Professional Documents
Culture Documents
Pilocarpne IOOS
21.. l,Jebma K. Otagiri M. Irie T. Seo H• Tsunao,..
L-
1'4. lat J Piloc:■q,ine Hydrochloride USP and Pilocarpine Nitn1C USP
PbafflUtCCUlics 1985;23: 3~2.
sbould be pcua wed in lipt. lighl--raistllal c:.oataiaen.
29, Jac:hc,wiez R. Int J Pharmace utics 1917;3S:7- l2.
30 Picaaar EW. Boncd\an s B. Koclcman HA · OrvI Dev · 0.../on ,u .
. Phann 1991:17(10):1397-I.O.C. Ind
Pilocarpioo Ocalu S ~ USP should be pcae,Wld ill liacle-
JI. easaami SM. Groves Ml. Int J Phannacicucic:s 1971:l:IS. dOIC coataiacn. iD a oolcl place.
~ Hydrodlloriclc Ophthalm ic Soluuoa .U SP.,_.. be
pr-. wed la 1.1,tal ma11iacr, aad Pilocarpine Nitrate Oplidlal-
mic Solulioa USP.la lipt. light-n:sisunt q,atai~
ltopeoCar pine abould bellofed in a cool place a111ray ha direct
sudabt- The container (with screw-on apJ. lboald lie lliepl
tiaf,ily doe,id. ..
,-e (ra•
......
M~ Piloc:arpiae Nicrafe should be scon,c1 ia
to IS") and aot ClpOIOCI 10 ICrOag sualipL .
Oc;aiertaysCcmalhou1d belton:d in a sd'riprac «atr10r. Do
SilCl Pio tbouW llellOfell llraoool place.and llioalcl .-lledil-
pwed rrocn any conwiler ocher lh■ a the origioal boalc.
=~!~-~~-~~WU
. ~ ~ , . sbifts to pilocarpic acid whaas ia acidic: aqu- F ~ " ·clcaionSU&led that aqueous sohllicNls ol pilocar.
eous _so,utlOIIS'it,_s hl~· l:b''piloc:arpinc. Epimerisatioa ocan at pine hydrochioride 2% (with sodium chlonde 0.4% and piayt-
~lltalinc p~ u:ct al_lhoup _ .~worltersJ rcpor1ed that cpianef• ~ 11itra1C 0.001%). of initial pH4.2. wiclllcoocl
au~~ii~iis ac 110" i'or lO minu&c:S and remained_ICable-ror at
.... .. . i~ble. (urther
-i'ei'cniblcnatweorthisracuora.Al ledi''12 moallll.,.. scoced at room tcmpcratan ia die daitc
pH 10.9. a~ ~ ~nc pH ftlue&. lhc equilibriuna was in (final pH J.S). At pH S. about S"• loss or initial cioaceatralioa
favou~ or_~ Ii was also shown that pilocarpinc or pilocarpine was clelcded1,. followin1 auc:xlaYias r« 24
and ~piloc:arpine ~d similar hydrolysis ,ale coascanu hours at 120". Piloaarpine eye .drops.. buft'c:red to pH S wida
(~.04/m•~ and 0.044/man. rcspcc:ahdy). Thus. in alkaline solution. acetic acid and sodi•lil hydroxide were stable to aUfq:laviaa at
~loc;arp1ne t1ndercocs 4:_0nc1ir·~t epi~tioa and hydroly• 120- for 20 nuauta and less than 10% de&uiposidoll wu
~ :~~~ of1Nlocarpine 90lulioas at pff-4 to de~ after...,.... ror S years. At pH6.I luwewu." die
.._.,.:&rc~plloc::upiaewuca~ted as 3"minulctat l»-com-
.• : . • _.,_ _ _to~~ ~ b l e stabe1ity. · .
The ktnetie:S of die overall ~ l i o n of p1ocarpine (pisucdo- parcd=to 66 days at room tanpaature (25").
ftrst~ ~ - . m-of'ilid hydrolysis and· epitnerisation
Pf00CSICS hawe·bceft cflSCUISCd.l-, · ·
i
.~1t~n l~TION. Conlributio~ recude de la llabilicc de
la pilocarpine en ailicii aqueu (Part 1-identific:atioa ofitocont-
£Keet of Canperature position proifucu of pik,carpine}-Baeschlia IC. Eucr JC: Moa
ti· (French); Plwm Acta Rdv ·1969:4':JOt-9; (Pa.rt :-tiacdc
The _tcla~~-impoiUIICIC or epirncrisation to bydrolyJis of ptl~ study or the hydrolysis of palocarpine}-Baadllia JC:. Eaiei' JC .
