NZ626535B2

NZ626535B2 - Transdermal delivery system comprising buprenorphine

Info

Publication number: NZ626535B2
Application number: NZ626535A
Authority: NZ
Inventors: Thomas Hille; Helen Elizabeth Johnson; Gillian Elizabeth Mundin; Kevin John Smith; Gabriel Wauer
Original assignee: Lts Lohmann Therapie Systeme Ag
Priority date: 2011-12-12
Filing date: 2012-12-12
Publication date: 2017-05-25

Abstract

Provided is a transdermal therapeutic system comprising: A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising: a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid and linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer. The polymer-based adhesive is based on polysiloxanes or polyisobutylenes. The transdermal system is used for the manufacture of a medicament for the treatment of pain where the system is applied to the skin for 168h aka 7 days aka 1 week. tive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid and linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer. The polymer-based adhesive is based on polysiloxanes or polyisobutylenes. The transdermal system is used for the manufacture of a medicament for the treatment of pain where the system is applied to the skin for 168h aka 7 days aka 1 week.

Description

PC 12/002973 TRANSDERMAL DELIVERY SYSTEM COMPRISING BUPRENORPHINE TKC]HNK'. AI, FIKLD OF THK IXVENTION j00:II.] Yh" present invention relates to 8 transdermal thcrapctltic system (YYS) for the transderrnal administration of buprexlorphine. 8xldl processes Qt nlanuf8ettxrc? uses thereof, and corrcspondixlg lods Qf trcaxtncnt thcrcwitl'l.

BACKGROX "??l0 OF fBK INVKNTIOF The active ient buprenorphine (5R,6R,7R,9R,13S,14S) Cyclopropylmethy1I(S)-3, 3- dimethylhydroxybutanyl]methoxy-4, 5-epoxy-6, 14- ethanomorphinanol) is a partiaHy synthetic opiate with high potency. Cancer patients may be treated with daily doses of around 1 mg. e its rather high molecular weight of 467.64 daltons, it is currently used for transdermal administration. The commercial TTS product Norspan, also known as BuTrans, delivers buprenorphine to the skin sufficiently to treat patients in pain for a time period of 7 days (about 168 hours) and allows therefore a use of the TTS over a time period of 7 days and allows in a fixed dosing regimen a once-weekly TTS exchange.

This is specif cally beneficial in terms of convenience and patient compliance. Thus the overall efficacy of the pain medicament is enhanced. However, the long administration periods may cause problems with skin irritation, which in combination with the considel able size (i.e., area of release) of the TTS may be probleniatic. Also„the large amount of excess drug m the Y S aty to sustain enough driving force for sustaining the appropriate drug delivery over the long period of tixne is costly and has thc potential to bc subjecx to Hlicit tisc. m003] lt is therefore desirable to reduce the ovexaH size (i.e., area ot release') of tbc YTS as wcH as thc total axnouBt Qf buprcBorphillc in thc Yi S bcforc ustratlon and also thc axnouxlt rc'xBalBlng in thc I I S atter ' usc, thc residual lt. v, the axnount of dnlg available for ilHcit use (before and affer proper use). and the amount to be wasted affer proper use are both reduced. US Patent Application +o r:010/01 195ti?Q describ s 8 ccltaxn 1 1S size and axBouxlt. Qf drug reduction in comparison with the commercial TTS product Transtec® approved for an up-to-4 days administration regimen. Thus, the TTS needs to be replaced after 4 days at the latest. It is recommended to change ec® twice a week always on the same days at specific times, e.g. Monday mornings and Thursday evenings.

[004] For convenience reasons it is, however, desirable to maintain the once weekly exchange mode (7 day dosing regimen) as, e.g., ed by the commercial product Norspan® d of the every three to four days exchange mode as provided by, e.g., Transtec®.

All references and publications cited herein are hereby orated by reference in their enteritis for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION [005a] A first aspect of the invention provides for use of a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a orphinecontaining self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said orphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, wherein said polymer-based pressure-sensitive adhesive is based on polysiloxanes or polyisobutylenes, b) an sically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid ed from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed ts in the said pressure-sensitive adhesive, for the manufacture of a medicament for the treatment of pain, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer, and wherein the ermal eutic system is for application to the skin for about 168h. (11591431_1):KZA [005b] A second aspect of the invention provides for method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine in accordance with the first aspect of the invention comprising the steps of 1. providing a buprenorphine-containing adhesive mixture or solution sing a) buprenorphine base or a pharmaceutically acceptable salt thereof b) a carboxylic acid, c) a polymer-based re-sensitive adhesive, wherein said polymer-based pressure ive adhesive is based on polysiloxanes or obutylenes, and d) solvent, 2. coating said buprenorphine-containing adhesive mixture or solution on a film in an amount to e the desired g dry weight, 3. drying said coated buprenorphine-containing adhesive mixture or solution to provide a buprenorphine-containing adhesive layer with the desired coating dry weight, 4. laminating said buprenorphine-containing adhesive layer to a backing layer to provide an buprenorphine-containing self-adhesive layer structure, . punching the individual systems from the buprenorphine-containing selfadhesive layer structure with the desired area of release, and 6. optionally ng to the individual systems an active-free dhesive layer structure comprising also a backing layer and an active agent-free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer structure.

It is an object of n embodiments of the present invention to provide a ermal therapeutic system for the transdermal administration of buprenorphine (e.g., buprenorphine base), which requires a relatively small amount of buprenorphine (e.g., buprenorphine base) contained therein.

It is an object of certain embodiments of the present invention to provide a transdermal therapeutic system for the transdermal administration of buprenorphine (e.g., buprenorphine base) which requires a relatively small area of release.

AH26(12048217_1):JIN It is an object of certain embodiments of the present invention to provide a transdermal therapeutic system for the transdermal administration of buprenorphine (e.g., orphine base) providing a release suitable for providing pain relief for about 168 hours sponding to 7 days or one week).

[009] These objects and others are accomplished by the present invention, which according to one aspect relates to a transdermal therapeutic system for the transdermal administration of buprenorphine (e.g., buprenorphine base), comprising a orphine (e.g., buprenorphine base) containing self-adhesive layer structure comprising (11161661_1):KZA PC T/IB2012/002973 A) a buprenorphine (e.g... orphinc base) imperEneablc g layer, 8) 8 buprcnorphlnc (c.g., orpllmc base) colllaEBEElg plcssurc-scBs!tive adhesive laycl on said buprcnorphillc-EEnpcrlncablc backing layer„ thc adhesive layer conlprlslng a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid ed from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures f, in an amount sufficient so that said analgesically effective amount of buprenorphine (e.g. buprenorphine base) is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer. [0010j According to further aspects the ion relates to a method of treating pain in a patient by ng a transdermal therapeutic system in accordance with the invention to the skin of a patient. in particular to a method of treating pain in a patient by applying a transdermal therapeutic system in accordance with the invention to the skin of said patient for more than about 96 hours (or for more than 4 days), or for about 120 hours (or for 5 days), or for about 144 hours (or for 6 days) or for about 168 hours (or for 7 days or for one week). [0011j According to one ic aspect, the invention relates to a method of treating pain in a patient by applying to the skin of said patient for about 168 hours (or for 7 days or for one week) a transdermal therapeutic system, sing a buprenorphine (e.g., buprenorphine base) containing self-adhesive layer structure comprising PC T/IB2012/002973 A) a buprenorphine (e.g., buprenorphine base) impermeable backing layer, B) a orphine (e.g., buprenorphine base) containing pressure-sensitive adhesive layer on said buprenorphine-impermeable g layer, the adhesive layer comprising a) at least one r-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group ting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures f, in an amount ient so that said analgesically effective amount of buprenorphine (e.g., orphine base) is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least one pressure-sensitive adhesive based on polysiloxane, b) an analgesically effective amount of buprenorphine base, and PC T/IB2012/002973 c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base e forms dispersed ts in said pressure-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the inventior. s to a method of treating pain in a patient by applying to the skin of said patient for about 168 hours (or for 7 days or for one week) a transdermal therapeutic system, comprising a buprenorphine base- containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine ontaining re-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer sing a) at least one pressure-sensitive adhesive based on polysiloxane, b) an analgesically effective amount of buprenorphine base, and c) levulinic acid, in an amount suff cient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid orphine base mixture forms sed deposits in said pressure-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer.

According to one aspect, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine, sing a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and PC T/IB2012/002973 8) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-unpeimeable backing lw'er tile adliesive layer coinpfiisino' a) at least one polynier-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt f, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of orphine is solubilized therein to form a mixture, and the ylic acid buprenorphine e forms dispersed ts in said re-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive ve layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

According to one aspect, the invention relates to a method of treating pain in a patient by applying to the skin of said patient for about 168 hours a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said orphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and PC T/IB2012/002973 c) 8 carboxylic acid selected from the group consistmg of oleic acid. 11Bolckc acKl Rnd nlc (fckd, lcviklkBlc acid and Bllxtul'cs fhcieof. Ul an t suffkcfcnt so Ehat said RITRlgcsfcRHy effective RInount of buprefToETihine is solubilized therein to form a e, and thc ylic acid bupk cnorphknc fnlxiln'c loriitis dispersed deposits Bl thc said prcssUi c-sensitive adhesive. (vhclclB said btiiplcnorphulc-coBfanBBg prcssure-scBslfivc adhesive laycl ks thc sknl 0,55 I contact lay cF Rnd coBfalns IBorc Ehafl about ktfg/cm or Inore thaB 0.6 ITEg/cnl" of bupFcflorphinc base or ail cqu'Blolar' RFBoUBt of 8 pharBIBccutkcally acceptable sal't thereof.

According to one aspect, the invention relates to a transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure sing A) a buprenorphine base-impermeable backing layer, and 8) 8 buprcBorphkBc base-contakIEiktg prcssUi c-scnsitivc adhesive laycl' on said buprenorphine base-inlpermeable backing layer„ the adhesive lavcr COFBPFiSlng a) at least one pressure-sensitive adhesive based on loxane, b) an sically ive amount of buprenorphine base, and c) lcviilhnkc acKI. IB RIE flnlount sUfflclcnt so 'that said RnalgcskcaHy cffcctivc Rfnoufif of bElplcnorphulc base ls hzcd thcl'ckB to 'korin 8 Inixrufc, RBd the EC RcEcl bupicnorptU'Bc base Blixtulc forms dispersed deposits in the said prcssure-seflsilive adhesive.

Evhcrein said buprenorphinc base-containing pressure-sensitive adhesive 1ayer Es the skirl contact layer RBd contains Blorc fhaB Rboul 0.55 IBg/cnl or Blorc than 0.6 Ing~'cm" buprenorphine base.

PC T/IB2012/002973 [001'7j Accordnig to one aspect, the invention relates to a method of treating pain i» a patieiit by applying to the skin ot said patient tor about. l 68 hours (or for 7 days oi' for orie week) a transdernial therapeutic system coiiiprising a buprcnorphine base- ning dhesv, e lager structure conipi Ising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least otic pressure-sensitive adhesive based mi polysiloxane, b) an analgesically ive arnourit ot buprenorpliine base, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a e, and the levulinic acid buprenorphine base e forms dispersed deposits in the said re-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 nip~'cm buprenorphine base, According to one aspect, the invention relates to a set of two to five ent transdermal therapeutic systems for the transdermal administration of orphine base selected from five different transdermal therapeutic systems, a first, a second, a third, a forth and a fifth ermal therapeutic system, each of the five different transdermal therapeutic systems comprising a buprenorphine-containing self- adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the ve layer comprising PC T/IB2012/002973 a) at. 1 ast one pfessiue-sensitive adhesive based on polysiioxanes, b) an analgesically eAective amount of buprenorphine base, and c) levulinic acid, in an amount sufficient so that said analgesically ive amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base mixture forms sed deposits in the said pressure-sensitive adhesive, wherein, the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.8 cm and contains from about 1 mg to about 4 mg buprenorphine base; the second transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive ve layer providing the area of release ranging from about 3 cm to about 9.5 cm and contains an amount of from about 3.5 mg to about 8 mg buprenorphine base; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm to about 19 cm and contains from about 6.5 mg to about 16 mg buprenorphine base; and the fourth transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 28.5 cm and ns f;om about 11.5 mg to about 24 mg orphine base; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive ve layer providing the area of release ranging from about 16 cm to about 38 cm and contains from about 15 mg to about 32 mg orphine base, wherein the five different transdermal therapeutic systems have increasing areas of release and amounts of buprenoiphine from the first to the fifth transdermal WO 88254 PC T/IB2012/002973 therapeulic system, in. paiticular For use in method of treating pain by applying one of said transdernial therapeutic systeYYES for about 1.68 hours on the skin of a patient. (0019j Accordilig to one aspect, the invention relates io a transdlermal cuhc systcnl colnprlslng bupl'cnoiphlnc lor Ehc ti HnsdcrnlRl 8dl'BinlsfraiEQB of buprenorphmc selected froln: 8 hrsi crmal therapeutic $ r'stem provldEEEg 8 size of fhc area of I clcasc rangulg groin about l cln to about ~1.8 crn' and ning an amount of said buprenorphinc froln 1 EYEg io about 'l rng buprcnorphlnc base QY' Hn equlrnolai REBQUEEt of 8 phainiaccutlcallv acceptable $8li thereof RYEd provldulg 8 BicRB A(!CE of morc tllan 8.000 pg. hr/Inl over about 168 hoUrs of adrmnlsfralaon RAcr 8 SEIEglc-dose HdirEImsfraf ion Io 8 subject population; 8 second trNEs(lcinlal fhcrapcutlc $%'sicm providing 8 s Izc of thc 8rca of c I'NiglBg froYB abioui 3 cD! Yo Hbouf 9.5 cYB Rnd coniHBMBg Rn Hmoul'it of said orphlnc f1oin about 3.3 Big fo about 8 mg buplcnorphlnc hRsc or Rn cqulmolRr 1 5 RIBount of 8 accuflcallx' acccpfHMC salt thereof Hnd provld Big 8 Bican AUCi of BEQYc than 16,000 pg. hr'Enl ovcY' about 168 hoUIS of administration Hficr 8 snlglc-dose RdYYEEBEstratEQEE fo R subgcct population; and 8 third fi'NIsdcrniRl therapeutic $%'stern provldEIEg R size of ihe 81'ca of I'clcasc r8Bglng front about 6 cnl io about 19 cln Rnd confalBEng 8B MYlounf of said orphhlc from Rbotii 6.5 DEg to about 16 Yllg buprcnoE phlBc bRsc or an cquntlolar HBEount of 8 Rccuflcallv ablc salt thcrcof RBd pfovidillg 8 BlcNE AbCt of EYIorc thaB 32 000 pg. hr/ml over about 1 b8 hours of adnnuistration after a smgle-dose HdIBBilstratlonl fo 8 sublccl. population: HIK1 a fourth transdermal Eherapeutic system providing 8 size ofthe area of r"lease rangnlg froIEE Hho'uf 12 cnl to about 28,5 clB HEEd conlalYUBg Rn RIBiiMBt of said hllprcBorphlil'lc from about 1 1,5 BEO io HboUi 24 trig bilprenorphiuc base QY' Rn cc[UEB iolHI' Hm oulii of 8 pharBiaceutlcallx' acccptahlc salt tllcreof Hnd prov idEIEg 8 YBCHB pU( t of inorc fhan 48 000 pg. hr/Enl ovcl HhoUi 168 hours of HdEBEEEEsrraf lou aficr 8. Single-dose adBIIBlstYailon fo R subgccf populRf, on: HEEd PC T/IB2012/002973 a fifth transdermal eutic system providing a size of the area of release ranging f;om about 16 cm to about 38 cm and containing an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a mean AUCt of more than 64,000 pg.hr/ml over about 168 hours of administration aAer a single-dose administration to a subject population, in ular for use in method of ng pain by applying said selected transdermal therapeutic system for about 168 hours on the skin of a patient.

According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from: a first transdermal therapeutic system providing a size of the area of release ranging from about 1 cm to about 4.8 cm and containing an amount of said buprenorphine &om 1 mg to about 4 mg buprenor=-hine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 pg/hr over about 168 hours of administration; a second transdermal eutic system providing a size of the area of release ranging from about"= cm 2 to about 9.5 cm 2 and containing an amountofsaid buprenorphine from about 3.5 mg to about 8 mg orphine base or an equimolar amourt of a ceutically able salt t and providing a nominal mean e rate of about 10 pg/hr over about 168 hours of administration; and a third transdermal therapeutic system providing a size ofthe area of release ranging from about 6 cm' to about 19 cm and containing an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean e rate of about 20 pg/hr over about 168 hours of administration; and a fourth transdermal therapeutic system providing a size of the area of release ranging from about12cm to about28. 5 cm and containing anamountofsaid buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a PC T/IB2012/002973 nominal mean release rate of about 30 pg/hr over about 168 hours of stration; a fifth transdermal therapeutic system providing a size ofthe area of release ranging from about 16 cm to about 38 cm and containing an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a l mean release rate of about 40 pg/hr over about 168 hours of administration, in particular for use in method of treating pain by applying said selected transdermal therapeutic system for about 168 hours on the skir. of a patient.

