METHOD FOR THE PREPARATION OF A SOFT GELATIN CAPSULE DOSAGE FORM WITH CHOLECALCIFEROL AND THE USE OF SUCH DOSAGE FORM

Abstract

The present invention relates to a method for the preparation of a soft gelatin capsule dosage form containing cholecalciferol for oral administration, consisting of the following steps: a) preparation of a gelatin-based solution consisting of gelatin, glycerol and purified water with a viscosity of 9.0 to 13.0 Pa*s, measured at a temperature between 58 and 62 °C, b) preparation of a pharmaceutical composition containing cholecalciferol and, furthermore, medium-chain triglycerides and an antioxidant as excipients, c) encapsulation of the pharmaceutical composition in a soft gelatin shell based on the gelatin-based solution using an encapsulation machine, and d) drying of the gelatin capsules until a capsule hardness between 7 and 14 N is obtained.The present invention also relates to a soft gelatin capsule dosage formulated for oral administration, and to such dosage forms for use in the treatment of diseases and / or conditions associated with cholecalciferol deficiency or insufficiency.

Description

BE2025 / 5023 2 Therefore,thereisaneedforanimprovedmethodforpreparingsoftgelatincapsules containingcholecalciferolthataddressesthesechallengeswhileensuringthestability andefficacyofthefinalproduct. SUMMARYOFTHEINVENTION5 Thepresentinventionandembodimentsthereofservetoprovideasolutiontoone ormoreofabove-mentioneddisadvantages.Tothisend,thepresentinvention relatestoamethodforthepreparationofasoftgelatincapsuledosageform comprisingcholecalciferolformulatedfororaladministrationaccordingtoclaim1.In particular,themethodcomprisesthestepsof:10 a)preparingagelatin-basedsolutioncomprisinggelatin,glycerol,andpurified waterhavingaviscosityof9.0–13.0Pa*sasmeasuredatatemperatureof between58and62°C,andallowingthegelatin-basedsolutiontomaturefor atleast3hoursatatemperatureofbetween58°Cand62°C, b)preparingapharmaceuticalcompositionwithcholecalciferolasactive15 ingredientandfurthercomprisingasexcipientsmediumchaintriglycerides (MCT)andanantioxidantwhichisanalpha-tocopheroloranesterthereof,andstirringthepharmaceuticalcompositionforatleast30minutestoobtain ahomogenouspharmaceuticalcomposition, c)encapsulatingthehomogenouspharmaceuticalcompositioninasoftgelatin20 shellbasedonthematuredgelatin-basedsolutionusingarotarydie encapsulationmachineinacontrolledenvironmentwithatemperature between17°Cand25°Candrelativehumiditynothigherthan24%,thereby formingoneormoregelatincapsulescomprisingagelatinshellwiththe homogenouspharmaceuticalcompositiondisposedinthegelatinshell,and25 d)dryingthegelatincapsulesinacontrolledenvironmentwithatemperature between17°Cand25°Candrelativehumiditynothigherthan24%untila capsulehardnessofbetween7and14Nisobtained,therebyobtainingthe softgelatincapsuledosageformformulatedfororaladministration. 30 Inasecondaspect,theinventionrelatestoasoftgelatincapsuledosageform formulatedfororaladministrationaccordingtoclaim8.Inparticular,thesoftgelatin capsuledosageformcomprises: a)asoftgelatinshellcomprisinggelatin,glycerol,purifiedwater,andoptionally acolorant,and35b)apharmaceuticalcompositiondisposedinthesoftgelatinshellcomprising: i)anactiveingredientcholecalciferol, ii)mediumchaintriglycerides(MCT),and 2025 / 5023 BE2025 / 5023 3 iii)anantioxidantwhichisanalpha-tocopheroloresterthereof, whereinthesoftgelatincapsuledosageformhasacapsulehardnessofbetween7 and14N. Inanotheraspect,thepresentinventionrelatestothesoftgelatincapsuledosage5 formforuseinthetreatmentdiseasesand / orconditionslinkedtocholecalciferol deficiencyorinsufficiencyaccordingtoclaim13. Preferredembodimentsofthemethodareshowninanyoftheclaims2to7,ofthe softgelatincapsuledosageforminanyoftheclaims9to12,andofthesoftgelatin10 capsuledosageformforuseinanyoftheclaims14to18. Inthemethodforthepreparationofasoftgelatincapsuledosageformcomprising cholecalciferolformulatedfororaladministration,theprocessparametersare controlledmeticulouslytoensureuniformqualityandstabilityofthefinalsoftgelatin15 capsuledosageform,andprovidesaiddosageformswhichmaintaintheirintegrityduringstorage,handling,anduse,makingthemparticularlysuitableforuseinthe treatmentdiseasesand / orconditionslinkedtocholecalciferoldeficiencyor insufficiency. 20 DETAILEDDESCRIPTIONOFTHEINVENTION Thepresentinventionconcernsamethodforthepreparationofasoftgelatincapsule dosageformcomprisingcholecalciferolformulatedfororaladministration,asoft gelatincapsuledosageformformulatedfororaladministration,andtosuchdosage formsforuseinthetreatmentdiseasesand / orconditionslinkedtocholecalciferol25 deficiencyorinsufficiency. Inthemethodforthepreparationofasoftgelatincapsuledosageformcomprising cholecalciferolformulatedfororaladministration,theprocessparametersare controlledmeticulouslytoensureuniformqualityandstabilityofthefinalsoftgelatin30 capsuledosageform,andprovidesaiddosageformswhichmaintaintheirintegrity duringstorage,handling,anduse,makingthemparticularlysuitableforuseinthe treatmentdiseasesand / orconditionslinkedtocholecalciferoldeficiencyor insufficiency. 35 DefinitionsUnlessotherwisedefined,alltermsusedindisclosingtheinvention,including technicalandscientificterms,havethemeaningascommonlyunderstoodbyoneof 2025 / 5023 BE2025 / 5023 4 ordinaryskillinthearttowhichthisinventionbelongs.Bymeansoffurtherguidance, termdefinitionsareincludedtobetterappreciatetheteachingofthepresent invention. Asusedherein,thefollowingtermshavethefollowingmeanings:5 “A”,“an”,and“the”asusedhereinreferstobothsingularandpluralreferentsunless thecontextclearlydictatesotherwise.Bywayofexample,“acompartment”refers tooneormorethanonecompartment. 10 “About”asusedhereinreferringtoameasurablevaluesuchasaparameter,an amount,atemporalduration,andthelike,ismeanttoencompassvariationsof+ / - 20%orless,preferably+ / -10%orless,morepreferably+ / -5%orless,evenmore preferably+ / -1%orless,andstillmorepreferably+ / -0.1%orlessofandfromthe specifiedvalue,insofarsuchvariationsareappropriatetoperforminthedisclosed15 invention.However,itistobeunderstoodthatthevaluetowhichthemodifier“about”refersisitselfalsospecificallydisclosed. “Comprise”,“comprising”,and“comprises”and“comprisedof”asusedhereinare synonymouswith“include”,“including”,“includes”or“contain”,“containing”,20 “contains”andareinclusiveoropen-endedtermsthatspecifiesthepresenceofwhat followse.g.componentanddonotexcludeorprecludethepresenceofadditional, non-recitedcomponents,features,element,members,steps,knownintheartor disclosedtherein. 25 Furthermore,thetermsfirst,second,thirdandthelikeinthedescriptionandinthe claims,areusedfordistinguishingbetweensimilarelementsandnotnecessarilyfor describingasequentialorchronologicalorder,unlessspecified.Itistobeunderstood thatthetermssousedareinterchangeableunderappropriatecircumstancesand thattheembodimentsoftheinventiondescribedhereinarecapableofoperationin30 othersequencesthandescribedorillustratedherein. Therecitationofnumericalrangesbyendpointsincludesallnumbersandfractions subsumedwithinthatrange,aswellastherecitedendpoints. 35Theexpression“%byweight”,“weightpercent”,“%wt”or“wt%”,hereand throughoutthedescriptionunlessotherwisedefined,referstotherelativeweightof therespectivecomponentbasedontheoverallweightoftheformulation. 2025 / 5023 BE2025 / 5023 5 Whereastheterms“oneormore”or“atleastone”,suchasoneormoreoratleast onemember(s)ofagroupofmembers,isclearperse,bymeansoffurther exemplification,thetermencompassesinteraliaareferencetoanyoneofsaid members,ortoanytwoormoreofsaidmembers,suchas,e.g.,any≥3,≥4,≥5,5 ≥6or≥7etc.ofsaidmembers,anduptoallsaidmembers. Unlessotherwisedefined,alltermsusedindisclosingtheinvention,including technicalandscientificterms,havethemeaningascommonlyunderstoodbyoneof ordinaryskillinthearttowhichthisinventionbelongs.Bymeansoffurtherguidance,10 definitionsforthetermsusedinthedescriptionareincludedtobetterappreciatethe teachingofthepresentinvention.Thetermsordefinitionsusedhereinareprovided solelytoaidintheunderstandingoftheinvention.Referencethroughoutthisspecificationto"oneembodiment"or"anembodiment"15 meansthataparticularfeature,structureorcharacteristicdescribedinconnection withtheembodimentisincludedinatleastoneembodimentofthepresentinvention. Thus,appearancesofthephrases"inoneembodiment"or"inanembodiment"in variousplacesthroughoutthisspecificationarenotnecessarilyallreferringtothe sameembodiment,butmay.Furthermore,theparticularfeatures,structuresor20 characteristicsmaybecombinedinanysuitablemanner,aswouldbeapparenttoa personskilledintheartfromthisdisclosure,inoneormoreembodiments. Furthermore,whilesomeembodimentsdescribedhereinincludesomebutnotother featuresincludedinotherembodiments,combinationsoffeaturesofdifferent embodimentsaremeanttobewithinthescopeoftheinvention,andformdifferent25 embodiments,aswouldbeunderstoodbythoseintheart.Forexample,inthe followingclaims,anyoftheclaimedembodimentscanbeusedinanycombination. Theterm"softgelatincapsule"refersinthepresentinventiontoadosageformfororaladministrationcomprisingasoft,flexibleshellmadeprimarilyofgelatin,and30 optionallyfurtherexcipientssuchasglycerolandwater,whichenclosesaliquidor semi-liquidfillpharmaceuticalcompositiongenerallycontainingtheactiveingredient andfurtherexcipients.Inthiscontext,a“softgelatinshell”referstotheouterlayer ofasoftgelatincapsule,composedprimarilyofgelatin,whichencapsulatesthe pharmaceuticalcomposition.35 Bytheterm"cholecalciferol"ismeantinthepresentinventionvitaminD3,afat- solublesecosteroidresponsibleforincreasingintestinalabsorptionofcalcium, 2025 / 5023 BE2025 / 5023 6 magnesium,andphosphate.Thecholecalciferolusedinthisinventionispreferably intheformofcrystallinecholecalciferolasdescribedintheEuropeanPharmacopoeia. Theterm"mediumchaintriglycerides”or“MCT"refersinthepresentinventiontoa triglyceridethatcontainsmedium-lengthchainsoffattyacids,inparticular5 comprisingcaprylicacidandcapricacid,whichcanbeusedasamatrixmaterial,carrier,and / orsolventinpharmaceuticalformulationsduetoitsstabilityandease ofabsorption. Bytheterm"antioxidant"ismeantinthepresentinventionasubstancethatinhibits10 oxidationandthusmaypreventthedegradationofanactiveingredient.The preferredantioxidantinthisinventionisanalpha-tocopherol,whichisaformof VitaminE,usedasanantioxidantinpharmaceuticalcompositionstoprevent oxidationanddegradationofanactiveingredient.Itcanbeintheformofalpha- tocopherolitselforitsesters,suchasall-rac-α-tocopherylacetate,asyntheticform15 ofvitaminE. Theterm"gelatin-basedsolution"refersinthepresentinventiontoamixture comprisinggelatin,andpreferablyfurtherexcipientssuchasglycerolandpurified water,whichispreparedandpreferablyallowedtomaturetoformauniformmass20 suitableforencapsulation.Inthecontextofpreparingthegelatin-basedsolution, "mature"referstotheprocessofallowingthemixturetorestorbemaintainedata specifiedtemperatureforacertainperiodtoachievethedesiredphysicaland chemicalproperties,suchasviscosityanduniformity. 25Bytheterm“viscosity”ismeantameasureofafluid'sresistancetoflow,expressed inPascal-seconds(Pa*s).Inthiscontext,itreferstothethicknessofthegelatin- basedsolution,whichiscrucialfortheencapsulationprocess.Viscositymaybe measuredusingaviscometer,andinthepresentcaserelatingtothethicknessof thegelatin-basedsolutionismeasuredatatemperatureofbetween58and62°C.30 Bytheterm"homogenouspharmaceuticalcomposition"ismeantinthepresent inventionamixtureinwhichtheactiveingredientandexcipientsareuniformly distributed,ensuringconsistentdosageandstabilitythroughoutthecomposition. 