- ~-l'J)I~ ICI 1M1UCOUS solution at pH 10.9 ;..cr,cascif'I with. an (French). Phann Acta- Hdv 1969;-44:339-47. Quaautatiw aaal)o.
• ~ ia ~ • • ~ froiii ti% at' 11• to 20% at W. · sis or dqradadoo proc1.::u ta pilocarpidc ,,c1roc:ldoride ·
Durins stcxqe at r or at 2J" the majordep'adation prodoct or ophthalmic rormuladons Neville GA. Hasan FB. Smith ICP.
pil~ne ~ydi1>chloride qcdrops was pilocarpic acid whereas . J Phann Sd 1977;66(S):63M2. High-perfonnaaoi:· liqaicl chto--
dunng heaung at 100" I.he major product was isopilocarpine.s r11atograpbic analysis of pilocarpine· hydrochloride. iso!)C1ociac-
''°" or
VaJuc:. fo:-. 3.6 ni;,nths. ! :nonth. and 1.7 hoi.rs at
20 • and tW. rcspccti\ldy. · were calculated. The eye drops
r.; pinc. pilocarpic · acid and isopilocarpic- acid in eye,:drop
~rations· ~ y available in Australial-Kenncdv
{ail·: ,..~ wuWU.cJ pik,..a,.,a,iuc- layJ,uclJuaiJG i::> taigiaiiL. bc:11·
zal_konium chloride 0.2 mg/mL boric acid 7 mg/ml.. borax
JM. McNamara PE. J Olromatogr 19~U;212:lJl.:g. Stabi1itJ ·
of p i l ~ hydrochloride and pilocaq,ioe nitrate opblhal- .
J.:IS mg/ml.. and disodiwn edelale I mg/ml.. and wue sterilised mic- sollllions 111balitted by US hospit.als-Kreienbamn MA.
at 100- for 30 minutes.' · Pap: DP. Am J Hosp Plaam: 1986;43: 1~17. {Sludy·or tbc
Aqueous solutioas orpilocarpine cnloride 2% w/w. buft"cted with hydrolysis of pilocnpine in. Carbopol b~tdsJ-Tcsta B.
sodium phosphate to pH 6.9. were stabirased by storage at -S" in Etccr JC (French). Caa J ~laann-Sci· 19.75;10C'·l):1~20• .
the fro:= state.' O¥Cr a period ot·28 weeks. 2% ~position
00c11r,'Cd at -S" 00mparcd with 9¾ .at 4•. and 38% at W ..
INCOMPATIBILITY/COMPATIBILITY-·- ... .
Baft"crs. ror eye
Co~n1 ~
. .
mops . ·.
.
Pilocarpine hydrQcbloride is incomp«tibk: with. c:blodaClicliac .
.exist conccming lhc influence ofd{ff'~t buf• acetate ~~ pbeft~ric• • salts. lncompatibili_ty is a~ - _
fers OQ~Ae~cli.\~i( of 1)!1ocl,fl)ine. In general.; phc:)sphate ~ With alblis. iocf'anc. "511,ia- salts. and mcmuous'chlcN'- ,..
and c:ar~~~fb~fl»9?~ -baff'm ann~ugbt to catalyse ..SC. . . .
decomposi_t i o a . : " ~·.a ,cd ·Vauafian'• ~ that _P.ilocarpi';'C ~ua1e ~ ~patible w.i)i
· -, ~· ·• · .~ d
-chJofbcxidinc ---.1e· . ··:
· aad soluUOC1$ Q)llflioina ~ ttiao I% p i ~ ni&rale are ·..
or die \IOiooised species was about double lhu-of tile loaised Ideue
,_,
aad llali (~"blc_a nd ~.t ).~ .U-·: l
ol pilocarpia e " ~ . . ..•·- . ' <
species. there was ~ence of trallll>C"l of ionised plocarpinc orWIOOIISmioti,c
aabaDONI ac1m11
1G1utions. ia rob61uwh al·~
Smilady. when pilocarpn • ~ ·•
cnitlUC,._ __
under ccrtaln pH conditions . The comcal ~bilit y or pilo- poAled intc a 2So/a pololwner
carpiac wu linearly mated to its OClanol- wala' pllltitioo cocf. CIOGlpaRd IO thal oran aqueous , e l . ~ actMq ill....,,,
solutioa WU deu.od.allil)I .