[0021] According to one aspect, the invention relates to a set of transdermal therapeutic systems including at least two transdermal therapeutic systems ed from the first, second, third, fourth ard fifth transdermal therapeutic systems as described in the previous paragraphs.

According to one , the invention relates to a method of treating pain in a patient by selecting for said patient the appropriate transdermal therapeutic system fiom the first, second, third, fourth and fifth transdermal therapeutic system as described in the previous paragraphs and subsequently applying said selected transdermal therapeutic system on the skin of said patient for about 168 hours.

According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the ermal administration of buprenorphine, wherein buprenorphine is t in the form of buprenorphine base and providing a non-cumulative release of orphine base as ed in a Franz diffusion cell with dermatomed human skin of 2 pg/cm to 10 pg/cm in the first 8 hours, 20 pg/cm to 80 pg/cm from hour 8 to hour 24, pg/cm to 80 pg/cm from hour 24 to hour 32, pg/cm to 120 pg/cm from hour 32 to hour 48, 40 pg/cm to 150 pg/cm from hour 48 to hour 72, 100 pg/cm to 300 pg/cm from hour 72 to hour 144, and WO 88254 PC T/IB2012/002973 pg/cm to 100 pg/cm from hour 144 to hour 168, in particular for use in method of treating pain by applying the transdermal eutic system for about 168 hours on the skin of a patient.

According to one aspect, the invention relates to a transdermal eutic system comprising buprenorphine for the transdermal administration of buprenorphine, wherein buprenorphine is present in the form of buprenorphine base and providing a non-cumulative release of orphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 pg/cm to 10 pg/cm in the first 8 hours, 20N, g/cm to 80 pg/cm from hour 8 24, p.g/cm to 80 pg/cm from hour 24 to hour 32, pg/cm to 120 pg/cm from hour 32 to hour 48, 40 pg/cm to 150 pg/cm' from hour 48 to hour 72, 100 N.g/cm to 300 pg/cm from hour 72 to hour 144, and pg/cm to 100 pg/cm from hour 144 to hour 168, and sing a buprenorphine base-containing self-adhesive layer structure comprising A) a orphine base-impermeable backing layer, and B)a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base, and optionally c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the carboxylic acid buprenorphine base solution forms dispersed deposits in the said pressure-sensitive adhesive, PC 12/002973 wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer, in particular for use in method of treating pain by applying the transdermal therapeutic system for about 168 hours on the skin of a patient.

Within the meaning of this invention, the term "transdermal therapeutic system" (or TTS) refers to the entire individual unit that is applied to the skin of a patient, and which ises the buprenorphine-containing self-adhesive layer structure and optionally an additional larger active-free self-adhesive layer ure on top of the buprenorphine-containing self-adhesive layer structure, which TTS es the percutaneous delivery of the active buprenorphine to the patient. During storage, such a TTS is normally located on a redetachable protective layer from which it is removed immediately before application to the surface of the patient' s skin. A TTS protected this way may be stored in a blister pack or a side sealed bag.

Within the meaning of this inventior. , the term "buprenorphine-containing self-adhesive layer structure" refers to the active containing structure providing the area of release of the active agem.

Within the meaning of this invention, "polymer-based pressure-sensitive adhesive" refers to a re-sensitive adhesive containing from 75% to 100% of said polymer based on the dry weight of the pressure-sensitive adhesive, e.g., 75% to 100% of polysiloxane. According to n embodiments the pressure-sensitive adhesive contains from 80% to 100%, or from 85% to 100%, or from 90% to 100%, or from 95% to 100% of the polymer (e.g., polysiloxane) based on the dry weight of the pressure sensitive adhesive. A pressure-sensitive adhesive is in part.'cular a material that adheres with finger pressure, is permanently tacky, exerts a strong holding force and should be removable from smooth surface without g a residue. Examples of useful pressure-sensitive ves based on polysiloxane which are commercially available include the rd Bio-PSA series (7-4400,7- 4500 and 7-4600 ), the amine compatible pped) Bio-PSA series (7-4100, 7-4200 and 7-4300 series) and the Soft Skin Adhesives series (7-9&00) manufactured by Dow Corning, Preferred pressure-sensitive adhesives based on polysiloxane are PC T/IB2012/002973 heptane-solvated re-sensitive ves including BIO- PSA 7-4201, BIO-PSA 7-4301, BIO-PSA 7-4501. [002S] Within the meaning of this invention, the term "additional larger active agent- free self-adhesive layer ure" refers to a self-adhesive layer ure that is free of active agent and larger than the active agent-containing structure and providing additional area adhering to the skin, but no area of release of the active agent, and enhancing y the overall adhesive ties of the TTS.

Within the meaning of this invention, the term "buprenorphine-containing pressure-sensitive adhesive layer" and "matrix layer" have the same meaning and refer to the layer ning the active in a matrix-type structure of active in- adhesive.

Within the meaning of this invention, the term "skin contact layer" refers to the part of the T'TS which is in direct contact with the skin of the patient during administration and is located in / co-extensive with the buprenorphine-contair. ing i5 self-adhesive layer structure. The sizes of the "skin contact layer" and the buprenorphine-containing self-adhesive layer structure are co-extensive and correspond to the area of release.

Within the meaning of this invention, the term it" refers to distinguishable, e.g., visually distinguishable, areas within the pressure-sensitive adhesive. Such deposits are e.g., droplets. Deposits that are visually distinguishable may be identified by use of a microscope.

Within the meaning of this invention, the parameter "mean cumulative skin permeation rate" is provided in pg/cm -hr and is calculated from the cumulative release as ed by in vitro experiments carried out with the Franz diffusion cell over the total time period of release, e.g., 168 hours, in pg/cm divided by the hours corresponding to said total time period of release, e.g., 168 hours.

Within the meaning of this invention, the parameter "mean non-cumulative skin tion rate" is provided in pg/cm -hr and is calculated from the non- cumulative release of a certain sample interval as measured in a Franz diffusion cell in pg/cm divided by the hours of said sample interval.

PC T/IB2012/002973 Within the meaning of this invention, the parameter "cumulative release" is provided in ij,g/cm and s to the total amount released over the total time period of release, e.g., 168 hours, as measured in a Franz diffusion cell. The value is a mean value of at least 3 experiments.

[0035] Within the meaning of this invention, the parameter umulative release" is provided in pg/cm' and s to the amount released in a sample interval at certain elapsed time within the total time period of release, e.g., hour 16 of release ponding to a sample interval of 8 hours from hour 8 to hour 16 of release within 168 hours of total time period of release, as ed in a Franz diffusion cell. The value is a mean value of at least 3 experiments.

Within the meaning of this invention, the parameter "mean e rate" refers to the mean release rate in pg/hr over the period of administration (e.g., 7 days) by which the active agent permeates through the human skin into the blood system and is based on the AUC obtained over said period of administration in a al study.

Within the meaning of this invention, the parameter "nominal mean release rate" refers to an assigned mean release rate determined by comparison with the ccmmercial reference product BuTrans which is applied for 7 days to the skir of the subjects and of which mean release rates are publicly available from the package insert. The ponding known nominal mean release rate of the 25 cm area of release BuTrans reference TTS containing 20 mg buprenorphine is 20 pg/hr. The mean release rate is proportional to the size of the area of release of a TTS and may be used to distinguish TTSs by the dosage strength. The BuTrans@ TTS with half the size (i.e. 12.5 cm area of release) and containing 10 mg of buprenorphine provides the known nominal mean release rate of 10 pg/hr. The s TTS with a size of 6.25 cm area of release and containing 5 mg of buprenorphine provides the known nominal mean release rate of 5 pg/hr. Accordingly, it can be assumed that a ponding TTS with a size of 50 cm 2 area of release and containing 40 mg ot buprenofplH!ke provicies a nominal mean release rale ot 40' )ig/hr, and a corresponding TTS with a size of 37,5 cm area. Are/ease and containing 30 mg ot PC T/IB2012/002973 buprenorphine provides a nominal mean release rate of "-0 pg/hr. The nominal mean e rates are assigned to the TTSs in accordance with the invention based on bioequivalence considerations by at least comparing the mean AUCt ofthe reference TTS s with the mean AUCt of the TTSs in ance with the invention obtained in the same clinical study.

W&thm the meBJltng ot tl'Hs (nvenAon. , the rneanutg of by applyntg ho the skut of said patient for about 168 hours" corresponds to "by applying to the skin of said patient for about 7 days or for one week" and refers to a once a week exchange mode or dosing regimen. Likewise, about 96 hours pond to 4 days, about 120 hours correspond to 5 days and about 144 hours correspond to 6 days. The term "applying to the skin of a patient for a certain period of time" has the same meaning as "administration for a certain period of time", Within the g of this invention, the term "patient" refers to a subject who has presented a clinical manifestation of a particular symptom or symptoms ting the need for treatment, who is treated preventatively or prophylactically for a condition, or who has been diagnosted with a condition to be treated.

If not indicated otherwise "%"refers to weight-%.

Within the meaning of this invention, the term "active", "active agent", and the like, as well as the term "buprenorphine" refers to buprenorphine base or a pharmaceutically acceptable salt thereof. Unless ise indicated the s of buprenorphine in the TTS relate to the amount of buprenorphine before administration ofthe TTS. The amounts ofbuprenorphine in the TTS after administration are referred to as residual amounts.

Within the meaning of this invention, values and ranges specifying the size of the area of release and the amount of buprenorphine contained in the transdermal therapeutic system are mean values of at least 3 measurements.

Within the meaning of this invention the term "pharmacokinetic parameters" refers to parameters describing the blood plasma curve, e.g. Cmax, AUCt and AUCINF obtained in a clinical study, e.g. by single-dose administration ofthe active agent TTS, e.g., the buprenorphine base TTS to healthy human subjects. The PC T/IB2012/002973 pharmacokinetic parameters of the individual ts are summarized using arithmetic and geometric means, e.g. a mean Cmax, a mean AUCt and a mean AUCINF, and additional tics such as the respective standard deviations and standard , the minimum value, the maximum value, and the middle value when the list of values is ranked (Median). In the context of the present invention, pharmacokinetic parameters, e.g. the mean Cmax, the mean AUCt and the mean AUCINF refer to geometric mean values if not indicated otherwise. It cannot be precluded that the absolute mean values obtained for a certain TTS in a al study vary to a certain extend &om study to study. To allow a comparison of absolute mean values between studies, a reference ation, e.g. the commercial reference product BuTrans or in the future any product based on the invention, may be used as internal standard. A comparison of the AUC per area of e, e.g. the mean AUCt per area of release of the respective reference product in the r and later study can be used to obtain a correction factor to take into account dif;erences from study to study. al studies according to the present invention refer to s performed in full compliance with the International Conference for Harmonization of Clinical Trials (ICH) and all applicable local Good Clinical Practices (GCP) and regulations.

Within the meaning of this invention, the term "healthy human subject" refers to a male or female subject with a body weight ranging from 55 kg to 100 kg and a body mass index (BMI) ranging from 18 to 29 and norma! physiological parameters, such as blood re, etc. Healthy human subjects for the purposes of the present invention are selected according to inclusion and exclusion criteria which are based on and in accordance with recommendations of the ICH.

[0046] Within the meaning of this invention, the term "subject population" refers to at least ten individual healthy human subjects.

Within the meaning of this invention, the term "geometric mean" refers to the mean of the log transformed data backtransformed to the original scale.

Within the meaning of this invention, the term "arithmetic mean" refers to the sum of all values of observation divided by the total number of observations, PC T/IB2012/002973 Within the meaning of this invention, the ter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the amount of active agent absorbed into the blood circulation in total and is hence a measure for the bioavailability.

[0050] Within the meaning of this invention, the parameter "AUCt" is ed in pg. hr/ml and relates to the area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration and is calculated by the linear trapezoidal method.

Within the meaning of this invention, the parameter "mean AUCt per area of release" is provided in pg.hr/ml-cm and is calculated from the geometric mean AUCt as determined for a certain TTS in pg.hr/ml divided by the area of e of said TTS.

Within the meaning of this invention, the parameter "AUCINF" is provided in pg. hr/ml and relates to the area under the plasma tration-time curve extrapolated to infinity and is calculated using the formula: AUCINF = AUCt+ where CLast is the last measurable plasma concentration and LambdaZ is the nt terminal phase rate constant.

Within the meaning of this invention, the parameter "Cmax" is provided in pg/ml and and relates to the maximum observed blood plasma concentration of the active agent.

Within the g of this invention, the parameter "tmax" is provided in hr and s to the time point at which the Cmax value is reached. In other words, tnax is the time point of the maximum observed plasma concentration.

[0055] Within the meaning of this invention, the parameter "LambdaZ" is provided in I/hr and relates to the apparent terminal phase rate constant, where LambdaZ is the magnitude ofthe slope of the linear regression of the log concentration versus time profile during the terminal phase.

WO 88254 PC T/IB2012/002973 W ithui thc g ot this uivcnrion& thc parameter 'il/:,Z' is provided in lir and relates to thc appRrcnt plasma terna!Bat phase halt-I inc and is coBBBonlv dctcriruiied as t I/2Z —(IB2)!LambdaZ, A ithin thc i'Bcanhig of IHBs invention. thc tcriB incan plasiria concentration' is ed in pg/m. ' and is a nican of thc individua( plasma coBccntiatioBs ot active agent, e.g. buprenorphine base, at each poirt in time.

Within the meaning of this invention, the term "b'oequivalent" is defined to refer to a T.S that provides geometric mean values of Cmax, AUCt, and AUCINF for buprenorphine, wherein the 90'/0 confidence intervals estimated for the ratio test/reference fall within the range of 80.00/o to 125.0010.

HRIKF DKSCRIPYK)Iv, OF THE LIRA'O'INGS Fig. I depicts the mean non-cumulative skin permeation rate for Examples 1 to 4 and Norspan.

Fig. 2 depicts the mean mulative skin permeation rate of the ermal therapeutic systems. The area of release of the transderinal therapeutic systems according to Examples I to 4 being 10 cm' and the area of release for Norspan being 25 cm . The amount of buprenorphine base for es I to 4 being 12 mg and the amount ofbuprenorphine base for Norspan being 20 mg.

Fig. 3 depicts the mean non-cumulative skin permeation rate for Comparative Example 5 and Norspan.

Fig. 4 depicts the mean non-cumulative skin permeation rate of the of the transdermal therapeutic systems. The area of release of the transdermal eutic system according to Comparative Example 5 being 15 cm and the area of e for Norspan being 25 cm . The amount of buprenorphine base for Comparative Example 5 being 6.75 mg and the amount of buprenorphine base for Norspan being mg.

Fig. 5 depicts the mean plasma concentration for es 1 and 2, Comparative Example 5 and BuTrans. The area of release ofthe transdermal PC T/IB2012/002973 therapeutic systems according to Examples 1 and 2 being 10 cm, the area of release of the transdermal therapeutic systems according to Comparative Example 5 being cm and the area of release for BuTrans being 25 cm . The amount of buprenorphine base for Examples 1 and 2 being 12 mg, the amount of buprenorphine base for ative Example 5 being 6.75 mg and the amount of buprenorphine base for BuTrans being 20 mg.

DKTAII.KD DKSCRIPY'MN According to the invention wherein the structure is concerned, the TTS for the transdermal administration of buprenorphine ses a orphine- containing dhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive ve layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a ylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of orphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer, WO 88254 PC T/IB2012/002973 According to an aspect of the invention the TTS for the transdermal administration of buprenorphine base comprises a buprenorphine base-containing self-adhesive layer structure sing A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the ve layer comprising a) at least one re-sensitive adhesive based on polysiloxane, b) an analgesically effective amount of bupi-enorphine base or a pharmaceutically acceptable salt thereof, and c) levulinic acid in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized n to form a mixture, and the levulinic acid buprenorphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer. Hence, the TTS according to the invention allows no additional layer in between the buprenorphine base-containing pressure-sensitive adhesive layer and the skin.

I0066j According to ceitain red embodiments. the invention relates to a TYS with a buprenorphine-containing self-adhesive layer structure consisting essentia!lv A) a buprenorphine base-impermeable backing layer, and B) a orphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least one re-sensitive adhesive based on polysiloxane, .

PC T/IB2012/002973 b) an analgesically ive amount of buprenorphine base or a pharmaceutically able salt thereof, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized n to form a mixture, and the levulinic acid orphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive.

