不溶性藥物遞送策略：回顧最近的進(jìn)展和商業(yè)前景Insoluble drug delivery strategies - review of recent advances and business prospects

ActaPharmaceuticaSinicaB2015;5(5):442–453

HOSTEDBY

NSO

ir

NO

ELSEVIER

ChinesePharmaceuticalAssociation

InstituteofMateriaMedica,ChineseAcademyofMedicalSciencesActaPharmaceuticaSinicaB

/locate/apsb

REVIEW

Insolubledrugdeliverystrategies:reviewcrSSMark

ofrecentadvancesandbusinessprospects

SandeepKalepua

,*,VijaykumarNekkanti

b

aDepartmentofPharmaceuticalTechnology,ShriVishnuCollegeofPharmacy,Bhimavaram534202,AndhraPradesh,

iegeofPharmaceuticalSciences,WesternUniversityofHealthSciences,Pomona,California91766,USA

Received9January2015;receivedinrevisedform9May2015;accepted26May2015

KEYWORDS

Bioavailability;Cocrystals;

Solubility;

Inclusioncomplexation;Nanoparticles;

Self-emulsifyingformulations;

Proliposomes

AbstractTheemergingtrendsinthecombinatorialchemistryanddrugdesignhaveledtothedevelopmentofdrugcandidateswithgreaterlipophilicity,highmolecularweightandpoorwatersolubility.Majorityofthefailuresinnewdrugdevelopmenthavebeenattributedtopoorwatersolubilityofthedrug.Issuesassociatedwithpoorsolubilitycanleadtolowbioavailabilityresultinginsuboptimaldrugdelivery.About40%ofdrugswithmarketapprovalandnearly90%ofmoleculesinthediscoverypipelinearepoorlywater-soluble.Withtheadventofvariousinsolubledrugdeliverytechnologies,thechallengetoformulatepoorlywatersolubledrugscouldbeachieved.Numerousdrugsassociatedwithpoorsolubilityandlowbioavailabilitieshavebeenformulatedintosuccessfuldrugproducts.Severalmarketeddrugswerereformulatedtoimproveef?cacy,safetyandpatientcompliance.Inordertogainmarketingexclusivityandpatentprotectionforsuchproducts,revitalizationofpoorlysolubledrugsusinginsolubledrugdeliverytechnologieshavebeensuccessfullyadoptedbymanypharmaceuticalcompanies.Thisreviewcoverstherecentadvancesinthe?eldofinsolubledrugdeliveryandbusinessprospects.

&2015ChinesePharmaceuticalAssociationandInstituteofMateriaMedica,ChineseAcademyofMedicalSciences.ProductionandhostingbyElsevierB.V.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

/licenses/by-nc-nd/4.0/

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*Correspondingauthor.Tel.:+919948444546;fax:+918816250863.E-mailaddress:

sandeepk@.in

(SandeepKalepu).

PeerreviewunderresponsibilityofInstituteofMateriaMedica,ChineseAcademyofMedicalSciencesandChinesePharmaceuticalAssociation.

ht:///10.1016/j.apsb.2015.07.003tp

2211-3835&2015ChinesePharmaceuticalAssociationandInstituteofMateriaMedica,ChineseAcademyofMedicalSciences.ProductionandhostingbyElsevierB.V.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

/licenses/by-nc-nd/4.0/

).

Insolubledrugdeliverystrategies443

1.Introduction

Thesearchforinnovativemedicinesindiseasemanagementwithoutcompromisingonsafetyandef?cacyisachallenge.Inspiteofsigni?cantsuccessinthediscoveryofnewdrugs,therearestillunmetmedicalconditionswhichneedeffectivetherapy.Marketpotential,competitionamongcompanies,drypipelineofdevelopmentalcandi-datesofvariouscompanieshavehastenedthedrugdiscoveryanddevelopmentprocess.Asaresult,asigni?cantnumberofdrugsgettingapprovalshavepoorbiopharmaceuticalproperties.Anestimated40%ofapproveddrugsandnearly90%ofthedevelopmentalpipelinedrugsconsistofpoorlysolublemolecules

1

.Severalmarketeddrugssufferfrompoorsolubility,lowpermeability,rapidmetabolismandelimina-tionfromthebodyalongwithpoorsafetyandtolerability

2

.