35 Theterm"encapsulationmachine"refersinthepresentinventiontoaspecialized pieceofequipmentusedinthepharmaceuticalindustrytoencapsulateliquidor semi-liquidpharmaceuticalcompositionswithinasoftgelatinshell.Themachine 2025 / 5023 BE2025 / 5023 7 forms,fills,andsealsthecapsules,preferablyinonecontinuousoperation.The encapsulationmachinemayforinstancebearotarydieencapsulationmachine.Bytheterm"controlledenvironment"ismeantinthepresentinventionan environmentwherespecificparameterssuchastemperatureandhumidityare5 regulatedandmaintainedwithinpredefinedlimitstoensurethequalityandstability ofthepharmaceuticalproductduringmanufacturingandstorage,suchasan environmentwherethetemperatureismaintainedbetween17°Cand25°Candthe relativehumidityisnothigherthan24%. 10 Theterm"capsulehardness"refersinthepresentinventiontoameasureofthe firmnessofthesoftgelatincapsule,typicallyquantifiedinNewtons(N).Itindicates thecapsule'sresistancetophysicaldeformation,whichiscrucialforhandling, packaging,andensuringtheproperreleaseoftheactiveingredientupon administration;andcanbemeasuredusingadurometer.15 Bytheterm"colorant"ismeantinthepresentinventionasubstanceusedtoimpart adistinctivecolortothegelatin-basedsolutionorthesoftgelatinshell.Itmaybea naturalorsyntheticdyeorpigmentandisincludedintheformulationtoprovide visualidentification,enhanceaestheticappeal,orserveafunctionalpurposesuchas20indicatingdosagestrength.PreferredcolorantsincludebluecolorantssuchasPatent BlueV,alsoreferredtoasE131,andtitaniumdioxide-basedwhitecolorantssuchas titaniumdioxide,alsoreferredtoasE171. Theterm"single-doseblisters"refersinthepresentinventiontoapackagingformat25 whereeachblistercavitycontainsasingleunitofthepharmaceuticaldosageform, designedtoprotecttheproductfromenvironmentalfactorsandfacilitateindividual dosing. Theterm“disintegrationtime”referstotheperiodrequiredforaformulation,inthe30 presentcontextinparticularthesoftgelatincapsule,tobreakdownintosmaller fragments,preferablyafteradministration,facilitatingthereleaseandabsorptionof theactiveingredient. Theterm"therapeuticallyeffectiveamount"refersinthepresentinventiontoan35 amountofthesoftgelatincapsuledosageformoramountofcholecalciferolsufficient toachievethedesiredtherapeuticeffectintreatingdiseasesand / orconditionslinked tocholecalciferoldeficiencyorinsufficiency.Thisamountissufficienttoincreasethe 2025 / 5023 BE2025 / 5023 8patient'stotalbloodserumcholecalciferolleveltoarangethatisconsiderednormal oroptimalforhealth,asdeterminedbymedicalguidelinesandpatient-specific factorssuchasage,weight,andbaselinevitaminDlevels. Bytheterm"treatmentofdiseasesand / orconditionslinkedtocholecalciferol5 deficiencyorinsufficiency"ismeantinthepresentinventionthetherapeutic interventionaimedatpreventing,alleviating,orcuringdiseasesandconditions associatedwithinadequatelevelsofcholecalciferolinthebody.Thisincludesbutis notlimitedtoconditionssuchasosteoporosis,rickets,osteomalacia,hypocalcemia, secondaryhyperparathyroidism,chronickidneydisease,cardiovasculardisease,10 diabetes,autoimmunediseases(e.g.,multiplesclerosis,rheumatoidarthritis), infectionsduetoimpairedimmunefunction,muscleweaknessandpain,seasonal affectivedisorder(SAD),cancers(e.g.,colorectal,breast,andprostatecancer), metabolicsyndrome,hypertension,asthma,anddepression. 15 "Consistingessentiallyof"meansthatthecompositionorstructureincludesthecomponentsorelementsspecificallylistedandanyadditionalcomponentsor elementsthatdonotmateriallyaffectthebasicessentialcharacteristicsofthe invention.Thetermallowsforthepresenceofadditional,non-essentialcomponents thatdonotaltertheinvention'sfundamentalpropertiesorperformance.20 Description Inafirstaspect,theinventionprovidesamethodforthepreparationofasoftgelatin capsuledosageformcomprisingcholecalciferolformulatedfororaladministration. Themethodcomprisesthestepsof:25 a)preparingagelatin-basedsolutioncomprisinggelatin,glycerol,andpurified waterhavingaviscosityof9.0–13.0Pa*sasmeasuredatatemperatureof between58and62°C,andallowingthegelatin-basedsolutiontomaturefor atleast3hoursatatemperatureofbetween58°Cand62°C, b)preparingapharmaceuticalcompositionwithcholecalciferolasactive30 ingredientandfurthercomprisingasexcipientsmediumchaintriglycerides (MCT)andanantioxidantwhichisanalpha-tocopheroloranesterthereof, andstirringthepharmaceuticalcompositionforatleast30minutestoobtainahomogenouspharmaceuticalcomposition, c)encapsulatingthehomogenouspharmaceuticalcompositioninasoftgelatin35 shellbasedonthematuredgelatin-basedsolutionusingarotarydie encapsulationmachineinacontrolledenvironmentwithatemperature between17°Cand25°Candrelativehumiditynothigherthan24%,thereby 2025 / 5023 BE2025 / 5023 9 formingoneormoregelatincapsulescomprisingagelatinshellwiththe homogenouspharmaceuticalcompositiondisposedinthegelatinshell,and d)dryingthegelatincapsulesinacontrolledenvironmentwithatemperature between17°Cand25°Candrelativehumiditynothigherthan24%untila capsulehardnessofbetween7and14Nisobtained,therebyobtainingthe5 softgelatincapsuledosageformformulatedfororaladministration. Inthismethodforthepreparationofasoftgelatincapsuledosageform,throughout thistextalsoreferredtoas‘capsules’,comprisingcholecalciferolformulatedfororal administration,theprocessparametersarecontrolledmeticulouslytoensure10 uniformqualityandstabilityofthefinalsoftgelatincapsuledosageform.Themethodinvolvesthepreparationofagelatin-basedsolution,thedissolutionofcholecalciferol inamedium-chaintriglyceride(MCT)solventwithanantioxidant,encapsulation,and dryingofthecapsulesunderspecifictemperatureandhumidityconditions. 15 Stepa)ofthemethodrequirespreparingagelatin-basedsolutioncomprisinggelatin, glycerol,andpurifiedwaterhavingaviscosityof9.0–13.0Pa∙s,preferably10.0to 12.0Pa*sasmeasuredatatemperatureofbetween58and62°C,andpreferably allowingthegelatin-basedsolutiontomatureforatleast3hoursatatemperature ofbetween58°Cand62°C.20 Gelatinisselectedforitsgellingproperties,whichareessentialforformingthesoft capsule.Glycerolactsasaplasticizer,providingflexibilitytothecapsuleshell,while purifiedwaterisusedtoensuretheappropriateconsistencyandviscosityofthe gelatinmass.25 Saidviscosityofthegelatin-basedsolutionintherangeof9.0–13.0Pa∙s,preferably 10.0–12.0Pa∙sasmeasuredatatemperatureofbetween58and62°Cisdesired asitmakestheencapsulationprocessmoreefficient,therebyreducingproductiontimeandcost.Viscositiesoutofthisrangemayhampertheencapsulationprocess30 ormakeitevenimpossible.Theoptimalviscositymaybeachievedbycombiningthe optimalamountsofgelatin,glycerolandwatertopreparethegelatin-basedsolution. Theoptimalviscositycanfurtherbeachievedbycontrollingthetemperature,here between58and62°C,andmixingconditionsduringthepreparationofthegelatin- basedsolution.Inanembodiment,thisstepmayoptionallyincludetheuseof35 vacuumduringthegelatin-basedsolutionpreparationtoensureanair-freegelatin solution.Theuseofvacuumispreferredasitleadstobettercapsuleintegrityand appearancebypreventingtheformationofairbubblesinthegelatinmass. 2025 / 5023 BE2025 / 5023 10 Glycerolisincludedinthegelatin-basedsolution,whichbecomestheshellofthe gelatincapsules,primarilybecauseitactsasaplasticizer,makingtheshellmore flexibleandpreventingitfrombecomingbrittleandbreaking.Thisflexibilityensures thecapsulesmaintaintheirintegrityduringmanufacturing,handling,andstorage.5Additionally,glycerolhelpsretainmoistureinthegelatinshell,whichiscrucialfor maintainingthedesiredtextureandconsistency,enhancingtheoverallstabilityand shelflifeofthecapsules.Italsocontributestoasmootherandmorepleasant mouthfeel,improvingpatientcompliance.Furthermore,glycerolhelpsprotectthe activeingredientsinsidethecapsulefromenvironmentalfactorslikeoxygenand10 light,therebypreservingthepotencyofthepharmaceuticalcomposition. Preferably,thegelatin-basedsolutionismaturedatatemperaturebetween58°C and62°Cforatleast3hours,resultinginamoreuniformandconsistentgelatin mass.Preferably,thematurationtemperatureisbetween50°Cand70°C,more15 preferablybetween55°Cand65°C,morepreferablybetween58°Cand62°C,and mostpreferablybetween59°Cand61°C.Thematurationtimeispreferablyatleast 2hours,morepreferablyatleast2.5hours,morepreferablyatleast3hours,such asforexampleabout2.5hours,about3hours,about3.5hours,orabout4hours. Thismaturationprocesssignificantlyimprovesthequalityofthesoftgelatincapsules20byensuringthatthegelatin-basedsolutionisuniformandfreeofairbubbles,which couldcausedefectsinthecapsules. Inanembodiment,stepa)maycomprisei)preparingapremixtureofglyceroland purifiedwater,ii)addinggelatintosaidpremixture,andiii)stirringthepremixture25 comprisinggelatintoobtainthegelatin-basedsolution.Preferably,stepsii)and / or iii)areperformedundervacuumtoavoidairbubblesinthegelatin-basedsolution. Thestepofpre-mixingglycerolwithpurifiedwaterallowsforamoreefficientand uniformdissolutionofgelatin.Thisprocessenhancementispreferredasit30 significantlyimprovesoverallprocessefficiencyandproductquality. Stepb)oftheinvention,asmentionedabove,relatestopreparingapharmaceutical compositionwithcholecalciferolasactiveingredientandfurthercomprising excipientsmediumchaintriglycerides(MCT)andanantioxidantwhichisanalpha-35 tocopheroloranesterthereof,andstirringthepharmaceuticalcompositionforat least30minutestoobtainahomogenouspharmaceuticalcomposition. 2025 / 5023 BE2025 / 5023 11TheuseofMCTasasolventinthepharmaceuticalcompositionprovidesanideal matrixfordissolvingcholecalciferol.MCTsareknownfortheirexcellentsolubilizing properties,whichhelpintheefficientdissolutionofcholecalciferol.Thisensuresthat theactiveingredientcanbehomogenouslydistributedthroughthecapsule,and furtherwillbereadilyavailableforabsorptioninthebody.MCTalsoensuresstability5 againstoxidation,andcompatibilitywithotherformulationcomponents.TheMCT alsocontributetotheoverallstabilityandbioavailabilityofthecholecalciferolinthe finalproduct. Theinclusionofanantioxidantinthepharmaceuticalcompositionwasalsoproven10 tobeessentialtotheinventiontoensuresufficientshelflifeoftheactiveingredient. Alpha-tocopherol,alsoknownasvitaminE,isafat-solubleantioxidantthatprotects cellsfromoxidativedamage.Anesterofalpha-tocopherolreferstoaderivative wherethehydroxylgroupofalpha-tocopherolischemicallyboundtoanorganicacid. Commonestersincludealpha-tocopherylacetateandalpha-tocopherylsuccinate.15Theseestersareoftenusedinpharmaceuticalanddietarysupplementformulations duetotheirenhancedstabilitycomparedtoalpha-tocopherolitself.Theantioxidant worksbyscavengingfreeradicalsthatcancauseoxidativedegradationof cholecalciferol,thusensuringthattheactiveingredientremainsstablethroughout theshelflifeoftheproduct.20 Inanembodiment,theantioxidantusedisall-rac-α-tocopherylacetate,aformof vitaminEknownforitsexcellentantioxidantproperties.Theinclusionofall-rac-α- tocopherylacetateintheformulationenhancesthestabilityofcholecalciferolby reducingoxidativedegradation.Thisensuresthattheactiveingredientremains25 effectiveovertheintendedshelflifeoftheactiveingredient. Theinclusionofthisantioxidantispreferablybasedonstabilitystudiesthat demonstratedaconsistentdecreaseincholecalciferolcontentovertimewithoutthe antioxidant.Byincorporatingall-rac-α-tocopherylacetate,thestabilityandshelflife30 oftheactiveingredientaresignificantlyimproved.Inanembodiment,theinclusionofthisantioxidantispreferablyinanamountof between0.04%and0.06%,preferablyabout0.05%(cholecalciferol / antioxidant; IU / IU),whichhasbeendeterminedtobeeffectiveinpreventingthedegradationof35 cholecalciferol.Thisensuresthattheactiveingredientretainsitstherapeuticefficacy overtime,providingconsistenttreatmentforvitaminDdeficiency. 