Tendered oral phosphate solution

Description

1 DESCRIPTION PALATABLEPHOSPHATEORALSOLUTION TECHNICALFIELD5 Thepresentinventionrelatestoapalatablephosphateoralsolution.This oralsolutionisadvantageousforuseinthetreatmentofhypophosphatemia andconditionsrelatedtophosphatedeficiency. 10 Thepalatablephosphateoralsolutionaccordingtoanembodimentofthe inventionisadvantageousforuseinpediatricswhereaccuratedosetitration isrequired.Furthermore,thephosphateoralsolutionaccordingtoan embodimentoftheinventionisstable,hasexcellentpalatabilityandlow sodiumcontent.15 Theinventionfurtherrelatestothepreparation,storageanduseofthe palatablephosphateoralsolution. BACKGROUND20 Phosphateisacrucialelementformaintainingnormalcellularfunctionsin thebody.Itcontainsphosphorus,amineralfoundinvariouspartsofthe body,includingbones,teeth,andblood,andisessentialfornumerousvital processes.Phosphateisakeycomponentofnucleicacids,aidinginthe25 replicationofDNAandRNA.Italsoservesasanenergysourceforcellular activitiesthroughitsroleinadenosinetriphosphate(ATP).Additionally, phosphateisincorporatedintocellmembranephospholipidsandhelps regulateproteinfunctionbyaddingorremovingphosphategroups,acting asanon / offswitchformolecularactivity.Givenitswidespreadinvolvement30 innearlyallcellularfunctions,disruptionsinphosphatelevelscan significantlyimpacthealth. Hypophosphatemiaisanelectrolyteimbalancecharacterizedbylow phosphatelevelsintheblood,definedasaserumphosphatelevelofless35 2025 / 5083 BE2025 / 5083 2 than2.5mg / dLinadults.Inchildren,thenormalserumphosphaterangeis significantlyhigher,typicallybetween4.0and7.0mg / dL.Thisconditionisa relativelycommonlaboratoryfindingandisoftendiscoveredincidentally. Symptomscanincludeweakness,difficultybreathing,andlossofappetite. Inmoreseverecases,complicationssuchasseizures,coma,5 rhabdomyolysis,orbonesofteningmayoccur. Whiletherearenoguidelinesavailableontheindications,dosingandlength ofreplacement,itisgenerallyacceptedthatmildandmoderate hypophosphatemiamustbetreatedwithoralreplacement.Oralreplacement shouldbeadministeredwithawelldilutedphosphateproductaccompanied10 byadequatehydration.Althoughtherearesomephosphatecontaining productsontheEuropeanMarketavailable,thosearenotreadytobeused, havetobefurtherpreparedandhaveaverybadtaste. Examplesofavailableproductsthatrequirepreparationbydissolvingin15 waterincludePhosphateSandozeffervescenttablets,whichcontain1.936g ofsodiumacidphosphate(NaH2PO4)anhydrous,K-Phostablets,whichoffer 126or250mgofphosphoruspersachet,andNeutraphos-Kpowder,which provides250mgofphosphoruspersachet. ThereisalsoacompoundedoralsolutionformulationknownasJoulie’s20 solution,usedasanextemporaneouspreparation.IntheNetherlands,a similarcompoundingformulationcalledFosfaatdrankFNAisavailable, containing1mmol / mLofphosphorus.However,asidefrombeingan extemporaneouspreparation,Fosfaatdrankisknownforitsunpleasantnasty taste,whichisoftencomparedtosoapywater.25 Astastemayinfluenceacceptabilityandpatientcompliancesubstantially, especiallyinchildren,thereremainsaneedforaphosphateoralsolution formulationwithanimprovedpalatability. Theobjectiveofthepresentinventionistofindasolutiontoatleastoneof30 theproblemsdescribedabove.Particularly,theobjectiveofthepresent inventionistoprovideapalatablephosphateoralsolutionformulationwith lowsodiumcontent,especiallyforpediatricpatients.Aproductaccordingto theinventionneedstohaveacommerciallyviableorlongshelflifesothat 2025 / 5083 BE2025 / 5083 3 productcanbedispensedofftheshelf.Also,arelevantin-usestabilityisof importance. SUMMARYOFTHEINVENTION 5 Inafirstaspect,theinventionprovidesapalatablephosphateoralsolution comprising: a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate b)asweetener c)atleastonesolvent10 whereinthepalatablesolutionscoresatleast3,preferablyatleast4,ona 5-pointtastehedonicscale. Theinventorshavesurprisinglyfoundthattheobtainedphosphateoral solutionhasanexcellentpalatability.Thismaybeadvantageousfororal15 solutionformulation,especiallyforpediatricpatients. Preferablythesweetenerispresentinanamountof0.5to5mg / mL,more preferably1to3mg / mL,evenmorepreferablytheamountofsweeteneris 2mg / mL.Mostpreferably,thesweetenerissucralose.20 Preferably,theatleastonesolventisselectedfrompropyleneglycol,glycerol oranymixturethereof,morepreferablytheatleastonesolventisamixture ofglycerolandpropyleneglycol. 25 Preferably,glycerolispresentinanamountof10to200mg / mL,more preferably50to150mg / mL,evenmorepreferablytheamountofglycerolis 100mg / mL. Preferablythepropyleneglycolispresentinanamountof10to200mg / mL,30 morepreferably50to150mg / mL,evenmorepreferablytheamountof propyleneglycolis100mg / mL. Preferably,thepalatablephosphateoralsolutionhasapHof3to5. 35 2025 / 5083 BE2025 / 5083 4 Preferably,thepalatablephosphateoralsolutionhasasodiumcontentof0.5 to2mmol / mL,preferably0.9to1.2mmol / mL,morepreferably1.00to1.10 mmol / mL,evenmorepreferablythesodiumcontentis1.01mmol / mL.Theinventorshavesurprisinglyfoundthattheobtainedphosphateoral5 solutionhasalowsodiumcontent.Thismaybeadvantageousforpatients onalowsaltdietandforuseinpediatrics. Preferably,thepalatablephosphateoralsolutionhasatleast3months, preferablyatleast6months,storagestabilitymeasuredat25°Cand60%10 RelativeHumidity(RH)(25°C / 60%RH)andat40°Cand75%Relative Humidity(RH)(40°C / 75%RH). Preferably,thepalatablephosphateoralsolutionhasanin-usestorage stabilityofatleast30daysmeasuredat25°Cand60%RelativeHumidity15 (RH)(25°C / 60%RH). Thepalatablephosphateoralsolutionaccordingtoanembodimentofthe invention,isadvantageousasitprovidesaformulationwithlongterm stabilitywhichenablesaready-to-useoralsolutionthatdoesnotneedtobe20 freshlypreparedordiluted. Inapreferredembodiment,thepalatablephosphateoralsolutioncomprises sodiumdi-hydrogenphosphatedihydrateasthephosphate,morepreferably inanamountof156.01mg / mL.25 Preferably,theadditionofpharmaceuticallyacceptableauxiliaryingredients includestheadditionofapreservative,aflavoringagent,andpurifiedwater. Preferably,thepreservativeispresentinanamountof0.1to5mg / mL,more30 preferably0.5to2mg / mL,evenmorepreferablytheamountofpreservative is1.5mg / mL.Mostpreferablythepreservativeissodiumbenzoate. Preferably,theflavoringagentispresentinanamountof0.1to2mg / mL, preferably0.5to1mg / mL,morepreferablytheamountofflavoringagentis35 2025 / 5083 BE2025 / 5083 5 0.85mg / mL.Evenmorepreferablythepreservativeisselectedfromorange, bloodorange,lemon,cherry,strawberry,raspberry,mint,novamintfresh peppermintflavorormixturesthereof,mostpreferablytheflavoringagent isbloodorange. 5 Preferably,thetotalvolumeofthepalatablephosphateoralsolutionis50to 500mL,morepreferably100to300mL,evenmorepreferablythetotal volumeofthepalatablephosphateoralsolutionis100or300mL. Inapreferredembodimentthepalatablephosphateoralsolutioncomprises:10 a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate b)asweetener,preferablysucralose c)atleastonesolvent,preferablyselectedfromglycerol,propylene glycolorcombinationsthereof d)apreservative,preferablysodiumbenzoate15 e)aflavoringagent,preferablyselectedfromorange,bloodorange, lemon,cherry,strawberry,raspberry,mint,novamintfresh peppermintflavorormixturesthereof f)purifiedwater. 