ficicn\ ud boch o( lbese pn,pcmes were linearly ldatcd 10 die Tliedwm oaofmio cicrapom c(m.__~u'F.' prof , f ~JJ
degree or ionisation. . . . pikicupiDc -.--cc r.4 wfY la Cubopol ~ ,'?C'_Ca,bopal ~I Fl
A CIOlllprebemi¥C study of lhe dlecls of the wbicle OD ocular waspcaa dwa thato(rGW ClllioaaJc ycdi'oploC
pio iepW W.
peactration of pilocarpin e in albint, r""6ltr .ma.led ~ -IS .,.,_ laaasia& che coarmsndoca o(_Canopol
.t40 (lY..,. to
the pH of an aqueous solution or piloc:arpinc wu fnaasc4 6% w/Y) iD the ·p t iDaaled chc dwauoil arespocs. MiliDII
(ISOIOllic S.rensen•, phosphate buffer, from pH S IO I) coneaJ « bcmalkoaium cbloridc. aatodawt
1 (at t2t'! r« 30 i a),
peactration of pilocarpin e iDCRUCCl.1' Tbis.WU auributc4 to or pmma undiaticn (2.S Mrad)
had no c&icl .oe.l&'lipCIIIII!=
the solubility dwacteris tic:s or pilocupino as ~ u -~
iniwioo and lacbrymal ioll in lhe. eye at aeatral ud aJbliDe allboup imldiatioll pcoducecl • . ~ulc-F.l_ ~ ~ cMor-
balol or disodium edduc to die Fis dcciasocl:w,111a 11c
pH, nthcr lhaa sp,ccific pH-panitio ca bebmoar ,
YIIC0lilics or thaic w1 ot1aer bydn,pls • mea :. L
The mapitudc aoci duration of the nidUdiol\ iD pH of ccar film Rbdogica
1 propcnics of bydrogds and byd~,lf ilocar·
following administration of p11ocarpiac eye ~ M was related pine baed
on carmdlosc_sodium, povidone, or pulp:ayic
to the ~tact time and acidic bull"er capacity as wdl as to ihe
acids were mvcstipte d and dift'usioa codficicGts m r ed_as
solution pH. Administr ation of commen:ial C)IC drops or srnys
(pH 4.4 t? S.S) of pilocarpin c sales to rol>6lts lowered tbe iar
ao illdicatioo of their po«entialfor IUSlaincd .rdcuc.• A IJapbi-
bd peparatio n or piJoc:uplne witb an aaylic-mdhacrJliclCid
liiw pn (iniuaiiy pH i .-.ij by i.i to i.6 uniu whcrcu c.onuou-
~ (Rub-AG . Swilmlan d) showed superior ttllllillity
ous administration of pilocarpin e buc as ocular lherapeud c sy1-
tam produced acpiga1>1e eft"ccts on the tear film pH. CIOalpared 10 z.n aqueous solutioo of p11oc:arpine. Stvdics - - -
Pauon•1 demoastra led that as the instilled volume of a pilocar- biu and in bumaos21 m,aJed tbat the miolic ac:d..-ta,-:ar-
pinc nitrate solulioir-was•~ecreascd. the fddicn of the dose piDe was proloaged and intensified in preparations .._. oa
absorbed ia,o the ialerior of the eye (nf rabbits) was ~ Carbopol 934 oron t h e ~ a c i d COl)Olyare11111- _ ..
For cwnplc, a S-micr-,litn:: dose of 1.61 x_10-zM paloc:arpinc paffll with an aqueous solution. further work" enc • 4 die
nitrate was expected to yield the same area Wider the aq,xous optimisation of the fonnu,latio n or a liquid prcparitioa 1-ed
humour coaoentration \'a'SUS ~ curve ias. a .l.S-~t re ,oa die latter ~ In.ritro and_in mo (m humans).
dose or I X IO-lM ploc:arpin e nitrate. .