2025 / 5023 BE2025 / 5023 12 Inanembodiment,cholecalciferolisintroducedinacrystallineform,preferablyto obtainastrengthofeither20,000IUor25,000IUperfinaldosageform.The pharmaceuticalcompositionispreferablyformulatedtoincludeanoverage, preferablyofatleast5wt%,morepreferablyofatleast10wt%,ofcholecalciferol toensuresufficientlevelsoftheactivesubstancearemaintainedthroughoutitsshelf5 life.Thisoverageispreferablydeterminedbasedonstabilitystudiesand experimentaldata,whichindicatethatsuchanoverageisdesirabletocompensate forthedegradationofcholecalciferolovertime. Inapreferredembodiment,themethodensuresthatthecholecalciferol,MCT,and10antioxidantarethoroughlymixedforamorehomogenouspharmaceutical composition.Thethoroughandsystematicpreparation,whichpreferablyincludes vacuumstirringandtemperaturecontrol,mayleadtoamoreefficientmanufacturing process,thuspotentiallyreducingproductioncosts.Thispreferredembodimentaims toachieveamoreconsistentbatchquality,resultinginfewerdiscrepanciesanda15 morereliablesupplyoftheactiveingredient. Inanembodiment,stepb)comprises: i)dispensingcholecalciferolandapartofabatchvolumeofMCTina, preferablystainlesssteel,vessel,andstirringthecholecalciferolandMCT20 inthevessel,preferablyforatleast20minutes,toobtainaclearpremix- solution, ii)dispensingtheremainderofthebatchvolumeofMCTandtheantioxidant inaprocesstankandstirring,preferablyundervacuum,whileheatingthe MCTandantioxidanttoatemperatureofbetween48°Cand52°C,25 optionallyagainstirringatleastfor15minutesat48°Cto52°C, preferablyallowingthemixturetocooldown,preferablytoabout25°C, andiii)combiningthecholecalciferolandMCTpremix-solutionwiththeMCTand antioxidantmixtureofii)intheprocesstankandstirring,preferablyfor30 atleast30minutes,preferablyundervacuum,therebyobtainingthe homogenouspharmaceuticalcomposition. Thispreparationmethodensuresthatcholecalciferolisevenlydistributedthroughout thepharmaceuticalcompositiontobeencapsulatedinasoftgelatinshell.This35 uniformdistributionispreferredbecauseitleadstoconsistentandreliabledoses, whichiscrucialforthetherapeuticefficacyoftheactiveingredient.Theabove- mentionedstepii)isfurtherpreferredasithelpstoobtainahomogeneousmixture 2025 / 5023 BE2025 / 5023 13 oftheantioxidantandMCT,whichinturnaidsintheuniformdistributionof cholecalciferolwhencombined. Preferably,apartofthetotalbatchvolumeofMCTispremixedwithcholecalciferol asinstepi)toobtainaclearpremix-solution,toensurecompletedissolutionof5 cholecalciferol.Saidpartmaybeabout10,15,20,30,40,50,60,65,70,80,or 90%,preferablybetweenabout40and70%.Preferably,thisstirringormixingtakesplaceatanRPMofbetween40and60,preferablybetween45and55,andmost preferablyatabout50rpm,andpreferablyforatleast20minutes,atleast25 minutes,atleast30minutes,andpreferablyatleastuntilaclearpremix-solutionis10 obtained.Preferably,thestirringtimerangesfrom20to30minutes.Thisensures completedissolutionofcholecalciferol,contributingtothehomogeneityofthe pharmaceuticalcomposition. Preferably,thetemperatureduringthemixingofMCTandantioxidantinstepii)is15 preciselycontrolled.Morepreferably,thetemperatureismaintainedbetween48°C and52°C,andmostpreferablyaround50°C;andpreferablystirringtakesplacefor atleast10minutes,preferablyatleast15minutes,oratleast20or30minutes. TheseconditionsallowobtainingahomogenousmixtureofantioxidantandMCT, mayhelpinminimizingtheoxidationoftheantioxidant,therebymaintainingthe20 integrityofcholecalciferol,andmayfurtheralsohelpinminimizingthepresenceof airbubblesinthepharmaceuticalcomposition. Thestirringtimeofthepremix-solutionofcholecalciferolinMCTwiththemixtureofMCTandantioxidantisalsopreferablycontrolled.Thistimeispreferablynotless25 than30minutes,morepreferablybetween30and45minutes,andmostpreferably around40minutes.Thisensuresauniformassayofcholecalciferolinthesolution, whichisessentialforbatchconsistencyandefficacyoftheactiveingredient. Inapreferredembodiment,theprocessofmixingthecholecalciferolwithMCTand30 theantioxidantiscarriedoutatacontrolledtemperature.Thetemperatureis preferablymaintainedbetween40°Cand60°C,morepreferablybetween45°Cand 55°C,morepreferablybetween47°Cand53°C,morepreferablybetween48°Cand 52°C,andmostpreferablyaround50°C. 35 Inanembodiment,forstirringinstepb),vacuumstirringisusedtopreventair exposure.Thevacuumconditionshelptoeliminateairbubblesandensureauniform mixture,whichiscriticalfortheconsistentqualityofthefinalproduct.Thevacuum 2025 / 5023 BE2025 / 5023 14 alsominimizestheriskofoxidativedegradation,ensuringthelongevityandpotency ofcholecalciferol.ThevacuumstirringispreferablyperformedatanRPMofbetween40and60,morepreferablybetween45and55,andmostpreferablystirringis performedatanRPMofabout50,andisfurtherpreferablyconductedunder conditionsthatmaintainalowoxygenenvironment,morepreferablylessthan1%5 oxygen,andmostpreferablyinacompletelyoxygen-freeenvironment.Inaddition, saidconditionstomaintainalowoxygenenvironmentpreferablyatavacuumofat leastabout600mm / Hgvacuum. Asusedherein,avacuumofatleast600mm / Hgreferstoapressurethatis60010 mmHgbelowatmosphericpressure(approximately760mmHgatsealevel).This correspondstoanabsolutepressureofapproximately160mmHg,whichis equivalenttoapressureof0.213barabsolute.Thus,avacuumof600mm / Hg effectivelyrepresentsasubstantialreductioninpressure,ensuringalowoxygen environmentsuitableforthedescribedprocesses.15 Inapreferredembodiment,themethodcomprisesusingadedicatedstainlesssteel vesselforthepre-mixingofcholecalciferolwithMCT,andstainlesssteelprocesstank formixingMCTandantioxidantsolutionandsubsequentcombiningwiththepremix-solution.Thisensuresahomogeneousblendoftheactiveandexcipientcomponents, contributingtoconsistentqualityanddosageineachcapsule.Thehomogeneityof20 themixtureiscrucialformaintainingthestabilityandpotencyoftheactive ingredient,therebyensuringitseffectivenessthroughoutitsshelflife. Theuseofdedicatedstainlesssteelvesselsandtanksforbothpre-mixingand processmixingoperationsispreferredtoavoidcross-contaminationandtoensure25 theintegrityoftheformulation.Thesevesselsaredesignedtofacilitateefficient mixingandtomaintainthedesiredtemperatureandvacuumconditionsthroughout theprocess.Thestainlesssteelmaterialispreferredduetoitsnon-reactivenature, whichpreventsanypotentialinteractionwiththeformulationcomponents. 30 Inanembodiment,stepsa)andb)maybeperformedinparallel.Inanother embodiment,stepsa)andb)areperformedpartlyinparallel.Inanother embodiment,firststepa)isperformedandthenstepb),orfirststepb)andthen stepa). 35 Asmentionedabove,methodstepc)relatestoencapsulatingthehomogenouspharmaceuticalcompositionofstepb)inasoftgelatinshellbasedonthematured gelatin-basedsolutionofstepa)usinganencapsulationmachine,preferablyrotary 2025 / 5023 BE2025 / 5023 15 dieencapsulationmachine,inacontrolledenvironment,preferablywitha temperaturebetween17°Cand25°Candrelativehumiditynothigherthan24%, therebyformingoneormoregelatincapsulescomprisingagelatinshellwithathe homogenouspharmaceuticalcompositiondisposedinthegelatinshell. 5 Methodstepd)relatestodryingthegelatincapsulesinacontrolledenvironment, preferablywithatemperaturebetween17°Cand25°Candrelativehumiditynot higherthan24%,untilacapsulehardnessofbetween7and14Nisobtained, therebyobtainingthesoftgelatincapsuledosageformformulatedfororal administration.10 Thecontrolledtemperatureandhumidityconditionsduringencapsulationanddrying arecrucialforminimizingdefectsandinconsistencies,therebyensuringuniform capsulequality.Specifically,theencapsulationprocessisconductedata temperaturerangeof17°Cto25°C,witharelativehumiditynotexceeding24%.15Preferably,theencapsulationtemperatureisbetween15°Cand30°C,more preferablybetween16°Cand28°C,morepreferablybetween17°Cand27°C,more preferablybetween17°Cand25°C,andmostpreferablybetween18°Cand23°C. Therelativehumidityispreferablykeptbelow30%,morepreferablybelow28%, morepreferablybelow26%,morepreferablybelow25%,andmostpreferablybelow20 24%.Thesecontrolledconditionsensurethatthecapsulesareformedcorrectlyand drieduniformly,whichisessentialforthestabilityandqualityofthefinalproduct. Inapreferredembodiment,thedryingprocessofthecapsulesinvolvesatwo-step procedure:initialdrying,forinstanceinatumbledryer,followedbyfurtherdrying25 indryingtunnels.Theairtemperatureduringbothstepsispreferablymaintained between17°Cand25°C,withrelativehumiditynotexceeding24%. Inanotherorfurtherpreferredembodiment,thehardnessofthedriedcapsulesis preferablybetween7and14N,morepreferablybetween7and12,morepreferably30 between8and10N,morepreferablybetween8.5and9.5N,andmostpreferablyaround9N.Thisensuresthatthecapsulesmaintaintheirstabilityandintegrity duringstorage,handling,anduse. Inanembodiment,thecholecalciferolispresentinthecapsuledosageforminan35 amountfromabout18.000IUtoabout27.500IU,preferablyinanamountofabout 18.000toabout22.000IUorinanamountofabout22.500IUtoabout27.500IU, mostpreferablyabout20.000IUorabout25.000IU. 2025 / 5023 BE2025 / 5023 16 Inanembodiment,thegelatin-basedsolutionofstepa)comprisesaoneormore colorants,therebyenhancingusercompliancebymakingthecapsuleseasily distinguishable.Theuseofcolorantsinthegelatin-basedsolutionsimplifiesthe sortingandpackagingprocessbyhelpingdifferentiatebetweendifferentproduct5 batchesorstrengths.Preferably,thecolorantsusedareabluecolorantsoratitanium dioxide-basedwhitecolorants,preferablywell-knownexcipients,whichincreases patienttrustandacceptanceofthemedication.Theinclusionofatitaniumdioxide- based,white,colorantmaypreferablyprovideenhancedstabilityofthecapsulesbyofferinglightprotection,therebyextendingtheireffectiveusageperiodandensuring10 patientsreceivethefulltherapeuticbenefitthroughouttheproduct'sshelflife.None- limitingexamplesofthecolorantsusedinthegelatinsolutionincludePatentBlueV (E131),titaniumdioxide(E171),andotherpharmaceuticallyacceptablecolorants. Inanembodiment,thefillamountforthecapsules,i.e.theamountof15 pharmaceuticalcompositionfilledinthesoftgelatinshellofthesoftgelatincapsule dosageform,iscontrolledtobewithintherangeof162mgto178mgforthe20,000 IUstrengthand190mgto210mgforthe25,000IUstrengthcapsules.More preferably,thefillamountforthe20,000IUstrengthisbetween165mgand175 mg,andforthe25,000IUstrength,itisbetween195mgand205mg.Most20 preferably,thefillamountforthe20,000IUstrengthisaround170mg,andforthe 25,000IUstrength,itisaround200mg.Controllingthefillamountensuresthe consistencyofthedosageunitsandthepropercontentoftheactiveingredient. Inanembodiment,cholecalciferolpresentinthesoftgelatincapsuledosageformis25preferablybetween0.5mgand0.7mg,morepreferablybetween0.54mgand0.69 mgpercapsule.Inanotherorfurtherembodiment,cholecalciferolpresentinthesoft gelatincapsuledosageformispreferablybetween0.20wt%and0.23wt%or between0.210wt%and0.230wt%. 