20 Inapreferredembodimentthepalatablephosphateoralsolutioncomprises: a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate b)0.5to5mg / mL,preferably1to3mg / mL,evenmorepreferably 2mg / mLofsucralose c)10to200mg / mL,preferably50to150mg / mL,evenmore25 preferably100mg / mLofpropyleneglycoland10to200 mg / mL,preferably50to150mg / mL,evenmorepreferably100 mg / mLofglycerol d)0.1to5mg / mL,preferably0.5to2mg / mL,evenmore preferably1.5mg / mLofsodiumbenzoate30 e)0.1to2mg / mL,preferably0.5to1mg / mL,evenmore preferably0.85mg / mLofbloodorangeflavor f)purifiedwater.2025 / 5083 BE2025 / 5083 6 Inafurtheraspecttheinventionprovidesamethodofmanufacturinga palatablephosphateoralsolutionaccordingtoanembodimentofthe invention,comprisingthestepsof: i)dissolvinginwateraphosphatesaltoracidinasufficientamount toobtain0.5to2mmol / mL,preferably1mmol / mL,ofphosphate5 ii)preferablyaddingapreservative iii)addingatleastonesolvent iv)addingasweetener v)preferablyaddingaflavoringagent whereintheobtainedpalatablephosphateoralsolutionscoresatleast3,10 preferablyatleast4,ona5-pointtastehedonicscale. Inapreferredembodimentthepalatablephosphateoralsolutionisforuse inthetreatmentofhypophosphatemiaandconditionsrelatedtophosphate deficiency.15 Preferably,thepalatablephosphateoralsolutionisforuseinthetreatment ofapediatricpatient. Inapreferredembodiment,thepatientisadministered16mLofthe20 palatablephosphateoralsolutionbetween4to6timesaday.Inafurtheraspect,theinventionprovidesanoralsyringecomprisingthe palatablephosphateoralsolutionaccordingtoanembodimentofthe invention;whereintheoralsyringeisprovidedfordosingof16mLofthe25 palatableoralsolution. Inafurtheraspect,theinventionprovidesanoralcapcomprisingthe palatablephosphateoralsolutionaccordingtoanembodimentofthe invention;whereintheoralcapisprovidedfordosingof16mLofthe30 palatableoralsolution. DETAILEDDESCRIPTIONOFTHEINVENTION 2025 / 5083 BE2025 / 5083 7 Unlessotherwisedefined,alltermsusedindisclosingtheinvention,including technicalandscientificterms,havethemeaningascommonlyunderstood byoneofordinaryskillinthearttowhichthisinventionbelongs.Bymeans offurtherguidance,termdefinitionsareincludedtobetterappreciatethe teachingofthepresentinvention.5 Theexamplesprovidedinthedefinitionspresentinthisapplicationarenon- inclusiveunlessotherwisestated.Theyincludebutarenotlimitedtothe recitedexamples.10 Whenintroducingelementsofthepresentdisclosureoranaspectthereof, thearticles"a","an","the"and"said"areintendedtomeanthatthereare oneormoreoftheelements.Theterms"comprising","including"and "having"areintendedtobeinclusiveandmeanthattheremaybeadditional elementsotherthanthelistedelements.15 Theterm"and / or"whenusedinalistoftwoormoreitems,meansthatany oneofthelisteditemscanbeemployedbyitselforincombinationwithany oneormoreofthelisteditems.Forexample,theexpression"Aand / orB"is intendedtomeaneitherorbothofAandB,i.e.Aalone,BaloneorAandB20 incombination.Theexpression"A,Band / orC"isintendedtomeanAalone, Balone,Calone,AandBincombination,AandCincombination,BandC incombinationorA,B,andCincombination. Aboutincludes+ / -10%ofthenumericalvalue.25 Ratiosandpercentagesaregenerallyexpressedbyweight(weight / weight) unlessotherwiseindicated. Bytheterm“ready-to-use”asusedhereinismeantaphosphateoralsolution30 compositionthatdoesnotneedfurtherpreparationandcanbedirectly administeredorallytoapatient.Bytheterm“multidose”asusedherein,ismeantmorethanonedose, meaningthatmultipledosesarecontained.35 2025 / 5083 BE2025 / 5083 8 Theinventiveformulationofthepresentinventionisbasedonthe developmentofaphosphateoralsolutioncomprisingasweetenerandat leastonesolventthatscoresatleast3ona5-pointtastehedonicscaleand canbeusedwithoutfurtherpreparationasaready-to-usecomposition.5 