超声增强的输送的物料进入并通过皮肤 翻译.docx

超声增强的输送的物料进入并通过皮肤 翻译.docx

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超声增强的输送的物料进入并通过皮肤翻译

Ultrasound-enhanceddeliveryofmaterialsintoandthroughtheskin

Amethodforenhancingthepermeabilityoftheskinorotherbiologicalmembranetoamaterialsuchasadrugisdisclosed.Inthemethod,thedrugisdeliveredinconjunctionwithultrasoundhavingafrequencyofaboveabout10MHz.Themethodmayalsobeusedinconjunctionwithchemicalpermeationenhancersand/orwithiontophoresis.

图片（11）

权利要求（21）

Weclaim:

1.Amethodforenhancingtherateofpermeationofadrugmediumintoaselectedintactareaofanindividual'sbodysurface,whichmethodcomprises:

（a）applyingultrasoundhavingafrequencyofabove10MHztosaidselectedarea,atanintensityandforaperiodoftimeeffectivetoenhancethepermeabilityofsaidselectedarea;

（b）contactingtheselectedareawiththedrugmedium;and

（c）effectingpassageofsaiddrugmediumintoandthroughsaidselectedareabymeansofiontophoresis.

2.Themethodofclaim1,whereinsaidultrasoundfrequencyisintherangeofabout15MHzto50MHz.

3.Themethodofclaim2,whereinsaidultrasoundfrequencyisintherangeofabout15to25MHz.

4.Themethodofclaim1,whereinsaidperiodoftimeisintherangeofabout5to45minutes.

5.Themethodofclaim4,whereinsaidperiodoftimeisintherangeofabout5to30minutes.

6.Themethodofclaim1,whereinsaidperiodoftimeislessthanabout10minutes.

7.Themethodofclaim1,whereinsaidintensityofsaidultrasoundislessthanabout5.0W/cm.sup.2.

8.Themethodofclaim7,whereinsaidintensityofsaidultrasoundisintherangeofabout0.01to5.0W/cm.sup.2.

9.Themethodofclaim8,whereinsaidintensityofsaidultrasoundisintherangeofabout0.05to3.0W/cm.sup.2.

10.Themethodofclaim1,whereinsaidareaofthestratumcorneumisintherangeofabout1to100cm.sup.2.

11.Themethodofclaim10,whereinsaidareaofthestratumcorneumisintherangeofabout5to100cm.sup.2.

12.Themethodofclaim11,whereinsaidareaofthestratumcorneumisintherangeofabout10to50cm.sup.2.

13.Themethodofclaim1whereinsaiddrugmediumcomprisesadrugandacouplingagenteffectivetotransfersaidultrasoundtothebodyfromanultrasoundsource.

14.Themethodofclaim13whereinsaidcouplingagentisapolymeroragel.

15.Themethodofclaim13whereinsaidcouplingagentisselectedfromthegroupconsistingofglycerin,water,andpropyleneglycol.

16.Themethodofclaim1whereinsaiddrugmediumfurthercomprisesachemicalpermeationenhancer.

17.Themethodofclaim1,whereinsteps（a）and（b）arecarriedoutapproximatelysimultaneously.

18.Themethodofclaim1,whereinstep（b）iscarriedoutbeforestep（a）.

19.Themethodofclaim1,whereinstep（a）iscarriedoutbeforestep（b）.

20.Themethodofclaim1,whereintheultrasoundisappliedcontinuously.

21.Themethodofclaim1,whereintheultrasoundispulsed.

说明

ThisapplicationisadivisionofapplicationSer.No.07/844,732filedMar.2,1992,nowU.S.Pat.No.5,231,975whichisadivisionalofapplicationSer.No.07/484,560,nowU.S.Pat.No.5,115,805,filedFeb.23,1990.

TECHNICALFIELD

Thisinventionrelatesgenerallytothefieldofdrugdelivery.Moreparticularly,theinventionrelatestoamethodofenhancingtherateofpermeationoftopically,transmucosallyortransdermallyappliedmaterialsusinghighfrequencyultrasound.

BACKGROUND

Thedeliveryofdrugsthroughtheskin（"transdermaldrugdelivery"or"TDD"）providesmanyadvantages;primarily,suchameansofdeliveryisacomfortable,convenientandnon-invasivewayofadministeringdrugs.Thevariableratesofabsorptionandmetabolismencounteredinoraltreatmentareavoided,andotherinherentinconveniences--e.g.,gastrointestinalirritationandthelike--areeliminatedaswell.Transdermaldrugdeliveryalsomakespossibleahighdegreeofcontroloverbloodconcentrationsofanyparticulardrug.

Skinisastructurallycomplex,relativelyimpermeablemembrane.Moleculesmovingfromtheenvironmentintoandthroughintactskinmustfirstpenetratethestratumcorneumandanymaterialonitssurface.Theymustthenpenetratetheviableepidermis,thepapillarydermis,andthecapillarywallsintothebloodstreamorlymphchannels.Tobesoabsorbed,moleculesmustovercomeadifferentresistancetopenetrationineachtypeoftissue.Transportacrosstheskinmembraneisthusacomplexphenomenon.However,itisthestratumcorneum,alayerapproximately5-15micrometersthickovermostofthebody,whichpresentstheprimarybarriertoabsorptionoftopicalcompositionsortransdermallyadministereddrugs.Itisbelievedtobethehighdegreeofkeratinizationwithinitscellsaswellastheirdensepackingandcementationbyordered,semicrystallinelipidswhichcreateinmanycasesasubstantiallyimpermeablebarriertodrugpenetration.Applicabilityoftransdermaldrugdeliveryisthuspresentlylimited,becausetheskinissuchanexcellentbarriertotheingressoftopicallyappliedmaterials.Forexample,manyofthenewpeptidesandproteinsnowproducedasaresultofthebiotechnologyrevolutioncannotbedeliveredacrosstheskininsufficientquantitiesduetotheirnaturallylowratesofskinpermeability.