30 Inanembodiment,theconcentrationofthecholecalciferolinthesoftgelatinshellis preferablybetween0.30wt%and0.36wt%,preferablybetween0.31wt%and0.35 wt%,preferablybetween0.32wt%and0.34wt%ofthetotalweightofthesoft gelatinshell. 35 Inanembodiment,gelatinpresentinthesoftgelatincapsuledosageformis preferablybetween50mgand80mg,morepreferablybetween55mgand75mg percapsule.Inanotherorfurtherembodiment,gelatinpresentinthesoftgelatin 2025 / 5023 BE2025 / 5023 17 capsuledosageformispreferablybetween20wt%and25wt%orbetween21wt% and24wt%. Inanembodiment,theconcentrationofthegelatininthesoftgelatinshellis preferablybetween60wt%and70wt%,preferablybetween62wt%and68wt%,5 preferablybetween65wt%and66wt%ofthetotalweightofthesoftgelatinshell.Inanembodiment,glycerolpresentinthesoftgelatincapsuledosageformis preferablybetween20mgand40mg,morepreferablybetween25mgand37mg percapsule.Inanotherorfurtherembodiment,glycerolpresentinthesoftgelatin10 capsuledosageformispreferablybetween9wt%and13wt%orbetween10wt% and12wt%. Inanembodiment,thesoftgelatinshellmayincludeplasticizers,suchasglycerol, toimproveitsflexibilityanddissolutionrate.Theconcentrationofplasticizersis15 preferablybetween20wt%and40wt%,morepreferablybetween25wt%and 35wt%,morepreferablybetween28wt%and33wt%,andmostpreferablybetween 32wt%to33wt%ofthetotalweightofthesoftgelatinshell. Inanembodiment,thesoftgelatincapsuledosageformoptionallyincludesablue20 colorantsuchasPatentBlueVforthe20,000IUstrengthcapsules,andtitanium dioxide-basedcolorantsuchastitaniumdioxideasacolorantforthe25,000IU strengthcapsules.Inanotherorfurtherembodiment,theconcentrationoftheblue colorantsuchasPatentBlueVispreferablybetween0.05and0.07mgpercapsule,preferablyabout0.06mgpercapsule,and / ortheconcentrationoftitaniumdioxide-25 basedwhitecolorantsuchastitaniumdioxideispreferablybetween0.70and0.90 mgpercapsule,preferablyabout0.8mgpercapsule. Inanembodiment,theconcentrationofthecolorantinthesoftgelatinshellis preferablybetween0.06wt%to0.08wt%forthebluecolorant,preferablybetween30 0.065wt%and0.075wt%,preferablybetween0.070wt%and0.072wt%ofthe totalweightofthesoftgelatinshell. Inanembodiment,theconcentrationofthecolorantinthesoftgelatinshellis preferablybetween0.6wt%to0.8wt%forthewhitecolorant,preferablybetween35 0.65wt%and0.75wt%,preferablybetween0.70wt%and0.75wt%ofthetotal weightofthesoftgelatinshell. 2025 / 5023 BE2025 / 5023 18 Inanembodiment,medium-chaintriglyceridespresentinthesoftgelatincapsule dosageformispreferablybetween140mgand200mgpercapsule,morepreferably between150mgand195mgpercapsule.Inanotherorfurtherembodiment,MCT presentinthesoftgelatincapsuledosageformispreferablybetween55wt%and 65wt%orbetween59wt%and63wt%.5Inanembodiment,theconcentrationofMCTinthepharmaceuticalcompositionis preferablybetween90wt%and95wt%,morepreferablybetween92wt%and94 wt%ofthetotalweightofthepharmaceuticalcomposition. 10 Inanembodiment,theantioxidant,preferablyall-rac-α-tocopherylacetatepresent inthesoftgelatincapsuledosageform,ispreferablybetween9mgand16mg,more preferablybetween10mgand15mgpercapsule.Inanotherorfurther embodiment,theantioxidantpresentinthesoftgelatincapsuledosageformis preferablybetween4wt%and5wt%orbetween4.1wt%and4.5wt%.15 Inanembodiment,theconcentrationoftheantioxidantispreferablybetween5 wt%and8wt%,morepreferablybetween6wt%and7wt%ofthetotalweightof thepharmaceuticalcomposition. 20 Inanembodiment,theinclusionofthisantioxidantispreferablyinanamountof between0.04%and0.06%,preferably0.05%(cholecalciferol / antioxidant;IU / IU), whichhasbeendeterminedtobeeffectiveinpreventingthedegradationof cholecalciferol.Thisensuresthattheactiveingredientretainsitstherapeuticefficacyovertime,providingconsistenttreatmentforvitaminDdeficiency.25 Inanembodiment,thesoftgelatincapsuledosageformsaredesignedwithdifferent shapesforvariousdosagestrengthstoenhancepatientidentificationandreducethe riskofincorrectdosageintake.Asanexample,the20,000IUdosagestrengthmay beprovidedinaroundcapsuleform,whilethe25,000IUdosagestrengthmaybe30 providedinanovalcapsuleform.Thisdifferentiationinshapeisintendedtoprovide aclearandimmediatevisualcuetopatients,caregivers,andhealthcare professionals,therebyminimizingthelikelihoodofdosageerrors. Preferably,asanexample,theroundshapelinkedtoonespecificdosemaybe35 selectedtoensureeaseofswallowingandtoofferadistinctcontrasttotheoval shapelinkedtoanotherspecificdose.Theovalshapemaybechosenforits ergonomicdesign,whichfacilitateshandlingandingestion.Thisdesignconsideration 2025 / 5023 BE2025 / 5023 19 isparticularlyadvantageousforpatientswithvisualimpairmentsorthosemanaging multiplemedications,asitallowsforquickandaccurateidentificationofthecorrect dosage.Inaddition,theuseofdifferentshapesforthecapsulesmayalsoservetoenhance5 compliancewithprescribedtreatmentregimens.Patientsaremorelikelytoadhere totheirmedicationscheduleswhentheycaneasilydistinguishbetweendifferent dosagestrengths,reducingtheriskofmissedorincorrectdoses.Thisaspectis particularlyimportantinthemanagementofconditionsrequiringprecisevitaminD supplementation,wheremaintainingappropriatelevelsofthevitaminiscrucialfor10 therapeuticefficacy. Furthermore,thedistinctshapesofthecapsulesmaybecomplementedbycolor differentiation,addinganadditionallayerofidentification.Forinstance,theround 20,000IUcapsulesmaybecoloredblue,whiletheoval25,000IUcapsulesmaybe15 white.Thiscombinationofshapeandcolordifferentiationprovidesarobustsystem forpreventingmedicationerrorsandenhancingpatientsafety. Overall,thepreferredembodimentofusingdifferentshapesforvariousdosage strengthsofferssignificantadvantagesintermsofpatientsafety,medication20adherence,andeaseofuse.Thesedesignfeaturesareintendedtosupportthe effectiveadministrationoftheactiveingredient,ensuringthatpatientsreceivethe correctdosageofcholecalciferolasprescribed. Inanembodiment,thesoftgelatincapsuledosageformsarepackagedinsingle-25 doseblisters.Thispackagingmethodpreferablyprovidesenhancedprotectionfrom environmentalfactorssuchasmoisture,light,andair,whichmayotherwise compromisetheintegrityandefficacyoftheproduct.Morepreferably,thesingle- doseblisterpackagingensuresthateachcapsuleremainsintactanduncontaminated untilthemomentofconsumption,therebymaintainingthestabilityandpotencyof30 theactiveingredient,cholecalciferol. Inanembodiment,theuseofsingle-doseblisterpackagingmayrelatetoimproving patientcompliancewiththetreatmentregimen.Byprovidingaconvenientandeasy- to-useformat,patientsaremorelikelytotakethecorrectdoseasprescribed.35 Preferably,thesingle-doseblistersareclearlylabeled,makingitstraightforwardforpatientstoidentifyandconsumetheappropriateamountofcholecalciferol.Thiscan 2025 / 5023 BE2025 / 5023 20 beparticularlybeneficialforindividualswhoaremanagingmultiplemedicationsor thosewhomayhavedifficultyrememberingtheirdosageschedule. Asnon-limitingexample,blistersmaybeAl / PVC / PVDCblisters.Al / PVC / PVDCblisters refertoaspecifictypeofblisterpackagingusedforpharmaceuticalproducts,5 comprisingaluminumfoil(Al),polyvinylchloride(PVC),andpolyvinylidenechloride (PVDC).Alprovidesastrongbarrieragainstmoisture,light,andoxygen,helpingto protecttheactiveingredientfromenvironmentalfactorsthatcancausedegradation. PVCisaplasticmaterialgenerallyusedtoformthecavityorpocketthatholdsthe capsuleortablet.PVDCisgenerallycoatedonthePVCtoenhanceitsbarrier10 properties,especiallyagainstmoistureandgases. Inapreferredembodiment,thepackagingofthecapsulesisdesignedtoprotect themfromlightandmoisture,whichcandegradetheactiveingredient.Thecapsules arepreferablypackedinAl / PVC / PVDCblisters,whicharethenplacedinacarton15alongwithapatientinformationleaflet.Thispackagingconfigurationcomplieswith regulatoryrequirementsandensuresthattheproductremainsstableandeffective throughoutitsshelflife. Inasecondaspect,thepresentinventionrelatestoasoftgelatincapsuledosage20 formformulatedfororaladministration,comprisingorconsistingessentiallyof: a)asoftgelatinshellcomprisinggelatin,glycerol,purifiedwater,andoptionally acolorant,and b)apharmaceuticalcompositiondisposedinthesoftgelatinshellcomprisingor consistingessentiallyof:25 i)anactiveingredientcholecalciferol, ii)mediumchaintriglycerides(MCT),and iii)anantioxidantwhichisanalpha-tocopheroloresterthereof, whereinthesoftgelatincapsuledosageformhasacapsulehardnessofbetween7 and14N.30 Apersonofordinaryskillintheartwillappreciatethatelementsoftheaspectofthe methodasdescribedabovereturnintheaspectofthesoftgelatincapsuledosage form,aswellasitsuseintreatmentoftheinvention.Consequently,allaspectsof thepresentinventionarerelated.Allfeaturesasdescribedinoneoftheaspects,as35describedaboveaswellasbelow,canrelatetoanyoftheseaspects,evenifthey aredescribedinconjunctionwithaspecificaspect. 2025 / 5023 BE2025 / 5023 21 Inanembodiment,thesoftgelatinshellispreparedasthegelatin-basedsolution describedinstepa)ofthemethodoftheinventionorinanyoftherelated embodimentsandsubsequentlydriedtoobtainahardnessofbetween7and14N. Inanotherorfurtherembodiment,thepharmaceuticalcompositionispreparedasin stepb)ofthemethodoftheinventionorinanyoftherelatedembodiments.Ina5 particularlypreferredembodiment,thesoftgelatincapsuledosageformisprepared accordingtothemethodoftheinvention,asdescribedinanyoneofthe embodiments. Thegelatinshellsoftgelatincapsuledosageformformulatedfororaladministration10 oftheinventioncomprisesgelatin,glycerol,water,andoptionallyacolorant.Gelatin isasuitablemediumfortheencapsulationofthepharmaceuticalcompositionandis selectedforitsgellingproperties,whichareessentialforformingthesoftcapsule. Glycerolactsasaplasticizer,providingflexibilitytothecapsuleshell,andhelpsretainmoistureinthegelatinshell,whichiscrucialformaintainingthedesired15 textureandconsistency,enhancingtheoverallstabilityandshelflifeofthecapsules. Purifiedwaterisusedtoensuretheappropriateconsistencyandviscosityofthe gelatinmass.Characteristics,examples,andadvantagesofgelatin,glycerol,purified water,andoptionalcolorantareasdescribedaboveinanyoneoftheembodiments. 