Itwassurprisinglyfoundthattheconditionsdescribedherein,resultedinan excellentpalatablesolutionthatcanbeespeciallyusedforchildren. Theinvention,inafirstaspect,providesapalatablephosphateoralsolution10 comprising: a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate b)asweetener c)atleastonesolvent whereinthepalatablesolutionscoresatleast3ona5-pointtastehedonic15 scale. Preferably,thepalatablephosphateoralsolutionscoresatleast4ona5- pointtastehedonicscale.20 Preferably,thesweetenerisselectedfromsucrose,dextrose,sucralose, sorbitol,neotame,aspartame,acesulfameK,fructose,mannitol,invert sugar,saccharinsodium,aspartameandmixturesthereof. Preferablythepalatablephosphateoralsolutionaccordingtoanembodiment25 oftheinventionisfreeofsaccharin. Thepalatablephosphateoralsolutionaccordingtoanembodimentofthe inventionpreferablydoesnothaveametallictasteinthemouth. 30 Inapreferredembodiment,thesweetenerissucralose. Inamorepreferredembodiment,theamountofsweetenercomprisedinthe palatablephosphateoralsolutionis0.5to5mg / mL,morepreferably1to3 mg / mL,evenmorepreferablytheamountofsweeteneris2mg / mL.35 2025 / 5083 BE2025 / 5083 9 Inapreferredembodiment,theatleastonesolventisselectedfrom propyleneglycol,glycerol,glycerin,polyethyleneglycol,benzylalcohol, ethanolormixturesthereof. 5 Inapreferredembodiment,theatleastonesolventisamixtureofglycerol andpropyleneglycol.Inamorepreferredembodimentglycerolispresentinanamountof10to 200mg / mL,morepreferably50to150mg / mL,evenmorepreferablythe10 amountofglycerolis100mg / mL. Inamorepreferredembodimentpropyleneglycolispresentinanamount of10to200mg / mL,morepreferably50to150mg / mL,evenmore preferablytheamountofpropyleneglycolis100mg / mL.15 Inapreferredembodiment,thepalatablephosphateoralsolutioncomprises aphosphatesaltoracid,oranyhydratesthereof,asthephosphateselected from: -Phosphoricacid(H3PO4)20 -SodiumPhosphate(Na3PO4) -Disodiumhydrogenphosphate,disodiumphosphate,ordibasicsodium phosphate(Na2HPO4) -sodiumdihydrogenphosphate,monosodiumphosphateormonobasic sodiumphosphate(NaH2PO4).25 Inamorepreferredembodiment,thepalatablephosphateoralsolution comprisesmonosodiumhydrogenphosphate(NaH2PO4)asthephosphate, preferablythedihydratemonosodiumhydrogenphosphate(NaH2PO4.2H2O). 30 Morepreferably,thepalatablephosphateoralsolutioncomprisesdihydrate monosodiumhydrogenphosphate(NaH2PO4.2H2O)asthephosphate,inan amountof156.01mg / mL. 2025 / 5083 BE2025 / 5083 10 Inapreferredembodiment,thepHofthepalatablephosphateoralsolution is3to5. Inapreferredembodiment,thepalatablephosphateoralsolutionhasa sodiumcontentof0.5to2mmol / mL,preferably0.9to1.2mmol / mL,more5 preferably1.00to1.10mmol / mL,evenmorepreferablythesodiumcontent is1.01mmol / mL. Inafurtherembodiment,thepalatablephosphateoralsolutionhasatleast 3months,preferablyatleast6months,morepreferablyatleast12months,10 evenmorepreferablyatleast24monthslongtermstoragestability measuredat25°Cand60%RelativeHumidity(RH)(25°C / 60%RH). Inafurtherembodiment,thepalatablephosphateoralsolutionhasatleast 3months,preferablyatleast6monthsstabilitymeasuredataccelerated15 conditions40°Cand75%RelativeHumidity(RH)(40°C / 75%RH). Inapreferredembodiment,thepalatablephosphateoralsolutionaccording toanembodimentoftheinventionhasatleast3months,preferablyatleast 6months,storagestabilitymeasuredat25°Cand60%RelativeHumidity20 (RH)(25°C / 60%RH)andat40°Cand75%RelativeHumidity(RH) (40°C / 75%RH).Inapreferredembodiment,thepalatablephosphateoralsolutionhasanin- usestoragestabilityofatleast30days,preferablyatleast3months,more25 preferablyatleast6months,evenmorepreferablyatleast9months measuredat25°Cand60%RelativeHumidity(25°C / 