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PatentEP2574333A1NacetylcysteineeffervescenttabletanditstherapeuticalapplicationsGooglePatents

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Nacetylcysteineeffervescenttabletandits
therapeuticalapplications

Publicationnumber
Publicationtype
Applicationnumber
Publicationdate
Filingdate
Prioritydate

EP2574333A1
Application
EP20110182999
Apr3,2013
Sep27,2011
Sep27,2011

Alsopublishedas

WO2013045566A1

aneffervescenttabletcomprising:

Inventors

LidiaPERRI,GermanoCoppi

(a)1200mgofNacetylcysteineand

Applicant

FriulchemSpA

(b)atleast1200mgofsodiumhydrogencarbonateand

ExportCitation

BiBTeX,EndNote,RefMan

(c)lessthan1200mgofanhydrouscitricacidand
(d)atleastonelubricantand/orglidantagentand

PatentCitations(3),NonPatentCitations(2),Classifications(12),
LegalEvents(7)

(e)atleastonesweetenerand/orflavouringagentand

ExternalLinks:Espacenet,EPRegister

EP2574333A1
ABSTRACT
ThepresentinventionisdirectedtoApharmaceuticalcompositionintheformof

saidpharmaceuticalcompositionhavingnosulfursmellandtasteaswellasa
pHintherangeof4.1and4.4aftertabletdissolution.
Amanufacturingprocessisalsodisclosed.
Theclaimedpharmaceuticalcompositionisusedinthetreatmentofabnormal,viscid,orinspissatedmucoussecretions.

IMAGES (2)

SearchReport(1)

SearchReport(2)

DESCRIPTION
[0001]

Thepresentinventionisrelatedtopharmaceuticalcomposition
comprisingNacetylcysteine(NAC)intheformofaneffervescenttablet
havingnosulfursmellandnosulfurtaste.

[0002]

Nacetylcysteine(NAC)isanacetylatedderivativeoftheaminoacidL
cysteinewhichhasafreethiolgroup.NACwasdescribedin

CLAIMS (15)
1.Apharmaceuticalcompositionintheformofaneffervescenttablet
comprising:
(a)1200mgofNacetylcysteineand
(b)atleast1200mgofsodiumhydrogencarbonateand

patentUS3,184,505.
[0003]

NACisindicatedasadjuvanttherapy(NACisusedincombinationwith
antibioticsorotherdrugs)forpatientswithabnormal,viscid,or
inspissatedmucoussecretionsinsuchconditionsaschronic

(c)lessthan1200mgofanhydrouscitricacidand
(d)atleastonelubricantand/orglidantagentand

respiratorydisorders,acutebronchopulmonarydisease,tracheostomy

(e)atleastonesweetenerand/orflavouringagentand

care,duringanesthesia,atelectasisduetomucousobstruction,and

saidpharmaceuticalcompositionhavingnosulfursmellandtasteas

diagnosticbronchialstudies.OralNACisaveryeffectivemucolytic

wellasapHintherangeof4.1and4.4aftertabletdissolution.

agentandisusefulindecreasingthenumberofexacerbationsin
patientswithchronicbronchitis.Whengivenincombinationwith

[0004]

2.Apharmaceuticalcompositionaccordingtoclaim1,whereinthe

cefuroxime,NACincreasestheantibiotic'spenetrationintobronchial

amountofsodiumhydrogencarbonateisbetween1250mgand

secretion.(DrugdexDrugEvaluations,2011).

1350mg,preferablyequalto1313mg.

Nacetylcysteine(NAC)isalsoindicatedasanantidotetopreventor
lessenhepaticinjurywhichmayoccurafteringestionofpotentially
hepatotoxicquantityofacetaminophen.NACisconsideredthedrugof
choiceforpreventionagainstliverdamageinsevereacetaminophen
intoxication.Inoneanalysis,11,195casesofsuspected
acetaminophenoverdosewerereviewed.ItwasconcludedthatNAC

3.Apharmaceuticalcompositionaccordingtoclaim1or2,wherein
theamountofanhydrouscitricacidisbetween1050mgand
1100mg,preferablyequalto1087mg.
4.Apharmaceuticalcompositionaccordingtoclaims1to3,
whereinthecompositioncontainsnosodiumchloride.

treatmentshouldbestartedwithineighthoursofoverdosebutitisstill
indicatedatleastaslateas24hoursafteringestion.Itwasalso

[0005]

5.Apharmaceuticalcompositionaccordingtoclaims1to4,

concludedthata72hourregimenoforalNacetylcysteineisas

whereinthelubricantisselectedfromthegroupconsistingof

effectiveasthe24hourregimenandmaybesuperiorwhentreatmentis

magnesiumstearate,sodiumstearylfumarate,sodiumbenzoate,

delayed(DrugdexDrugEvaluations,2011).

polyethyleneglycolwithmolecularweightsof6000andabove

Nacetylcysteineisalsoindicatedinmanyothersituations,like:

andcolloidalsilicondioxide.