Recentstudieshaverevealedthatdiscoveryanddevelopmentofnewdrugsalonearenotsuf?cienttoachievetherapeuticexcellenceandcapturemarketeconomies

3

.Therefore,modi?edformulationsofexistingdrugsaregainingmoreimportance.Theimprovedfor-mulationofexistingdrugsisturningouttobelucrativebusinessforpharmaceuticalindustrywhichisfacinginnovationde?citthesedaysfornewmolecules

4

.Newdosageform,changeofformsofdrugs(ester/salt),prodrug/activemetaboliteofdrug,differentroutesofadministrationarefewchangesthatpharmaceuticalcompaniesareexploringfor505(b)(2)?llings

5

.Signi?cantnumberofinsolubledrugsinthemarketprovidespro?tablestrategiesforpharmaceuticalcompaniesto?leNDAunder505(b)(2)withimprovedformulationsprovidingfasterdissolutionandenhancedbioavailability.Hencethisreviewsummarizesvarioussolubilizationtechnologies.Therecentadvances,clinicalbene?tsandbusinesspotentialsofthesetechnol-ogiesarediscussedindetail.Thepotentialbene?tsofinsolubledrugdeliverytechnologiesaredepictedin

Fig.1

.

2.Insolubledrugdeliverytechnologies

2.1.pHmodi?cationandsaltforms

Nearly70%ofdrugsarereportedtobeionizable,ofwhichamajorityareweaklybasic.ApH-dependentsolubilityisexhibitedbyionizabledrugs,whereinweaklyacidicdrugsaremoresoluble

Figure1Bene?tsofinsolubledrugdeliverystrategies.

atpH>pKa(ionizationconstant)andweaklybasicdrugsaresolubleatpH<pKa

6

.ThispHdependentsolubilitywasexploredextensivelytoformulateinsolubledrugs.Ontheotherhand,saltformationofweaklyacidicorbasicdrugsprovidedalternatestrategiesforformulationofdrugswhichhavepHdependentsolubility.PharmaceuticallyacceptablecounterionsinthesaltcanprovidefavorablepHconditionsupondissolutioninwater,andthusthepHofresultingsolutionwouldbeclosetomaximumpHofdrugs.HencesaltformsmaysometimesavoidpHadjustmentsnecessaryforsolubilizationofdrugs.Inaddition,saltformationhasbeenreportedtoimprovecrystallinity,stabilityandpharma-ceuticalprocessibilityofdrugs

6

.

TherearemanyinsolubledrugsonthemarketwhichareformulatedwithpHmodi?cationtechnology.Cipro?oxacinisaclassicdrugwhichisweaklybasicandpracticallyinsolubleinwateratneutralpH.HoweveritexhibitspH-dependentsolubilitywithhighersolubilityatacidiccondition.MostoftheintravenousformulationscontainlacticacidaspHmodi?ertoimprovesolubility

7

.Intravenouscipro?oxacininfusionsareessentialfortreatingdifferentkindsofseverebacterialinfections.TelmisartanisanotherdrugwhichexhibitspH-dependentsolubility.Thecurrentlymarketedoralformulationoftelmisartancontainalkalis,suchassodiumhydroxideandmeglumineforpHmodi?cation

7

–

10

.TelmisartanformulationmarketedunderbrandnameMicardissismanufacturedusingaexpensivespray-dryingprocess,whereindrugandalkalisalongwithotherexcipientsaredissolvedinwaterandspray-driedtoproducegranules

11

.Thespray-driedgranulesobtainedwerereportedtohaveapH-independentdissolutionpro?le.However,genericversionsofthetelmisartanformulationarehardtocomeby,owingtotheinsolublenatureofthedrug'sfree-acid-formandthecriticalstepsinvolvedinitsmanufacturingprocessthatprovidedanadditionalmarketcapitalizationtotheinnovator

12

.