60%RH). Inafurtherembodiment,thepalatablephosphateoralsolutionfurther comprisesatleastoneadditionalpharmaceuticalexcipientselectedfrom30 preservatives,flavoringagentsandmixturesthereof. Inapreferredembodiment,thepalatablephosphateoralsolutioncomprises apreservative.Examplesofpreservativesinclude,butarenotlimitedto, parabenssuchasmethylparaben,propylparaben,butylparabenandtheir35 2025 / 5083 BE2025 / 5083 11 salts,sorbicacid,sodiumsorbate,potassiumsorbate,calciumsorbate, benzoicacid,sodiumbenzoate,potassiumbenzoate,calciumbenzoate, methylhydroxybenzoate,ethylpara-hydroxybenzoate,sodiumethyl parahydroxybenzoate,sodiummetabisulphite,chlorhexidine,diazolidinyl urea,sodiumcitrate,butylatedhydroxyltoluene(BHT),butylatedhydroxyl5 anisole(BHA),tocopherol,ethylenediaminetetraaceticacid,propylgallate, quaternarycompounds,e.g.benzalkoniumchlorideandcetylpyridinium chloride,phenylethylalcoholandmixturesthereof.Preferably,the preservativeisselectedfromsodiummethylparaben,sodiumpropyl parabenandsodiumbenzoate.10 Inamorepreferredembodiment,thepalatablephosphateoralsolution comprisessodiumbenzoateaspreservative. Preferably,thepreservativeispresentinanamountof0.1to5mg / mL,more15 preferably0.5to2mg / mL,evenmorepreferablytheamountofpreservative is1.5mg / mL.Inapreferredembodiment,thepalatablephosphateoralsolutioncomprises aflavoringagent.Examplesofflavoringagentsinclude,butarenotlimited20 to,banana,lemon,gingerlemon,orange,bloodorange,grape,lime, grapefruit,vanilla,andfruitessence,includingapple,banana,pear,peach, strawberry,raspberry,cherry,plum,wildcherry,walnut,chocolate, pineapple,apricot,novamintfreshpepermintsyntheticflavoroilsand flavoringaromaticsand / ornaturaloils,extractsfromplantleaves,flowers,25 fruitssuchascinnamonoil,oilofwintergreen,peppermintoils,cloveoil, citrusoil,bayoil,aniseoil,eucalyptus,thymeoil,cedarleafoil,oilof nutmeg,oilofsage,oilofbittertoalmonds,mintandcassiaoil,maltol,ethyl vanillin,menthol,citricacid,fumaricacid,ethylmaltol,andtartaricacidand combinationsthereof.Preferably,theflavoringagentisselectedfromcherry,30 raspberry,orange,bloodorange,gingerlemon,novamintfreshpeppermint, mint,strawberryandmixturesthereof.Evenmorepreferablytheflavoring agentisselectedfrombloodorange.2025 / 5083 BE2025 / 5083 12 Inamorepreferredembodiment,thepalatablephosphateoralsolution comprisesbloodorangeasflavoringagent. Preferablytheflavoringagentispresentinanamountof0.1to2mg / mL, preferably0.5to1mg / mL,morepreferablytheamountofflavoringagentis5 0.85mg / mL. Inafurtherembodiment,thetotalvolumeofthepalatablephosphateoral solutionispreferably50to500mL,morepreferably100to300mL,even morepreferablythetotalvolumeofthepalatablephosphateoralsolutionis10 100or300mL. Inafurtherembodiment,thepalatablephosphateoralsolutioncomprises: a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate b)asweetener15 c)atleastonesolvent d)apreservative e)aflavoringagent f)purifiedwater. 20 Inapreferredembodiment,thepalatablephosphateoralsolutioncomprises: a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate b)sucralose c)atleastonesolventselectedfromglycerol,propyleneglycolor combinationsthereof25 d)apreservativeselectedfromsodiummethylparaben,sodiumpropyl paraben,sodiumbenzoateandmixturesthereof e)aflavoringagentselectedfromorange,bloodorange,lemon,cherry, strawberry,raspberry,mint,novamintfreshpeppermintflavoror mixturesthereof30 f)purifiedwater. Inapreferredembodiment,thepalatablephosphateoralsolutioncomprises: a)0.5to2mmol / mL,preferably1mmol / mL,ofphosphate 2025 / 5083 BE2025 / 5083 13 b)0.5to5mg / mL,preferably1to3mg / mL,evenmorepreferably2 mg / mLofasweetener c)10to200mg / mL,preferably50to150mg / mL,evenmorepreferably 100mg / mLofafirstsolventand10to200mg / mL,preferably50to 150mg / mL,evenmorepreferably100mg / mLofasecondsolvent5 d)0.1to5mg / mL,preferably0.5to2mg / mL,evenmorepreferably 1.5mg / mLofapreservative e)0.1to2mg / mL,preferably0.5to1mg / mL,evenmorepreferably 0.85mg / mLofaflavoringagent f)purifiedwater.10 Inamorepreferredembodiment,thepalatablephosphateoralsolution comprises: a)1mmol / mLofphosphate b)2mg / mLofasweetener15 c)100mg / mLofafirstsolventand100mg / mLofasecondsolvent d)1.5mg / mLofapreservative e)0.85mg / mLofaflavoringagent f)purifiedwater. 20 Inasecondaspectoftheinvention,thepalatablephosphateoralsolution accordingtoanembodimentoftheinventionisforuseinthetreatmentof hypophosphatemiaandconditionsrelatedtophosphatedeficiency. Inapreferredembodiment,thepatientisadministered16mLofthe25 palatablephosphateoralsolutionbetween4to6timesaday. Inapreferredembodimentoftheinvention,thepatientisapediatricpatient. Inathirdaspect,theinventionprovidesamethodofmanufacturinga30 palatablephosphateoralsolutionaccordingtoanembodimentofthe invention,comprisingthestepsof: i)dissolvinginwateraphosphatesaltoracidinasufficientamount toobtain0.5to2mmol / mL,preferably1mmol / mL,ofphosphate ii)preferablyaddingapreservative35 2025 / 5083 BE2025 / 5083 14 iii)addingatleastonesolvent iv)addingasweetener v)preferablyaddingaflavoringagent whereintheobtainedpalatablephosphateoralsolutionscoresatleast3, preferablyatleast4,ona5-pointtastehedonicscale.5 Inapreferredembodiment,thephosphatesaltoracidofstepi)isselected from: -Phosphoricacid(H3PO4) -SodiumPhosphate(Na3PO4)10 -Disodiumhydrogenphosphate,disodiumphosphate,ordibasicsodium phosphate(Na2HPO4) -sodiumdihydrogenphosphate,monosodiumphosphateormonobasic sodiumphosphate(NaH2PO4). 15 Inamorepreferredembodiment,thephosphatesaltoracidofstepi)isthe dihydratemonosodiumhydrogenphosphate(NaH2PO4.2H2O).Evenmore preferably,theamountofdihydratemonosodiumhydrogenphosphate (NaH2PO4.2H2O)is156.01mg / mL. 20 Inamorepreferredembodiment,thesweetenerofstepiv)issucralose. Preferably,theamountofthesweetenerofstepiv)is0.5to5mg / mL,more preferably1to3mg / mL,evenmorepreferablytheamountofsweeteneris 2mg / mL.25 Inamorepreferredembodiment,thepreservativeofstepii)isselectedfrom sodiummethylparaben,sodiumpropylparabenandsodiumbenzoate.Even morepreferably,thepreservativeofstepii)issodiumbenzoate. Inamorepreferredembodiment,thepreservativeofstepii)ispresentinan30 amountof0.1to5mg / mL,morepreferably0.5to2mg / mL,evenmore preferablytheamountofpreservativeis1.5mg / mL. Inamorepreferredembodiment,theatleastonesolventofstepiii)is selectedfrom35 2025 / 5083 BE2025 / 5083 15 propyleneglycol,glycerol,glycerin,polyethyleneglycol,benzylalcohol, ethanol,waterormixturesthereof.Evenmorepreferably,theatleastone solventofstepiii)isamixtureofglycerolandpropyleneglycol. Inamorepreferredembodimentglycerolispresentinanamountof10to5 200mg / mL,morepreferably50to150mg / mL,evenmorepreferablythe amountofglycerolis100mg / mL. Inamorepreferredembodimentpropyleneglycolispresentinanamount of10to200mg / mL,morepreferably50to150mg / mL,evenmore10 preferablytheamountofpropyleneglycolis100mg / mL.Inamorepreferredembodiment,theflavoringagentofstepv)isselected fromcherry,raspberry,orange,bloodorange,gingerlemon,novamintfresh peppermint,mint,strawberryandmixturesthereof.Evenmorepreferably15 theflavoringagentofstepv)isselectedfrombloodorange. Preferablytheflavoringagentofstepv)ispresentinanamountof0.1to2 mg / mL,preferably0.5to1mg / mL,morepreferablytheamountofflavoring agentis0.85mg / mL.20 Inafurtheraspect,theinventionprovidesaready-to-usestoragecontainer