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1.1.Inarandomized,2center,doubleblindstudyinpatientswith
chronickidneydisease,volumesupplementationbysodium
bicarbonateplusNACwassuperiortothecombinationofnormal
salinewithNACaloneorwiththeadditionofascorbicacidin
preventingcontrastagentinducednephrotoxicity(CIN)in
patientsatmediumtohighrisk.(DrugdexDrugEvaluation,
2011).
2.2.OtherpotentialusesofNACincludeprotectionagainst
oxidant(freeradicals)damageandasprotectionagainst
cytotoxicagentssuchasifosfamideandcyclophosphamide.
(DrugdexDrugEvaluation,2011).
3.3.Glutathionedepletionhasbeenimplicatedinthepathologyof
anumberofdiseasesincludinginfectionbyimmunodeficiency
virus(HIV).InHIVinfection,cysteine/glutathionedepletionis

6.Apharmaceuticalcompositionaccordingtoclaim5,whereinthe
lubricantispolyethyleneglycol6000.
7.Apharmaceuticalcompositionaccordingtoclaims1to6,
whereinsweetenersareselectedfromthegroupconsistingof
sucralose,sucrose,fructose,glucose,galactose,xylose,
dextrose,levulose,lactose,maltose,maltodextrin,mannitol,
maltitol,maltol,sorbitol,xylitol,erythritol,lactitol,isomalt,corn
syrup,saccharin,saccharinsalts,acesulfamepotassium,
aspartame,Dtryptophan,monoammoniumglycyrrhizinate,
neohesperidin,dihydrochalcone,thaumatin,nicotame,alitame,
steviosideandcyclamate.
8.Apharmaceuticalcompositionaccordingtoclaim7,whereinthe
sweetenerisaspartame.

knowntoimpairTcellfunctionandisassociatedwithimpaired
survivalofsubjectswithlessthan200CD4Tcellsperl.Thus

9.Apharmaceuticalcompositionaccordingtoclaims1to8,

pharmaceuticalcompounds,likeNacetylcysteine,thatreplenish

whereinflavouringagentsareselectedfromthegroupconsisting

orelevatedglutathionelevels,work,atleastinpart,through

ofnaturalaromaoils(e.g.peppermintoil,Partridgecurrantoil,

enhancementofthedefensemechanismseeminglyutilizedto

clovebudoil,parsleyoil,eucalyptusoil,lemonoil,orangeoil,

normallyprotecttissuefromreactiveoxidativeintermediates

etc.),menthol,mint,anethole,methylsalicylate,eucalyptol,

(ROI)mediatedamage.

cinnamon,1methylacetate,salvia,eugenol,oxanone,alpha

4.4.Nucleosidereversetranscriptaseinhibitors(NRTIs),likefor

ionone,marjoram,lemon,orange,propenylguaethol,cinnamon,

exampleazidothymidine(AZT,zidovudine),areoftengivenin

vanilla,thymol,linalool,cinnamaldehyde,glycerolacetal,N

combinationtherapieswithotherantiretroviraldrugstotreat

substitutedpmenthane3carboxyamideand3,1methoxy

HIV.LongtermtherapywithAZTiscommonlyassociatedwith

propane1,2diol.

dosedependenthematologictoxicitywhichshowslow
erythrocytecountsandelevatedmeanredcellvolume,andwith
musclefibertoxicity.SomestudiesindicatethatAZT'stoxic
interactionsresultfromgenerationofreactiveoxygenspecies
(ROI)thatreactanddepleteintracellularglutathionelevels.Also

10.Apharmaceuticalcompositionaccordingtoclaim9,whereinthe
flavouringagentislemonoil.
11.Aprocessforpreparingapharmaceuticalcompositionaccording
toclaims1to10,whichcomprises

inthiscasethetreatmentwithNacetylcysteinecanbevery
useful.
[0006]

RegardingthesafetyofNAC,thisdrugisverywelltolerated(RTECS,
2010)(Fluimucil600mgleaflet).TheToxicDoseLow(TDLO)in
humanafterintravenousrouteis150200mg/kg.TheTDLOinratsafter
intraperitonealrouteis150200mg/kg.TheTDLOinmouseafter

[0007]

theremainingexcipientsand
(3)thecompressionofthetabletfromtheformulation
obtainedafterstep(1).

Thedataobtainedfromthechronictoxicityinratsrevealedano
12.Thepharmaceuticalcompositionaccordingtoclaims1to10for

months(Johnstonetal.,SeminarsinOncology,1983,10Suppl,:17

itsuseinthetreatmentofabnormal,viscid,orinspissated

24).

mucoussecretionsinparticularforsecretionsresultingof:

NACiscurrentlycommercializedunderthetrademarkFluimucil.In

chronicrespiratorydisorders,acutebronchopulmonarydisease,

Fluimucileffervescenttablets,600mgofactiveingredientNACis

tracheostomycare,duringanesthesia,atelectasisduetomucous

mixedwith680mgcitricacid,573mgsodiumhydrogencarbonate,200

obstruction,anddiagnosticbronchialstudies.

TheFluimucileffervescenttabletscompriseimportantamountsof
lemonflavourtomaskthesulfurictastewhichneverthelessispresent.
Inaddition,afterdissolutiontheFluimucileffervescenttabletshavean
unpleasantsulfuricsmellandamarkedlemontaste.