According to certain embodiments of the invention, the TTS comprises in on to the buprenorphine-containing self-adhesive layer structure attached thereto a larger active agent-free dhesive layer structure, e.g., a eral adhesive or overlying adhesive, for enhancing the adhesive properties of the overall transdermal therapeutic system. Said active free self-adhesive layer structure ses also a backing layer, e.g., beige colored, and in this case an active agent free pressure-sensitive adhesive layer of polymer-based pressure-sensitive adhesive, e.g., based on polyacrylates or polysiloxane. The area of said second active agent agent-free self-adhesive layer structure adds to the overall size of the TTS but does not add to the area of release. The pressure-sensitive adhesive in the active agent containing and the active agent-free self-adhesive layer structures may be the same or different. If the adhesive in the active agent free self-adhesive layer is different from that ofthe buprenorphine-containing layer, then pressure-sensitive adhesives selected from the group of poly acrylate based or poly isobutylene based pressure- sensitive adhesives can be used, and poly acrylate based pressure-sensitive adhesives are preferred, in particular re-sensitive adhesives based on an acrylate- vinylacetate polymer, e.g., such as those available from Henkel under the tradename Duro Tak, e.g., Duro Tak 387 2051. Such pressure-sensitive adhesives are provided in an organic solution of ethyl acetate and heptane. Such pressure-sensitive adhesives provide a 180'Peel at 20 minutes of at least about 20 , and at 24 minutes of at least about 25 N/25cm, and at one week of at least about 30 N/25mm and a Loop tack of at least 15 N/25mm, or of at least 20 N/25mm, or of at least 22 N/25mm~, PC T/IB2012/002973 ACTIVE AGENT The TTS according to the invention compr.'ses an analgesically effective amount of buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof. ceutically acceptable salts may be selected from those known in the art, such as the hydrochloride, sulphate, phosphate, tartrate, maleinate, oxalate, acetate and lactate salts. According to a preferred embodiment of the invention the active agent is buprenorphine base.

[0069] An analgesically effective amount may vary from about 1 mg to about 50 mg, in particular from about 2 mg to about 30 mg of orphine base or an lar amount of a pharmaceutically acceptable salt, or from about 2 mg to about 25 mg of buprenorphine base or an equimolar amount of a phar naceutically acceptable salt thereof. ing to certain ments, the TTS contains according to five different dosages from about 1 mg to about 4 mg, or from about 3.5 mg to about 8 mg, or from about 6.5 mg to about 16 mg, or from about 11.5 mg to about 24 mg, or from about 15 mg to about 32 mg of buprenorphine base or a an equimolar amount of a pharmaceutically acceptable salt thereof, or the TTS contains according to five different dosages from about 1 mg to about 4.5 mg, or about 3 mg, or from about 4 mg to about 9 mg, or about 6 mg, or from about 8 mg to about 14 mg, or about 12 mg, or from about 15 mg to about 20 mg, or about 18 mg or from about 20 mg to about 28 mg, or aboui 24 mg of orphine base or a an equimolar amouiit of a pharmaceutically acceptable salt thereof.

PRESSURE-SENSITIVE ADHESIVE The Pressuie-sensitive adhesives used for the present invention are polymer- based pressure-sensitive adhesives. Such polymer-based pressure-sensitive ves may e.g., be based on polysiloxanes or polyisobutylenes. For the present invention polysiloxane based pressure-sensitive adhesives are preferred. Such polysiloxanes PC 12/002973 adhesives need, unlike other organic pressures-sensitive adhesives, no additives like antioxidants, stabilizers, plasticizers, catalysts or other potentially extractable ingredients. These pressure-sensitive ves provide for suitable tack for quick bonding to various skin types, ing wet skin, suitable adhesive and cohesive qualities, long lasting adhesion to the skin of up to 7 days, a high degree of ility, a permeability to moisture, and ibility to many actives and film- substrates. It is possible to provide them with ient amine resistance and therefore enhanced stability in the presence of amines. Such pressure-sensitive adhesives are based on a resin-in-polymer concept wherein, by condensation reaction of silanol end blocked polydimethylsiloxane with a silica resin, a polysiloxane is prepared which for amine stability the residual silanol functionality is additionally capped with trimethylsiloxy groups. Tne dimethiconol content contributes to the viscous component of the visco-elastic or, and impacts the wetting and the spreadability properties ofthe adhesive. The resin acts as a tackifying and reinforcing agent, and participates in the elastic ent. The correct balance between dimethiconol and resin provides for the correct adhesive properties.

The adhesive strength ofthe polysiloxanes may be sufficient for the desired skin contact. In certain embodiments of the invention a plasticizer or a ying agent is incorporated into the formulation to improve the adhesive characteristics of the re-sensitive adhesive layer. It may be advantageous in an individual case to improve the tack by adding small amounts of tackifiers such as polyterpenes, rosin derivatives, or silicone oils. In preferred embodiments, the tackifying agent is a ne oil (e.g., 360 Medical Fluid, available from Dow Corning Corporation, Midland, Mich. ).

[0072] The pressure-sensitive adhesives are supplied and used in solvents like e, ethyl acetate or other volatile silicone fluids. For the prese .t invention heptane is preferred. The solids content is usually between 60 and 80 %.

The preferred pressure-sensitive adhesives based on loxanes in accordance with the invention are characterized by a solution viscosity at 25'C and 60 % solids content in heptane of more than about 150 mPa s, or from about PC T/IB2012/002973 ,00 BiPa s 'Lo about 700 I'AP8 s, in particular ffoni RboUE 350 BEPR s to about 600 mPa s, more preferred &om about 480 mPa s to about 550 mPa s, or most preferred of about 00 mPa s or alternatively from about 400 IAPR s to about 480 rAPa s, or most preferred of about 4""0 mPR s . Theses may also be characterized by a complex viscosity at 0.01 rad/s at:0 C of less than about 1 x10 Poise Qr from about t0 RboUt 9x10 POESC, Qr BiorC piefCIrCIl &Om about 1 x10 to abOUt 1 x10 1 x10' Poise, ol. Biosr pic fcrrcil about 5x 0" Poise 1E ol IEltcrEiativclv n'lore preferred frOm abOUt 2x 0' tO 1 abOut 9x O' POISe„OIIBOSt Ted 1 abOut 1 x 1 0" POESe.

Suitable pressure-sensitive adhesives based on polysiloxanes may be obtained from DQEv CorEEEng@3 BIO-PSA Standard Slhcone Adhesives. Pleterred are the BIO- PSA ". 4301 and BIO-PSA ", 4201 Silicone ves. According to certain embodntients BI()-PSA 7 4301 Es preterred and mg to ceitmn other embodiments A 7 4a01 issprctcrrcd, BIO-PSA 4201 has 8 sohitlorE viscosity Rt 25'( Rnd al QUt 60 /o solid~ conlcnl Bi hcptRBc of 4y0 rBPR s and 8 coinplcx vlscositv Rt 0 01 rad/s ar 30"C of 1 x10 Poise. A 4301 has 8 solution viscosity Rt 25' C Rncl about 60 io solids t IB IC of 500 BIPR s Rild 8 complex viscosity at 0.01 rad/s 81 30'"C Qf 5x10' Poise.

I hc pI'cssurc-scnslnvc Rdhcslvc )ay cr ot thc I'IS of thc Invention Diay fUI ther comprise iri addition to thc above EBCEIr!QBcd Engrcdieiits EE), b) Rnd c), BREBcly 8 polynicr-bascll prcssure-scnsltlvc Rdhcslvc. , thc bupr'CBorphinc and thc carboxylic acid selected fTQIB thc group Qt olclc acid. , hnolclc acid, lEnolcnic acid Rnd lcvuImlc acid Rs described hei cul., Qtlilcr val ious cxcipients Qr Rdditlvcs, foI' cxanlpllc fl oirE tfEc groUp Qf solubillzcrs, fEHcrs, Eackificis, sUbstanccs vvhlch Biflucncc tlte r pl'opcltics of Ehc srrarum corncuni ui thc scnsc ot incr'casiBg t)Ic active RgcBt perineability, pH rcgulRtors, REId prcscrvativcs.

Substances Wvhich influcilcc thc baiTlcr plopcrtlcs Qf rhc m cornctun Hl the sense ot incl.easmg the active agent perineabHity Rre n to the skiHed vvorker and the substance apprc priate for the respective active agents Ernlst-if necessary-be lounel by rncans of pciAIcation studies. Soine CXRIBplcs arc lh le Rlcohols such 8s dipropylcnc glycoi. propvlcnc glvcol, Nid polvcthylcnc glycol," oills such as ohvc PC T/IB2012/002973 oil, squalene, and n; fatty ethers such as cetyl ether and oleyl ether; fatty acid esters such as isopropyl myristate; urea and urea derivatives such as allantoin; polar solvents such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethyllaurylamine, dodecylpyrrolidone, bitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide, and ylformamide; salicylic acid; amino acids; benzyl nicotinate; and higher molecular weight aliphatic surfactants such as lauryl sulfate salts. Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. The TTS of the ion may addirionally comprise according to n embodiments in which the pressure- sensitive adhesive layer ses a) the polymer-based pressure-sensitive adhesive, b) the buprenorphine and c) levulinic acid or linolenic acid or mixtures of both as the carboxylic acid as described herein, oleic and linoleic acids as substances influencing the barrier properties of the stratum corneum in the sense of increasing the active agent permeability.

Such substances as described in the previous aph may be included in a TTS and may be t in an amount of about 1%to about 10% by weight. In a preferred embodiment of the present invention such onal nces are however not necessary. According to an embodiment of the invention the TTS does not comprise such additional substances as mentioned in the previous paragraph.

In addition to the carboxylic acid selected from oleic acid, linoleic acid, linolenic acid, levulinic acid, the lity of the drug can be f'urther altered by the optional addition of an agent that increases the solubility of drug or inhibits drug crystallization in the transdermal composition, such as polyvinylpyrrolidone, vinyl acetate/vinylpyrrolidone copolymer and cellulose derivatives.

Viscosity-increasing substances are preferably used in conjunction with an active agent solution. Suitable substances for increasing the viscosity of the active agent solution are, for exan-. pie, cellulose derivatives such as ethylcellulose, hydroxylpropylcellulose and high molecular mass rylic acids and/or their salts and/or their derivatives such as esters.

PC T/IB2012/002973 [OOSO] Fillers such as silica gels, titanium dioxide and zinc oxide may be used in conjunction with the polymer in order to influence certain physical parameters, such as cohesion and bond strength, in the desired way.

BUPRENORPHINE-CONTAINING SELF-ADHESIVE LAYER STRUCTURE In accordance with the invention, the orphine-containing self-adhesive layer structure comprises a buprenorphine-impermeable backing layer, and a buprenorphine-containing pressure-sensitive ve layer coated thereon. In a preferred embodiment, the buprenorphine-containing self-adhesive layer structure consists of these two elements.

The buprenorphine-containing pressure-sensitive adhesive layer may be coated ai any dry weight, but is preferably coated at a dry weight of more than about 6 mg/cm (about 60 g/m ), or of more than about 8 mg/cm (about 80 g/m ), or ranging from about 6 mg/cm (about 60 g/m ) to about 14 mg/cm (about 140 g/m~), or from about 8 mg/crn (about 80 g/m ) to about 14 mg/cm (about 140 g/m ). ically, the dry weight is more than about 10 mg/cm (about 100 g/m ), or ranges trom about 10 mg/cm (about 100 g/m ) to about 13 mg/cm (about 130 g/m ), or ranges from about 11.5 mg/cm (about 115 g/m ) to about 12.5 mg/cm (about 125 g/m ), or is specifically about 12 mg/cm (about 120 g/m ).

The dry buprenorphine-containing pressure-sensitive adhesive layer ably contains buprenorphine base, but may contain equimolar amounts of pharmaceutically acceptable salts. According to the invention preferably more than %, or more than about 6%, or more than about 7%, or more than about 8%, or more than about 9%, or from about 6% to about 20%, or from about 7% to about 20%, or from about 8% to about 20%, or from about 9% to about 20%, or from about 6% to about 15%, or from about 7% to about 15%, or from about 8 to about 15% or from about 9 to about 15% orphine base or equimolar amounts of pharmaceutically acceptable salts based on the total dry weight of the dry buprenorphine-containing pressure-sensitive ve layer are contained in the dry buprenorphine-containing PC T/IB2012/002973 re-sensitive adhesive layer. In a specific embodiment, about 10% buprenorphine base is contained in the dry buprenorphine-containing pressure- sensitive ve layer.

Preferably, the TTS contains in the pressure-sensitive adhesive layer more than about 0.55 mg/cm, or more than about 0.6 mg/cm, or moie than about 0.7 mg/cm, or more than about 0.8 mg/cm, or more than about 0.9 mg/cm, or more than about 1 mg/cm, or more than about 1.1 mg/cm, buprenorphine base, or from about 0.55 mg/cm to about 2 mg/cm, or from about 0.6 mg/cm to about 2 mg/cm, or from about 0.7 mg/cm to about 2 mg/cm, or from about 0.8 mg/cm to about !0 2 mg/cm, or from about 0.9 mg/cm to about 2 mg/cm, or from about 1 mg/cm to about 2 mg/cm, or from about 1.1 mg/cm to about 2 mg/cm buprenorphine base or contains about 1.2 mg/cm buprenorphine base. The TTS may also contain equimolar amounts of pharmaceutically acceptable salts.

In order to provide the desired delivery rate of buprenorphine, a carboxyclic acid is present. The ylic acid may be selected from the group ting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, wherein levulinic acid is preferred. The buprenorphine is in mixture with, e.g., dissolved in, the carboxylic acid, e.g., the levulinic acid, and this mixture, e.g., solution, is dispersed in the form of small deposits, e.g., droplets, in the matrix layer.

Buprenorphine, with its known physicochemical properties, namely its poor lity, its comparatively high melting point of 216' C, and its high molecular weight, tends readily towards crystallization. For this reason, a solubilizer with at least one acidic group is used in order to prevent the buprenoiphine from crystallizing during the e of the pharmaceutical form. Buprenorphine and levulinic acid have an extremely low solubility in polysiloxanes. As a consequence of this, it is le to solubilize buprenorphine in levulinic acid and to disperse this re in the form of small deposits in a matrix layer prepared on the basis of polysiloxanes as described herein. [00S6] Levulinic acid is sparingly soluble in the organic solvents of the adhesives.

Consequently, the liquid mixture ofbuprenorphine and levulinic acid can be WO 88254 dispersed in the solution of the adhesive, with the dispersion being retained ing removal of the solvent. In a matrix layer of this kind, the solubility of the buprenorphine is dependent virtually only on the amount ofthe levulinic acid.

The amount of the dispersed mixture of buprenorphine, e.g. , buprenorphine base, and the carboxylic acid, e.g., nic acid, can be up to about 40'/o by weight, it being red not to exceed about 25'/o or about 20'/o by weight and ranges from about 15'/o to about 25'/o, or from about 15'/o to about 20'/o, or Rom about 1 7'/o to about 20/o. The deposit„e.g., t, size (diameter) itself ought preferably not to exceed about 150 pm, or ranges from about 1 to about 150 pm, preferably from about 1 to about 50 pm, or from about 5 to about 50 ljm, or from about 1 to about 25 pm or from about 5 to about 25 pm. The preferred size is dependent, furtl-. ermore, on the thickness of the matrix layer.

Since the carboxylic acid, e.g., the levulinic acid, can likewise be absorbed through the skin, the amount in the TTS becomes less as the t me of application elapses, and leads to a reduction of the solubility of buprenorphine. As a , the decrease in the thermodynamic activity of buprenorphine due to depletion is compensated by the reduced drug solubility in the buprenorphine/levulinic acid deposits.

According to the invention the dry orphine-containing pressure- sensitive adhesive layer contains more than about 5'/o, or more than about 6'/o, or more than about 7/o, or more than about 8'/o, or more than about 9'/o, or from about 6'/o to about 20'/o, or from about 7/o to about 20'/o, or from about 8 to about 20'/o, or from about 9 to about 20'/o, or from about 5 '/o to about 15'/o, or from about 6 '/o to about or from about 6 /o to about 9/o, or from about 9 '/o to about 15 /o 1 5/o, carboxylic acid, e.g., levulinic acid based on the total dry weight of the dry buprenorphine-containing pressure-sensitive adhesive layer. In a specific embodiment the dry buprenorphine-containing pressure-sensitive adhesive layer contains from about 6'lo to about 1 1'/o levulinic acid, or from about 6 '/o to about 9'/o or from about 9 /o to about 15'/o levulinic acid, or about 7'/o levulinic acid or about 10/o levulinic acid. According to a specific embodiment the pressure-sensitive PC T/IB2012/002973 adhesive layer contains the same %-amount of levulinic acid and buprenorphine base or equimolar amounts of pharmaceutically acceptable salts. ing to another ic embodiment, the pressure-sensitive adhesive layer contains less %-amount of levulinic acid than it contains %-amount of buprenorphine base or lar amounts of pharmaceutically able salts.

According to a ic embodiment, the pressure-sensitive ve layer contains from more than 9% to about 15% buprenorphine base and from about 6% to about 9% levulinic acid or from more than 9% to about 15% buprenorphine base and from about 9% to about 15% levulinic acid based on the total dry weight.