RepaglinideisanexampleofZwitteriondrugwithpoorwatersolubilityof37μg/mL

13

.Currentlyrepaglinide,marketedasPrandinsinUSA,isformulatedwithmeglumineaspHmodi?er.Variouspatentsdisclosetheuseofmeglumineintheformulationandspray-dryingastheprocessforpreparingthegranules

14

–

17

.Trickyprocessandcriticalformulationsometimesprovetobehardtomakegenericcopies.Incaseofbothtelmisartanandrepagli-nide,actualsaltformsofdrugsarenotusedintheformulation,insteadthebasessuchasmeglumineandsodiumhydroxidewereaddedtotheformulation.Thiscouldbeduetotechnicalreasons,suchaslackofcrystallinity,poorstabilityanddeliquescentnatureofresultingsalts.Onotherhand,includingbasesintheformula-tioncouldbeduetocommercialreasons,inordertobuildcomplexityintheprocessandproduct,suchthatitishardtomakegenericversions.Theseareafewexamplesofhowaclinicallyandcommerciallybene?cialdrugproductcouldbelaunchedinthemarketbyalteringtheformulationstrategies.

Aspiriniscenturyoldnon-steroidalanti-in?ammatorydrug(NSAID),yetcurrentlyexploredbyvariouscompaniesforcommercialbene?ts.Solubleformulationsofaspirinarecurrentlyavailableonthemarket.AsproClear,issoluble,effervescenttabletcontainingaspirin.TheeffervescenceandfavorablepHconditionrequiredforsolubilityofaspirinarefacilitatedbyincorporatingsodiumbicarbonateandcitricacidintheformulation.AsproClearreportedtoprovidefasterreliefofpainthanplainaspirintablets

18

.Thisisanotherexample,howinsolubledrugformulationtechnol-ogycanbeexploredforcommercialandclinicalbene?ts.

Insolubledrugsaremostlyformulatedusingthesaltformsofweaklyacidandbasicdrugs.Varioussaltformsofdrugshave

444SandeepKalepu,VijaykumarNekkanti

beentheareaofinterestforpharmaceuticalcompaniesforcommercialandclinicalbene?ts.Inthefollowingsection,fewexamplesofsuchinventionsarediscussed.Identi?cationofbisulfatesaltformofatazenavirisaninterestingexampleofhowsaltscreeningcouldhelpamoleculetoprogressfrombeingdroppedatpreclinicaldevelopmenttoclinicalstudiesand?nallytomarketingapproval.Atazenavirasfreebaseispracticallyinsolubleinwater(<1μg/mL)andhadpoororalbioavailabilityinpreclinicalanimalmodels

19

.Lackofsuf?cientabsorptionwasreportedtobeahurdleinthedevelopmentofthismolecule.Inanefforttoidentifyviableoptiontoimprovethebioavailability,seriesofsaltswerescreenedand?nallyatazenavirbisulfatewasselectedforfurtherdevelopment

19

,

20

.Atazenavirbisulfateexhib-iteddistinctadvantageoverothersaltssuchasmethanesulfonateandhydrochlorideintermsofsolubilityandsolidstatestability.Hydrochlorideandmethanesulfonatesaltsofatazenavir,whendissolvedinwaterbeyondsaturationsolubilityofsalts,therewassolidstatetransformationleadingtodissociationofsalttofreebaseatpH>pHmax.Analysisofexcessofsolidinthesuspensionrevealedthatmaterialwasindeedfreebase.Undersimilarexperimentalconditionsbisulfatewasfoundtobestableanddidnotconverttofreebase,andratherexcessofsolidwasfoundtobeinhydratedsulfatesalt

20

.Therefore,theabsolutebioavailabilityofbisulfatewasmultifold-higherthanthefreebase.Thisinventionnotonlyleadtosuperiorproteaseinhibitoronthemarketbutprovidedadditionalpatentprotectionandmarketingexclusivitytoinventorcompany.