[0010]

(2)themixingofthegranulateobtainedafterstep(1)with

routeis300mg/kg.

mglemonflavouring,and20mgaspartame.
[0009]

citricacidandoptionallysodiumhydrogencarbonate,then

intraperitonealrouteis408450mg/kg.TheTDLOinmouseafteroral

observedeffectlevel(NOEL)doseofabout1000mg/kg/dayfor12

[0008]

(1)thewetgranulationofNacetylcysteinewithanhydrous
granulation

NACisrapidlyabsorbedafteroraladministrationinbothanimalsand
humans.Themaximumplasmaconcentrationisreached23hoursafter
administrationandtheplasmahalflifeis6.3hours.NACundergoes
extensivehepaticmetabolism,resultinginlowbioavailabilityofabout
10%fortheunchangedmolecule.Asexpected,NACcannotbe
detectedinplasmaorbronchoalveolarlavagefluidfollowingoral

13.Thepharmaceuticalcompositionaccordingtoclaims1to10for
itsuseinthetreatmentofhepaticinjuryafteringestionof
hepatotoxicquantityofacetaminophen.
14.Thepharmaceuticalcompositionaccordingtoclaims1to10for
itsuseinthelongtermtreatmentofHIVwithAZT.
15.Thepharmaceuticalcompositionaccordingtoclaims1to10for
itsuseinthepreventionofoxidantdamagesand/orinthe
protectionagainstcytotoxicagentssuchasifosfamideand
cyclophosphamide.

administrationfor414days.Incontrast,cysteineandGSHlevels
increasedtransientlyinplasmaandlungafteradministrationofNAC
600mgoncedaily.Inpatientswithchronicobstructivepulmonarydisease(COPD),however,plasma
concentrationofGlutathione(GSH)wereunchangedafterthisdoseofNAC,whereas600mgthreetimesdaily
increasedplasmaGSHlevels.
[0011]

Theaimoftheinventionistoproposetabletscomprising1200mgofNAC.Thisdoseisexpressedinmg/kgequal
to1200:60kg=20mg/kgwhichis50timeslessreferredtoNOELinratsalwaysfororalroute.Thisvalueisalso
about10timeslessreferredtoTDLOinhumanafterintravenousroute.Consequently,the1200mgoraldoseof
NACwillnotcausetoxiceffectsinhumans.

[0012]

WO2010/090611disclosescompositionscomprising9002500mgofNAC.InparticularWO2010/090611discloses
compositionscomprising:1200mgNAC,60mgsodiumchloride,1035mgcitricacidanhydride,770mgsodium

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hydrogencarbonate,30mgaspartame,20mglemonflavor,25mgPEG6000,and60mgPVPK30.Sodium
chlorideisaddedastasteregulator.Theprocessformanufacturingthetabletsisnotdisclosed.

[0013]

HoweveritremainsneedofpharmaceuticalcompositionscontainingNACwhichdonothavesulfursmelland/or
sulfurtasteandwhichdoesnotcomprisesodiumchloride,whichmaybecontraindicatedinsomepatients.

[0014]

Thecompositionsoftheinventionhavenosulfursmelland/orsulfurtaste.Inthepresentinvention,the
pharmaceuticalcompositionintheformofaneffervescenttabletcomprises:
1.(a)1200mgofNacetylcysteineand
2.(b)atleast1200mgofsodiumhydrogencarbonateand
3.(c)lessthan1200mgofanhydrouscitricacidand
4.(d)atleastonelubricantand/orglidantagentand
5.(e)atleastonesweetenerand/orflavouringagentand
saidpharmaceuticalcompositionhavingnosulfursmellandtasteaswellasapHintherangeof4.1and4.5after
tabletdissolution.

[0015]

ThecompositionoftheinventionpreferablycontainsNACastheactiveingredientinanamountrangingfrom30to
35%byweight,onthebasisofthetotalweightofthecomposition.

[0016]

Sodiumhydrogencarbonateandanhydrouscitricacidareusedasdisintegrantandeffervescentagents.

[0017]

Sodiumhydrogencarbonateispreferablypresentinthecompositioninanamountrangingfrom30to40%by
weight,onthebasisofthetotalweightofthecomposition.Inapreferredembodiment,inthepharmaceutical
compositionoftheinventiontheamountofsodiumhydrogencarbonateisbetween1250mgand1350mg,
preferablybetween1250mgand1300mg,morepreferablyequalto1313mg.

[0018]

Anhydrouscitricacidcarbonateispreferablypresentinthecompositioninanamountrangingfrom20to30%by
weight,morepreferably25to30%byweight,onthebasisofthetotalweightofthecomposition.Inapreferred
embodiment,inthepharmaceuticalcompositionoftheinventiontheamountofanhydrouscitricacidisbetween
1050mgand1100mg,preferablyequalto1087mg.

[0019]

Inapreferredembodiment,thelubricantand/orglidantagentisselectedfromthegroupconsistingofmagnesium
stearate,sodiumstearylfumarate,sodiumbenzoate,polyethyleneglycolwithmolecularweightsof6000and
above,andcolloidalsilicondioxide.Morepreferably,thelubricantand/orglidantagentisalubricantagent,in
particularapolyethyleneglycolwithmolecularweightsof6000andabove,preferablypolyethyleneglycol6000.

[0020]

Thelubricantand/orglidantagentispreferablypresentinthecompositioninanamountrangingfrom0.2to2%by
weight,morepreferably0.4to1%byweight,onthebasisofthetotalweightofthecompositionInthe
pharmaceuticalcompositionoftheinventiontheamountoflubricantand/orglidantagentispreferablybetween5
mgand60mg,morepreferablybetween10mgand50mg,evenmorepreferablyequalto30mg.