Sdlocnwald ~, ol1' in-..cstiptc d the dfcicu of chc ~ o(
pi~llil ralc gds Oft miocic ~ in ""'6its. Qds W1R
Ea'eccol'W ers prepared with ethylene maleic anhydride. ~rbomer (Onapoi
940). hydroxyctby1c:dhdose polyaaylamide,.: · edl)li,at.w:- ·
When aqueous isoto~ pilocarpi ~-nitratc l¾.:w/v_ s o l ~ yctbylcdlutose.. hydroXJPl'C)pylceUut
buffered at pH<l.1S with 0.07SM buff'er, were ~ ocubity dbcMnatcic anla,dride ). osc. and ·p o l y ( ~ •
· · · · . - .
to ro66its, the pba1111.1COlogjc:at e«ect (iniotic rcspo~ or thc
diff'Cffllt formulatio ns deaased in the order: aQbuff'ffl'd > oa roar•~
s.et,one ~, o/:tO ~ ~ :opbtbalmic_m-. liaicd-
aOC:UIC-buft"ertd .> phosphatc-buft'eted > c:iirate-bu&ftcl11 pylcellulosc, thatconw llcd p1ocarpin
or ~nyl alcohol and \wo types oCh)(IN&Jiiio- .
Methods of predicting the relative oculat bioavailabt1ity G(plo- polyaeryfte acid ah. Mechanism
e·,:liuatc or-a piloc:aipR/
carpine from such solurioris as a function of concentra tioe or cat and physicoch
s of release In w,ro ud clam-
cmat .factoruft' ecting release illttt-tbldicd.
these bull'crs were discussed. The sameworkers" had PfC· All inserts pcoduced • significant incrcuc in ·bionailialiiity
viously '1emo!l~rated ,hat the i-hanntcc~gi_cal activity of plo- (area ·under miosis vecs~ time
carpine in solution (as the nitrate) was dependc1il on the pared to a S1apdanl ophthalmic solutionin albino ~ ~ ·
curves)
of pilo:arpi oc...._ -
concentration of the bulfer (citrate) in the formulatio n. Preliminary studies ;,. wi;r~ of ophthalmi c inserts of piocapnc
Ahmed and Chaudhuri:?O examined the influence orbu,cr c:ap;l· nitr.tte prepared with pepsin-tre
ated telopcptide-poor foclllcair
cityon the ocular absorptio n (in rabbits) ot,piloca rpinef~m ,kin collagen as a carrier revealed
zero-order -kinetics (or the
solutior.s of pilocarpin e'nitrate t •/.-w/v·at. pH ◄.O ·tbat w n ~ rdcase of pilocarpinc follo.w ini an-·
initi:.&.I ·boost rdea,c\>t
acetate. phosphate . <'r citrate bulfers and inulin 0.2"1• • ' ,·. 0.-u- Three types of collagen
film (plain. cross-linked. aad a
lar absorption from the solutions (calculated by SCYC'r.11 1111:th· lagen-hydratide deriv-4tive) were
used; aher4lion of the hit of
col-
ods) decreased in the order: unbuffered > acctat~~ ctt\l. > rc~5C was achieved by modiiicati
on of the collagCll carrier. .
phosphate-buffered > citrate-buf fered. However. ot~f (j.,-'tors . lncfellscd amounts of pilocarpin
c were detected in the aqueous
◄
"I
i
1008 Piperazinc
h~mo~r of rabbits ~ollowin& admini$tralion or a IO-lM pilocar· -J. Nunes MA. Brochmann-Hansscn E. J Phann Sci
pne oenunent; whic:11 consisted of a sor, paraffin-based vchidc: 1974;6)(S):716-21.
and ~% -la': comP:'n,d to an equivalent dose o( an aqucollS 4. Bundgaard H. Hamcn SH. Int J Pharma~tics
SC?lutiOCI ofJJ1locarp1ne." ' 'The mc:reue wu aUributed to a 1982:10:211-9.
hash« dl'cicm,c concentration of pilocarpinc: in the: ointment S. Kults PFl'.t. Wcckers LEA. Goldhoom PB. Phann Weckbl
and an iac:rcue in contact time. (Sa1 199;0;12(S):l~.
~Ui• and Ha~t,ll measured die iatra,ocul11r pressure and mio- 6. Lanen~- ti.mt Tldsskr Fann 1971:45:317-19.