Oneoflargest-sellinganticancerdrugsimatinibismarketedasasaltform,imatinibmesylate.Thedrugexhibitspoorsolubilityandhencemesylatesaltwasusedforitsdevelopment,whichissolubleinwateratpH<5.5

21

,22

.Amongthetwopolymorphicforms(αandβ),generatedbyimatinibsalt,theβformismorestablewithacceptablepharmaceuticalproperties.However,additionalmarketingrightswereassignedtotheinnovatorduetotheirpatentprotectionoftheβform

23

.Manyolddrugshavebeenreformulatedassaltformsforcommercialpurposes.Onesuchexampleisfeno?brate,whichwasapprovedin1993andwasincludedingenericcompetitionfromtheyear2000

24

.Sincethen,Abbottlaboratories

24

continued?lingNDA'salteringthedoseinordertogainmarketexclusivity.Interestingly,theactiveformofallfeno?brateformulationswasfoundtobefeno?bricacid,anactivemetaboliteoffeno?bratewhichwasresponsibleforthetherapeuticactivity.ThisfactwaswellexploredbyAbbotanddevelopedcholin-feno?brate,asolubleandlight-stablesaltoffeno?bricacid

25

.ThissaltformwasdevelopedintoadelayedreleasecapsuleformulationandwasapprovedbytheFDA.Thisdelayedreleaseformulationwasprovedtobeoneofblockbusterproductintherecenttime.Inthetimesofinnovationdrought,suchinventionsarebecominghugecommercialsuccessthusimprovingoverallinvestmentdriveinpharmaceuticalresearchanddevelopment.

Theuseofaspirinforclinicalmanagementofmigrainewastestedrecently.Thesolubleaspirin-D,L-lysinesaltwasformulatedforintravenousinjection(IV).Theclinicalstudiesrevealedthatintrave-nousadministrationofaspirinwaseffectiveinrelievingmigraineattack.AlthoughsumatriptanwasslightlymoreeffectivethanaspirinIVinheadacherelief,aspirinwaswelltolerated

26

,27

.Hencethenewsaltformofaspirindemonstratedsafe,effectiveandaffordablealternativetherapyforthetreatmentofmigraine.Similarlyaspirin-calciumwasutilizedintheformulationofsolubletablet(Solorpins).Theformulationshowedfasteronsetofactioncomparedtothetabletwithplainaspirin

28

.Improvedclinicalbene?ts,aswellascommercialpro?ts,wereaccomplishedwiththesesaltforms.

Clopidogrelisananti-plateletagentthatworksthroughirreversiblebindingofitsactivemetabolitetotheP2Y12subtypeofadenosinediphosphate(ADP)chemoreceptorsonplateletscellmembrane.Initially,itwasavailableasPlavixs,consistingofthesaltform,clopidogrelbisulfate.However,othersaltformslikeclopidogrelbesilateandclopidogrelhydrochloridewereapprovedinEurope.Inthiscasesaltformsareexploredbygenericmakerformarketexclusivity

29

.RecentlyFDAapprovedAdvils,asodiumsaltofibuprofen.ThisproductissuperiorintermsofitsrapidonsetofactionascomparedtoAdvilLiqui-Gelscapsulescontainingibuprofen

30

.Apartfromenablingfasterpain-relieftopatients,thisnewsaltformofibuprofenprovidedmarketexclusivityofatleast3–5yearsforthemanufacturer.