20 Thehardnessofthesoftgelatincapsuledosageformispreferablybetween7and14 N,morepreferablybetween7and12,morepreferablybetween8and10N,more preferablybetween8.5and9.5N,andmostpreferablyaround9N.Thisensures thatthecapsulesmaintaintheirstabilityandintegrityduringstorage,handling,and use.25 Thesoftgelatincapsulepreferablycomprisesagelatinshellthatisformulatedto dissolvequicklyinthegastrointestinaltract.Thedissolutionpropertiesofthegelatin shellarepreferablyenhancedbyoptimizingitscompositionandmanufacturing process.30 Inapreferredembodiment,thesoftgelatincapsuledosageformisdesignedorformulatedtograduallydissolveafteringestion / oraladministration,andpreferably fullydissolvewithin30minutesafteringestion / oraladministration.Thisensures rapidreleaseandabsorptionofcholecalciferol,leadingtofastertherapeuticeffects.35 Thedissolutiontimeispreferablywithin30minutes,morepreferablywithin25 minutes,morepreferablywithin20minutes,morepreferablywithin15minutes,and mostpreferablywithin10minutes.Byfullydissolvingwithinthesetimeframes,the 2025 / 5023 BE2025 / 5023 22 softgelatincapsuleensuresquickandenhancedbioavailabilityofthecholecalciferol, providingreliabletherapeuticbenefits. Inanembodiment,thesoftgelatinshellcomprisesacolorant.Thecolorantmaybe anycolorantasknownintheart,andmayforinstancebeasdescribedabovein5 relationtothemethod.Inparticular,thecolorantmaybeabluecolorantsuchas PatentBlueV,atitaniumdioxide-basedwhitecolorantsuchastitaniumdioxide,or anyotherpharmaceuticallyacceptablecolorants. Thepharmaceuticalcompositiondisposedinthesoftgelatinshellcomprises10cholecalciferol,MCT,andanantioxidant. Inanembodiment,thecholecalciferolispresentinthecapsuledosageform,inthe pharmaceuticalcomposition,inanamountfromabout18.000IUtoabout27.500 IU,preferablyinanamountofabout18.000toabout22.000IUorinanamountof15 about22.500IUtoabout27.500IU,mostpreferablyabout20.000IUorabout 25.000IU. Thepharmaceuticalcompositionispreferablyformulatedtoincludeanoverage, preferablyovertheamountsasdescribedabove,preferablyofatleast5wt%,more20 preferablyofatleast10wt%,ofcholecalciferoltoensuresufficientlevelsofthe activesubstancearemaintainedthroughoutitsshelflife.Thisoverageispreferably determinedbasedonstabilitystudiesandexperimentaldata,whichindicatethat suchanoverageisdesirabletocompensateforthedegradationofcholecalciferol overtime.Thispreferredembodimentensuresthatthecapsulesmaintain25 appropriatelevelsofcholecalciferolthroughouttheirshelflives,therebyproviding effectivetreatmentandpreventionofvitaminDdeficiency.Preferably,theMCTserveasthesolventforthecholecalciferol,enhancingtheactive ingredient’sstabilityandbioavailability.TheuseofMCTasmatrixispreferreddue30 toitsexcellentsolventpropertiesandabilitytoenhancetheabsorptionoffat-soluble vitaminslikecholecalciferol.Inanembodiment,alpha-tocopheroloranesterof alpha-tocopherolisusedasantioxidant,andpreferablyall-rac-α-tocopherylacetate actsasanantioxidanttopreventthedegradationofcholecalciferol. 35 Inamostpreferredembodiment,thesoftgelatincapsuledosageformcomprises thefollowingcomponentsinthefollowingamounts(inmg / capsule);preferably±15 wt%,preferably±14wt%,preferably±13wt%,preferably±12wt%,preferably 2025 / 5023 BE2025 / 5023 23 ±11wt%,preferably±10wt%,preferably±9wt%,preferably±8wt%,preferably ±7wt%,preferably±6wt%,preferably±5wt%,preferably±4wt%,preferably ±3wt%,preferably±2wt%,andmostpreferably±1wt%rangesareapplicable tooneormoreofthedifferentcomponents,preferablytoeachofthecomponents. 5 ComponentQuantity(mg / softcapsule)Function 20,000IU25,000IUPharmaceuticalcomposition Cholecalciferol*0.5500.688Activeingredient Triglycerides,medium-chain158.450185.562Solvent All-rac-α-tocopherylacetate11.00013.750Antioxidant Softgelatinshell: Gelatin56.0072.00Gellingagent Glycerol27.0035.00Plasticizer PatentBlueV(E131)0.06-Colorant Titaniumdioxide(E171)-0.80Colorant Water,purified1.942.20Solvent Theoreticalmasstotal255.0310.0- Overages*:20,000IU25,000IU Cholecalciferol10%10% Inanembodiment,thesoftgelatincapsuledosageformcomprisesthefollowing componentsinthefollowingamounts(wt%tototalcapsulemass);preferably±15 wt%,preferably±14wt%,preferably±13wt%,preferably±12wt%,preferably ±11wt%,preferably±10wt%,preferably±9wt%,preferably±8wt%,preferably10 ±7wt%,preferably±6wt%,preferably±5wt%,preferably±4wt%,preferably ±3wt%,preferably±2wt%,andmostpreferably±1wt%rangesareapplicable tooneormoreofthedifferentcomponents,preferablytoeachofthecomponents. PercentageofEachComponentBasedonTotalTheoreticalMass:15 ComponentQuantity(mg); totalmass= 225.0mg 20,000IUwt%ofTotal Mass Quantity(mg); totalmass= 310.0mg 25,000IU wt%ofTotal Mass PharmaceuticalComposition Cholecalciferol0.5500.2160.6880.222 Triglycerides, medium-chain 158.45062.137185.56259.860 2025 / 5023 BE2025 / 5023 24 All-rac-α- tocopheryl acetate 11.0004.31413.7504.435 SoftGelatinShell Gelatin56.0021.96172.0023.226 Glycerol27.0010.58835.0011.290 PatentBlueV (E131) 0.060.024-- Titanium dioxide (E171) 0.80-0.800.258 Water, purified 1.940.7612.200.710 TheoreticalMassTotal100100 Inanembodiment,thesoftgelatincapsuledosageformcomprisesthefollowing componentsinthefollowingamounts(wt%topharmaceuticalcompositionmassor tosoftgelatinshellmass);preferably±15wt%,preferably±14wt%,preferably±5 13wt%,preferably±12wt%,preferably±11wt%,preferably±10wt%, preferably±9wt%,preferably±8wt%,preferably±7wt%,preferably±6wt%, preferably±5wt%,preferably±4wt%,preferably±3wt%,preferably±2wt%, andmostpreferably±1wt%rangesareapplicabletooneormoreofthedifferent components,preferablytoeachofthecomponents.10PercentageofEachComponentWithinItsRespectiveSection(compositionorshell): ComponentQuantity(mg)20,000IU wt%Section Quantity(mg)25,000IU wt%Section PharmaceuticalComposition Total Pharmaceutical Composition 170.000mg100200.000mg100 Cholecalciferol0.5500.3240.6880.344 Triglycerides, medium-chain 158.45093.206185.56292.781 All-rac-α- tocopheryl acetate 11.0006.47113.7506.875 2025 / 5023 BE2025 / 5023 25 SoftGelatinShell TotalSoft GelatinShell 85.000mg100110.000mg100 Gelatin56.0065.88272.0065.455 Glycerol27.0031.76535.0031.818 PatentBlueV (E131) 0.060.071-- Titaniumdioxide (E171) 0.80-0.800.727 Water,purified1.942.2822.202.000 Inanembodiment,thefillamountforthecapsules,i.e.theamountof pharmaceuticalcompositionfilledinthesoftgelatinshellofthesoftgelatincapsule dosageform,iscontrolledtobewithintherangeof162mgto178mgforthe20,000 IUstrengthand190mgto210mgforthe25,000IUstrength.Morepreferably,the5 fillamountforthe20,000IUstrengthisbetween165mgand175mg,andforthe25,000IUstrength,itisbetween195mgand205mg.Mostpreferably,thefill amountforthe20,000IUstrengthisaround170mg,andforthe25,000IUstrength, itisaround200mg.Controllingthefillamountensurestheconsistencyofthedosage unitsandthepropercontentoftheactiveingredient.10 Inanembodiment,cholecalciferolpresentinthesoftgelatincapsuledosageformis preferablybetween0.5mgand0.7mg,morepreferablybetween0.54mgand0.69 mgpercapsule.Inanotherorfurtherembodiment,cholecalciferolpresentinthesoft gelatincapsuledosageformispreferablybetween0.20wt%and0.23wt%or15 between0.210wt%and0.230wt%. Inanembodiment,theconcentrationofthecholecalciferolinthesoftgelatinshellis preferablybetween0.30wt%and0.36wt%,preferablybetween0.31wt%and0.35 wt%,preferablybetween0.32wt%and0.34wt%ofthetotalweightofthesoft20 gelatinshell. Inanembodiment,gelatinpresentinthesoftgelatincapsuledosageformis preferablybetween50mgand80mg,morepreferablybetween55mgand75mg percapsule.Inanotherorfurtherembodiment,gelatinpresentinthesoftgelatin25capsuledosageformispreferablybetween20wt%and25wt%orbetween21wt% and24wt%. 2025 / 5023 BE2025 / 5023 26 Inanembodiment,theconcentrationofthegelatininthesoftgelatinshellis preferablybetween60wt%and70wt%,preferablybetween62wt%and68wt%, preferablybetween65wt%and66wt%ofthetotalweightofthesoftgelatinshell. Inanembodiment,glycerolpresentinthesoftgelatincapsuledosageformis5 preferablybetween20mgand40mg,morepreferablybetween25mgand37mg percapsule.Inanotherorfurtherembodiment,glycerolpresentinthesoftgelatin capsuledosageformispreferablybetween9wt%and13wt%orbetween10wt% and12wt%. 10 Inanembodiment,thesoftgelatinshellmayincludeplasticizers,suchasglycerol, toimproveitsflexibilityanddissolutionrate.Theconcentrationofplasticizersis preferablybetween20wt%and40wt%,morepreferablybetween25wt%and 35wt%,morepreferablybetween28wt%and33wt%,andmostpreferablybetween 32wt%to33wt%ofthetotalweightofthesoftgelatinshell.15 Inanembodiment,thesoftgelatincapsuledosageformoptionallyincludesabluecolorantsuchasPatentBlueVforthe20,000IUstrengthcapsules,andtitanium dioxide-basedcolorantsuchastitaniumdioxideasacolorantforthe25,000IU strengthcapsules.Inanotherorfurtherembodiment,theconcentrationoftheblue20 colorantsuchasPatentBlueVispreferablybetween0.05and0.07mgpercapsule, preferablyabout0.06mgpercapsule,and / ortheconcentrationoftitaniumdioxide- basedwhitecolorantsuchastitaniumdioxideispreferablybetween0.70and0.90 mgpercapsule,preferablyabout0.8mgpercapsule. 25 Inanembodiment,theconcentrationofthecolorantinthesoftgelatinshellis preferablybetween0.06wt%to0.08wt%forthebluecolorant,preferablybetween 0.065wt%and0.075wt%,preferablybetween0.070wt%and0.072wt%ofthe totalweightofthesoftgelatinshell. 30 Inanembodiment,theconcentrationofthecolorantinthesoftgelatinshellis preferablybetween0.6wt%to0.8wt%forthewhitecolorant,preferablybetween 0.65wt%and0.75wt%,preferablybetween0.70wt%and0.75wt%ofthetotal weightofthesoftgelatinshell. 35Inanembodiment,medium-chaintriglyceridespresentinthesoftgelatincapsule dosageformispreferablybetween140mgand200mgpercapsule,morepreferably between150mgand195mgpercapsule.Inanotherorfurtherembodiment,MCT 2025 / 5023 BE2025 / 5023 27 presentinthesoftgelatincapsuledosageformispreferablybetween55wt%and 65wt%orbetween59wt%and63wt%. Inanembodiment,theconcentrationofMCTinthepharmaceuticalcompositionis preferablybetween90wt%and95wt%,morepreferablybetween92wt%and945 wt%ofthetotalweightofthepharmaceuticalcomposition. Inanembodiment,theantioxidant,preferablyall-rac-α-tocopherylacetatepresent inthesoftgelatincapsuledosageform,ispreferablybetween9mgand16mg,more preferablybetween10mgand15mgpercapsule.Inanotherorfurther10 embodiment,theantioxidantpresentinthesoftgelatincapsuledosageformis preferablybetween4wt%and5wt%orbetween4.1wt%and4.5wt%. Inanembodiment,theconcentrationoftheantioxidantispreferablybetween5wt% and8wt%,morepreferablybetween6wt%and7wt%ofthetotalweightofthe15 pharmaceuticalcomposition.Inanembodiment,theinclusionofthisantioxidantispreferablyinanamountof between0.04%and0.06%,preferablyabout0.05%(cholecalciferol / antioxidant; IU / IU),whichhasbeendeterminedtobeeffectiveinpreventingthedegradationof20 cholecalciferol.Thisensuresthattheactiveingredientretainsitstherapeuticefficacy overtime,providingconsistenttreatmentforvitaminDdeficiency. itwillbecleartoaskilledpersonthatthepercentagesofthevariouscomponentsof thesoftgelatincapsuledosageform,ofthepharmaceuticalcomposition,orofthe25 softgelatinshell,togethermayneverexceed100wt%ofthesoftgelatincapsule dosageform,ofthepharmaceuticalcomposition,orofthesoftgelatinshell respectively. Inafurtheraspect,thepresentinventionalsorelatestothesoftgelatincapsule30 dosageform,asdescribedaboveinanyoneoftheembodiments,foruseinthe treatmentdiseasesand / orconditionslinkedtocholecalciferoldeficiencyor insufficiency. Non-limitingexamplesofsaiddiseasesand / orconditionsareosteoporosis,rickets,35osteomalacia,hypocalcemia,secondaryhyperparathyroidism,chronickidney disease,cardiovasculardisease,diabetes,autoimmunediseasessuchasmultiple sclerosisandrheumatoidarthritis,infectionssuchasinfectionsduetoimpaired 2025 / 5023 BE2025 / 5023 28 immunefunction,muscleweaknessandpain,seasonalaffectivedisorder(SAD), cancerssuchascolorectal,breast,andprostatecancer,metabolicsyndrome, hypertension,asthma,anddepression. Inanembodiment,thesoftgelatincapsuledosageformisadministeredtoahuman5 patient. Inanembodiment,thesoftgelatincapsuledosageformisadministeredorallytoa patient,orisadministeredthroughoraladministration,orisadministeredperos. 10 Inanotherorfurtherembodiment,thesoftgelatinshellgraduallydissolvesor disintegratesafteroraladministration,andpreferablyfullydissolvesordisintegrates notlongerthan30minutesafteroraladministration.Thisensuresrapidreleaseand absorptionofcholecalciferol,leadingtofastertherapeuticeffects.Thedissolutiontimeispreferablywithin30minutes,morepreferablywithin25minutes,more15 preferablywithin20minutes,morepreferablywithin15minutes,andmost preferablywithin10minutes.Byfullydissolvingwithinthesetimeframes,thesoft gelatincapsuleensuresquickandenhancedbioavailabilityofthecholecalciferol, providingreliabletherapeuticbenefits. 