providedforholdingmultipleunitdosesofthephosphateoralsolution.Itis advantageousthattheoralsolutioncanbedirectlyusedwithoutfurther dilutionorpreparation,asareadilyavailablesolution.25 Inapreferredembodiment,thepalatablephosphateoralsolutionaccording toanembodimentoftheinvention,isfilledinastoragecontainer,preferably madeofplastic.TheplasticcanbeHighDensityPolyEthyleneorPolyester. ThepolyesterispreferablyPolyethyleneterephthalate(PET).30 Theinventionalsoprovidesakitofpartscomprisingthestoragecontainer accordingtoanembodimentoftheinvention,anoraldosingsyringe,abottle adaptorforholdingthecontainerandthedosingsyringe,andaleafletwith instructionsforstorageanduseofthekit.35 2025 / 5083 BE2025 / 5083 16 Theinventionalsoprovidesakitofpartscomprisingthestoragecontainer accordingtoanembodimentoftheinvention,anoraldosingcap,anda leafletwithinstructionsforstorageanduseofthekit. 5 Thekitofpartspreferablyhasaleafletforstorageanduseofthekit,wherein instructionsforstorageincludestorageatroomtemperature(20°Cto25°C [68°Fto77°F])forupto30daysoncetheoralsuspensionisprepared. EXAMPLES10 Themostpreferredlistofingredientsandconcreteexamplesareprovided below. Example1.Qualitativecomposition 15 Table1providesthequalitativecompositionofpreferredembodiments accordingtotheinvention.Thetablealsoliststhefunctionoftheingredients selected.Table1:Qualitativecompositionofpalatablephosphateoralsolution,20 accordingtotheinvention IngredientsFunction 1mmol / mLphosphate DrugSubstance, ActivePharmaceuticalIngredient(API) SucraloseSweetener PropyleneglycolSolvent GlycerolSolvent SodiumbenzoatePreservative BloodorangeFlavor WaterSolvent Example2:Quantitativecomposition 25 Table2providesthequantitativecompositionofpreferredembodiments accordingtotheinvention. 2025 / 5083 BE2025 / 5083 17 Table2:Quantitativecompositionof1mmol / mLpalatablephosphateoral solution,accordingtotheinvention Example2.12.22.32.42.52.62.72.82.92.102.11 Component s mgpermL SodiumDi- hydrogen Phosphate Dihydrate 156. 01 156. 01 156. 01 15 6.0 1 15 6.0 1 15 6.0 1 156. 01 15 6.0 1 156. 01 156. 01 156. 01 Sodium benzoate 1.501.501.50 1.5 0 1.5 0 00.75 1.1 25 1.87 5 1.501.50 Propylene glycol 100. 00 100. 00 100. 00 10 0.0 0 10 0.0 0 10 0.0 0 100. 00 10 0.0 0 100. 00 100. 00 100. 00 Glycerol 100. 00 100. 00 100. 00 80. 00 12 0.0 0 10 0.0 0 100. 00 10 0.0 0 100. 00 100.00 100. 00 Sucralose2.001.602.40 2.0 0 2.0 0 2.0 0 2.002.0 0 2.00 2.002.00 Blood orange flavor 0.850.850.85 0.8 5 0.8 5 0.8 5 0.85 0.8 5 0.85-- Cherry Raspberry Flavor ---------0.85- Novamint fresh Pepermint Flavor ----------0.85 Purified water q.s.q.s.q.s. q.s . q.s . q.s . q.s. q.s . q.s.q.s.q.s. Total 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 1 mL 5 Example3:Preparationoftheoralsolutions Theoralsolutionswerepreparedasfollows: 1.Allingredientsweredispensedandweighed 2.Purifiedwaterwascollectedandchargedintomanufacturingvessel10 andstirred.Thensodiumdi-hydrogenphosphatedihydrateunder continuedstirringwasaddedtoformaclearsolution 3.Sodiumbenzoatewasthenaddedunderstirring.Stirringwas continueduntilaclearsolutionwasformed 2025 / 5083 BE2025 / 5083 18 4.Sucralosewasthenaddedunderstirring.Stirringwascontinueduntil aclearsolutionwasformed 5.Glycerolandpropyleneglycolwerethenaddedunderstirring.Stirring wascontinueduntilaclearsolutionwasformed 6.Bloodorangeflavorwasfinallyaddedunderstirring.Stirringwas5 continueduntilaclearsolutionwasformed 7.Thefinalvolumewasmadeupbyusingpurifiedwaterandthe solutionwasstirredfor10minutes 8.ThepHoftheresultingsolutionwas3.0to5.0 9.Thesolutionwasfilledandpackedinaplasticcontainer,inparticular10 