:1e ruc,oa,cs 1n robblts rollowiq adn1hdsualioa oC o/w. wfo. 7. it.ieFfmu S. Vau&h■n OG. J Am ~rm Assoc: (Prac:t
:1;:{::,S_~ emulsions ud an oil nspemion. adt c:oa• Phann) 19'1:19(1):474-7. .
wiiniclict.llOi·com1a==·~~!ft"usioa cod&aeats"' :: ~~ ~ ~:"'~=3;· Phann
~•TH~-I N~MATibtf. ~ pha~inetic model of 1967(41:SIOl-9. •
~ : . I IV ~ta-~ ke~ aact. · .·n_.ibution
&
, •• It bi the ~yc.,fia ,_.
_ 10. Baachlia IC Etter JC (FRIIChl- ~ ·Acta ·Hdv
...,.,._ 1969;1$4~.5.5. . .
-:6-iw_...,_..:, '. . •. ... . : 1r.-.-.uoa TF.-J ~ Sci
..._
1~ ••· '':".'.-A. ~ad~~ enhiatioa or topically applied . .,,. E. ,.,._ IN ....___ _._ IE. w-•...._
11. e~ 1...:. Dyer A. """""'."' •--- ....""" oc.
P l ~ ~ Ill Che ~eco.neal .._ fin na6611,t-TitorabC'c AO. ~ ~ ~- ~ 1966:l(May)"~ •
H•~• !CJ·
J · Phann Sci 1914;73(2)-.219-22. Meclianaaic: • ,2. Gibbs IS. T ~ ~M. J l'llarm_Sci l974;63(2):276-9.
and qaallli1alffl: eYaluation or·pn,co.lieal pa1ocarpinc: d " ~ ll. Fap:rsu&a R. J Pharm Phanwol 196J;IS:4'19-ll.
lion in albino td6#u (inlluence or precorncal loss parametcrS • 14. · Rieadfflu S. Vaupa1,1 OG. J Am Pbana Assoc {Pr.ct
on bioaY&Jlab.lityf--t.ct· VH4., llobinlon ·JR. J Pba Sci Phann) 19.51;19(9):537-40. •
1919;61(6~7).;.14: Piloc:arpiiie fdeasc·
l"' l'itro) fi rm _ ,s. Sica JW. Robiason JR. J Pharm Sci 1~>:1m_.,
~~~#ci4iitad :··aaa~r::
M. M ~-.Q~ t~J~ 191S-.2S:i65:-7l ·Sys-
~J:fn
16. Loapdl .A. 1 h S. Kdlcr N. Moore D. J Pbarm Sci
1976;6S(ll):1~7. .
lanic abiorption oC'ocuiar°sifocupiae is moclilled-~
~ r 17. Padon TF. J Pharm Sci 1977;66(7):I0Sl-9.
'!'9trica-Urtti A. Saltmnen t.; Miinalainen 0. lnt'J-~ -- 18. M~ AK. M i ~TJ. lntJ Pli■nnaccalics 1917;37:19-26.
tics 1915~147-61'. Pl1~rpiatbioavailabl1ity(in nl661t.r) rrom a 19. M,ua . · AK. M1kt.dsoa TJ. Int J ~ -
m ~ v i e·ljposomal ~~ dtug ddiw:ty" sysiea. (bued 1982;10-.219-29.
on Carbopo( IM.)-~~Ouninf~~ Qa~ NM. Tbomas M. ICdl- . ?O. Ahmed I. Chaudhuri B. · Int J Pharmaceutics I ffl;"'!9'7-
away lW. l ~ J ' ~ 1?92;11.~IS.0Jmiolled·rdeuc · 10S. . . .
. of pi1ocaqiinc f!O"' coated ~ymeric: ophthalaiic imiena t-"' ?I. Ahmed _l. PattoaTF. latJ ~ 1914;1~:'.l~~27;
paml b y . ~ : o n c MF~ Torracca"MT: ?apno A. !2.. LeucutaSE. latJ Plwmaceutn-1919-.$4:71-1.-- · .
Giuaacciai B. Rodripct L . Oai M. Int J ~ ::J. Grass · OM. Cobby ·1. Maltoid MC;_· J: · ~rm· :;a
I 992;16:1.59:-66. Optimis~uioa or pilocarpinc: loaidins onto nano- I 984;7l(S):6ll-ll. .• . · · ·
particles by soq,tion ·pm:lCdures-Harmia T. Spei.1et !'. IC.l'etlta i4._ Miller SC. · Do'IOvan . MD; Int J Phar.n&CCV.":Cs
J. :n, J Pbanaaceutics t986;3t:'4~sc: Enbancement ortbe m,o- 1982:12:141-Sl. ·
· ti.: m.-,..;.-..; vr •~IL. with P'~P•~cd po;ylNtJicyaaoa-.· 1 ~ · ~~~nde SG: Sh!~!bi S-: ! ~-=.