[0091] According to a certain embodiment the pressure-sensitive adhesive layer is coated at a dry weight of from about 10 mg/cm to about 14 mg/cm, or from about 11.5 mg/cm to about 12.5 mg/cm or is about 12 mg/cm, and the dry pressure- sensitive adhesive layer contains fiom about 7% to about 13% or from about 8 % to about 12 %, or from about 9 % to about 11%or about 10% buprenorphine base and from about 6 % to about 8%, or about 7% levulinic acid. In a specific embodiment the dry pressure-sensitive ve layer has a dry weight of about 12 mg/cm and contains about 7% levulinic acid and about 10% buprenorphine base.

According to a certain otlier embodiment, the pressure-sensitive adhesive layer is coated at a dry weight of from about 10 mg/cm to about 14 mg/cm, or fi-om about 11.5 mg/cm to about 12.5 ing/cm, or is about 12 mg/cm, and the dry pressure-sensitive adhesive layer contains from about 7 % to about 13% or from about 8 % to about 12 %, or from about 9 % to about 11%or about 10% buprenorphine base and from about 8 to about 12 % or about 10% levulinic acid. In a specific embodiment, the dry pressure-sensitive adhesive layer has a dry weight of about 12 mg/cm, and contains about 10% levulinic acid and about 10% buprenorphine base.

In accordance with the above, the TTS contains more than about 0.55 mg/cm, or more than about 0.6 mg/cm, or more than about 0.7 mg/cm, or more than about 0.8 mg/cm, or more than about 0.9 mg/cm, or more than about 1 mg/cm, or more than about 1.1 mg/cm buprenorphine base or from about 0.6 PC T/IB2012/002973 B to 8bouf 2 mg/cn1, or from about 0. I 1 to about ": 111@/cnx . or front about 0.8 mv/cnr to about 2 1|1@'cion',or Born about 0,9 mg cm to about 2 rng cm', or fmrn about 1 mg/cm (0 about 2 B1g/cm . or froYB about 1.l n ro Rbout 2 Klg/cm buprcnorphinc base o1 confa1ns about f. .2 Btg/ctn buprcnorphine base or 8B cq!Bmolar Hrnounf of 8 p11NTBRccut1cRHy acceptable sajt thereof, buprcnorphrnc base rs prc(crrcd, Acco1durg to 8 sp c1frc cmbodHBcrrt, thc pfcssu1'c-scnstfrvc adhcs1vc layer contains the same s of levulinic acid and buprenorphine base.

According to another specific embodiment, the pressure-sensitive adhesive layer contains less levulinic acid than it contains buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

According to a certain embodiment of the ion, the pressure-sensitive adhesive in the orphine-containing layer and in the active agent-free layer are ent, and the adhesive in the active agent-free layer is a pressure'-sensitive adhesive based on polyacrylates. According to certain other embodiments the adhesive in the active agent-containing and the active free layer are the same and are an amine-resistant pressure-sensitive adhesive based on polysiloxane wherein the polysiloxane is a product of the condensation reaction of silanol endblocked polydimethylsiloxane with a silica resin and the residual silanol functionality is capped with trimethylsiloxy groups and terized by a solution viscosity at 25'C and about 60% solids content in heptanes of about 500 mPa s or of about 450 mPa s, and the orphine-containing layer pressure-sensitive adhesive layer is coated at a dry weight of about 12 mg/cm and contains about 10% Buprenorphine base and about 10% levulinic acid.

According to certain embodiments, the area of release ranges from about 1 cm to about 38 cm', or the area of release is less than 25 cm, or less than 22 cm, or ranges from about 1.5 to about 25 cm, or from about 1.5 to about 22 cm, or from about 1.5 to about 20 cm, or is about 3 cm or about 6 cm, or about 10 cm, or about 15 cm or about 20 cm, According to certain embodiments, the TTS contains from about 1 mg to about 32 mg ofbuprenorphine base or an equimolar amount of a pharmaceutically PC T/IB2012/002973 acceptable salt thereof, or from about 1 mg to about 28 mg, or 2 mg to about 25 mg, or from about 2 mg to about 24 mg of buprenorphine base or an equimolar amount of a pharniaceutically acceptable salt thereof. Considering five different increasing dosage strengths, the TTS in specific cases preferably contains a) from about 1 mg to about 4 mg, or from about 1 mg to about 4.5 mg, preferably from about 1 mg to about 3.5 mg, or from about 2 mg to about 4 mg, more preferably from about 1 mg to about 3 mg, or from about 2.5 mg to about 4 mg, or about 3 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt f, or b) from about 3.5 mg to about 8 mg, or from about 4 mg to about 9 mg, preferably Rom about 3.5 mg to about 7 mg, or from about 5 mg to about 8 mg, more preferably from about 3.5 mg to about 6 mg, or from about 5 mg to about 7 mg, or about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or c) from about 6.5 mg to about 16 mg, or from about 8 mg to about 14 mg, preferably from about 6.5 mg to about 14 mg, or from about 10 mg to about 14 mg, more preferably from about 6.5 mg to about 11 mg, or from about 11 mg to about 13 mg, or about 12 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or d) from about 11.5 mg to about 24 mg, or from about 15 mg to about 20 mg, preferably from about 11.5 mg to about 21 mg, or from about 16 mg to about 19 mg, more preferably from about 11.5 mg to about 14 mg, or from about 17 mg to about 19 mg, or about 18 mg buprenorphine base or an equimolar an:ount of a pharmaceutically acceptable salt thereof, or e) from about 15 mg to about 32 mg, or from about 20 mg to about 28 mg, ably from about 15 mg to about 28 mg, or from about 21 mg to about 26 mg, more preferably from about 15 mg to about 24 mg, or from about 22 mg to about 25 mg, or about 24 mg of buprenorphine base or an equimolar amount of a ceutically able salt thereof.

PC T/IB2012/002973 pondingly the area of release ranges from about 1 cm to about 38 cm, or from 1.5 cm to about 24 cm, or ranges from 1.5 cm to about 22 cm, or ranges from 1.5 cm to about 20 cm and with respect to the five specific preferred dosage strengths a) to e) a) ranges from about 1 cm to about 4.8 cm, or from about 1.5 cm to about 5.5 cm, ably from about 1 cm to about 4.5 cm, or from about 2 cm to about 4 cm, more preferably from about 2.5 cm to about 4 cm, or f;om about 2 cm to about 3 cm, or is about 2.5 cm, or b) ranges from about 3 cm to about 9.5 cm, or from about 3 cm' to about 9 cm, preferably from about 3 cm to about 9 cm, or from about 4.5 cm to about 7.5 cm, more preferably from about 5 cm to about 8 cm', or from about 4.5 cm to about 6 cm, or is about 5 cm, or c) ranges from about 6 cm to about 19 cm, or from about 6 cm to about 14 cm, preferably from about 6 cm to about 18 cm, or &om about 8 cm' to about 12 cm, more preferably from about 10 cm to about 16 cm, or from abouts cm to about 11 cm, or is about 10 cm, or d) ranges from about 12 cm to about 28.5 cm, or from about 13 cm to about 17 cm, preferably f:om about 12 cm to about 27 cm, or &om about 13 cm to about 16 cm, more preferably from about 17 cm to about 23 cm, or from about 14 cm to about 16 cm, or is about 15 cm, or e) ranges from about 16 cm to about 38 cm, or from about 16 cm to about 24 cm, preferably or from about 16 cm to about 35 cm', or from about 17 cm to about 22 cm', more preferably from about 23.5 cm to about 32 cm, or from about 18 cm to about 21 cm', or is about 20 cm .

In such embodiments the dry pressure-sensitive adhesive layer preferably comprises a pressure-sensitive adhesive based on polysiloxanes and has preferably a dry weight of about 6 mg/cm, 7.5 mg/cm, 8 mg/cm, 9 mg/cm, 10.5 mg/cm, or 12 mg/cm' and contains 10% buprenorphine base.

According to certain preferred ments, the TTS contains with respect to five dosage strengths a) to e) the following amounts ofbuprenorphine base or an PC T/IB2012/002973 cqETETBoiRT' RBEOT3Bt 01 8 phRETBaceutfcaiiv Rcccptabic sait tiEctcot RTEd pf ovEdcs Tbc 'EBg coT.cspoBUIBEg Rtca oi Tcicase T'RBgcs: RbQUt I cfB to: about i cBT to out 2.5 cBE" to 8) about &i.8 CTB, about 4.5 CBT" about 4 cTB , about i 3YEg to RbOU'f: 4 Tug about i TBg to abOU't 3.5 BEg aboELT i fffg to about 3 BEg RboUt 5 CBE to about 9.5 cTB about 9 cBT about 8 cTB aboUt 3.3 Bfg t0 about 7 Big l about 3.5 TBg to ' Rbou't 6 ETEg about 6 CBE to BE)(.Eut 6 CBE to about i 0 CEYI to 340U1 19 "IH Rbo Dt 183 m about i6 cTB about TE. D BEg TO about I. 4 TTEg ; about 6.3 BEg to about ii [ Tug about l2 cBE" to to ,'about i2 cTB to about i, cm 28, ~ 2 about CBT ' about: / CBE about 23 cEA Rboff( i ],5 fBg to 8bout: 4 TBg PC T/IB2012/002973 ,'about 11.5 mg i to about 14 tug j about 16~etna to,:' about 16 cin' to about 38 cni about 35 cm about 15 mg to about 32 mg about 15 mg to about 28 mg about 15 mg to about 24 mg SKT OF TRANSDERMAL EUTIC SYSTEMS

[0098] For the treatment of pain a patient needs to be titrated to the individual dose of buprenorphine to adequately l the pain. In order to meet the dual requirements five different dosage ths are provided in accordance with the invention. [0099[ According to one aspect, the invention relates to a set oftwo (first and second, or second ar d third, or third and fourth, or fourth and fiAh TTS, or any other combination of two ofthe five different dosage strengths), three (first to third, or second to fourth or third to fifth TTS, or any other combination of three ofthe five different dosage strengths), four (first to fourth or second to fifth TTS, or any other combination of four of the five different dosage strengths) or five (first to fifth TTS) different transdermal therapeutic systems in accordance with the invention, wherein: the first transdermal therapeutic system es a size of said buprenorphine- ning pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.8 cm, or from about 1.5 cm to about 5.5 cm and ns an amount of said buprenorphine from about 1 mg to about 4 mg, or from Rbout 1 mg io Rbout 4.5 ing buprcnorplliiic base oF Rii cquunoIRF Rinount ot a pharniaceutically acceptable salt thereoF; and tlic second traBsdcrBial thci'Rpcutic systcin pi'ovidcs a size of said buprcnorpbuic- containing pressure-sensitive adhesive layer providing thc area of release ranging PC T/IB2012/002973 from about 3 cm to about 9.5 cm, or from about 3 cm to about 9 cm and contains an amount of said orphine from about 3.5 mg to about 8 mg, or from about 4 mg to about 9 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm' to about 19 cm, or from about 6 cm to about 14 cm and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg, or from about 8 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 28.5 cm, or from about 13 cm to about 17 cm and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg, or from about 15 mg to about 20 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fifth ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging from about 16 cm to about 38 cm, or from about 16 cm to about 24 cm and contains an amount of said buprenorphine from about 15 mg to about 32 mg, or from about 20 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f.

] The invention relates also to set of transdermal therapeutic systems, wherein: the first ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.5 cm, or from about 2 cm to about 4 cm and contains an amount of said buprenorphine from about 1 mg to about 3.5 mg, or from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and PC T/IB2012/002973 the second ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm to about 9 cm, or from about 4.5 cm to about 7.5 cm' and contains an amount of said buprenorphine from about 3.5 mg to about 7 mg, or from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f; and the third ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e g from about 6 cm to about 18 cm, or from about 8 cm to about 12 cm and contains an amount of said buprenorphine from about 6.5 mg to about 14 mg, or from about mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 27 cm, or from about 13 cm to about 16 cm and contains an amount of said buprenorphine from about 11.5 mg to about 21 mg, or from about 16 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm to about 35 cm, or from about 17 cm to about 22 cm and contains an amount of said buprenorphine f:om about 15 mg to about 28 mg, or from about 21 mg to about 26 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

[00101] The invention relates also to set of ent transdermal therapeutic, wherein: the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm to about 4 cm, or from about 2 cm to about 3 cm and ns an amount of said buprenorphine from about 1 mg to about 3 mg, or from about 2, 5 PC T/IB2012/002973 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the second transdermal therapeutic system provides a size of said buprenorphine- ning pressure-sensitive adhesive layer providing the area of release g from about 5 cm to about 8 cm, or from about 4.5 cm to about 6 cm ard contains an amount of said orphine from about 3.5 mg to about 6 mg, or from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 10 cm to about 16 cm, or from about 9 cm to about 11 cm and contains an amount of said buprenorphine from about 6.5 mg to about 11 mg, or from about 11 mg to about 13 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fourth transdermal therapeutic system provides a size of said orphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 17cm to about 23 cm, or from about14cm to about16cm and contains an amount of said buprenorphine from about 11.5 mg to about 14 mg, or from about 17 mg to about 19 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release g from about 23.5 cm to about 32 cm, or from about 18 cm to about 21 cm and contains an amount of said buprenorphine from about 15 mg to about 24 mg, or from about 22 mg to about 25 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

In a further aspect of the invention a transdermal therapeutic system selected from a set of transdermal eutic systems as described in the previous paragraphs is provided wherein buprenorphine is present in the form of buprenorphine base and wherein PC 12/002973 the first transdermal eutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 6.25 cm and providing a nominal mean release rate of about 5 pg/hr over about 168 hours of administration, the second transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of e of about 12.5 cm and providing a nominal mean release rate of about 10 pg/hr over about 168 hours of administration, the third transdermal therapeutic system when tested in a comparative al study is bioequivalent to a reference product having an area of release of about 25 cm and providing a nominal mean release rate of about 20 pg/hr over about 168 hours of administration, the fourth dermal therapeutic system when tested in a ative clinical study is bioequivalent to a reference product having an area of release of about 37.5 cm and providing a nominal mean release rate of about 30 pg/hr over about 168 hours of administration, the fifth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 50 cm providing a nominal mean release rate of about 40 |j.g/hr over about 168 hours of administration, wherein the reference t is prepared by the following steps: 1. homogenizing of 1,139 g of a 47.83 '/o polyacrylate solution of a self- crosslinked acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate:heptanes:isopropanol:toluene:acetylacetonate in the ratio of 37:26:26:4:1),100 g of nic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100 g of buprenorphine base to provide a mixture; PC T/IB2012/002973 2. stirring the e of step 1 for about 2 hours and controlling the dissolution of all solids visually whereas controlling the evaporation loss reweighing and replenishing the possible solvent loss by ethyl acetate; 3. subsequently applying the mixture on a transparent polyester film in such a manner that the mass per unit area of the dry adhesive layer amounts to about 80 g/m wherein the polyester film is rendered removable by means of siliconization and serves as protective layer; 4. removing the solvents of the mixture applied on a arent polyester film in step 3 by drying with heated air which is led over a ri:oist lane resulting in ation of the solvents, but also in melting of the levulinic acid and ng the adhesive film with a polyester foil; . punching the area ofrelease of 6.25 cm, 12.5 cm, 25 cm, 37.5 cm and 50 cm, tively, by means of suitable cutting tools and removing the edges left between the individual systems.

[00103] According to one aspect, the irvention relates to a transdermal therapeutic system described as first transdermal therapeutic system in the previous wherein buprenorphine is present in the form of buprenorphine base and paragraphs which is when tested in a comparative clinical study bioequivalent to the commercial t BuTrans, also known as Norspan, having an area of release of 6.25 cm .

[00104] According to one aspect, the invention relates to a transdermal therapeutic system described as second transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the commercial product BuTrans, also known as n, having an area of e of 12.5 cm .

According to one aspect, the invention s to a transdermal therapeutic system described as third transdermal therapeutic system in the previous paragraphs wherein buprenorphine is present in the form of buprenorphine base and which is when tested in a comparative clinical study bioequivalent to the cial product s, also known as Norspan, having an area of release of 25 cm .