[0021]

Whenthelubricantand/orglidantagentisamixtureofalubricantagentandaglidantagent,themasseratio
lubricant:glidantispreferablycomprisedbetween70:30and90:10,morepreferablybetween80:20and85:15.

[0022]

Inapreferredembodiment,thesweetenersareselectedfromthegroupconsistingofsucralose,sucrose,fructose,
glucose,galactose,xylose,dextrose,levulose,lactose,maltose,maltodextrin,mannitol,maltitol,maltol,sorbitol,
xylitol,erythritol,lactitol,isomalt,cornsyrup,saccharin,saccharinsalts,acesulfamepotassium,aspartame,D
tryptophan,monoammoniumglycyrrhizinate,neohesperidindihydrochalcone,thaumatin,nicotame,alitame,
steviosideandcyclamate.Morepreferably,thesweetenerisaspartame.

[0023]

Thesweetenerispreferablypresentinthecompositioninanamountrangingfrom0.2to2%byweight,more
preferably0.3to0.8%byweight,onthebasisofthetotalweightofthecompositionInthepharmaceutical
compositionoftheinventiontheamountofsweetenerispreferablybetween5mgand30mg,morepreferably
between15mgand25mg.Inapreferredembodiment,thecompositioncontains20mgofaspartame.

[0024]

Inapreferredembodiment,theflavouringagentsareselectedfromthegroupconsistingofnaturalaromaoils(e.g.
peppermintoil,Partridgecurrantoil,clovebudoil,parsleyoil,eucalyptusoil,lemonoil,orangeoil,etc.),menthol,
mint,anethole,methylsalicylate,eucalyptol,cinnamon,1methylacetate,salvia,eugenol,oxanone,alphaionone
marjoram,lemon,orange,propenylguaethol,cinnamon,vanilla,thymollinaloolcinnamaldehydeglycerolacetal,N
substitutedpmenthane3carboxyamideand3,1methoxypropane1,2diol.Morepreferably,theflavouringagentis
lemonoil.

[0025]

Theflavouringagentispreferablypresentinthecompositioninanamountrangingfrom2to10%byweight,more
preferably3to8%byweight,onthebasisofthetotalweightofthecomposition.Inthepharmaceutical
compositionoftheinventiontheamountofflavouringagentispreferablybetween100mgand300mg,more
preferablybetween150mgand250mg.Inapreferredembodiment,thecompositioncontains200mgoflemonoil.

[0026]

Thecompositionoftheinventionpreferablycontainssolelythecomponentsquotedinpoints(a),(b),(c),(d)and(e)
above.Inparticular,thecompositionoftheinventiondoesnotcompriseasulphurtasteregulator,suchassodium
chloride,otherthanmaskingagent(sweetenerand/orflavouringagent).Indeed,ithasbeensurprisinglydiscovered
thattheformulationoftheinventionhasnosulfursmellandnosulphurtastealthoughnotasteregulatorisadded.
Inparticular,ithasbeensurprisinglydiscoveredthattheformulationoftheinventionhasnosulfursmellandno
sulphurtastealthoughnotasteregulatorisaddedandthequantityofmaskingagent(sweetenerand/orflavouring
agent)islessthanthedoubleofthequantityofmaskingagentinFluimucileffervescenttablets.

[0027]

Inthemostpreferredembodiment,thepharmaceuticalcompositioncontainssolely:1200mgofNAC,1313mgof
sodiumhydrogencarbonate,1087mgofanhydrouscitricacid,30mgofPEG6000,20mgofaspartameand200
mgoflemonoil.ThepHofthisformulationaftertabletdissolutionisof4.3

[0028]

Thedisintegrationtimeoftheeffervescenttabletsaccordingtotheinventioninwaterislessthan3min,preferably
lessthan2min.

[0029]

Themanufacturingofeffervescenttabletscomprising1200mgofNACpresentstechnicaldifficultiesnotablydue
tothehighweightanddimensionoftabletsandtothebadprocessabilityofNAC.Inordertosolvetheabove

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problems,manufacturingprocessofeffervescenttabletisproposedinthepresentapplication.

[0030]

Thepresentinventionisalsodirectedtoaprocessforpreparingapharmaceuticalcompositionaccordingtothe
invention,whichcomprises
(1)thewetgranulationofNacetylcysteinewithanhydrouscitricacidandoptionallysodiumhydrogen
granulation
carbonate,then
(2)themixingofthegranulateobtainedafterstep(1)withtheremainingexcipientsand
(3)thecompressionofthetabletfromtheformulationobtainedafterstep(2).

[0031]

Wewillnowexplaintheprocessinmoredetails,accordingtothebestembodiment.

[0032]

Instep(1),Nacetylcysteine,anhydrouscitricacidandoptionallysodiumhydrogencarbonatearemixedunderdry
conditions.Powdersaremixedduringsufficienttime,attheappropriatespeed,toobtainablendvisually
homogeneousbeforestartinggranulation.
granulation

[0033]

TheamountofNACiscalculatedissuchawaythatfinaltabletscomprise1200mgofNAC.

[0034]

Theamountofanhydrouscitricacidiscalculatedissuchawaythatfinaltabletscompriselessthan1200mg,
preferablybetween1050mgand1100mg,morepreferably1087mg,ofanhydrouscitricacidtakinghoweverin
considerationthatapartoftheanhydrouscitricacidcanbeprovidedbythegranulationsolutionusedinthe
granulation
followingstepsoftheprocess.