Rosuvastatin(sparinglysoluble)isavailableinthemarketasitscalciumsalt.Recentlygeneric-makerWatsonpharmaceuticals,Inc.,gainedapprovalforitsNDAcontainingrosuvastatinzincundersection505(b)(2)

31

,thusgettingmarketingexclusivitymorethantypicalANDA.However,theapprovalissubjecttoacourtdecisionduetoalegalpetition?ledbyAstraZeneca.Pharmaceuticalcompaniesarecontinuouslyexploringthesaltformsofdrugsforbetterclinicalperformance.Sometimesitseemslikereformulationisanalternativepathforthepharmaceuticalcompaniestoexploitmarketingexclusivityandcaptivity

32

.Furtheradvancementsinthistechnologywillbemoreinteresting,sincetherewouldbemanymoreNDA'sdrugstobeapprovedwithnewsaltformsinthefuture.

2.2.Co-solvencyandsurfactantsolubilization

Formulationofinsolubledrugsusingco-solventsisalsooneoftheoldestandwidelyusedtechnique,especiallyforliquidformulationintendedfororalandintravenousadministration.Reductionofthedielectricconstantispossiblebytheadditionofco-solvents,whichfacilitatesincreasedsolubilizationofnon-polardrugmolecules.Inordertomaximizethesolubilityandpreventprecipitationupondilution,co-solventsareusedinconjunctionwithsurfactantsandpHmodi?ers

33

,34

.

Taxol,anintravenousinjectionofpaclitaxel,isthemostdebatedformulationusingthisapproach.Thiswasdevelopedusing49%ofdehydratedalcoholand527mgofcremophoreEL

35

,whichmustbedilutedbeforeinfusion.Additionally,pretreatmentofpatientswithantihistaminesisessentialowingtoahypersensi-tivityreactionduetohighercontentofcremophoreELintheformulation.Later,severalformulationsofpaclitaxelexcludingcremophoreELwereattemptedandcoupleofthemgainedFDAapprovalaftermakingasmoothmeansofaccessthroughclinicaltesting.FormulationsdevoidofcremophoreELincludedAbraxane(albuminmicrospherescontainingPaclitaxel)andGenexol(PEG-PLApolymericmicelleswithPaclitaxel)

36

,

37

.

Similarly,docetaxelisanotherwidelyusedanticancerdrugandtheoriginalformulationsoftaxoterecontainsethanolandTween80tosolubilizethedrug(0.54gpolysorbate80and0.395gdehydratedalcohol)

38

.However,hypersensitivityreactionsusingthisproductwerereportedduetothesurfactantsintheformula-tion.Sandoz,Inc.,HospiraInc.andApotexInc.eachhasdocetaxelcontaininganewdrugproductapprovedundersection505(b)(2)

39

–

41

.MostofthenewformulationshavePEG300asadditionalcosolventandTween80contentsigni?cantlylessthantaxotere.Thesenewformulationswereclaimedtobesaferandstablethantaxotere.Insolubledrugdeliverytechnologyutilizingtheco-solvent-surfactantapproachhadindeedprovedvitalinprovidinganeffectivetreatmentoptionforcancerpatients.Furtherimprovementintheformulationoftaxol'sresultedinmorepatient

Insolubledrugdeliverystrategies445

Table1Listofparenteraldrugformulationscontainingco-solventsandsurfactants.

SolventPercentageinmarketedformulation(%)

Percentageadministered(%)

Routeof

administration

Example

CremophorEL

CremophorRH60Dimethylacetamide

(DMA)Ethanol

Glycerin

N-methyl-2-pyrrolidonePEG300

PEG400

Polysorbate80

Propyleneglycol

SolutolHS-15

11–6520

6

5–8015–32100

≤60

18–67

0.075–10010–80

50

≤10

≤0.08≤3

≤6≤15 100≤50≤18≤4≤8050

IVinfusionIVinfusionIVinfusion

SC

IM,SC,IVSubgingivalIM,IVbolusIM

IMIMIV

PaclitaxelTacrolimusTeniposide

DihydroergotamineDihydroergotamine

Doxycyclin

Methocarbamil

Lorazepam

ChlordiazepoxideLorazepam

Propanidid

IM:intramuscular;IV:intravenous;PEG:polyethyleneglycol;SC:

subcutaneous.