PC 12/002973 According to one aspect, the invention relates to a transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from: a first transdermal eutic system providing a size of the area of release ranging from about 1 cm to about 4.8 cm and containing an amount of said buprenorphine from 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 pg/hr and/or providing a mean AUCt of more than 7,000 pg. hr/ml, preferably more than 8,00Q pg. hr/ml, or of from more than 7,000 pg. hr/ml to about 16,000 pg. hr/ml, or of from more than 8,000 pg. hr/ml to about 16,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; a second transdermal therapeutic system providing a size of the area of e ranging from about 3 cm to about 9.5 cm and containing an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and ing a l mean release rate of about 10 pg/hr and/or providing a mean AUCt of more than 14,000 pg. hr/ml, preferably of more than 16,000 pg. hr/ml, or of Rom more than 14,000 pg. hr/ml to about 32,000 pg. hr/ml, or of from more than 16,000 pg. hr/ml to about 32,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a third ermal therapeutic system providing a size ofthe area of release ianging from about 6 cm to about 19 cm and containing an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f and providing a nominal mean release rate of about 20 p, g/hr and/or providing a mean AUCt of more than 28,QQQ pg. hr/ml, preferably of more than 32,000 pg. hr/ml, or of from more than 28,000 pg. hr/ml to about 64,000 pg. hr/ml, or of from more than 32,000 pg.hr/ml to about 64,000 pg. hr/ml over about 168 hours of administration after a -dose administration to a subject population; and PC T/IB2012/002973 a Fourth Eransdernial therap "utic system providikig R size ol the area of e YRnging FEQEEE aboU't 1 . CI'A to aboiEt 28.5 CYB Rnd coBEMning RA aniount of said bupreBorphEBc FTQBI about 1 ],5 Big to about 24 Erkg bupi cnorphinc base QY' RB cclUBBolar RBEQUAI. QFR pharniaccUE. ically Rcc' ptaMC salt thcrcof REKl providing a nominal mean release rate of about 30 up~'hr and'or providikig a mean AI. Ct ot more than 42„000pg.hr/AIJ. prctcrably of BEQYc tha'A 48.000 p~&~.hr/Bkl, of ot troBE BEQI'c thNI 42,000 pg. hr,'ml to about 96,00E') pg. hr ml, or of t.Om more than 48,000 pg.hr/ml to about 96,1)00 pg. hr!ml over about 168 hours Ql admmistration after a single-dose adnlinistTatioki to R sut)jcct tion; Rnd lk) R Filth traEIsdcrBERI thcrapcUtic systcrn provKhBg a size ot thc area of kclcRsc rangkrv~ FE'OBE Rbotkt 16 cin" to about 38 CBE arid coBtaEEimg NI Rrnount. Qt said buprcnokphkBc FYQBE RboUt 15 Big Io Rboui 32 Big bkiprcnorphEBc base QI' aii cquiknolar It QFR phak maceuYically able salt tbei'eof and ing a nonunal mean release rate of about 40 Ekg/hr and/or providing R Biean „~kl1Ct QF more than 62,000 pg. hr!Inl, preFcrably of more than 64,000 pg.hr/ml, oi ot trom more than 62,000 pg. hr, 'ml to about 1 8,000 p .hr/ml, or of from nior ' than 64,000 pg. l to about ].28,000 pg. hr/Bll ovci' aboUt 168 hours QF RdEBEEIESETRY!oii RFtcr R sIBglc-dose RdBEEYEEstTation to R subgcct popk. latkon. [00107j According Yo one aspect, the invention relates to a YYNIsdermal ther'apcunc systckri CQBEpr'IskBg bikprcYKEI'phinc tok tlkc lcrIBal Rdniknkstratkoki of. bUpfcnoiphinc selected FTQYA: a First transdernial therapeutic system piovidirig a size of the area of release ranging 4.5 cni t FTQIB aboUE 1 cni to aboUt and CQBYainuig RB RBEount ot said buprcBorphn'Ec froAI 1 Big to RbQUt 3.5 Erig norphknc base QY' Rn cquEIBolar N'AQUBt ot a pharinaceutically acceptable salt thereof and providikig R nominal mean release rate of ahoy 5 pg/ltr and, 'or providing a mean AI JCt of more than 7 000 pg. hr/ml, preferably more thari 8,000 pg. hr'ml, or ot' from more than ", ,000 pg. hr, 'ml to about QE' of froYA morc than 8,000 pg. hE'/Bkl io abou'I 16,000 pg. hi'/IBl ovek' k 6,01)0 pg. hi'!Bil, about 168 hours of stration RFYer a single-dose stration to a subject PC T/IB2012/002973 a second transdermal eutic system providing a size ofthe area of release ranging from about 3 cm to about 9 cm and containing an amount of said buprenorphine from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 10 pg/hr and/or providing a mean AUCt of more than 14,000 pg. hr/ml, preferably of more than 16,000 pg.hr/ml, or of from more than 14,000 pg. hr/ml to about 32,000 pg. hr/ml, or of from more than 16,000 pg. hr/ml to about =2,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a t population; and a third ermal therapeutic system providing a size of the area of release ranging from about 6 cm to about 18 cm and containing an amount of said buprenorphine from about 6.5 mg to about 14 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 20 pg/hr and/or providing a mean AUCt of more than 28,000 pg.hr/ml, preferably of more than 32,000 pg. hr/ml, or of from more than 28,000 pg.hr/ml to about 64,000 pg. hr/ml, or of from more than 32,000 pg.hr/ml to about 64,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a fourth transdermal therapeutic system providing a size of the area of release ranging from about 12 cm to about 27 cm and containing an amount of said orphine from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and ing a nominal mean release rate of about 30 pg/hr and/or providing a mean AUCt of more than 42,000 pg. hr/ml, preferably of more than 48,000 pg. hr/ml, or of from more than 42,000 pg. hr/ml to about 96,000 pg. hr/ml, or of from more than 48,000 pg.hr/ml to about 96,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a fifth transdermal therapeutic system providing a size of the area of release g &om about 16 cm to about 35 cm and containing an amount of said buprenorphine from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a PC T/IB2012/002973 phcEfmaccutically acccpfabie salt f Mid pi'ovldlng 8 BQBiiB81 Blcan. I'clcase fate of Rboillt 40 IE~+f BEId/or piovidiilg 8. ETECBB A,UCt of ffiolc than 62&000 pg. hr/TEIL preferably of more than 64,000 pg. hr!ml, or offroin more than 6'"„000pg. hr'rnl to Rbout 1 8,000 pg.hr!BT], of of froETE EBOE c than 64,0tE0 pg. hr/Enl to BboUt 128,000 pg. hf/Bll over about 1 68 hoUE s ot RdfBiTEEstfation BAGS 8 siBgic-dose RdiniilisErafilOEE fo a subject population. a001081 According to Bile , the BivcnEEQB I'ciafcs 8 crrnal therapeufic system comprising bupreIEorphiEEC for the tfansdermal stration of buiprenofphme ed from: a first transdermai thefapeiitic system providhlg 8 size of the area of release rangmg frOBI about 2.5 CBE to about 4 CKB Mid Contan'Ung BB MBOUBt Of SRid bUpKCBOfphlBC from 1 Blg To BboUE 3 Big bUplcnofphHlc base ot' an cqulBEQIBK Rmounr of 8 pharnlaceutically acceptable salt thereof and providing a nominal mean release rate ot about 5 Ug!hr and/or providing a ITEcan!WUCt of more than ", ,00EE pg. hr!EBl, pKcfcfably ETEorc than 3,000 pg. li'/iltli, of of froITE Tnofc EhRQ 7,000 pg. hi'/IT11 to about 16,000 pg. hr, 'ml, or of ffoBE Tnore than 8,000 pg.hf/ml fo about 16,000 pg. hr, 'ml over BboUt 1 68 hours Qf RdEEIEEEEstfation Bficf R sEETgle-dose BdB1EBEstfEETEQB fo ia sub]cct hon; 8 second cfmal therapeutic systcBE pfovidnlg 8 size offhc Brea of 1clcasc raliglng from RbQUt 5 clri fo abouf. 8 cB1 Bnd confalning BB anlount of saKI bupfcnolphnic froETI BboUt 3.3 TBg to BboUf. 6 fng ilorphlne base of dn cqUEBEolar RETEQUnlt of 8 phafnlaccuiLEcally acceptable salt thcfcof RE il piovldulg 8 BQIBEQR1 mcME release rate ot about 10 Ng/1EK and/or providing a mean AUCf of more than 14„000 pg. hl!BlL pfcfcfRbly of Blolc fhRB l. 6.000 pg. hI'/Tni„of of froBE Tnofc thBB 14,000 pg. hf/Bii to about 3".000 pccc.hl /Bli. Of Qt ffonl BlofC 'EhN1 16,000 pg. hf/Bi! to Rbout 3:„000pg.hi'/Bll Over Rbolif. 168 hoUE s of RdIBIBEstratlon after' 8 single-dose Bdnlmisffaflo! i 10 8 sub)cct popuiafion', BBd 8 third traTEsdcfnlai therapeutic E providing 8 size of thc Brea of I clcRsc fanglng fiom about 10 cm" to about 16 crn" and confaming an amount of said buprenorphhle &QBE RboU't 6,5 mg fo about 11 Big hUpT'cBofphinc base of N'I cquifnolaf RIBount of 8 PC T/IB2012/002973 aceuficaHy acccpfablc sRlt thcFcof Mld providulg 8 BomiB81 IBctiB Fclcasc rate oi about 20 fig/hr and/or providing a mean AUCt of more than 28,000 pg. hr ml, pl cfcrablp of rilorc than 3".000 pg.ln/Btl, or of froiil Blorcth8B 28,000 pg. hr/IBl to Rboilt 64,000 pg. hT?ETEl, or of fromi Tnorc than 3 .,000 pg. hr!mll Eo about 64„000 pg. hr!'ml over about 168 hours of administration after a single-dose administration to 8 subject popUlation; and a foluth transdernlal euiic systenl providiilg a size of the area of release '? '? TMlgirlg &QEIE about 17 cFB to aboilt 23 cITE RBd containing RB RFBQUBE of sRid orph~nc .1Y01B abouf '1 1,.') IBg to about 14 Erig buplcnorphlnc base or RB equimolar arnoimt of a pharmaccutically acccptablle sall thereof and providing a Boirlillal Blcail Fclcasc I'Rtc of abQUt 30 jig hr REEd/or pFovicllng 8 TncRB AUCt Of Biol'c thaB 42 000 pP, .hr/Inl preferably of IBorc thRB. 48,000 pg. hninll 01 of fr'onl 1'Bore than 4:,000 nil to aboui 96,000 pg. hr. 'mL or of f Qirl morc than 48,000 pg, hi!ml to about 96,000 pg. hr!ml over about 168 hours of adlninistrahon after a single-dose RdministratEQEE io R sub)ect populatilon; RBd 8 fifth fransdcl nial thcI'RpcUtic systcBE provKling 8 size of fhe area of Fcleasc I'Rnglng fT'QIB about 23.5 cm to abi)ut 3 cnl and CQBEMB1Bg Rn RBEOUB(of sMd bilpl'cnoFph! Hc lYQIB abouf 15?Bg to about 24 Big bUpE cBQE phlBc base 01 an cquiBK)laI' amount of a pharinaceuticaHy acceptable salt thereof and providing a nominal nlean TclcErse Fate of 8bout 40 pg. 'REF and/or providiiig 8 Incan AUCf of Inorc thRB 6:,000 pg. hr, 'ml. preferablly of nlorc than, 64„000pg.hr/ml, or of from more than 62.000 pg. hr/Bll io about 1 8,000 pg. hr/ml„oE of fYQE'B moI'c thRB 64.000 pg. hr/BE] to Rbout 128,000 pg, hi'!'mj ovcI' about 168 hoUIs of adiTBBESBRElon 8jicr 8 -dose Rdnlinlstration lio 8 sub)cct populalion. .

REX KASK CKARACYKRISTIC p)010q'I ln accordance vvith fh- Invention the 11!)Es turthei characterized bv the skin peETneation rate determined by in vitro experimerlts carried out ivith the FI'anz ion cell (c.g., 8 9 IB1 Franz difftlsion ccH), using lmnYRB splif. thickness PC T/IB2012/002973 skin. Skin from cosmetic surgeries (female , date of birth 1989)can be used. A dermatone is used to prepare skin to a thickness of 800 pm, with an intact epidermis, in accordance with the OECD Guideline (adopted April 13, 2004). Due to the prolonged test (168 hours) 800 p,m skin is used instead of the recommended 200 to 400 pm skin. The receptor medium used is a phosphate buffer solution pH 5.5 with 0.1% saline azide as antibacteriological agent is used at a temperature of 32 + 1'.

Example formulations with an area of 1.163 cm are d from laminates, and in the present examples are each tested against1. 163 cm samples of the commercial product Norspan. .The concentrations of orphine in the acceptor medium of the Franz cell are measured.

The TTS according to the ion provides a mean cumulative skin permeation rate of more than about 1.3 pg/cm -hr, or more than about 1.5 Ng/cm -hr or more than about 1.7 pg/cm -hr over a 168 hours test, or of more than about 2 pg/cm -hr over a 168 hours test, or of more than about 2.5 pg/cm -hr over a 168 hours test, or of more than 2.7 pg/cm -hr over a 168 hours test, or of more than about 3 pg/cm -hr over a 168 hours test, or from about 1.3 pg/cm -hr to about 4 pg/cm -hr, or from about 1.7 pg/cm -hr to about 4 pg/cm -hr, or from about 2 pg/cm -hr to about 4 pg/cm -hr, or from about 2.5 pg/cm -hr to about 4 pg/cm -hr, or from about 2.7 pg/cm -hr to about 4 pg/cm -hr, or from about 3 p,g/cm -hr to about 4 pg/cm -hr, over a 168 hours test. The commercial product Norspan provides a mean cumulative skin permeation rate of about 1 pg/cm -hr over a 168 hours test in said test.

According to certain embodiments, the TTS provides a tive release as measured in a Franz diffusion cell as mentioned above of about 220 pg/cm to about 640 Ng/cm over a time period of 168 hours, or of about 400 pg/cm to about 640 pg/cm, or of about 450 pg/cm to about 640 pg/cm, or of about 500 pver a N, g/cm tp abput 640 pg/cm, or of about 600 pg/cm to abput 640 pg/cm time period of 168 hours. The commercial product n provides a cumulative release of about 175.29 pg/cm in said test. As can be seen from Figure 2, comparable skin permeation rates are measured using the 25 cm Norspan TTS WO 88254 PC T/IB2012/002973 irlchiding 20 mg buprenorphine base and TYS examples 1 to 4 hi accordance ivith thc Biventlon %'Eth an. area of ] 0 cIB Mid lnchidEQEJ 12 BE& bupr'eBorphlne base. This corresponds to about 8. 60 co si7' reduction Mid 8. reductEOIE oi aboUt 40~/o EQ the amomlt of used buprenorphine base. [001.I.ZI Accorfling to certalll nlellts, the D S plovides 8 Qon- cuIBuiatlve sknl perBEeatlon rale of bilpl enorphlBe base as Bleasured in 8 Franz diNEsion cell of -: ug/cm to ]0 Ei.g'cBE Bl rhe first 8 ho'UI's, ii~v'cm' 10 80 ifg'cm" from hour 8 to hour 24„ 0 pg/cln to 80 ifg!cm fronl hour:4 to holil' 32, pg/cfn to 120 ifg/cin f~oEEE hoUr 32 to hollr 48 40 g&z/CEIE to 1'i0 ln trom hoU1 48 to hour 72 100 If~a,'/crn to 300 EEp~'CBE ff'0IB hoUE 72 to hour 1.44 Rnd 1fg/cin to 100 EE~~/cnl' tloBE hour 144 to houif. 1(&8. ] 5 (001I3] According to certairl embod „ the TTS provides a norl- cumulative skin permeation rate of buprenorphine base as measured in 8 Franz diffusion ceil of 2 l.fg/cnl to 6 pg/cln nl the first 8 hours, pg/cm to 60 Lfg'CBE fronl hour 8 to hour 24 25 ifg/CEB" to 60 llg'cm from hour 24 to hour 32. 40 IEg/cm' to 100 if@/CEB" from hour 32 to hour 48, 50 if g/cin' to 140 ifg'cm from hour 48 to hour 72, 100 Ii~o/cin" to 280 pg/cnl from houf !2 E0 hoUr ] 44„Mid pg/cYB to!00 p~o/cm troln hour ]44 to hour 168. 2.'5 [001X4] According to certMB enlbodiBlef its. the "TS pl'ovldes 8 Bon- cumlalative skin tiion rate of buprenorphme base as ed in a Franz diffusion cell of' 3 I.fg/CBE to 6 ifg'cm in the tlrst 8 hours, Ll, g/CBE to 30 ug/cnl from houl' 8 to horn 24, 30 iig!cln to 50 ug!cnl from hour 24 io hour 3 PC T/IB2012/002973 60 N, g/cm to 90 pg/cm from hour 32 to hour 48, 100 pg/cm to 130 pg/cm from hour 48 to hour 72, 200 pg/cm to 280 pg/cm from hour 72 to hour 144, and 60 p, g/cm to 100 pg/cm from hour 144 to hour 168.

The commercial product Norspan provides a non-cumulative skin permeation rate of buprenoi phine base as measured in a Franz diffusion cell in the same setting of 3.19 pg/cm in the first 8 hours, 22.40 pg/cm from hour 8 to hour 24, 13.83 pg/cm from hour 24 to hour 32, 26.17 pg/cm from hour 32 to hour 48, 32.43 pg/cm from hour 48 to hour 72, 60.10 pg/cm from hour 72 to hour 144, and 17.17 pg/cm from hour 144 to hour 168.

METHOD OF TREATMENT / MEDICAL USE ] According to one , the transdermal therapeutic system in accordance with the invention and as described above in detail is for use in a method of treating pain. The Method ses in particular the application of the TTS for about 168 hours (corresponding to 7 days or one week) on the skin of a patient.

According to other methods in accordance with the invention the TTS can be d for more than about 96 hours corresponding to more than 4 days, or about 120 hours corresponding to 5 days and about 144 hours corresponding to 6 days. The application for about 168 hours is preferred.