Polyethyleneterephthalate(PET).Thevolumeofthecontaineris selectedtohouseamultipleofunitdoses,i.e.amultidosebottle. Example4:OralsolutionPalatability 15 ThresholdofbitternessconcentrationofExamples2.1,2.2and2.3were determinedbyapanelofatleasttenhealthyvolunteers.Eachvolunteerwas giventeaspoonfuloftestandthentheparticipantswereaskedto immediatelydocumenttheiroverallperceptionofthetasteofthe administeredproductusingahedonicscale1to5,wherein1meanssuper20 badtaste,2badtaste,3maybegoodormaybebad,4goodand5super good.Toavoidbiasbetweensamples,thevolunteerswereaskedtorinse theiroralcavitywithwateratleastfivetimes,andaminimumgapof10 minuteswasmaintainedbetweentwosuccessivetasteevaluations.TasteresultsareshowninthefollowingTable3.25 Table3:PalatabilityresultsofcompositionsExample2.1,2.2 &2.3 TestsamplesMeanTaste value(1to5) Taste CompositionExample2.15Excellent CompositionExample2.24Good CompositionExample2.34Good FosfaatdrankFNA extemporaneouspreparation 2Bad 2025 / 5083 BE2025 / 5083 19 Samplesaccordingtoanembodimentoftheinvention(CompositionExample 2.1,2.2&2.3)presentedexcellentpalatabilityincomparisontoan extemporaneouslypreparedsolutionFosfaatdrankKNA. Example5:OralsolutionPhysicochemicalproperties5 Thephysicochemicalpropertiesofcompositionsexample2.1,2.4to2.11 weretested.AssaydeterminationisbasedonthemonographmethodBP 2023ofSodiumdihydrogenphosphatedihydrate.Physicochemicalresults arepresentedintable4.10 Table4:Physicochemicalresultsofcompositionsexample2.1,2.4to2.11 Example s 2.12.42.52.62.72.82.92.102.11 Descript ion Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n Clear colorle ss solutio n pH(25 oC) 3.824.194.184.204.184.204.194.374.37 Assay (%) 101.4 5 99.2197.7998.2999.4097.60 101.7 6 101.0 3 100.0 8 Samplesaccordingtoanembodimentoftheinvention(Composition15 Examples2.1,2.4to2.11)presentedexcellentphysicochemicalproperties. Example6:Inuseassay(%) Anin-usestabilitystudyhelpsdeterminetheperiodduringwhichamultiple-20 dosedrugproductremainsacceptableintermsofqualityspecificationsafter thecontainerisopened.Thisinformationiscriticalforpatientswhousethe productoveranextendedperiod,ensuringthattheyreceiveconsistent qualityandefficacythroughoutthedesignatedusageperiod.In-usestability wascarriedouttoevaluatethephysicalandchemicalinstability(pHand25 2025 / 5083 BE2025 / 5083 20 assay(%)).AssaydeterminationisbasedonthemonographmethodBP 2023ofSodiumdihydrogenphosphatedihydrate. TheresultsofSample2.1,in-usestorageassay(%)at25°C / 60%RHfor 1montharepresentedintable5. Table5:In-useassay(%)at25°C / 60%RHfororalsolutionaccordingto5 anembodimentoftheinvention,after1month. TestExample2.1 DescriptionT0 T30days (1month) pH(25oC)4.374.2 Assay(%)100.3998.26 Example2.1presentedgoodin-usestabilityafteratleast1month25°C / 60%RHconditions. 10 Example6:Storagestability Inordertoevaluatethesuitabilityofthephosphateoralsolutionastability studywasperformed,forexample2.1.Assay(%)andpHwererecordedat zerotimeandunder3monthsstorageatlong-termandaccelerated15 conditions.AssaydeterminationisbasedonthemonographmethodBP2023 ofSodiumdihydrogenphosphatedihydrate.Thestabilitydataare summarizedinthefollowingtables. Allcriticalqualityattributesarewellwithinacceptancecriteriaatleastat3 monthsstorageunderlongtermandacceleratedstorageconditions.20 Table6:ResultofstoragestabilityExample2.1(uprightandinverted) Formulation Example2.1. Zero time 25°C±2°C / RH:60%±5% 40°C±2°C / RH:75%±5% 3 month s 6 month s 1 mont h 2 month s 3 month s 6 months upright Assay(%)101.4599.61-99.8398.92101.71- pH(25oC)3.824.2-4.214.24.21- inverted Assay(%)101.45101.30-99.7999.21100.56- pH(25oC)3.824.2-4.214.24.21- 2025 / 5083 BE2025 / 5083.