complianceandnewintellectualpropertiesforpharmaceuticalcompanies.Alistofpharmaceuticalformulationscontainingthehighestamountsofco-solventsandsurfactantsareprovidedin

Table1

42

.Thoughco-solvencyandsurfactantsolubilizationtechniquesarewidelyusedforenhancingthesolubilityofhydrophobicdrugs,theyhavesomedisadvantages:tolerabilityofformulationswithhighlevelsofsyntheticsurfactantsmaybepoorincaseswherelongtermchronicadministrationisintended;uncontrolledprecipitationmayoccurupondilutionwithaqueousmediaorphysiological?uids.Precipitatesmaybeamorphousorcrystallineandcanvaryinsize;precipitationofdrugfromaco-solventmixturemayresultinembolismandlocaladverseeffectsattheinjectionsite;concomitantsolubilizationofotheringredientssuchaspreservativesmayleadtoconsequentalterationinstabilityandeffectivenessofthedrugproduct.

2.3.Amorphousforms,soliddispersionsandcocrystals

Stablecrystalformsofdrugsposeprobleminsolubilizationduetohighlatticeenergy.Thus,disorderedamorphousformsofferdistinctadvantageovercrystalformswithregardstosolubility.Hence,changingthesolidstatecharacteristicsofactivepharmaceuticalingredient(API)rendersthemoleculemorewatersoluble.But,excessofenthalpy,entropyandfreeenergiesofamorphousformsmakesthempronetocrystallization,leadingtotheformationofstablecrystals

43

.However,theadventofnewtechniquestoimprovestabilityofamorphousformsimprovedchancesoftheiruseinpharmaceuticalformulations

44

.Complicatedprocessofmakingamorphousdrugsystemsandvariousfactorsaffectingthestabilityofthoseformsresultedinreducedgenericcompetitionforalreadyapprovedamorphousproducts.CefuroximeaxetilpracticallywasinsolubleinwaterandintroducedasCeftinsbyGSKinamorphousformandwasprotectedbyacoupleofpatents,whichbarredtheentryofgenericplayersforareasonableperiod

45

,46

.Anotherdrugproduct,theamorphousza?rlukastisavailablecommerciallyasAccolates.Theamorphousformissubjecttovariouspatentswhichprecludedearlygenericentry

47

,48

.Amorphousformsofotherdrugslikenel?navirmesylate,quinaprilhydrochlorideandrosuvastatincalciumarealsocommerciallyavailableinthemarket.

Soliddispersiontechnologywasextensivelyexploredinrecentdecadesforthedeliveryofinsolubledrugs.Physically,soliddispersionsareeutecticmixturesorsolidsolutionsinwhichdrugs

existeitherinanamorphousformdispersedinthecarrierorasamoleculardispersioninthecarrier

49

–

51

.Soliddispersionsfavorenhanceddissolutionofdrugsduetotheformationofahigh-energyamorphousformorincreasedsolubilityleadingtosuper-saturation.Theincreasedsolubilitycanbeattributedtothedispersionofdrugsatthemolecularleveland/orsolubilizationeffectsofthepolymer.Thedrugremainsinametastableformforconsiderabletimeinthesupersaturatedstateandpolymericcarrierinturncanstabilizethemetastablestatebypreventingnucleation

51

.Advancesinmelt-extrusionandspray-dryinghaveacceleratedindustrialapplicationsofsoliddispersionsforthedeliveryofinsolubledrugs.