] According to one aspect, the invention relates to a method of treatment wherein a set of five different transdermal therapeutic s corresponding to different dosage strengths and corresponding different nominal mean release rates and/or mean release rates over about 168 hours of administration is used, wherein: PC 12/002973 the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release g from about 1.5 cm to about 5.5 cm and contains an amount of said orphine from about 1 mg to about 4.5 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 Ng/hr or Rom about 4 to about 6 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 pg/hr over about 168 hours of stration; and the second transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging from about 3 cm 2 to about 9 cm 2 and contains an amount of said buprenorphine from about 4 mg to about 9 rng buprenorphine base or an equimolar amount of a pharmaceutica!ly acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 8 to about 12 pg/hr or from about 9 to aboutl 1 pg/hr, and/or provides a nominal mean e rate of buprenorphine of about 10 pg/hr over about 168 hours of stration; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm to about 14 cm and contains an amount of said orphine from about 8 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 15 to about 25 pg/hr or from about 17 to about 22 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 pg/hr over about 168 hours of administration; and the fourth transdermal therapeutic system provides a size of said orphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 13 cm to about 17 cm and contains an amount of said buprenorphine from about 15 mg to about 20 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 26 to about 35 pg/hr or from about 27 to about PC 12/002973 32 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 ug/hr over about 168 hour- of administration; and the fish t:ansdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive ve layer providing the area of release ranging from about 16 cm to about 24 cm and ns an amount of said buprenorphine from about 20 mg to about 28 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenoi phine ranging front abour 36 to about 45 pg/hI or from about 38 to about 4 pg~'hr„and/or provides a nominal ntean release rate ot buprenorphine of about 40 pg!'hr over about 168 hours ok admnnstratloilx.

The invention relates also to set of transdermal therapeutic systems, wherein: the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive ve layer providing the area of release ranging from about 2 cm to about 4 cm and contains an amount of said orphine from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 p.g/hr or from about 4 to about 6 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 pg/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm to about 7.5 cm and contains an amount of said orphine from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 8 to about 12 pg/hr or from about 9 to aboutl 1 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 pg/hr over about 168 hours of stration; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer ing the area of release ranging PC T/IB2012/002973 from about 8 cm to about 12 cm and ns an amount of said buprenorphine from about 10 mg to about 14 mg buprenorphine base or an lar amount of a pharmaceutically able salt thereof and provides a mean release rate of buprenorphine ranging from about 15 to about 25 pg/hr or from about 17 to about 22 pg/hr, and/or provides a l mean release rate of buprenorphine of about 20 N, g/hr over about 168 hours of administration; the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 13 cm to about 16 cm and ns an amount of said buprenorphine from about 16 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof and provides a mean release rate of buprenorphine ranging from about 26 to about 35 pg/hr or from about 27 to about 32 pg/hr, and/or provides a nominal mean release rate of orphine of about 30 pg/hr over about 168 hours of administration; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm to about 22 cm and contains an amount of said buprenorphine from about 21 mg to about 26 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 36 to about 45 pg/hr or from about 38 to about 42 pg/hr, and/or provides a nominal mean e rate of buprenorphine of about 40 pg/hr over about 168 hours of administration.

The on relates also to set of different transdermal therapeutic, wherein: the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 2 cm to about 3 cm and contains an amount of said buprenorphine from about 2.5 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 2.5 to about 7.5 pg/hr or from about 4 to about PC T/IB2012/002973 6 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 gg/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said buprenorphIne- containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm' to about 6 cm and contains an amount of said buprenorphine from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof and provides a mean release rate of buprenorphine ranging from about 8 to about 12 pg/hr or from about 9 to aboutl 1 pg/hr, and/or provides a l mean release rate of orphine of about 10 pg/hr over about 168 hours of administration; and the third transdermal therapeutic system provides a size of said buprenorphine- ning pressure-sensitive adhesive layer providing the area of release ranging from about 9 cm to about 11 cm and contains an amount of said buprenorphine from about 11 mg to about 13 mg buprenorphine base or an equimolar amoum of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 15 to about 25 pg/hr or from about 17 to about 22 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 pg/rh over about 168 hours of administration; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer ing the area of release ranging from about 14 cm to about 16 cm and ns an amount of said buprenorphine from about 17 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine ranging from about 26 to about 35 pg/hr or from about 27 to about 32 pg/hr, or about 30 pg/hr over about 168 hours of administration; and the fifth ermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 18 cm 2 to about 21 cm 2 and contains an amount of said buprenorphine from about 22 mg to about 25 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and es a mean release rate of PC T/IB2012/002973 buprenorphine ranging from about 36 to about 45 pg/hr or from about 38 to about 42 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 pg/hr over about 168 hours of administration. ing to one aspect, the invention relates to a method of ng pain in a patient wherein said patient is treated with one appropriately selected TTS from a set of two (first and second, or second and third, or third and fourth, or fourth and fifth TTS, or any other combination of two of the five different dosage strengths), three (first to third, or second to fourth or third to fifth TTS, or any other combination of three of the five different dosage strengths), four (first to fourth or second to fifth TTS, or any other combination of four of the five different dosage ths) or five (first to ffth TTS) ent transdermal therapeutic systems corresponding to different dosage strengths and corresponding different nominal mean release rates and/or mean release rates over about 168 hours of administration is used, wherein; the first transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.8 cm and ns an amount of said buprenorphine f:om about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 pg/hr, or of from about 2.5 to about 7.5 pg/hr or from about 4 to about 6 pg/hr, and/or provides a nominal mean e rate of buprenorphine of about 5 pg/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said orphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm to about 9.5 cm and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 6 pg/hr, or of f;om about 8 to about 12 pg/hr or from about 9 to aboutl 1 pg/hr, and/or provides a l mean release rate of buprenorphine of about 10 pg/hr over about 168 hours of administration; and PC T/IB2012/002973 the third transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging f;-om about 6 cm' to about 19 cm and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of orphine of at least about 11 pg/hr, or of from about 15 to about 25 llg/hr or from about 17 to about 22 lI,g/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 llg/hr over about 168 hours of administration; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 28.5 cm and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof RBd provides a mean release rate of buprcnorphinc 0f Rt least about 21 r OI ot fronl Rbout 26 to about 35 r OI.

I 5 troIB about: ! to aboUt 32 Ug!'ln „and/or provtdcs 8 noBIIBR] nlcan I'clcasc rate of buprcnorphuze of about 30 ling/lu over about 1 b8 hours ok adnumstratlon; and thc fifth transdcrlnal thcrapcutlc systcnl pro'vldcs 8 sIzc ot said bUpI'cnorphlnc- contauung pI'cssUIc-scnsltrvc Rdhcslvc layer providing thc area ol I'clcRsc ranging fronI Rbo'Ut 1.6 cm to about 38 cnl 2 and contains Rn RIBoullt ot said bUprcnorphulc froBI about 15 rng to RboUt 3: mg buplcnorphlnc base or Rn lar RInoutl't of 8 phartnaceutically acceptable salt thereof and provides a mean release rate of bUpl cNiorpl'UBc of at least about 3 1 ugj hl' or ot from about 36 to about 45 p.g~'hr oI' AOIB about 38 to about 4: Ir, and/or provides a nominal mean release;ate of buprenol'phine of about 40 Ilg!Ilr over about. I 68 houls of administration.

WBOI21 The invention relate;. also to set ok enIIR) therapeutic systems, wherein: the first transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.5 cm and contains an amount of said buprenorphine from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a PC T/IB2012/002973 pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 pg/hr, or of from about 2.5 to about 7.5 pg/hr or from about 4 to about 6 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 pg/hr over about 168 hours of administration; and the second transdermal therapeutic system provides a size of said orphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm to about 9 cm and ns an amount of said buprenorphine from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt f and provides a mean release rate of buprenorphine of at least about 6 pg/hr, or of from about 8 to about 12 pg/hr or from about 9 to aboutl 1 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 pg/hr over about 168 hours of administration; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging from about 6 cm to about 18 cm and contains an amount of said buprenorphine from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean e rate of buprenorphine of at least about 11 pg/hr, or of Rom about 15 to about 25 Ng/hr or from about 17 to about 22 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 20 pg/hr over about 168 hours of stration; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer ing the area of release g from about 12 cm to about 27 cm and contains an amount of said buprenorphine from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 21 pg/hr, or of from about 26 to about 35 pg/hr or from about 27 to about 32 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 30 pg/hr over about 168 hours of administration; and tire fifth transderrnal therapeut!c system provfdes a srze of said buprenorpkHne" contaInuv~ pressure-sensst]ve adhes&ve layer prov&dmg the area ot release rangjng PC T/IB2012/002973 from about 16 cm 2 to about 35 cm 2 and contains an amount of said buprenorphine from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f and provides a mean release rate of buprenorphine of at least about 31 pg/hr, or of &om about 36 to about 45 pg/hr or from about 38 to about 42 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 pg/hr over about 168 hours of administration.

The invention relates also to set of ent transdermal therapeutic, wherein: the first transdermal therapeutic system provides a size of said buprenorphine- containing piessure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm 2 to about 4 cm 2 and contains an amount of said orphine from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 2 pg/hr, or of from about 2.5 to about 7.5 lig/hr or from about 4 to about 6 ljg/hr, and/or provides a nominal mean release rate of buprenorphine of about 5 pg/hr over about 168 hours of administration; and the second ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 5 cm to about 8 cm and ns an amount of said buprenorphine from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceuticaaly acceptable salt thereof and provides a mean release rate of buprenorphine of at least about 6 li, g/hr, or of from about 8 to about 12 pg/hr or from about 9 to aboutl 1 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 10 pg/hr over about 168 hours of administration; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive ve layer providing the area of e ranging from about 10 cm to about 16 cm and contains an amount of said buprenorphine from about 6.5 mg to about 1 i mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f and provides a mean release rate of buprenorphine of at least about 11 pg/hr, or of from about 15 to about 25 pg/hr or PC T/IB2012/002973 from about 17 to about 22 p, g/hr, and/or es a nominal mean release rate of buprenorphine of about 20 pg/hr over about 168 hours of administration; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm to about 23 cm and contains an amount of said buprenorphine from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a mean e rate of orphine of at least about 21 pg/hr, or of from about 26 to about 35 pg/hr or from about 27 to about 32 pg/hr, and/or es a nominal mean release rate of buprenorphine of about 30 pg/hr over about 168 hours of administration; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging from about 23.5 cm to about 32 cm and contains an amount of said buprenorphine from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt f and provides a mean e rate of buprenorphine of at least about 31 pg/hr, or of from about 36 to about 45 pg/hr or from about 38 to about 42 pg/hr, and/or provides a nominal mean release rate of buprenorphine of about 40 pg/hr over about 168 hours of administration.

According to one aspect, the invention relates to a method of treating pain in a patient wherein a patient is treated with one appropriately selected TTS from a set of different transdermal therapeutic systems as described in the previous paragraphs, wherein: the first transdermal therapeutic system provides a mean AUCt of more than 7,000 pg. hr/ml, preferably more than 8,000 pg. hr/ml, or of from more than 7,000 pg. hr/ml to about 16,000 pg.hr/ml, or of from more than 8,000 pg. hr/ml to about 16,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject tion; and the second transdermal therapeutic system provides a mean AUCt of more than 14,000 pg. hr/ml, preferably of more than 16,000 pg.hr/ml, or of from more than 14,000 pg.hr/ml to about 32,000 pg. hr/ml, or of from more than 16,000 pg.hr/ml to PC T/IB2012/002973 about 32,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the third transdermal therapeutic system provides a mean AUCt of more than 28,000 pg. kr/ml, preferably of more than 32,000 pg.hr/ml, or of from more than 28,000 pg. hr/ml to about 64,000 pg. hr/ml, or of from more than 32,000 pg. hr/ml to about 64,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the fourth transdermal therapeutic system provides a mean AUCt of more than 42,000 pg. hr/ml, preferably of more than 48,000 pg. hr/ml, or of from more than 42,000 pg. hr/ml to about 96,000 pg. hr/ml, or of from more than 48,000 pg. hr/ml to about 96,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the fifth transdermal eutic system provides a mean AUCt of more than 62,000 pg. hr/ml, preferably of more than 64,000 pg.hr/ml, or of from more than 62,000 pg.hr/ml to about 128,000 pg. hr/ml, or of from more than 64,000 pg.hr/ml to about 128,000 pg.hr/ml over about 168 hours of administration after a -dose stration to a subject population.

According to one aspect, the invention relates to a method of treatment described in the previous paragraphs, wherein the transdermal therapeutic system provides a mean AUCt per area of e of more than 1,700 pg. cm, or of more than 1,900 pg.hr/ml-cm, or of more than 2,300 pg. hr/ml-cm over about 168 hours of administration aAer a -dose administration to a subject population or provides a mean AUCt per area of release of f:om more than 1,700 pg. hr/ml-cm' to about 5,000 pg. hrin-. l-cm, or of from more than 1,900 pg. hr/ml-cm to about 5,000 ml-cm, or of from more than 2,300 pg.hr/ml-cm to about 5,000 pg. hr/ml-cm over about 168 hours of administration after a single-dose administration to a subject population.

According to one aspect, the invention relates to a method of treatment described in the previous paragraphs, wherein the transdermal therapeutic system es an arithmetic mean tmax of from about 60 hr to about 120 hr, PC 12/002973 preferably from about 66 hr to less than 108 hr, or from about 72 hr to about 96 hr after a -dose administration to a subject population.

MKYJNOD OF &IAXUFACYIL lRK According to one r aspect, the invention relates to a method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising the steps of l. providing a buprenorphine-containing adhesive mixture or solution comprising a) buprenorphine base or a pharmaceutically able salt thereof b) a carboxylic acid (e.g., levulinic acid), c) a polymer-based re-sensitive adhesive, and d) solvent (e.g., heptane and ethanol) 2. coating said buprenorphine-containing adhesive mixture or solution on a film (e.g., polyethylene terephthalate film) in an amount to provide the d dry weight, 3. drying said coated buprenorphine-containing adhesive mixture or solution to provide a buprenorphine-containing adhesive layer with the desired dry weight, l. laminating said buprenorphine-containing adhesive layer to a backing layer (e.g., Scotchpak 1220 from 3M) to provide an buprenorphine-containing self- adhesive layer structure, . punching the individual systems from the buprenorphine-containing self- adhesive layer structure with the desired area of release, and 6. optionally ng to the individual systems an active-free self-adhesive layer structure sing also a backing layer and an active agent-free pressure- sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer ure.

) In step 1 of said method of manufacture preferably buprenorphine base and levulinic acid are used and are suspended in ethanol and subsequently PC T/IB2012/002973 combined with the polymer-based pressure-sensitive adhesive based on polysiloxane in e to provide the buprenorphine-containing adhesive mixture or solution.

EXAMPLES [0012S] The present invention will now be more fully described with reference to the accompanying examples. It should be understood, however, that the following description is rative only and should not be taken in any way as a restriction of the invention.

EXAMPLE 1 The composition of the orphine base-containing adhesive on is summarized in Table 1 below.

[00130] Table 1 Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 3.65 Levulinic acid 3.65 Ethanol 1.97 Polysiloxane adhesive in n-heptane 40.0 Solids content of 73% by weight (BIO-PSA 7-4301 from Dow Corning care) n-heptane 2.87 Total 52.14 In a stainless steel vessel, 3.65 kg of buprenorphine were suspended in 3,65 kg of levulinic acid and 1.97 kg of ethanol. With stirring, 40.0 kg of a PC T/IB2012/002973 polysiloxane ve in the form of a solution in n-heptane having a solids content of 73% by weight and 2.87 kg of e were added. The mixture was stirred until the buprenorphine base was fully dissolved, to give 52.14 kg of a buprenorphine- containing adhesive solution with 7% of buprenorphine, with a. solids content of 70% (buprenorphine ontaining adhesive solution).

Tne buprenorphine base-containing adhesive solution was coated on ,::,';" adhesive hylene terephthalate film (e.g., Scotchpak &om 3M) using an Erichsen coater and the solvent was removed by drying at approximately 45'C for 20 minutes. The coating thickness was chosen such that l of the solvents results in a coating weight ofthe matrix layer of 120 g/m . This results in the 10 % by weight of buprenorphine base and 10 % by weight of levulinic acid in this matrix layer. The dried film was laminated with the backing layer (e.g Scotchpak from 3M) to provide the buprerorphine-containing self-adhesive layer ure.

The individual systems (TTS) were then punched from the buprenorphine-containing self-adhesive layer structure. In specific embodiments a TTS as described above can be provided with a r self-adhesive layer of larger surface area, preferably with rounded corners, comprising a pressure-sensitive adhesive matrix layer which is free of active ingredient and has a preferably skin- colored backing layer. This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere sufficiently to the skin and/or when the buprenorphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners e or rectangular shapes). The plasters are then punched out and sealed into pouches of the y packaging material.