Ph::~::.;!
c:ryla,te nanopulicles-Ha T.-Kreutu J. Speiser P.-Bo,-:T. 198-9:..1:-191-200.
Gumy R. Kubis A.. -~ • J Pharmaceutics 1916;31:117-93. · 26. Pelpllde . G •. -Keipcrt S (German). P1w;a.c.ie
Vehicle eff'cctl ouie'ialar drug bioavailability. Ill. Shear..f'acili- · ·· 1990l4S(Hl):.512-6.· =
taled (mecbanical ~ a g oc blinking) ~ : ,eJcasc 27. · Pergande G. Kcipen S. Klatt A (Gcmian]. Plaarmazie
from oi~rs (w.atec-in-oil emulsion 1n "'"°
and in ,_. 1990;4S(Hl):5n-9t.
biu)-Sieg JW. Robinsolk JR. J Phltrm Sci -1919;68(E);ti4-I...,.
Stabi~tr-indicat~ng -assay method ror piloc:arpiile nitrate in
18. · Kcipen S. · S:cbcnbrodt I (German] . ~ :.;cc·
. 1990;4S(Hl):596-9. . - . •
raervoirs used~ ~ cystic-fibnnis indictouystcm-Wong O. ~- . Schoen~ RD. Ward RL. De Sanlis LM. Roehr. !lE.. J
~ C . ~·L.-hhmaa!a.,.._.. R. LattiaG. latJ _f'bar.. . Pharm¥ 1978;67(9):12I0-3.· . .
~ ~L•~!;.?~t~_J-?.;:,'.~ conuollcd.dnic cldiwn 30- ·, Saete.tPoncha_ MF. Giaaltaelcini B; Oetoai P.<n.lliG~ Qio:tini
~cm:usi ·: 1 ~-....i.....~ _~i,aha . "" Ha M. y _· ·1
nap "~·~Y~~~
pr..c ~ :~-:~Y!'~- p b ~ -pn,pcnies aad
,,:.U:25~ Piao:. rm Plunnacol 1984·~.c.-..-...
boKP.~~
3 1. . Vasantba R. Sehgal PK.
. 198~~7~.5-102. . . . . . .
.- .
J ~tics
_.
kiadica.of~~·•,Jw ~..,P!'f~ " ilicidltiiolio)........a · · 32. Atua MA. ff■-,.1, FS. STP Pbanna:
; _ .... i.,,.. .,.-,:,.:..:~,;~ ~ ~,., -r.f............. ·• .
~ " •."-:J ·,~~ -..~~~~/~-1~--•~ ~T.1. J Pbann ·"'° ~ •' . ·. .·
~
. . ... ·
-1916-.2(1~~- . ·
..
_.- . ·-·-- ..
I· 1916;'.JS(l~t';~ ~ ~ -11. Synthesis. subility•.
biocion~_~ :~ ~"'
:a..... ~ '.ac:idlf'
labile Pl-I!'~ . ... •...~
~ or scqi°i:ntia11y · ·Pipe · • · ·
"ii,;? ..!I::·,..,c:nd--'• ... H--F: lc:h ·E. I - - -
.. _ . .. .,. a ■...ncn
. razane
C. Mosbei.Ot,.-M.i ~ ~:"fJ.;;, ~ S c i 1986;7S(8):775-8l• . Pipcrazine ·
Ocular bioavailabttiC..r.·
. . .--,·r. ~i:-,::l>.''iw-i=i~.-...:
,r.-,;~r-JJ '7f"°.. .ar.ono- and,~•-estcl'
•· pro- .. C~H,0N2 =- 16.14
d ~ .&$ ~ J~y;,~~•!f a,;tlll~ilil 'l~ rahbit-Moshcr OL:
Eund;u.rd tl,-F ~,l;.-1.a~~-~~kk•n TJ~ Int J Pharma-
ceutics 1987;39;1,Q-':~ ~--.: · •••.;··
REF£R~CES
.<' -·
2. Ch_~ng . P•H; . ~in T-F. ilach J-L. J Phann Sci Pipcrazine Adipate .
I970;S9(9): 1300-S. · C.H,nN?,C,H 100 4 = :n:u·