[0035]

Inoneadvantageousembodimentoftheinvention,theamountoftheanhydrouscitricacidinthemixisofatleast
80%byweight,comparedtothetotalweightofanhydrouscitricacid,preferablyfrom80%to98%byweight,more
preferablyfrom85%to98%byweight,evenmorepreferablyfrom90%to98%byweight,comparedtothetotal
weightofanhydrouscitricacid.

[0036]

Thentheblendissubmittedtothegranulationprocess.Thegranulationsolutionisaliquidcompositioncomprising
granulation
granulation
waterandeventuallytheremainingpartofanhydrouscitricacid.

[0037]

Inapreferredembodiment,theliquidcompositioncompriseswaterandanhydrouscitricacid.Themassratio
water:anhydrouscitricacidpreferablyrangesfrom70:30to30:70,morepreferablyfrom50:50to30:70,evenmore
preferablyfrom50:50to40:60.

[0038]

Theagitationisstoppedwhenthegranulesshowtherequiredappearance,easilydeterminedbytheskilledperson.

[0039]

Thegranulesarethedriedasatemperaturepreferablyrangingfrom30Cto70C,morepreferablyfrom40Cto
60C.Duringthedryingphase,thetemperatureoftheproductshallpreferablynotexceed45C.Thedrying
conditions(temperature,duration)aresuchthattheresidualhumidityofthegranulesislessthan0.2%,preferably
lessthan0.15%.Then,granulesarecooleddownuntilthetemperatureoftheproductispreferablylowerthan
28C.

[0040]

Thegranulesobtainedaftertheabovestepsarescreened,preferablythroughasieveof1.25mmmeshsize.

[0041]

Inindustrialprocess,onecancontemplatetoperformthegranulationprocessinatleast2timemeaningthat
granulation
beforeperformingthegranulation,thegranulationsolutionisdividedinto2partsforthe2granulations(orinto3
granulation
granulation
granulation
partsforthe3granulations,etc.).
granulation

[0042]

Afterthescreeningstep,allthegranulesareputtogetherinasametank.

[0043]

Rawmaterialsoftheexternalphase(sodiumhydrogencarbonate,lubricantand/orglidantagent,sweetenerand/or
flavouringagent),inamountsappropriatetoobtainthedesiredquantitiesinthefinaltablet,arescreened,preferably
throughasieveof1.25mm.Thescreenedmaterialsarethenpouredintothetankcontainingallthegranules.

[0044]

Then,allthematerialsaremixed.

[0045]

Tabletsarepressedfromtheresultingfinalmixing.Anexternallubrication,withmagnesiumstearateforexample,
canbeusedtoavoidstickingduringthetabletingoperation.Theresultingtabletsarethenpackaged.

[0046]

Thedisintegrationtimeoftheeffervescenttabletsobtainedbytheprocessoftheinventioninwaterislessthan3
min,preferablylessthan2min.Thefriabilityoftheeffervescenttabletsobtainedbytheprocessoftheinventionin
waterislessthan2%,preferablylessthan1%.Thehardnessofthetabletsisbetween14and18Kp.

[0047]

Thetabletsarepreferablypreparedinacontrolledfacilitywithcontrolledtemperatureandlowrelativehumidity
(20C1CRH15%5%).

[0048]

ThetabletsoftheinventioncanbeusedinmanytherapiesandinmanyproblemswheretoxicityduetoROI
activityispresent.

[0049]

Theinventionisdirectedtotabletsoftheinventionfortheiruseinthetreatmentofabnormal,viscid,orinspissated
mucoussecretions.Inparticularthesecretionsmaybetheresultsof:chronicrespiratorydisorders,acute
bronchopulmonarydisease,tracheostomycare,duringanesthesia,atelectasisduetomucousobstruction,and
diagnosticbronchialstudies.

[0050]

Thetabletsoftheinventioncanbeusedincombinationwithantibiotics,suchascephalosporinantibioticin
particularcefuroxime.

[0051]

Theinventionisdirectedtotabletsoftheinventionfortheiruseinthetreatmentofhepaticinjuryafteringestionof
hepatotoxicquantityofacetaminophen.NACisconsideredthedrugofchoiceforpreventionagainstliverdamage
insevereacetaminophenintoxication.

[0052]

TheinventionisdirectedtotabletsoftheinventionfortheiruseinthelongtermtreatmentofHIVwithAZT.NAC
willreducethetoxiceffectslinkedtotheuseofAZT.

[0053]

Theinventionisdirectedtotabletsoftheinventionfortheiruseinthepreventionofoxidantdamagesand/orinthe
protectionagainstcytotoxicagentssuchasifosfamideandcyclophosphamide.

[0054]

Thetabletscanbeadministereduptothreetimesperday.

[0055]

Thefollowingexamplesareputforthsoastoprovidethoseordinaryskillintheartwithacompletedisclosureand
descriptionofhowtomakeandusethepresentinvention,andarenotintendedtolimitthescopeofwhatthe
inventorsregardastheirinventionnortheyintendedtorepresentthattheexperimentsbelowallortheonly
experimentsperformed.