Variousmethodshavebeenusedtoincreaseskinpermeability,andinparticulartoincreasethepermeabilityofthestratumcorneum（i.e.,soastoachieveenhancedpenetration,throughtheskin,ofthedrugtobeadministeredtransdermally）.Theprimaryfocushasbeenontheuseofchemicalenhancers,i.e.,whereindrugiscoadministeredwithapenetrationenhancingagent（or"permeationenhancer"）.Whilesuchcompoundsareeffectiveinincreasingtherateatwhichdrugisdeliveredthroughtheskin,therearedrawbackswithmanypermeationenhancerswhichlimittheiruse.Forexample,manypermeationenhancersareassociatedwithdeleteriouseffectsontheskin（e.g.,irritation）.Inaddition,controlofdrugdeliverywithchemicalenhancementcanbequitedifficult.

Iontophoresishasalsobeenusedtoincreasethepermeabilityofskintodrugs,andinvolves

（1）theapplicationofanexternalelectricfield,and

（2）topicaldeliveryofanionizedformofdrug（orofaneutraldrugcarriedwiththewaterfluxassociatedwithiontransport,i.e.,via"electroosmosis"）.Whilepermeationenhancementviaiontophoresishas,aswithchemicalenhancers,beeneffective,thereareproblemswithcontrolofdrugdeliveryandthedegreeofirreversibleskindamageinducedbythetransmembranepassageofcurrent.

Thepresentlydisclosedandclaimedmethodinvolvestheuseofultrasoundtodecreasethebarrierfunctionofthestratumcorneumandthusincreasetherateatwhichadrugmaybedeliveredthroughtheskin."Ultrasound"isdefinedasmechanicalpressurewaveswithfrequenciesabove20,000Hz（see,e.g.,H.Lutzetal.,ManualofUltrasound:

1.BasicPhysicalandTechnicalPrinciples（Berlin:

Springer-Verlag,1984））.

AsdiscussedbyP.Tyleetal.inPharmaceuticalResearch6（5）:

355-361（1989）,drugpenetrationachievedvia"sonophoresis"（themovementofdrugsthroughskinundertheinfluenceofanultrasonicperturbation;seeD.M.SkauenandG.M.Zentner,Int.J.Pharmaceutics20:

235-245（1984））,isbelievedtoresultfromthermal,mechanicalandchemicalalterationofbiologicaltissuesbytheappliedultrasonicwaves.Unlikeiontophoresis,theriskofskindamageappearstobelow.

Applicationsofultrasoundtodrugdeliveryhavebeendiscussedintheliterature.See,forexample:

P.Tyleetal.,supra（whichprovidesanoverviewofsonophoresis）;S.Miyazakietal.,J.Pharm.Pharmacol.40:

716-717（1988）（controlledreleaseofinsulinfromapolymerimplantusingultrasound）;J.Kostetal.,Proceed.Intern.Symp.Control.Rel.Bioact.Mater.16（141）:

294-295（1989）（overviewoftheeffectofultrasoundonthepermeabilityofhumanskinandsyntheticmembranes）;H.Bensonetal.,PhysicalTherapy69

（2）:

113-118（1989）（effectofultrasoundonthepercutaneousabsorptionofbenzydamine）;E.Novak,Arch.Phys.Medicine&Rehab.45:

231-232（1964）（enhancedpenetrationoflidocainethroughintactskinusingultrasound）;J.E.Griffinetal.,Amer.J.Phys.Medicine44

（1）:

20-25（1965）（ultrasonicpenetrationofcortisolintopigtissue）;J.E.Griffinetal.,J.Amer.Phys.TherapyAssoc.46:

18-26（1966）（overviewoftheuseofultrasonicenergyindrugtherapy）;J.E.Griffinetal.,Phys.Therapy47（7）:

594-601（1967）（ultrasonicpenetrationofhydrocortisone）;J.E.Griffinetal.,Phys.Therapy48（12）:

1336-1344（1968）（ultrasonicpenetrationofcortisolintopigtissue）;J.E.Griffinetal.,Amer.J.Phys.Medicine51

（2）:

62-72（1972）（same）;J.C.McElnay,Int.J.Pharmaceutics40:

105-110（1987）（theeffectofultrasoundonthepercutaneousabsorptionoffluocinoloneacetonide）;andC.Escoffieretal.,Bioeng.Skin2:

87-94（1986）（invitrostudyofthevelocityofultrasoundinskin）.

Inadditiontotheaforementionedart,U.S.Pat.Nos.4,767,402and4,780,212toKostetal.relatespecificallytotheuseofspecificfrequenciesofultrasoundtoenhancetherateofpermeationofadrugthroughhumanskinorthroughasyntheticmembrane.

Whiletheapplicationofultrasoundinconjunctionwithdrugdeliveryisthusknown,resultshaveforthemostpartbeendisappointing,i.e.,enhancementofskinpermeabilityhasbeenrelativelylow.

SUMMARYOFTHEINVENTION

Thepresentinventionprovidesanovelmethodforenhancingtherateofpermeationofagivenmaterialthroughaselectedintactareaofanindividual'sbodysurface.Themethodcomprisescontactingtheselectedintactareawiththematerialandapplyingultrasoundtothecontactedarea.Theu