PC T/IB2012/002973 EXAMPI K 2 I001I.343 The composition of the buprenorphine base-contaimng adhesive soiutlon ls sunnnarlzcd ul Tabic '. , Amtlullit In~redierlt (I'1ade Seine) Lcvuilnlc Bc!d Ethanol Polyslfoxanc vc ln n-heptane Soiids content of 3~/0 bv v'clght (BIO-PSA 7-4301 from Dole Coming 'Heafthcare) n-hcplanc 100136] The process of nlanlltacture vvas as described for Exarnpie 1. Yhe coRtlng thickness o'Bs B1so chosen such tha( removal ot the soivcnts rcsufts ln R coating w-ight of the lnatl. ix 1ayel of 120 g/m' and thus resuited in ] 0'io by weight buprenorphine base Bnd 7',~o by vveight icvuiinic acid in this matrix layer.

PC T/IB2012/002973 KXAMPX, E 3 The ition of the buprenorphine base-containing adhesive solution is summarized in Table 3 below. [00 ll.38] j alMe 3 Amt/unit Ingredient (Trade Name) (kg) Buprenorphine base 3.65 Levulinic acid 3.65 Ethanol 1.97 Polysiloxane adhesive in n-heptane 39.46 Solids content of 74% by weight (BIO-PSA 7-4201 from Dow Corning Healthc are) n-heptane 3.41 Total 52.14 The s of cture was as described for Example L The coating thickness was also chosen such that removal ofthe solvents results in a coating weight of the matrix layer of 120 g/m and thus resulted in 10% by weight buprenorphine base and 10% by weight levulinic acid in this matrix layer.

PC T/IB2012/002973 The composition of the buprenorphine base-containing adhesive solution is summarized in Table 4 below.

[00141] Table 4 Buprenorphine base 3.65 Levulinic acid 2.56 Ethanol 1.83 Polysiloxane adhesive in n-heptane 40.93 Solids content of 74% by weight : (B10-PSA 7-4201 from Dow Corning Healthc are) n-heptane 3.17 Total 52.14 The process of cture was as described for Example 1.The coating thickness was also chosen such that removal of the ts results in a coating weight of the matrix layer of 120 g/m and thus resulted in 10% by weight buprenorphine base and 7% by weight levulinic acid in this matrix layer.

PC T/IB2012/002973 CO%'IPALRAYIVK KXAMPLK 5 In Comparative e 5, a transdermal therapeutic system comprising an -agent-free skin contact layer on a buprenorphine-containing fnRfrfx lavcf' was pf'cpaf'cd.

Thc cofApositioff ot tltc bffprf.'ffofphfnc base-contafnirfg adhesive solutfon fs rfzcd fn TRMc DR below Rffd thc composftfon of Eklc actfvc"Rgcnt- frce skin contact layer is summar'zed m Table 5b below.

Tawe Sa Amt/unit Ingredient (Trade Name) (kg) orphine base 0.42 Levulinic acid 0.56 Ethanol 0.28 Polysiloxane adhesive in n-heptane 6.25 Solids content of 74 % by weight (BIO-PSA 7-4201 from Dow Corning Healthcare) G-heptane 0.49 PC T/IB2012/002973 ] Table 5b Amt/unit 'icnt (Trade %arne) (kg) Polyacrylate ve prepared from 2- 3.69 ethylhexyl acrylate, vinyl acetate and 2- hydroxyethyl acrylate in Ethyl acetate Solids content 50.5 % Ethyl acetate 1.64 Total 5.33 In a stainless steel vessel, 0.42 kg of buprenorphine were suspended in 0.56 kg of levulinic acid and 0.28 kg of ethanol. With stirring, 6.25 kg of a polysiloxane adhesive in the form of a solution in n-heptane having a solids content of 74% by weight and 0.49 kg of heptane were added. The mixture was stirred until the buprenorphine base was fully ved, to give 8.00 kg of a buprenorphine- containing adhesive solution with 5.25% of buprenorphine, with a solids content of 70% (buprenorphine base-containing ve solution).

] For the skin t layer, a polyacrylate adhesive prepared from 2- ethylhexyl acrylate, vinyl acetate and 2-hydroxyethyl acrylate were used. 3.69 kg of a solution of this adhesive, with a solids content of 50.5% by weight, was d with 1.64 kg of ethyl acetate, following homogenization resulting in 5.33 kg of active-agent-free rylate solution with a solids content of 35% (buprenorphine base-free adhesive solution) The buprenorphine base-containing adhesive solution was coated on an adhesive polyethylene terephthalate film (e.g., Scotchpak from 3M) using an Erichsen coater and the solvent was removed by drying at approximately 50'C for about 10 minutes to provide the buprenorphine base-containing matrix layer. The coating thickness was chosen such that removal of the solvents results in a coating weight of the buprenorphine base-containing matrix layer of 60 g/m . This results in PC T/IB2012/002973 the 7.5 % by weight of buprenorphine base and 10 % by weight of levulinic acid in this buprenorphine base-containing matrix layer. The dried film was laminated with the backing layer (e.g Scotchpak from 3M).

] The active-agent-free polyacrylate adhesive solution was likewise coated onto an adhesively treated film (the later protective film to be d before the systems are used) and the organic solvents were removed to produce the skin contact layer. The coating thickness of the resulting skin contact layer ought to , ing removal of the solvents, to approximately 20 g/m, The adhesively treated film was then removed from the buprenorphine base-containing matrix layer produced first, and the buprenorphine base-containing matrix layer was laminated onto the skin contact layer.

The individual systems (TTS) were then punched from the orphine-containing self-adhesive layer structure. In specific embodiments a TTS as bed above can be provided with a further self-adhesive layer of larger surface area, ably with rounded corners, comp-. ising a pressure-sensitive adhesive mat:ix layer which is free of active ingredient and has a preferably skin- colored backing layer. This is of advantage when the TTS, on the basis of its physical properties alone, does not adhere suAiciently to the skin and/or when the buprenoiphine-containing matrix layer, for the purpose of avoiding waste, has pronounced corners (square or rectangular shapes). The plasters are then punched out and sealed into pouches of the primary packaging material, PC T/IB2012/002973 EXAMPLE.;K 6 t00152j In Example 6 the ro releases and the corresponding skin permeation rates ot Examples i to 4, Coinpai alive Example 5 and Norspanof: v, ere dctcrnllned h$' IB vitfo cxperinlcnts ln Rccoldailcc xvi! h the ( IFCLI Guideline (adopted Apfli ] 3, 004) carried out A'iih 8 9 IHl Franz diffusion ceH. Split thllckBcss hunlan skiB fronl cosnlctic surgeries (fclnafc hrcast, date of hlrth 1989) v'as useii. A dci'iriRtonc vt'Rs used lo prepare skIB to R tilrckness of 800 iim„'A'Ith Rn ml'tact epidermis toi ail pics i to 4, rative EXRIBpic 5 and thc comIBcfclai i 0 product n@. Diecuts Ivith an area of ).163 cm &vere punched (loin exampies I to 4 and Comparative Exarnpile 5, and Ivere each tested against diccuts of the comincfcia) product NofspancYX', Tile conccn'IraiioBs of ofphine in Ihc lcccptof Incdnull ot thc FfaBz ci W (phosphate btrffcf soiutlon pH 5.5 vvlth 0.1~Fo sa]inc Rzldc as antihactcfiologicai aucnt) Rt a. ti';Alpifaturc oi 32 + i Co'crc mcasulcd. The rcsuIts Rfc shov'B in Tabics 6.1 to 6.8 and Figures I to 4.

PC 12/002973 Table 6.1 Non-cnmnlatiive release Ipg,'em ] n = 3 (SD) Elapsed Example 1 Example 2 Example 3 Example 4 ,:'Norspan time 0 0 0 0 0 4.06 3.53 I 2.35 3.33 (1.49) (0.70) ' (0.65) (1.89) (0.77) 24 44.60 33.60 36 47 28.73 (16.99) (7.10) ) (8.84) (3.76) 34.00 31.93 I 36 47 K 22.10 (11.58) (13.14)::(11.37) I (5.54) 73.77 58.17 94.53 49.60 (20.38) (6.62) (20.48) (11.47) 72 113.83 87.83 131.67 74.10 (23.49) (8.76) (12.70) (14.25) (2.23) 144 272.00 210.67 166.00 181.33 (22.52) (8.08) (28.62) (28.22) 168 78.30 65.60 26.73 60.97 17.17 (2.65) (6.25) (5.09) (9.69) (1.72) PC T/IB2012/002973 Table 6.2 Noa-emnulstsve eel!ease [pg/c~xP] r. = 3 (SO) Elapsed COB'kpaF81tkVe a035 Kxample 5 ltJIBM 0 0 0 2.12 3.19 (1.44) (0.77) 24 28.60 22.40 (10.19) (3.76) 32 26.37 13.83 (6.47) (2.32) 53.03 26.17 (5.80) (2.46) 58.47 ~32.43 (2.42) (2.23) 144 73.27 60.10 (4.63) (2.02) 168 17.87 17.17 (1.35) (1.72) PC T/IB2012/002973 Table 6.3 Mean non-cumulative skin permeation rate [pg/cm -hr] n = 3 (SD) I Elapsed Sample Example m Example Kxam pie Example n 1 2 3 4 time interval (hr) (hr) 0.51 0.44 0.29 0.42 0.40 (0.19) (0,09) (0.08) {0.24) (0.10) 16 2.79 2.28 1.80 1.40 (1.06) (0,64) (0.55) (0.24) 32 4.25 3.99 4.56 2.76 1.73 (1.45) (1.64) (1.42) (0.69) (0.29) 16 4.61 3.64 5.91 3.10 1.64 (1.27) (0.41) (1.28) (0.72) (0.15) 72 24 4.74 3.66 5.49 3.09 1.35 (0.98) (0.37) (0.53) (0.59) (0.09) 144 3.78 2.93 2.31 2.52 0.83 (0.31) (0.11) (0.40) (0.39) {0.03) 168 24 3.26 2.73 1.11 2.54 0.72 (0.11) (0.26) (0.21) (0.40) (0.07) PC T/IB2012/002973 [001563 Table 6.4 Meaa camalatlve skkB perme"ktloB rate Ipg/em'-hrl a = 3 (SD) Elapsed, : Sample Compar at4'e;:Norspan time (hr) interval (hr) 0 0 0 0 0.27 0.40 (0.18) (0.10) 1.79 1.40 (0.64) (0.24) 32 8 3.30 1.73 (0.81) (0.29) 48 16 3.31 1.64 (0.36) (0.15) 72 24 2.44 144 72 1.02 0.83 (0.06) ws 24 0.74 0.72 (0.07) PC T/IB2012/002973 Table 6.5 Mean boa-cumvkmtiive skin permemtiien rate Ipg/em -hr] n =- 3 (SD) aM per area Of e (pg/hjr] Fkkpse@ Exmmp1le Fxample Example iNOFSp8IBZ) 2 3 4 time (25 cm ) 0 T 0 0 0 0 0.5 1 0.44 0.29 0.42 0.40 (0.09) (0.08), (0.24) (0.10) 5.08 4.42 T 2.93 4.16 9.97 7.61 6.63 4.40 9.97 18.75 8.28 5.50 I 7.80 9.97 24 16 2.79 2.10 2.28 1.80 1.40 (1.06) (0.44) (0.64) (0.55) (0.24) 27.SS 21.00 22.79 17.96 35.00 41.81 31.50 34.19 26.94 35.00 18.75 52.27 39.38 42.73:;33.67 35.00 32 4.25 3.99 4.56 2.76 1.73 (1.45) (1.64) ' (E .42),; (0.69) (0.29) 42.50 39.92 45.58 27.63 43.23 63.75 59.88 I 6S.38 41.44 43.23 WO 88254 PC T/IB2012/002973 18.75 79.69 74.84 85.47 : ;. 51.80; 43.23 48 16 4 61 m 1.64 m 3.64 5.91 3.10 (1.27):;(0.41) (1.28) (0.72) m (0.15) 46.10 36.35 59.08 31.00 I 40.89 54.53 88.63 46.50 18.75 86.45 6S.16 I 110.78 5S.13 40.S9 4.74 3.66 5.49 3.09 1.35 (0.98) (0.37) (0.53) (0.59) (0.09) 47.43 36.60 54.86 30.88 I 33.78 71.15 54.90,.'82.29 46.31 33.78 18.75 88.93 68.62 102.86 57.89 33.78 144 3.78 2.93 2.31 2.52 0.83 (0.31) (0.11) (0.40) (0.39) (0.03) 37.78 29.26 23.06 25.19 20.87 56.67 34.58 37.78 20.87 18.75 70.83 43.23 47.22 I 20.87 3.26 2.73 1.11 2.54 0.72 (0.11) (0.26) (0.21) {0.403 (0.07) 32.63 27.33 11.14 2 40 17.88 48.94 41.00, 16.71 38.10 18.75 61.17 51.25 20.89 I 47.63 17.88 PC T/IB2012/002973 Table 6.6 non-cumulative skin permeation rate [pg/cm 2 ' -hr] , Mean n= 3 (SD) and per area of release [pg/hr] lEIapsed Area of' IL'omp. n(R: rele'lee Exam';Ie 5 time Area of (cm ) release 0 0 0 0 0.27 0.40 (0.18) (0.10) 2.65 9.97 3.98 18.75 4.98 9.97 24 16 1.79 1.40 (0.64) (0.24) 17.88 35.00 26.81 35.00 33.52 35.00 32 3.30 1.73 (o.s&) (0.29) 32.96 43.23 43.23 WO 88254 PC T/IB2012/002973 62.15 40.89 24.36 36.54 PC T/IB2012/002973 Cumulatllve release after 168 hours oi release cm ] n = 3 Example R.xam pie ComparatD'e Norspan& 2 3 Example 5 620.56 491.33 494.22 420, 16 259.72 175.29

[00160] Table 6.8 Mean tive skin permeation rate over 168 hours 2 [pg/cm -hr] Example Example Example Example Comparative, Norspan ' 1 2 3 4 Example 5 3.69 2.92 2.50 1.55 ' 1 04 WO 88254 PC T/IB2012/002973 ln Example !,a. pharmacokmettc study m healthv adult male and female subjects was conducted as part of a 2 stage, randomised, open-label, single- dose, 4-part crossover design pharmacokinetic study to assess the pharmacokinetics and potential of Example 1 TTS, Example 2 TTS and Comparative Example 5 TTS formulations for equivalence to the existing commercial product BuTrans, also known as Norspan.

The study treatments were as follows: Test treatments: I Example 1 TTS - the amount of buprenorphine base being 12 mg; the area of release being 10 cm 2 - applied for 7 consecutive days.

Example 2 TTS - the amount of buprenorphine base being 12 mg, the area of e being 10 cm 2 - d for 7 consecutive days.

Comparative Example 5 TTS —the amount of buprenorphine base being 6.75 mg; the area of e being 15 cm - applied for 7 consecutive days.

Reference treatment: BuTrans 20 pg/hr (the amount of buprenorphine base being mg; the area of release being 25 cm ) —applied for 7 consecutive days.

The treatments were each worn over a 7-day period. Each t was randomised to both the order, and TTS site of the treatments to be delivered over the study periods.

As this study was conducted in healthy human subjects, the opioid nist naltrexone was co-administered to reduce opioid-related adverse events. 50 mg naltrexone were administered with 100 ml of water every 12 hours beginning -13 hours prior to TTS ation and continuing until 215 hours post-TTS application, PC T/IB2012/002973 ct selection /V M'nber ofsll. ?/ecjs jt)0165j It was HntKIpRtcd that jnlatcly '?2 sub]ccts would bc landorBizcd IB'to stage 1 of thc study, with 26 subjc' ts lalgctcd 'to cojnplctc StRgc 1 of thc Srudy. AB adcG[UREC Bujnbcr of subjects werc Screened iirE thc prc-trcatYBejkt phase, 21 days prior to the treatment phase to achieve this sample size.

E.e. within ing procedure ScrccnlBg procedures werc perfojHBcd foI' all poitcn'tlai subjects 8t 8 [001I66j scrcejljng vlsiit conducted wnhln 21 days prior' t0 thc Ercatjncjlt phase, l, c. pI'lor tQ subje'"t Day -1 of'study period 1. The following evaluations were pcrtorjned after the has signed thc study spccltK consent forj: inclusion:Y xchjsion criteria. ~ aphy t',sex„date ot. bish, race) and body mass index j'BMI) Vfcdjcal hjstorv (Bkcludjng cont jrjnatjojl ot cllglblhtv trojn thc t s Pl nrERry cRrc PiEyslcERB) al exalnijjation including height, weight and body mass index.