20 Inanembodiment,adailydoseofabout18.000IUtoabout27.500IU,preferably about18.000toabout22.000IUorabout22.500IUtoabout27.500IU,most preferablyabout20.000IUorabout25.000IUisadministeredtoapatient. Inanembodiment,atherapeuticallyeffectiveamountisadministeredtoapatient,25 whereinthetherapeuticallyeffectiveamountissufficienttoincreasethepatient’s totalbloodserumcholecalciferolleveltoatleast50nmol / L. Itwillbecleartoaskilledpersonthatthepresentinventionalsorelatestoamethod fortreatingadiseaseand / orconditionlinkedtocholecalciferoldeficiencyor30 insufficiencyinahumanpatient,comprisingorallyadministeringthesoftgelatin capsuledosageform,asdescribedinanyonetheembodimentsabove,tothepatient;andtoatheuseofthesoftgelatincapsuledosageformforthemanufacture orpreparationofamedicamentforthetreatmentofadiseaseand / orconditionlinked tocholecalciferoldeficiencyorinsufficiencyinahumanpatient.35 Thepresentinventionwillbenowdescribedinmoredetails,referringtoexamples thatarenotlimitative. 2025 / 5023 BE2025 / 5023 29 EXAMPLES Thepresentinventionwillnowbefurtherexemplifiedwithreferencetothefollowing examples.Thepresentinventionisinnowaylimitedtothegivenexamplesortothe embodimentspresentedinthefigures.5 Example1.ManufacturingProcessforCholecalciferolSoftCapsules Thefollowingexamplesprovidesonepossible,non-limiting,embodimentofthe methodaccordingtothepresentinvention.Amountsusedarepreferablyas describedinthetablesbelow.10 ComponentQuantity(mg / softcapsule)Function 20,000IU25,000IU Pharmaceuticalcomposition Cholecalciferol*0.5500.688Activeingredient Triglycerides,medium-chain158.450185.562Solvent All-rac-α-tocopherylacetate11.00013.750Antioxidant Softgelatinshell:Gelatin56.0072.00Gellingagent Glycerol27.0035.00Plasticizer PatentBlueV(E131)0.06-Colorant Titaniumdioxide(E171)-0.80Colorant Water,purified1.942.20Solvent Theoreticalmasstotal255.0310.0- Overages*:20,000IU25,000IU Cholecalciferol10%10% PercentageofEachComponentBasedonTotalTheoreticalMass: ComponentQuantity (mg);total mass=225.0 mg 20,000IU wt%ofTotal Mass Quantity (mg);total mass=310.0 mg 25,000IU wt%ofTotal Mass PharmaceuticalComposition Cholecalciferol0.5500.2160.6880.222 Triglycerides, medium-chain 158.45062.137185.56259.860 All-rac-α- tocopheryl acetate 11.0004.31413.7504.435 SoftGelatinShell Gelatin56.0021.96172.0023.226 Glycerol27.0010.58835.0011.290 2025 / 5023 BE2025 / 5023 30 PatentBlueV (E131) 0.060.024-- Titanium dioxide (E171) 0.80-0.800.258 Water, purified 1.940.7612.200.710 TheoreticalMassTotal100100 PercentageofEachComponentWithinItsRespectiveSection(compositionorshell): ComponentQuantity(mg)20,000IU wt%Section Quantity(mg)25,000IU wt%Section PharmaceuticalComposition TotalPharmaceutical Composition 170.000mg100200.000mg100 Cholecalciferol0.5500.3240.6880.344 Triglycerides, medium-chain 158.45093.206185.56292.781 All-rac-α- tocopheryl acetate 11.0006.47113.7506.875 SoftGelatinShell TotalSoft GelatinShell 85.000mg100110.000mg100 Gelatin56.0065.88272.0065.455 Glycerol27.0031.76535.0031.818 PatentBlueV (E131) 0.060.071-- Titaniumdioxide (E171) 0.80-0.800.727 Water,purified1.942.2822.202.000 SeealsoCriticalprocessparametersandprocessstepstobefollowedbelowin Example3.5 1.Preparationofthecapsulefillsolution(=pharmaceuticalcomposition) Cholecalciferol,all-rac-α-tocopherylacetate,andmedium-chaintriglycerides(MCT) aredispensedaccordingtothetechnologicalformula.AportionoftheMCTisset asideforpreparingthedrugsubstancepre-mixtureandplacedinastainlesssteel10 vessel.Cholecalciferolisaddedtothevessel,andbothingredientsaremixedby stirringforatleast20minutesuntilaclearsolutionisobtained.TheremainingdispensedMCTistransferredtotheprocesstank,whereall-rac-α-tocopherylacetate isaddedandmixedwiththeMCTundervacuumwhileheatingtoatemperatureof 48°C–52°C.Oncethespecifiedtemperatureisreached,mixingcontinuesfora15 minimumof15minutes.Themixtureisthencooled,andthepre-mixtureof 2025 / 5023 BE2025 / 5023 31 cholecalciferolisaddedtotheprocesstank.Thesolutionisstirredundervacuumfor atleast30minutesandthentransferredtoastoragetank. 2.Preparationofthegelatinemass(=softgelatinshell) Purifiedwaterismixedwithglycerolandheatedinaprocesstank.Apre-mixtureof5 therelevantcolorantisprepared(e.g.,PatentBlueVinwaterfor20,000IUstrength ortitaniumdioxideinglycerolfor25,000IUstrength)andaddedtotheprocesstank. Attheappropriatetemperature,gelatineisaddedundervacuum.Theingredients arestirredundervacuumuntilthegelatinemassisuniform,freeofairbubbles,and hastheappropriateviscosity(10.0–12.0Pa∙s),measuredat58-62°C.Thegelatine10 massisthenmaturedfor3hoursatatemperaturebetween58°C–62°C. 3.EncapsulationThepreparedfillsolutionisencapsulatedusingarotarydieencapsulationmachine. Theprocessroomtemperatureismaintainedbetween17°C–25°C,witharelative15 humiditynotexceeding24%.Duringencapsulation,thecapsulefillamountis controlledandadjustedtoremainwithinthespecifiedrange(20,000IUstrength: 162mg–178mg;25,000IUstrength:190mg–210mg). 4.Capsulesdrying20 Capsulesarefirstdriedinatumbledryer.Thepartiallydriedcapsulesarethen spreadondryingtrays,andthedryingprocesscontinuesindryingtunnels.During bothdryingsteps,theairtemperatureismaintainedbetween17°C–25°C,andthe relativehumiditydoesnotexceed24%.Thedryingprocessisconsideredcomplete whenthecapsules'hardnessfallswithinthespecifiedrange(7-14N,preferably8–25 10N). 5.Capsulessorting Thedriedcapsulesundergovisualinspectionandsortingusingasortingmachine, wheredefectivecapsules(e.g.,emptycapsulesorthosewithairbubbles)are30 rejected.Ifnecessary,thecapsulescanbepolishedinatumblepolishingmachine. 6.CapsulespackagingThecholecalciferolsoftcapsulesarepackedinAl / PVC / PVDCblisters.Theseblisters, alongwithapatientinformationleaflet,areplacedincartonswithimprintedlabel35 text.Ifrequired,capsulesmaybestoredforupto6monthsundercontrolledroom temperature(17°C–25°C)inapolyethylenebaginsideacontainerbeforebeing packedinblisters. 2025 / 5023 BE2025 / 5023 32 Example2:Formulationdevelopment 1.Formulationtest1–nooveragesofcholecalciferol–noantioxidant Thefollowingcompositionwasusedforafirstformulationtest,preparedinlinewith theabovedescribedmethod.NooveragesofCholecalciferolwereappliedinthis5 productionprocess.Noantioxidantwasused,Ponceau4Rwasusedascolorant. ComponentQuantity(mg / softcapsule)Function 20,000IU Pharmaceuticalcomposition Cholecalciferol*0.500Active ingredient Triglycerides,medium-chain169.500Solvent Softgelatinshell: Gelatin56.00Gellingagent Glycerol27.00Plasticizer Ponceau4R(E124)0.175Colorant Water,purified1.825Solvent Theoreticalmasstotal255.0- Overages*:20,000IU Cholecalciferol0%Stabilitystudieswereconductedasfollows: Allbatcheswereplacedonstabilityatthelongterm,intermediateandaccelerated10 storageconditions,asfollows:25°C±2°C / 60±5%relativehumidity(RH),30°C± 2°C / 65±5%RH,and40°C±2°C / 75±5%RH;testedforthreedifferentbatches. Detailsofthebatchesmanufactured,andresultsofanalysisarepresentedinthe tablesbelow,whereND=notdetected. 15 Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:25°C±2°C / 60±5%RH Specification03 months 6months9months Appearance: Transparent,red,round,soft capsuleswithaseaminthemiddle, filledwithlightyellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 170.0mg167.1mg169.3mg171.9mg 2025 / 5023 BE2025 / 5023 33 Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis <(1−L2x0.01)Mor>(1+L2x 0.01)M L1=15.0,L2=25.0 complies (AV=3.2) complies (AV=1.3) complies (AV=5.4) complies (AV= 12.5) Disintegrationtime:Notlongerthan30min. 06’12”05’27”03’47”04’30” Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 497.9µg (99.6%) 495.7µg (99.1%) 474.5µg (94.9%) 441.1µg (88.2%) Relatedsubstances: -Trans-cholecalciferol(impurityA): NMT1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% ND ND ND 0.21% ND 0.21% 0.33% ND 0.33% <0.52% ND <0.52% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --- Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:30°C±2°C / 65±5%RH Specification03months6months Appearance: Transparent,red,round,softcapsules withaseaminthemiddle,filledwith lightyellowviscousliquid. compliescompliescomplies Averagefillingmass: 153mg–187mg 170.0mg166.8mg170.2mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis <(1−L2x0.01)Mor>(1+L2x0.01)M L1=15.0,L2=25.0 complies(AV =3.2) complies(AV =3.0)complies(AV =13.4) Disintegrationtime: Notlongerthan30min. 06’12”05’30”04’31” Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 497.9µg (99.6%) 486.2µg (97.2%) 427.8µg (85.6%) Relatedsubstances: -Trans-cholecalciferol(impurityA): NMT1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% ND ND ND 0.34% ND 0.34% 0.56% ND 0.56% Microbialcontamination:TAMC notmorethan103cfu / gTYMCnot<10cfu / g-- 2025 / 5023 BE2025 / 5023 34 morethan102cfu / gAbsenceof Escherichiacoliin1g <10cfu / g absent Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:40°C±2°C / 75±5%RH Specification01month3months6months Appearance: Transparent,red,round,softcapsules withaseaminthemiddle,filledwithlight yellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 170.0mg170.2mg175.0mg173.6mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis <(1−L2x0.01)Mor>(1+L2x 0.01)ML1=15.0,L2=25.0 complies (AV= 3.2) complies (AV= 2.3) complies (AV= 4.3) complies (AV= 14.2) Disintegrationtime: Notlongerthan30min. 06’12”04’00”04’20”03’38” Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 497.9µg (99.6%) 487.5µg (97.5%) 476.6µg (95.3%) 422.8µg (84.6%) Relatedsubstances: -Trans-cholecalciferol(impurityA):NMT 1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% ND ND ND 0.30% ND 0.30% 0.53% ND 0.53% 0.46% ND 0.46% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --<10cfu / g <10cfu / g absent Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:25°C±2°C / 60±5%RH Specification03 month s 6 months 9 months 12 months 18 months Appearance: Transparent,red,round,soft capsuleswithaseaminthe middle,filledwith lightyellowviscousliquid. compliescompliescompliescomplie s compliescomplies Averagefillingmass: 153mg–187mg 171.1mg169.0mg170.6mg172.6mg172.8mg171.6mg2025 / 5023 BE2025 / 5023 35 Uniformityofdosageunits bymassvariation: AV(10softcapsules)≤L1 IfAV>L1→AV(30soft capsules)≤L1andno individualcontentofthe dosageunitis <(1−L2x0.01)Mor>(1+ L2x0.01)M L1=15.0,L2=25.0 complie s(AV= 1.3) complie s(AV= 1.4) complies (AV = 1.9) complie s(AV= 7.6) complies (AV= 7.3) doesnot comply (AV= 24.0) Disintegrationtime: Notlongerthan30min. 06’50”05’49”04’47”05’11”04’32”04’32” Assayofcholecalciferolina capsule: 450.0–550.0µg(90%– 110%) 507.9µg (101.6%) 502.9µg (100.6%) 492.7µg (98.5%) 470.5µg (94.1%) 467.6µg (93.5%) 379.2µg (75.8%) Relatedsubstances: -Trans-cholecalciferol (impurityA):NMT 1.0% -Anyunknownimpurity:NMT 1.0% -Totalimpurities:NMT2.0% ND ND ND 0.17% ND 0.17% 0.19% ND 0.19% 0.32% ND 0.32% 0.39% ND 0.39% 0.52% ND 0.52% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1 g <10 cfu / g <10 cfu / g absent ----- Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:30°C±2°C / 65±5%RHSpecification03 months 6months9months Appearance: Transparent,red,round,softcapsules withaseaminthemiddle,filledwith lightyellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 