU;"šJ3 ?34DU'ƒ /"[13]Ô)#±B@0 "U;"B$".E)) Ì.J" " «U }"."36-#&"""D'.E)"U0)}/0viêm, B6-3ã" -Y) ¢BJ34X36-Ó36-3ã" -Y) " '" )ˆ3 ^/04'%>339'WH¢

3 @"4" Eƒš+3Y) ÷Ó Fƒ3 U3 U;)4F3) @-|3•;" 6")7U) &

3 F0)–)3 U;) š+"&2#') 7'WH)S"%>3 Eƒ3 6-) F33"3 F-[48]

’ +"."#±""2&¢346")ˆ <UU?34&"?-"U0)}3–ƒ –3 ž4ƒž•

•"  #™) 4" Eƒ -) ž4ƒž• •"  #™) 3 " ƒ ? «U 34J šË" WH34&"-|33 '"#2[27]

–)#Y"š2&) >)9'WH% –.'#Y"" ")ˆ-Ô3346"3 J34")?34&""!))I"" 346"3 >! SU >3B$"12)–)#Y"š2&) >U!)

STT =),}s‚•e %*cgjke$l ... A)3>346"Ó) œ"3+3>" 2" bc$)d*ef+gjke$l và

mo*$c)op)*$q$rst*c viên nang aciclovir }oest*cq~ksj) B!các -™)

tiêu sau:

^3...

L-valin-D-valin-3 7 L-valin-D-valin-3A L-valin-D-valin -aciclovir > L-Valin-L-valin -aciclovir > Valaciclovir >D-valin-L-valin -aciclovir

Các 3«"#E)) F3 alanin-ACV, serin-ACV,... UWHU''."36U ˆ''

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