Sporanoxsisaclassicexampleofadrug(itraconazole)formulatedusingsoliddispersiontechnology.AtneutralpHitraconazolehasanegligiblesolubilityof1ng/mL

52

.Forpreparingsoliddispersionsofitraconazole,spray-layeringtechnologywasusedinwhichanorganicsolutionofdrugandhydroxylpropylmethylcellulose(HPMC)wassprayedoversugarbeadstoformathin?lmconsistingofmolecularlydisperseddrugandpolymer.Thisamorphousformulationsigni?cantlyenhancedbioavailabilitycomparedtocrystallineitraconazole.Apartfromspraylayering,itraconazolesoliddispersionswerealsopreparedusinghot-meltextrusionwithvaryingpolymerssuchasHPMC,Eudragitandpolyvinylpyrrolidone(PVP)mixture.InvitrostudiesrevealedafasterdissolutionofsoliddispersionscontainingEudragitincomparisontoHPMCandsporanox

52

.Incontrast,clinicalstudiesrevealedasimilaritybetweensoliddispersionscontainingHPMCandsporanox,whichcanbeattributedtothesolubilizationandstabilizationeffectsofHPMCinphysiologicalconditions(invivo).

Alistofcurrentlymarketedsolid-dispersionproductsisshownin

Table2

51

.Allthelistedproductshavegeneratedclinicallybene?cialresultsbyproducingadequatedruglevelsinthebodyatdesiredtherapeuticconcentration,leadingtoimprovedbioavail-ability.Apartfrompotentialclinicalbene?ts,theseproductshavegeneratedconsiderableintellectualpropertyandcommercialsuc-cesstothemanufacturer.

Pharmaceuticalcocrystaltechnologyhasreceivedgreateratten-tioninthelastdecadeowingtoitssuccessfuldeliveryofinsolubledrugs.Stoichiometricsolidsofdrugandconformer(secondcomponent),whichexistascrystalsatambienttemperaturearereferredtoascocrystals.Non-covalentforceslikeacid–amide,acid–acid,andamide–amideinteractions,usuallyofhydrogenbondingnature,holdthedrugandconformertogetherinthecocrystal.Theenhancedsolubilityofdrugincocrystalisachieved

446SandeepKalepu,VijaykumarNekkanti

Table2ListofmarketedproductsinUnitedStatesutilizing

soliddispersiontechnology.

Drug

Brandname

Carrier

Manufacturer

YearofFDAapproval

ItraconazoleTacrolimus

Lopinavir/Ritonavir

Nabilone

NimodipineFeno?brateEtravirine

SporanoxsPrografsKaletras

CasametsNimotopsFenoglidesIntelences

HPMC

JanssenPharmaceuticals,Inc.,USA

1992

HPMC

AstellasPharma,USInc.

1994

PVP/VA

AbbotLabarotaries,USA

2005

PVP

MedaPharmaceuticalsInc.,USA

2006

PEG

Bayer(Pty)Ltd.,USA

2006

PEG/Poloxamer

Santarus,Inc.

2007

HPMC

JanssenTherapeutics,USA

2008

bylowerlatticeenergyandhighersolventaf?nity

53

.Anyofthegenerallyregardedassafe(GRAS)-listedexcipients,organicacids(suchasfumaricacid,malicacid,glutaricacid,succinicacid,oxalicacid),nutraceuticals(suchaspterostilbene,quercetin,p-coumaricacidandsaccharine)canactasaconformer.Co-crystaltechnologyhasbeenexploredforsolubilityenhancementofdrugslikeitraconazole,carbamazepine,gabapentinin,moda?nil,piroxi-cam,caffeine,etc

.53

.Thecocrystaltechnologyhavebeenusedtocreateintellectualpropertyandlargenumberofpatentshavebeen?led

54

.Howeverthereisnoapprovedproductwithdrugcocrys-tals,withenormouspotentialfordeliveryofinsolubledrugstilltoday,butthefutureofcocrystalsispromising.

2.4.Polymericmicelles

Waterinsolubledrugsoftenhavegreateraf?nityforhydrophobicsolventsbecauseofhydrophobic–hydrophobicinteractionsandalsohaveaf?nityforhydrophobicregionofmicelles.Henceencapsulationofthosedrugsinmicellesenablestheirformulationinaqueousvehicle.Initiallythehydrophilicsurfactantswereusedtosolubilizethedrugfororalandintravenousadministration.However,limitedsolubilization,highercriticalmicellearconcen-trations(CMC)and