171.1mg168.4mg170.4mg174.2mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthe dosageunitis <(1−L2x0.01)Mor>(1+L2x 0.01)M L1=15.0,L2=25.0 complies (AV=1.3) complies (AV=2.0) complies (AV=5.2) complies (AV= 13.5) Disintegrationtime: Notlongerthan30min. 06’50”05’14”05’43”04’05” 2025 / 5023 BE2025 / 5023 36 Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 507.9µg (101.6%) 492.4µg (98.5%) 479.6µg (95.9%) 438.4µg (87.7%) Relatedsubstances: -Trans-cholecalciferol(impurity A):NMT1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% ND ND ND 0.22% ND 0.22% 0.35% ND 0.35% 0.53% ND 0.53% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent--- Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:40°C±2°C / 75±5%RH Specification01month3months6months Appearance: Transparent,red,round,softcapsuleswith aseaminthemiddle,filledwithlight yellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 171.1mg170.7mg171.7mg173.8mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis <(1−L2x0.01)Mor>(1+L2x0.01)M L1=15.0,L2=25.0 complie s(AV= 1.3) complie s(AV= 1.7) complie s(AV= 3.2) compli es(AV =6.4) Disintegrationtime: Notlongerthan30min. 06’50”04’30”04’31”04’25” Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 507.9µg (101.6%) 500.4µg (100.1%) 481.9µg (96.4%) 470.8µg (94.2%) Relatedsubstances: -Trans-cholecalciferol(impurityA):NMT 1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% ND ND ND 0.19% ND 0.19% 0.43% ND 0.43% 0.37% ND 0.37% Microbialcontamination: TAMCnotmorethan103cfu / gTYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --<10cfu / g <10 cfu / g absent 2025 / 5023 BE2025 / 5023 37 Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:25°C±2°C / 60±5%RH Specification03 month s 6 months 9 months 12 months 18 months Appearance: Transparent,red,round,soft capsuleswithaseaminthe middle,filledwith lightyellowviscousliquid. compliescompliescompliescomplie s compliescomplies Averagefillingmass: 153mg–187mg 171.9mg168.6mg171.4mg173.4mg173.8mg172.0mg Uniformityofdosageunits bymassvariation: AV(10softcapsules)≤L1 IfAV>L1→AV(30soft capsules)≤L1andno individualcontentofthe dosageunitis <(1−L2x0.01)Mor>(1+ L2x0.01)M L1=15.0,L2=25.0 complies (AV= 1.9) complies (AV= 2.8) complies (AV= 1.9) complies (AV= 6.5) complies (AV= 8.9) doesnot comply (AV= 28.2) Disintegrationtime: Notlongerthan30min. 06’15”05’16”05’19”04’39”04’40”04’41” Assayofcholecalciferolina capsule: 450.0–550.0µg(90%– 110%) 503.8µg (100.8%) 499.3µg (99.9%)494.9µg (99.0%) 471.0µg (94.2%) 461.8µg (92.4%) 359.2 µg (71.8%) Relatedsubstances: -Trans-cholecalciferol (impurityA):NMT1.0% -Anyunknownimpurity:NMT 1.0% -Totalimpurities:NMT2.0% ND ND ND 0.13% ND 0.13% 0.20% ND 0.20% < 0.33% ND < 0.33% <0.40% ND <0.40% <0.50% ND <0.50% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1 g <10 cfu / g <10 cfu / g absent ----- Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:30°C±2°C / 65±5%RH Specification03 months 6months9months Appearance: Transparent,red,round,softcapsules withaseaminthemiddle,filledwith lightyellowviscousliquid. compliescompliescompliescomplies 2025 / 5023 BE2025 / 5023 38 Averagefillingmass: 153mg–187mg 171.9mg169.1mg172.8mg175.3mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis <(1−L2x0.01)Mor>(1+L2x 0.01)M L1=15.0,L2=25.0 complies (AV=1.9) complies (AV=1.8) complies(AV=5.7) complies (AV=12.0) Disintegrationtime: Notlongerthan30min. 06’15”05’31”04’37”04’18” Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 503.8µg (100.8%) 492.8µg (98.6%) 473.0µg (94.6%) 435.0µg (87.0%) Relatedsubstances: -Trans-cholecalciferol(impurityA): NMT1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% ND ND ND 0.23% ND 0.23% 0.38% ND 0.38% 0.56% ND 0.56% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --- Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:40°C±2°C / 75±5%RH Specification01month3months6months Appearance: Transparent,red,round,softcapsuleswith aseaminthemiddle,filledwithlight yellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 171.9mg172.5mg175.8mg172.7mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis<(1−L2x0.01)Mor>(1+L2x0.01)M L1=15.0,L2=25.0 complies (AV=1.9) complies (AV= 5.3) complies (AV= 4.6) complies (AV=6.7) Disintegrationtime: Notlongerthan30min. 06’15”04’15”04’32”03’31” Assayofcholecalciferolinacapsule: 450.0–550.0µg(90%–110%) 503.8µg (100.8%) 503.0µg (100.6%) 481.2µg (96.2%) 468.6µg (93.7%) Relatedsubstances: -Trans-cholecalciferol(impurityA):NMT 1.0% -Anyunknownimpurity:NMT1.0% ND ND ND 0.19% ND 0.19% 0.39% ND 0.39% 0.38% ND 0.38% 2025 / 5023 BE2025 / 5023 39 -Totalimpurities:NMT2.0% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --<10cfu / g <10cfu / g absent Concluding,regardingFormulationtest1(nooveragesofcholecalciferol–no antioxidant): Theresultsoftheanalysisperformedatreleasewerewithintheproposed acceptancecriteria.However,duringthecourseofthestabilitystudiessignificant5 dropinthecholecalciferolcontentwasreported.Incaseoffirstbatchoutofspecificationresultswerealreadyobtainedafter6monthsstorage,whileforother twoafter9monthsstorageatintermediateconditionsand18monthsstorageat long-termconditions.Basedontherateofdecreaseoftheamountofcholecalciferol inthecapsuleitwasdecidedtouseoverageofthedrugsubstanceinthe10 formulation. Overagesshouldbeapplied. 2.Formulationtest2–10%overageofcholecalciferol–noantioxidant Onebatchof20000IUstrengthinaproductionscalewasmanufacturedwith10%15 overageofcholecalciferol.Theprocessofmanufacturecomprisedofthesame stepsasincaseofthepreviousbatches. Stabilitystudieswereconductedasfollows: ComponentQuantity(mg / softcapsule)Function 20,000IU Pharmaceuticalcomposition Cholecalciferol*0.550Active ingredient Triglycerides,medium-chain169.450Solvent Softgelatinshell: Gelatin56.00Gellingagent Glycerol27.00Plasticizer Ponceau4R(E124)0.175Colorant Water,purified1.825Solvent Theoreticalmasstotal255.0- Overages*:20,000IU Cholecalciferol10% 20 2025 / 5023 BE2025 / 5023 40Thebatchwasanalysed,andsampleswereplacedonstabilityatthelongterm, intermediateandacceleratedstorageconditionsasdescribedbefore.Detailsofthe batchmanufactured,andresultsofanalysisarepresentedinthetablesbelow. Product:Cholecalciferol20000IUsoftcapsules;CCS:Al / PVC / PVDC blister Storageconditions:25°C±2°C / 60±5%RH Specification03 months 6 months 9 months 12 months 18 months Appearance: Transparent,red,round, softcapsuleswithaseam inthemiddle,filledwith lightyellowviscousliquid. compliescompliescompliescompliescomplie s complies Averagefillingmass: 153mg–187mg 168.8mg166.7mg168.8mg168.9mg169.9 mg 167.8mg Uniformityofdosage unitsbymassvariation: AV(10softcapsules)≤L1 IfAV>L1→AV(30soft capsules)≤L1andno individualcontentofthe dosageunitis <(1−L2x0.01)Mor>(1 +L2x0.01)M L1=15.0,L2=25.0 complies (AV=6.5) complies (AV=4.8) complies (AV= 2.8) complies (AV= 2.6) complies (AV= 5.7) does not comply (AV= 22.0) Disintegrationtime: Notlongerthan30min. 03’45”04’10”03’55”03’24”03’51”04’14”Assayofcholecalciferol inacapsule: 450.0–575.0µg(90%– 115%) 563.7µg (112.7%) 565.7µg (113.1%) 544.4µg (108.9%) 510.2µg (102.0%) 476.2 µg (95.2%) 394.2 µg (78.8%) Relatedsubstances: -Trans-cholecalciferol (impurityA):NMT 1.0% -Anyunknownimpurity: NMT1.0% -Totalimpurities:NMT2.0% <0.1% ND <0.1% 0.19% ND 0.19% 0.12% ND 0.12% <0.1% ND <0.1% <0.1% ND <0.1% 0.21% ND 0.21% Microbialcontamination: TAMCnotmorethan103 cfu / gTYMCnotmorethan 102cfu / gAbsenceof Escherichiacoliin1g <10cfu / g <10cfu / g absent ----- 5 2025 / 5023 BE2025 / 5023 41 Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:30°C±2°C / 65±5%RH Specification03 months 6 months 9 months Appearance: Transparent,red,round,softcapsules withaseaminthemiddle,filledwith lightyellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 168.8mg165.7mg168.2mg170.6mg Uniformityofdosageunitsbymass variation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosageunitis <(1−L2x0.01)Mor>(1+L2x 0.01)M L1=15.0,L2=25.0 complies (AV=6.5) complies (AV=3.3) complies (AV=3.6) complies (AV=4.1) Disintegrationtime: Notlongerthan30min. 03’45”04’32”03’48”03’16” Assayofcholecalciferolinacapsule: 450.0–575.0µg(90%–115%) 563.7µg (112.7%) 555.8µg (111.2%) 521.2µg (104.2%) 484.8µg (97.0%) Relatedsubstances: -Trans-cholecalciferol(impurityA): NMT1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% <0.1% ND <0.1% 0.18% ND 0.18% 0.13% ND 0.13% <0.12% ND <0.12% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --- Product:Cholecalciferol20000IUsoftcapsules;CCS: Al / PVC / PVDCblister Storageconditions:40°C±2°C / 75±5%RH Specification01month3months6months Appearance: Transparent,red,round,softcapsules withaseaminthemiddle,filledwithlight yellowviscousliquid. compliescompliescompliescomplies Averagefillingmass: 153mg–187mg 168.8mg170.3mg169.4mg167.2mg Uniformityofdosageunitsbymass variation:AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1 andnoindividualcontentofthedosage unitis complie s(AV= 6.5) complies (AV=2.8) complies (AV=1.9) complies (AV= 1.3) 2025 / 5023 BE2025 / 5023 42 <(1−L2x0.01)Mor>(1+L2x 0.01)M L1=15.0,L2=25.0 Disintegrationtime: Notlongerthan30min. 03’45”04’02”03’45”03’34” Assayofcholecalciferolinacapsule: 450.0–575.0µg(90%–115%) 563.7µg (112.7%) 550.8µg (110.2%) 538.2µg (107.6%) 512.6µg (102.5%) Relatedsubstances: -Trans-cholecalciferol(impurityA):NMT 1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% <0.1% ND <0.1% 0.14% ND 0.14% 0.32% ND 0.32% 0.31% ND 0.31% Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent --<10cfu / g <10cfu / g absent Concluding,regardingFormulationtest2(10%overagesofcholecalciferol–no antioxidant): Theresultsoftheanalysisperformedatreleasewerewithintheproposed acceptancecriteria.However,duringthecourseofthestabilitystudiesconsistent5decreaseinthecholecalciferolcontentwasnoted.Trendanalysisperformedafter 9monthsofproductstorageshowedthattheoverageusedwillnotassuresufficient shelflifeofthedrugproduct(thiswasconfirmedat18-monthstoragetimeby assayresultbeingoutofthelimit). Thus,itwasdecidedtoincludeantioxidantinthecompositionofthecapsulefill.10 3.Antioxidanttestingforuseintheformulation Laboratoryexperimentswereperformedtoestablishedrequiredlevelof antioxidantintheproduct.Forthispurpose,variouscapsulefillmixtureswere preparedandplacedinthe2mlglassvialsthatwerethentightlyclosedand15 exposedtodifferenttemperatureconditions.Atdefinedtimepointssampleswere testedforcontentofcholecalciferolandantioxidant,whenapplicable.Theobtained resultsarepresentedinthetablesbelow.Itshouldbenotedthattheconcentration ofeachingredientinthesamplecorrespondtointendedcompositionofthecapsule fill,andpercentageconcentrationofantioxidantgiveninthetablesbelowwas20 calculatedonIU / IUbasis. Sample:25000IUcholecalciferolinMCTParameter / Timepoint02weeks4weeks Assayofcholecalciferol 25°C102.2%98.7%95.0% 40°C102.2%97.3%95.0% 50°C102.2%96.2%94.0% 25°C--- 2025 / 5023 BE2025 / 5023 43 Assayofantioxidant40°C--- 50°C--- Sample:25000IUcholecalciferol+0.00004%all-rac-α-tocopherylacetatein MCT Parameter / Timepoint02weeks4weeks Assayofcholecalciferol 25°C97.5%96.7%92.9% 40°C97.5%95.8%92.0% 50°C97.5%95.7%92.1% Assayofantioxidant 25°C94.5%96.9%95.0% 40°C94.5%97.0%94.1% 50°C94.5%93.8%96.4% Sample:25000IUcholecalciferol+0.0003%all-rac-α-tocopherylacetateinMCT Parameter / Timepoint02weeks4weeks