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Example1
[0056]

Apatienthavingafevercanbetreatedwithacetaminophenwithaformulationcomprising15mg/kg
acetaminophenandNacetylcysteineeffervescenttablet(1200mg)administeredtwoorthreetimesaday.Fora
childthedosagesarehalftablettwoorthreetimesaday.

Example2
[0057]

Apatienthavingliverfailureorliverdamageorhavingelevatedliverenzymesandfeverwhoisalready
compromisedcanbetreatedwithacold,pain,antipyreticorotherformulationNacetylcysteineeffervescenttablet
istoadministeredtwoorthreetimesday.Forachildthedosagesarehalftablettwoorthreetimesaday.

Example3
[0058]

ApatienthavingHIVinfectioncanbetreatedwithaformulationcomprisingatherapeuticallyeffectiveamountof
AZTasapartofamultidrugantiviralregimenandatoxicityreducingamountofNacetylcysteineeffervescent
tabletadministeredtwoorthreetimesday.Forachildthedosagesarehalftablettwoorthreetimesaday.

Example4
[0059]

AZTandNacetylcysteinecanbeadministeredperinatallyandneonatallytopreventverticaltransmissionofthe
HIVvirustothechild.AlsointhiscasetheNacetylcysteinewasadministeredtothemotheraseffervescent
tablettwoorthreetimesperday.

Example5
[0060]

Apatientwithabnormal,viscidorinspissatedmucoussecretioninchronicrespiratorydisorder,acutepulmonary
disease,tracheotomycare,duringanesthesia,atelectasisduetomucousobstructionanddiagnosticbronchial
studieshastobetreatedwithNacetylcysteineeffervescenttabletstwoorthreetimesdailyunderdirectionofa
physician.Forachildthedosagesarehalftablettwoorthreetimesaday.

Examples6
[0061]

InadultswithchronickidneydiseaseNacetylcysteineeffervescenttablettwoorthreetimesdailyisusefulto
preventcontrastagentinducednephrotoxicity(CIN)inpatientsatmediumtohighrisk.

Example7
[0062]

Inadulttreatedwithcytotoxicagentssuchasifosfamideandcyclophosphamide,Nacetylcysteineaseffervescent
tabletisadministeredtwoorthreetimesdailytoincludeprotectionagainstoxidant(freeradicals)damage.

Example8manufacturingprocess
[0063]

Theeffervescenttabletsoftheinventionsaremanufacturedbythefollowingprocess.

[0064]

Residualhumidityandtemperatureoftheroomarecontrolledduringeachstepexceptfortheweighingandthe
mixingforthepreparationofNacetylcysteineeffervescenttablet.

Step0:rawmaterialsweighin.
[0065]

Rawmaterialsareweighedintheweighingstation.

Step1:preparationofthesolutionforgranulation.
granulation
[0066]

3.940kgofpurifiedwaterareweighedandputunderagitation.Then,5.440kgofanhydrouscitricacidarepoured
intothewateranddissolvedinthankwiththeagitation.Thesolutionisconformingforthegranulationstepwhenit
granulation
islimpid.
Onceitislimpid,thesolutionisdividedinto2parts(forthe2granulations).
granulation

Step2a:drymixing.
[0067]

5.440kgNacetylcysteineand51.630kganhydrouscitricacidareintroducedinagranulatingblender.Powdersare
mixedduring10minutesat125rotationsperminutetoobtainablendvisuallyhomogeneousbeforestarting
granulation
granulation.

Step2b:granulation.
granulation
[0068]

Theblendisputunderagitationandthesolutionforgranulationispouredintoagranulatingblenderthrougha
granulation
funnel.Thenthegranulationprocessisstarted.Theagitationisstoppedwhentheappearanceofthegranulesis
granulation
good.Thedurationofthegranulationstep2bwas6minutes.
granulation

Step2c:dryingcooling.
[0069]

Granulateisquicklydriedinthefluidbeddryeratthetemperatureof50C.Residualhumiditywas0.15%.
Duringthedryingphase,thetemperatureoftheproductdidnotexceed45C.Then,granuleiscooleddowninthe
sameequipmentat5Cuntilthetemperatureoftheproductislowerthan28C.Therelativehumidityofthegranule
islessthan0.15%.

Step3:granulesscreening.
[0070]

Granules(2parts)arescreenedthroughasieveof1.25mmmeshsizeandpouredintothesame900Ltank.

Step4:externalphasescreening.
[0071]

Rawmaterialsoftheexternalphase(131.300kgsodiumhydrogencarbonate,20.000kglemonflavour,2.000kg
aspartameand3.000kgPEG6000)arescreenedthroughasieveof1.25mmmeshsizeandpouredintothetank
containingthe2partsofgranules.

Step5:Finalmixing
[0072]

Afinalmixingisperformedwithallrawmaterialsinthetankatthespeedof10rpm.Thedurationwas10minutes.
Theresidualhumidityislessthan0.25%.

Step6:tablettingoperationwithanexternallubrication.
[0073]

Tabletsarepressedfromthefinalmixing.Anexternallubricationwithmagnesiumstearateisusedtoavoidsticking
duringthetablettingoperation.
RotarypressCourtoyR190FTorFette2200iorsimilarequipmentswereused.
Theaveragemassofthetabletis3850mg.Theuniformityofthemaswascontrolledandgood.
Thediameterofthetabletis23mm.Thethicknessis3.10to3.30mm.Thehardnessis16KpThefriabilityisless
than1%.