Assayofcholecalciferol 25°C100.1%100.1%94.9% 40°C100.1%99.5%95.7% 50°C100.1%99.0%96.1% Assayofantioxidant 25°C97.7%99.5%98.6% 40°C97.7%97.2%96.6% 50°C97.7%97.5%97.4% Sample:25000IUcholecalciferol+0.0004%all-rac-α-tocopherylacetateinMCT Parameter / Timepoint02weeks4weeks Assayofcholecalciferol 25°C101.6%101.8%98.2% 40°C101.6%101.0%98.6% 50°C101.6%101.6%98.7% Assayofantioxidant 25°C100.5%100.3%100.0% 40°C100.5%99.6%99.5% 50°C100.5%100.0%101.1%Sample:27500IU(25000IU+10%)cholecalciferolinMCT Parameter / Timepoint02weeks4weeks8weeks12weeks Assayofcholecalciferol 25°C110.1%104.5%101.3%100.8%100.7% 109.9%104.8%101.3%101.0%100.8% 40°C110.1%105.9%103.5%95.5%96.1% 109.9%106.9%104.3%95.6%96.5% 50°C110.1%103.5%97.1%93.4%91.7% 109.9%102.0%98.4%94.7%92.1% Assayofantioxidant 25°C----- ----- 40°C----- ----- 50°C----- ----- 5 2025 / 5023 BE2025 / 5023 44 Sample:27500IU(25000IU+10%)cholecalciferol+0.005%all-rac-α- tocopherylacetate(1.375IU)inMCT Parameter / Timepoint02weeks4weeks8weeks12weeks Assayofcholecalciferol 25°C109.1%105.6%103.8%100.4%100.6% 108.9%106.0%105.3%101.3%101.2% 40°C109.1%107.0%104.9%97.4%96.9% 108.9%107.3%105.0%97.1%97.1% 50°C109.1%105.0%96.4%95.0%93.7% 108.9%105.5%97.6%95.1%93.7% Assayofantioxidant 25°C100.5%99.5%99.5%97.8%98.0% 100.4%100.9%102.3%98.3%98.2% 40°C100.5%98.9%101.7%96.3%97.9% 100.4%100.2%100.4%97.7%99.3% 50°C100.5%100.5%100.7%97.2%96.2% 100.4%100.9%102.6%98.1%97.5%Sample:27500IU(25000IU+10%)cholecalciferol+0.04%all-rac-α- tocopherylacetate(11IU)inMCT Parameter / Timepoint02weeks4weeks8weeks12weeks Assayofcholecalciferol 25°C109.6%105.4%106.4%100.3%101.3% 109.5%105.1%106.3%100.7%101.4% 40°C109.6%105.4%104.5%96.3%95.9% 109.5%105.4%104.5%97.1%96.0% 50°C109.6%105.2%102.9%96.7%96.7% 109.5%105.9%104.0%96.5%96.4% Assayofantioxidant 25°C100.8%100.2%100.2%97.4%95.7% 100.7%100.4%100.7%97.6%96.1% 40°C100.8%101.0%99.8%99.2%95.4% 100.7%101.2%99.8%99.2%95.7% 50°C100.8%100.4%98.6%99.2%97.0% 100.7%99.9%99.5%100.0%97.4% Sample:27500IU(25000IU+10%)cholecalciferol+0.05%all-rac-α- tocopherylacetate(13.75IU)inMCT Parameter / Timepoint02weeks4weeks8weeks12weeks Assayofcholecalciferol 25°C108.9%104.4%104.6%101.9%101.9% 110.1%104.4%105.6%101.8%101.9% 40°C108.9%103.9%106.0%98.9%99.0% 110.1%104.6%105.6%98.8%98.9% 50°C108.9%105.0%104.3%99.1%96.9% 110.1%105.5%105.1%99.0%97.4% Assayofantioxidant 25°C101.0%99.7%98.9%98.5%97.9% 101.4%99.9%99.4%98.3%98.4%40°C101.0%99.6%100.5%99.6%99.8% 101.4%100.4%100.5%99.1%100.1% 50°C101.0%100.2%100.1%100.5%99.2% 101.4%100.5%100.0%100.5%99.3% Concluding,regardingantioxidanttesting: Basedontheobtainedresultsitwasconcludedthattoensuresufficientshelflife5 2025 / 5023 BE2025 / 5023 45 ofthedrugproduct0.05%(IU / IU)oftheantioxidantand10%overageofthe drugsubstanceshouldbeapplied. 4.Formulationtest3–10%overageofcholecalciferol–withantioxidant0.05% ofdrugproduct5 Asanextstep,itwasdecidedtomanufacturetheproductinacommercialscaleof 1000000and500000unitsfor20000IUand25000IU,respectively.As concluded,overageofthedrugsubstancewasused,andantioxidantwasaddedto thelistofthecapsulefillcomponents. Inaddition,itwasdecidedtoreplacecolorantusedinthe20000IUstrength.i.e.10 cochinealred,withthePatentBlueV.Inordertofacilitatedifferentiationof capsulesofbothstrengthsitwasdecidedtousetitaniumdioxideinthecapsule shellof2500IUstrength. Additionally,ascapsulesof20000IUstrengthwereround,itwasdecidedthatcapsulesof25000IUstrengthwillbeoval.15 ThemanufacturingprocesswasasdescribedaboveinExample1. ComponentQuantity(mg / softcapsule)Function 20,000IU25,000IU Pharmaceuticalcomposition Cholecalciferol*0.5500.688Activeingredient Triglycerides,medium- chain 158.450185.562Solvent All-rac-α-tocopherylacetate11.00013.750Antioxidant Softgelatinshell: Gelatin56.0072.00Gellingagent Glycerol27.0035.00Plasticizer PatentBlueV(E131)0.06-Colorant Titaniumdioxide(E171)-0.80Colorant Water,purified1.942.20Solvent Theoreticalmasstotal255.0310.0- Overages*:20,000IU25,000IU Cholecalciferol10%10% Duetolowcontentofthedrugsubstanceinthecapsulethebatchesweresubjected toprocessvalidationstudies.Allbatcheswereplacedonstabilityatthelongterm,20 intermediateandacceleratedstorageconditionsasdescribedabove. 2025 / 5023 BE2025 / 5023 46 Resultsoftheanalysisandstudiesperformedwerepositiveandsatisfactory, indicatingthattheformulationoftheproductiswellestablished.Detailsofthebatchesmanufactured,andresultsofanalysisarepresentedinthe tablesbelow.5 SpecificationResults 20000IU; batch1 20000IU; batch2 20000IU; batch3 Appearance: 20000IU:Transparent,blue,round,softcapsules withaseaminthemiddle,filledwithlightyellow viscousliquid. compliescompliescomplies Averagefillingmass: 20000IU:153mg–187mg 168mg169mg168mg Uniformityofdosageunitsbymassvariation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1andno individualcontentofthedosageunitis<(1−L2x 0.01)Mor>(1+L2x0.01)M; L1=15.0,L2=25.0 compliescompliescomplies Identificationofcholecalciferol: Retentiontimeofcholecalciferolpeakinthe chromatogramoftestsolutionshouldcorrespondto retentiontimeofcholecalciferolpeakinthe chromatogramofreferencesolution. compliescompliescomplies Identificationofcholecalciferol: UVspectrumofthepeakofretentiontimeof cholecalciferoloftestsolutionshouldbein accordancewithUVspectrumofthepeakof cholecalciferolofthereferencesolution. compliescompliescompliesIdentificationofthedye–PatentBlueV: UVspectrumofthetestsolutionshouldbein accordancewithUVspectrumofthereference solution. compliescompliescomplies Disintegrationtime: Notlongerthan30min. 05’27”05’34”05’56” Assayofcholecalciferolinacapsule–atrelease: 20000IU:500.0–600.0µg(100.0%–120.0%) 536.8µg (107.4%) 535.6µg (107.1%) 531.3µg (106.3%) Assayofantioxidantinacapsule–atrelease: 20000IU:9.9–12.1mg(90.0%–110.0%) 10.9mg (99.1%) 10.9mg (99.1%) 11.0mg (100.0%) SpecificationResults 20000IU; batch1 20000IU; batch2 20000IU; batch3 Relatedsubstances: -Trans-cholecalciferol(impurityA):NMT 1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% 2025 / 5023 BE2025 / 5023 47 Microbial contamination: TAMCnotmorethan 103cfu / gTYMCnot morethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent <10cfu / g <10cfu / g absent <10cfu / g <10cfu / g absent SpecificationResults 25000IU; batch1 25000IU; batch2 25000IU; batch3 Appearance:25000IU:Whitetoalmostwhite,oval,soft capsuleswithaseaminthemiddle,filledwithlight yellowviscousliquid. compliescompliescomplies Averagefillingmass: 25000IU:180mg–220mg 198mg199mg200mg Uniformityofdosageunitsbymassvariation: AV(10softcapsules)≤L1 IfAV>L1→AV(30softcapsules)≤L1andno individualcontentofthedosageunitis<(1−L2x 0.01)Mor>(1+L2x0.01)M; L1=15.0,L2=25.0 compliescompliescomplies Identificationofcholecalciferol: Retentiontimeofcholecalciferolpeakinthe chromatogramoftestsolutionshouldcorrespond toretentiontimeofcholecalciferolpeakinthe chromatogramofreferencesolution. compliescompliescomplies Identificationofcholecalciferol: UVspectrumofthepeakofretentiontimeof cholecalciferoloftestsolutionshouldbein accordancewithUVspectrumofthepeakof cholecalciferolofthe referencesolution. compliescompliescomplies Identificationofthedye–titaniumdioxide: Anorange-redcolourappears. compliescompliescomplies Disintegrationtime: Notlongerthan30min. 07’21”07’29”08’09” Assayofcholecalciferolinacapsule–atrelease: 25000IU:625.0–750.0µg(100.0%–120.0%) 667.1µg (106.7%) 657.2µg (105.2%) 659.3µg (105.5%) Assayofantioxidantinacapsule–atrelease: 25000IU:12.4–15.1mg(90.0%–110.0%) 13.9mg (100.9%) 13.8mg (100.2%) 13.9mg (100.9%) SpecificationResults 25000IU; batch1 25000IU; batch2 25000IU; batch3 Relatedsubstances: -Trans-cholecalciferol(impurityA):NMT1.0% -Anyunknownimpurity:NMT1.0% -Totalimpurities:NMT2.0% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% <0.1% 2025 / 5023 BE2025 / 5023 48 Microbialcontamination: TAMCnotmorethan103cfu / g TYMCnotmorethan102cfu / g AbsenceofEscherichiacoliin1g <10cfu / g <10cfu / g absent <10cfu / g <10cfu / g absent <10cfu / g <10cfu / g absent Concluding,regardingFormulationtest3(10%overagesofcholecalciferol–with antioxidant0.05%ofdrugproduct): Resultsoftheanalysisandstudiesperformedwerepositiveandsatisfactory, indicatingthattheformulationoftheproductiswellestablished.5 Example3:FinalmanufacturingProcessDevelopment Theprocessofmanufacturecomprisesof: -Dispensingofallcomponents-Preparationofthefillsolution.i.e.cholecalciferolwithtriglycerides,10 medium-chain(MCT)andantioxidant -Preparationofthegelatinemass -Encapsulation,whencapsulesareformed,filledandsealedinoneoperation -Drying,polishingandsortingofthecapsules -Packaging.15 Thecontrolsofthecriticalstepsofthemanufacturingprocessarewelldefined.In thetablebelow,crucialparametersandprocessstepsarelisted.Compliancewith therequirementsset,givesguaranteethatfinishedproductofrequiredqualityis manufactured. 20 No.Manufacturing processstep ParameterRequirementRationale 1.Preparation ofthe gelatine solution Gelatinesolution appearance Gelatinemassis uniformanddoes notcontainair bubbles Relevantpropertiesof thegelatinemass definefinalappearance ofthecapsules. Gelatinesolution viscosity 9.0–13.0, preferably10.0– 12.0Pa∙s[after preparation]as measuredata temperatureof between58and62 °C Viscosityoutofthe limitcanmake encapsulationprocess impossible. 2.Preparationof thecapsulefill Timeof cholecalciferol dissolvingNotlessthan20 minutesanduntil solutionisclear Thetimeneededto ensurecomplete dissolutionof cholecalciferol. Temperatureand mixingtimeofthe Temperature48ºC -52ºCNotless Conditionsneededto obtainhomogenous 2025 / 5023 BE2025 / 5023 49 mainpartofMCT withantioxidant than15minutesmixtureofantioxidant andMCT. Mixingtimeofthe pre-solutionof cholecalciferolwith themixtureofMCT withantioxidant Notlessthan30 minutes Thetimeneededto obtainuniformassay ofcholecalciferolinthe solution. 3.Encapsulation Temperature andhumidityin theprocess room Temperature17ºC- 25ºC Relativehumidity≤ 24% Thehightemperature andhumiditycan causeproblemswith capsulesformingand drying. Fillamount Foradoseof20000 IU: 162mg–178mg Foradoseof25 000IU:190mg– 210mg Notproperfillamount cancauseoutof specificationresultfor thecontentofthedrug substance. 4.Capsulesdrying Temperatureand humidityinthe processroom Capsules hardness Temperature17ºC- 25ºC;Relative humidity≤24% 7-14N,preferably8- 10N Thehightemperature andhumiditycancauseproblemswith capsulesdrying. Notpropercapsules hardnesscaninfluence capsulesstability. Example4:preferredContainerClosureSystem Cholecalciferolsoftcapsulesarepackedin: –polyethylenebags(bulkcapsules) –Al / PVC / PVDCblisterswhichareplacedinacartonwithimprintedlabel5 texttogetherwithpatientinformationleaflet(marketingpack). PrimarypackagingmaterialscomplywiththerequirementsofCommission Regulation(EU)No10 / 2011onplasticmaterialsandarticlesintendedtocome intocontactwithfood,andwiththeEuropeanPharmacopoeia(chapter3.1.1110 “Materialsbasedonnon-plasticisedpoly(vinylchloride)forcontainersforsolid dosageformsfororaladministration”andchapter3.1.3“Polyolefins”). Basedonavailablestabilitydata,itisconsideredthatthebulkcontainerand marketingpackissuitableforthestorage,transportationanduseofthedrug15 product.Themarketingpackalsoadequatelyprotectsproductfromexposureto light. Thepresentinventionisinnowaylimitedtotheembodimentsdescribedinthe examplesand / orshowninth