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PatentEP2574333A1NacetylcysteineeffervescenttabletanditstherapeuticalapplicationsGooglePatents
Thedisintegrationtimeislessthan3minutes.
Thetabletsdonotsmellsulphur.Afterdissolutionintowater,thelimpidsolutiondoesnotsmellsulphurortaste
sulphur.Thelimpidsolutiondoesnothaveasaltedand/orfizzytaste.

Step7:primarypackaging.
[0074]

Tabletsareindividuallypackagedintoanaluminium/PEcomplex.Eachstripcontains4tablets.

Example9comparativestudies
[0075]

Weperformedcomparativestudiesofthetabletsoftheinvention,thesimplesyntheticmixofNACandits
excipientswithouttabletingandthetabletsproducedinlaboratoryaccordingtoexample2ofWO2010/090611
(correspondingtotheproductsoldunderthetrademarkMucoplus1200).
Theformulationofthetabletsisgivenintable1below.Table1Formulationofthetablets

[0076]

Ingredient

Mucoplus1200(M+1200)(mg) tabletsoftheinventionNAC1200(mg)

NAC

1200

1200

NAHC03

770

1313

Citricacid

1035

1087

Lemonflavour 20

200

Aspartame

30

20

NaCl

60

PEG6000

30

ThetestspH/solubility/effervescencewereperformedonnormaldrinkingwater,thatisthesolventactuallyusedby
theenduser.Thereferencevolumeis150mL,thatisthevolumeofanormalglassofwaterusedduringmeals.
Whenappropriate,1tabletwasdissolvedin150mlofnormaldrinkingwater,withashortmanualagitationatthe
end.

[0077]

Theresultsaregivenintable2below:Table2results
NAC1200

NAC1200SM

Tabletsexample2WO2010/090611

Rapidandvigorous:2'3'
Regularandvigorouseffervescence
effervescencewithverysmall withsmallbubbles.Aftera
withsmallbubbles.Thetablet
firstphaseofremarkable
boubblesthatendsin23'
disintegratesprogressivelyflocculating
effervescencedueto
withnoneedofagitation.
Effervescence
fragmentsofmaterialthatdepositon
productionofCO2,itis
Clearsolution,withsome
/dissolution
thewallsofthebeker.Onthesurface
residuesassupernatant
obtainedasolutionslightly
oftheliquiditremainsapellicular
visuallysimilartoM+1200.
opalescentbutglobally
coatingthatincorporatesair,maybe
Residuescouldbelongtothe clear,withoutflocculusor
duetoPEG.Itissaltedandoily.
twosalts.
deposit.
Regular,notvigorous

Disintegrationanddissolutionare
completein23minutes.
Thesolutionisopalescentand
flocculusofmaterialremainin
suspension.
pH

4.35

4.46

Lemonflavoursmelland
taste.Thelemonflavouris
Odour/taste

notmarket,itisratheran
equilibriumbetweensweet
andsalty.Nosulfurictaste.

Lemonflavourodour.Salted
andfizzytaste,withfinal
aftertaste.Lemonflavour
cannotbetasted.

3.46
Slightlemonflavourodour.Mainly
saltedtaste,withveryslightlemon
flavourtaste,slightfinalaftertaste

Example10comparativestudies
[0078]

Weperformedcomparativestudiesof:
1.1.Fluimucil600Zamboneffervescenttablets(FMC600Z)
2.2.Mucoplus1200Turkisheffervescenttablets(M+1200)boughtfromtheturkishmarket
3.3.EffervescenttabletsNAC1200mgaccordingtotheinvention(NAC1200)
4.4.Laboratorymix(FMC1200SM)ofNACactiveprincipeingredientandexcipientsinthesameratiothan
FMC600Zbutwithdoublequantity.

[0079]

TheformulationofMucoplus1200andNAC1200isgivenintable1above.TheformulationoftheFMC600Zand
FMC1200SMisgivenintable3below.Table3Formulation

[0080]

Ingredient

FMC600Z(mg) FMC1200SM(mg)

NAC

600

1200

NAHCO3

573

1146

Citricacid

680

1360

Lemonflavour 200

400

Aspartame

40

20

ThetestsofpH/solubility/effervescencewerecarriedoutinwaterHPLCgradeandindrinkingwater(thesolvent
actuallyusedbythepatient),inordertoverifyeventualvariationsduetothechemicophysicalqualityofthe
solvent.Thereferencevolumewas150mL,thatisthevolumeofaglassofwatercommonlyusedduringmeals.

[0081]

Thecharacteristicsofthetablets/laboratorymixaregivenintable4belowTable4characteristics

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[0082]

PatentEP2574333A1NacetylcysteineeffervescenttabletanditstherapeuticalapplicationsGooglePatents
Characteristic FMC600Z

M+1200

NAC1200

Appearance

intact,white

intact,white

intact,whiteintact,white Whitepowder

FMC1200SM

Smell

Mainlysulfuric,massebythelemonflavour Lemonflavour Lemonflavour

Lemonflavour

ThedissolutionofthesamplesinHPLCgradewater/pHaregivenintable5belowTable5dissolutioninHPLC
gradewater
Characteristic FMC600Z M+1200

Rapid:1
2'.Clear

Effervescenve

solution,

/dissolution

withbig
boubbles.

pH

3.82
Sulfuric
smell.

Smell/taste

Marked
lemon
taste.

[0083]

NAC1200

FMC1200SM

Rapid:12'.Vigorous

Regular,notvigorous

effervescence.Clear

effervescencewithverysmall

solution,withmany

boubblesthatendsin23'withno

smallboubbles.

needofagitation.Clearsolution,

Residuesofexcipients

withsomeresiduesassupernatant

remainassupernatant

visuallysimilartoM+1200.

andonthewallsofthe

Residuescouldbelongtothetwo

becker

salts.

3.42

4.28

Markedlemontaste.

Lemonflavoursmellandtaste.The

Thetasteissaltyand

lemonflavourisnotmarket,itis

butslowerthantablets.
Dissolutioniscomplete
after5'.Notclear,
opalescentsolution,but
stableandhomogenous.
Noresiduesofexcipients.
3.83

thelemonflavourcanbe ratheranequilibriumbetween
noticed.

Vigorouseffervescence,

Markedlemonflavour
smellandtaste.

sweetandsalty.Nosulfurictaste.

Thedissolutionindrinkingwater/pHisgivenintable6below:Table6pHindrinkingwater
Characteristic FMC600Z M+1200 NAC1200 FMC1200SM
pH

[0084]

3.88

3.50

4.35

3.87

TheonlydifferencecomparedtotheHPLCgradewateristhepHvalues,slightlyhigherbecauseofdissolvedsalts
ofdrinkingwater.
TabletsM+1200andNAC1200areequivalentintermsofapperanceofthefinalsolution.Asfarastasteis
concerned,thesaltyM+1200isabitinconvenient,whileNAC1200tasteisverygentle.
Bothformulationgiveacompletedissolution,evenifthefinalpHvaluesaredifferentcomparedtothereference
product(FMC600Zoranalogouslabmix2X).Inthesameconditionsofsolubilization,higherpHispreferrablein
termoftaste.ThehigherpHcomparedtothereference(FMC600Zorlabmix2X)isduetothehigherquantityof
NaHCO3andlowerquantityofcitricacid.

[0085]

Whilethepresentinventionhasbeendescribedwiththereferencetothespecificembodimentsthereof,itshould
beunderstoodbythoseskilledintheartthatvariouschangesmaybemadeandequivalentsmaybesubstituted
withoutdepartingfromthetruespiritandscopeofinvention.Inaddition,manymodificationsmaybemadetoapdat
aparticularsituation,material,compositionofmatter,process,processsteporstep,totheobjective,spiritand
scopeofthepresentinvention.Allsuchmodificationsareintendedtobewithinthescopeoftheclaimsappended
hereto.

PATENTCITATIONS
CitedPatent

Filingdate

Publicationdate

Applicant

Title

Processforthenmonoacylationofcysteine

US3184505

Jun18,1962

May18,1965

Mead
Johnson&Co

WO2010090611A2

Feb2,2010

Aug12,2010

BilgicMahmut

Tasteandodormaskedpharmaceuticalcompositionswithhigh
bioavailability

WO2010090612A1*

Feb2,2010

Aug12,2010

BilgicMahmut

Stable,tasteandodormaskedpharmaceuticalcompositionscomprising
acetylcysteinandvitaminc

*Citedbyexaminer

NONPATENTCITATIONS
Reference

"DrugdexDrugEvaluation",MICROMEDEXHEALTHCARESERIES,2011

JOHNSTONETAL.,SEMINARSINONCOLOGY,vol.10,1983,pages1724

CLASSIFICATIONS
InternationalClassification

A61K9/00,A61P11/00,A61K31/198,A61K9/20,A61P1/16,A61K9/46,A61K31/7072

CooperativeClassification

A61K9/0007,A61K31/198,A61K9/2031,A61K9/2095,A61K31/7072

LEGALEVENTS
Date

Code

Event

Description

Apr3,2013

AX

Requestforextensionof
theeuropeanpatentto

Countriesconcerned:BAME

Apr3,2013

AK

Designatedcontracting
states:

Kindcodeofrefdocument:A1
Designatedstate(s):ALATBEBGCHCYCZDEDKEEESFIFRGBGRHRHUIEISITLI
LTLULVMCMKMTNLNOPLPTRORSSESISKSMTR

Designatedcontracting

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PatentEP2574333A1NacetylcysteineeffervescenttabletanditstherapeuticalapplicationsGooglePatents

Nov13,2013

RBV

states(correction):

Designatedstate(s):ALATBEBGCHCYCZDEDKEEESFIFRGBGRHRHUIEISITLI
LTLULVMCMKMTNLNOPLPTRORSSESISKSMTR

Nov13,2013

17P

Requestforexamination
filed

Effectivedate:20131002

Dec11,2013

17Q

Firstexaminationreport

Effectivedate:20131107

Oct14,2015

RIC1

Classification(correction)

Ipc:A61P11/0020060101ALN20150908BHEP
Ipc:A61P1/1620060101ALN20150908BHEP
Ipc:A61K31/707220060101ALI20150908BHEP
Ipc:A61K9/4620060101ALI20150908BHEP
Ipc:A61K9/2020060101ALI20150908BHEP
Ipc:A61K31/19820060101ALI20150908BHEP
Ipc:A61K9/0020060101AFI20150908BHEP

Oct28,2015

INTG

Announcementofintention
togrant

Effectivedate:20150930

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