Hacmatoiogy (hacjIjogiobjB, rcd blood cell count, hacmatocrjt, plRtclcts, white blood cell count and diAerential (ncutrophils, iyjnphocytes, monocytes. coslnophlls Rjld ils)) 8]ood E .hcnlisW" (Sodiujn, calcluIn„potassEUEB. hkcRI'boBRitc, chloride, Urea, creatininc. Uric acid, albkjmin, total protein, alkaiijle phosplhatase, globulijl, Rspartate REBHlotransfcrRsc„R1RBEBc Rmjr?QtraBSfclasc, a ghjtanlyl- tlansfcrasc, totR1 ln. direct bilkjubjll, glucose, Enorganic phosphate, lactate dehydrogenase, tr'glyceride and cholesterol) Urinal'E sls (specif]c gravity„pH, protcljl, kcEQAC, occult blood. glucose; Hnd onal microscopy analysis will be ujlderEaken ifany abnormahties are dctccted to Rnai~ sc tor rc(1 blood cells. white blood cells, cplthclllal cells„ bactcE'la„casts RBd crystals j PC T/IB2012/002973 Urine drugs of abuse {opiates, ***e metabolites, barbiturates, amphetamines, methadone, benzodiazepines, phencyclidine, methamphetamine, tricyclic antidepressants and cannabinoids) and alcohol test (urine or breath) Serology testing (Human immunodeficiency virus (HIV), Hepatitis B surface antigen {HBsAg), Hepatitis C antibody) e 12-lead Electrocardiogram (ECG) Serum ncy test for females of child-bearing ial Serum FSH for post-menopausal females Vital signs {Pulse oximetry! oxygen tion (SpOz), supine respiration rate, supine blood pressure, sup!ne pulse rate and oral temperature) Medication history and concomitant medications will also be recorded.

Inclusion criteria ts who met the following citeria were included in the study. 1. Provide n informed consent. 2. Healthy male or female subjects aged 18 to 55 inclusive. 3. Female subjects who are sexually active or become sexually active must be g to use highly effect.'ve methods of contraception throughout the study.

A highly effective method of birth control is d as one which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as sterilisation, implants, injectables, combined oral contraceptives, some IUDs (Intrauterine Device), or vasectomised partner. 4. Female subjects including those up to 1 year post-menopausal must have a negative serum pregnancy test. 5. Female subjects who have been post-menopausal for & 1 year and have elevated serum follicle-stimulating hormone (FSH/ or are d with hormone replacement therapy (HRT).

PC 12/002973 6. Male subjects who are g to use contraception with their partners throughout the study and for 10 days after completion of the study and agree to inform the Investigator if their partner becomes pregnant during this time. 7. Body weight ranging from 55 to 100 kg and a BMI & 1S and & 29. 8. Healthy and free of significant abnormal findings as determined by medical history, physical examination, vital signs, laboratory tests and ECG. 9. Willing to eat all the food supplied throughout the study.

. The subject's primary care physician has confirmed within the last 12 months that there is nothing in the subject's medical history that would preclude their enrolment into a al study. 11. Will refrain from strenuous exercise during the entire study. They will not begin a new exercise program nor participate in any unusual!y strenuous physical exertion.

Exclusion criteria [0016S] The following citeria excluded potential subjects from the study. 1. Female subjects who are pregnant or lactating. 2. Any history of drug or alcohol abuse. 3. Any history of conditions that might interfere with drug absorption, distribution, metabolism or ion. 4. Use of opioid or opioid antagonist-containing medication in the past 30 days.

. Any history of frequent nausea or vomiting less of aetiology. 6. Any history of seizures or symptomatic head trauma. 7. Participation in a clinical drug study during the 90 days preceding the initial dose in this study or participation in any other study during this study.

S. Any icant illness during the 4 weeks ing entry into this study. 9. A history of additional risk factors for es de Pointes (e.g. heart failure, hypokalaemia, personal or family history of long QT syndrome, syncope, or family history of sudden death). 10, Abnormal cardiac conditions including any of the following: PC T/IB2012/002973 I Q 1 c Interval r than 450 msec at screemng or at check-m before lnci case in QYc ot Alofc than 60 Aisec Rbove pfc-dose values of each Study period.

I 'sc ot Blcdication wlFhul 5 BB'1csIhc halt-lite 03 UIB 14 days tor prese!I ipiion Blcdication 0! 7 davs IQE over-thc-count r preparations (including vitamins, herbal and/or mineral supplemcilts), whichever is longer, betore the first dose of sludy treatment and duriilg the study (Evith the exception ot the continued usc of HRY and colltraceptives). Note: SEEbjCCES taking Oral Conti'RCCptiYCS COBtainilng 3 $ P3.A4 Enhibitoi'S SUCh 8$ gestodene Should be exciiuded as this may leail to ed pLzsma conccntTatioBs.

RctusR1 to abstaiB 1 QIB ne of xRINhlnc contRAIEBg bcvcl ages cBtircly until the last Study PK. sample has been taken. 13. "11eckly l EBtak" cxcccdulg thc equivalent ot 14 UBits v'cck tof s and 21 UBEts/wcck fof' AERlcs. 14. ConsUETEption of alcoholic bcvcTagcs viithiEI 48 houfs bctore study clE'ug adEI!UUstfatEQB, Rnd Tctusal to abstain ffoTA Rico'hol for thc ClurRtion of thc srucly confn;cnicBE And for at least 72 houfs after thc last xonc dose. 15. I-iistory of smoknlg Evithm 45 days ot study drug adinnustration and relusal to Rbstain ffonl snlokulg dufit g ihc study. 16. Blood of bloo(1 ts donated within 90 dRvs pi'iof to study drug adnlinisiration OI' RIEy Arne during the study, cxccpt 8$ r'cquElcd by this pf otoco1. 17. Positive results of Urme drug screen„alcohol test, pregnancy test. HBSAg, Hepatitis C antibody„or MV tests. 18. KBOEVB hypelscTEsitivlty QF scBsitivity to buprenofphEIEC, Aaltrcxonc QT fclatcd coIBpounds 03 Rnv of the cxcipicnts 01' RBV contrauldECRAOBs 8$ detailed in the Summary of Product Characteristics.

PC 12/002973 19. Clinically significant history of allerg.'c reaction to wound dressings or elastoplast.

. Subjects with tattoos or any dermatological disorder at the proposed sites of TTS application, or with a history of eczema/cutaneous atrophy. 21. Subjects who will not allow hair to be d at the proposed TTS application sites which may t proper placement of the TTS. 22. Refusal to allow their primary care physician to be informed. ts meeting all the inclusion criteria and none of the exclusion criteria were randomized into the study. ent phase procedures Randomisation Randomisation was completed once all inclusion and exclusion criteria are verified. Randomisation order was determined on a central isation list held at site (one list per site).

[00171] Subjects were randomised to the order of the treatments and the skin TTS application sites.

There are 4 possible TTS application sites: e Deltoid region of the non-dominant arm Deltoid region of the dominant arm Right upper back Left upper back.

Check-in procedures On each day prior to treatment (e.g. Day -1 or Day 17), subjects were checked in to the study unit. The following ures were undertaken: Review of consent and eligibility Urine pregnancy test (Female subjects of child bearing potential only) Alcohol screen (by breath test) and Urine drug screen as per screening visit PC T/IB2012/002973 ~ Naltrexone HC1 dosing ~ Adverse events Concomitart medications will be recorded.

Randomisation d once in the study on Day -1.

Study procedures The treatment phase included study periods with a single dose application. The following procedures were undertaken in each period: Pre-dosing biochemistry (fasting) as per screening ~ TTS ation ~ Vital signs (supine respiration rate, supine blood pressure, supine pulse rate) SpOp Blood samples for drug concentration measurements obtained pre-dose and at pre-specified times throughout the on of the study for each subject; 1TS was removed at 168 hours after TTS application; blood draw must be performed immediately prior to TTS removal 12-lead ECG (taken before each TTS application, at 72, 120, and 168 hours after each TTS ation in each study period and at the Post-Study Medical) Oral temperature was recorded at ied times throughout the study Adverse events; recorded throughout the study on an ongoing basis whilst confined to the study unit and through open questioning. Any ed skin reactions will also be recorded as adverse events.

Concomitant medications; recorded at Screening and throughout the study TTS site skin ment and duration and observation assessments; duration of TTS wear assessments were rated just after application and then at the same time each day of 1TS wear. TTS observation assessments were performed just before TTS removal. Skin site reaction will be assessed 30 min after TTS removal.

PC T/IB2012/002973 [001/4] Where more than one procedure was scheduled at the same time- point, the following order of procedures was ideally followed: BTDS blood sample collection within + 5 minutes of scheduled sampling time post dose. se sample must be taken within the hour before study drug dosing Vital signs and ECG (within + 15 minutes of scheduled time) Pulse oximetry (within + 15 minutes of scheduled time) Skin reaction assessment at application site (within + 5 minutes of scheduled time) Duration of TTS wear observations (within + 30 minutes of scheduled time) Observation of TTS at removal (within - 30 s of scheduled time) ~ Food and fluids (start time within + 30 minutes of scheduled time).

Throughout the Study Period when subjects had the TTS applied, they were allowed to have a shower (not bath) but they had to refrain from washing, or rubbing the site of TTS application. The subjects should also refrain from showering until the day after TTS application. The TTS was removed on the eighth day of the Study Period following the blood draw at 168 hours afler TTS application. 8'ashout period There was a m 10 day washout period between removal of one TTS and ation of another.

Confinement to the study unit Subjects were confined to the study unit from Check-In on the day before study drug administration until the time that the 192 hour post-TTS application procedures were completed. Subjects returned to the unit for the 216, 240, 264 and 288 hours tudy procedures and the tudy l. During confinement in the unit, subjects will e standardised meals.

PC T/IB2012/002973 PPRZPMC'OKÃJCiic NeiiSBf'erpteriiS [001'78] Blood samples for pharmacokinetic assessments were obtained for each subject at predose and at 2, 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 169, 172, 176, 180, 192, 216, 240, 264 and 288 hours post-TTS ation. !00179] For each sample, 4 ml of blood were drawn into 4 ml tubes containing K2EDTA solution, an anticoagulant. Samples were centrifuged within 30 minutes of collection. Following centrifugation (1500 CJ, 4'C, 15 minutes), the plasma was transferred, via pipette, into 2 labelled 3 ml polypropylene tubes, and stored at -20'C within 1 hour of collection.

Plasma concentrations of analytes were quantified by liquid chromatography —tandem mass spectrometric ology /MS) using a previously validated assay.

For each t, the following pharmacokinetic parameters were calculated based on the plasma concentrations of buprenorphine: AUCt (pg.hr/ml) —the area under the plasma concentration-time curve from hour 0 to the last measurable plasma concentration, ated by the linear trapezoidal method; AUCINF (pg.hr/ml) —the area under the plasma concentration-time curve extrapolated to infinity, calculated using the a = AUCt +—,whereQua AUCINF ' CLast ls the last measurable plasma Lstssali@aZ concentration and LambdaZ is the apparent terminal phase rate constant; e Cmax (pg/ml) —the maximum observed plasma concentration; trnax (hr) -- tlie tune to maximuni plasma concent'ration; LambdaZ (1/hr) —the apparent terminal phase rate constant, where LambdaZ is the magnitude of the slope of the linear regression of the log tration versus time profile during the terminal phase; PC T/IB2012/002973 t I/2Z (hr) —thc appa) cnt plasn)R tern))BRI phase half-I)fc (vi lixcncvcr poss)blcJ. where tI,'7Z = (h)2), ' LambdaZ, [001821 Plasma conccnrrat)on values bcIow thc lcvcl of qURBtltatloB wc)'c set to equal zero for the analysis. [00183) A(JC values were calculated using the linear trapezoidal method.

After l ot thc 8I OS. whet'c poss)hlc, Lait)bdaZ vRIues werc cstUBatcd Using those poults deter)n)ned to be Ui the iermu)al. r, ear phase. Z was deter)n)ned fro)B thc Fat)o ot IB 2 to Lan lbdaZ.

Individual Subject Stopping C6tc).la [00184j Subjects who Bict onc oF )Bore of thc follow)Bg stopp)ng crftcr)a wc"c tinued from the study: ly Abnormal Liver Function Tests or Creatuline )esr Oz satulatlon 85 'o or less lnc)'case )B QYc of FBoI'c than 60 )t)scc above pi'c-dose vahics of each study period or (pTc greater than 500 Fnsec s adverse drug reaction SCVCI'C Bai)SCR Rnd Vonlitulg Severe reaction at TTS site or a loca/ reaction which itates removal of thc TTS or discontBFURtlon of Ihc infusion Systolic bllood pressure (BP) -- 180BI)BHg PlcaI't )Rtc (HRJ .+ 140 bpnl Other BP RI)d HR values Rnd changes frofli oascllnc if assoclatcd wiith cardiovascular coniproniisc, Study Restrictions [00185j As per the inclusion/exclusion criteria. subjects had to be willing to eat al! the food supphed throuohout th" studv. Menus were standardised while sublccts Ric ln the study Unit. Thc FncnUs AvcI'c tile san)c fo)' each stUdy period.

Hov, ever. the menus for each day needed Bot be identical. Subjects had to consuinc PC T/IB2012/002973 Only thc food glvcB Eo Ehcln willie 3B thc Unit. Food and water will bc fcstrlctcd as folio+, s: SUbjccts wcl'c given 811 evening Tncal Rnd sliack foliov "lng check-1B to thc study ulllt. QD thc day bcfolc dosulg lto bc cQnsUEBcli -&8 hoUrs before dosing.

Subjects receiv' d a hght breakfast 1 hour before comnlencement of treatment. lhcl'e was tice access to dfDEklBg wRtcf ghout thc day& cxccpt wlthlB 30 cs before vEEal sigil EncasufcETEcnts of coIDDlcnccmcBt of Ercatlncnt. A low faE lunch (&30,'0 fat), dinner„alld an cvcnlng sBack wcle pE'Qvldcd Rt 4, Rnd 14 hours RAc3 1TS 8ppilcatlon. DE"Inks of decaffcEEEatcd tca of decatYeinated coffee were supplied with meals.

Meals werc pfovldcd Rt thc sREBc tlnlc each (lay (Rs QB Day 1). Ihcfc wRs fi'cc access to drillking water and de-caffeinated drmks throughout the day, except v.ithin 30 minutes before vita) sign measurements.

Breaktast will be option«1 after ail study procedures have been completed. j Subieei» had tO abStaui trOm SmOkmg Wlthm 45 daVS Ot Study druo adDE&EEEstfatEOEE Rnd dufiilo ti3c efltu e s'EEEdv. Sub)ects had to abstain trclnl aicollol '&QDE 48 hoUE's bctoilc thc hrst stEEdv dl'Ug adEDEDEstratlon until ii2 hoU1 s after Ehc last naltrcxollc dose Qf thc last study pe3 Eod. Bc of lnc coBlalnlng tood QE' beverages were not permitted during the SEndy from check-Dl betore treatlnent, until Rftcl. Thc last study acoklnctlc saDEple has bccl' takcB.

Follow-I lp PCE"iod [0018",j Subjects that completed the ent phase or v ho discoEEtiliued trcatfncnt cafl y werc followed Up YiEthul 7 to 10 de s Rtrcr thc Subject's .last visit/dose of studv EEEedlcatEQB.

Study piction PE occdures I.88[ Subjects that COEEEplcted the Treatment Phase carried out the following CODEplCTEOB/01SCOEltllmatlOB 3' liSlt ploCCdufCS: PC T/IB2012/002973 Subjects ed a tudy Medical Visit 7 to10 days after removal of their last TTS if this was the last ent received in the case of completion/discontinuation from the study.

Safety was monitored and Post-Study Medical procedures were carried out including the following: o Physical examination including weight measurement o Haematology (as for screening visit) o Blood chemistry (as for screening visit) o Urinalysis (as for screening visit) o Serum pregnancy test for females of child bearing potential o 12-lead ECG o Vital signs (supine respiration rate, supine blood pressure, supine pulse rate) o Pulse ry o Oral temperature o Review of adverse events o Review of concomitant therapy, PC T/IB2012/002973 t00189] The s of this study are shown in in Figure 5 and Tables 7.1 to 7.11 below: Tab]e 7.1 StarlstKB] fesu]ts for pharBMcokmet)e parameters (hE]] ana]ysts popu]at8ort): ' 10 GBA Fxaxnpie ] :mg / ]0 em ) and L'xarnp]e 2 T 1'S (].2 n)g re]ative to BBTrarL9% (20 mg. 25 ern ) ~Exam &Ie 7 TTS Exs~nlls 2 TTS BuTrans Mean" 312.20 301.28 383.63 169.48 ].6 9.41 176.63 3.24 30.88 33.38 u' 270.93 346.47 0.552 0.467 0.108 0.106 '; 0088 92.80 80.80 I 120.03 Medk8n 260.87 283,00 ] 376.74 708.13 829.94~ 872.38 AIUCt...,,,~.....~T(I3~48.]br/mk) IP'xamnie 1 TTN~I Exam le 2 TTS BuTransl, 24'I n' 28 Mean" 31223.49 SD' 15305.33 19273.58 SE' 2892.44, 3642,36 GeoMean' 27468.57 I 4063.3.23 io@ESD' 0.534 0.428 lo98 SE~ 0.101 Min 12II.4.7 9263.5 Median' 26981.95 63874.7 100315.6 E~xample 1 YTS Example 2 TTS BuTraus~a) Mean, ...,,... 23 ' 3 33483.34 45108.89 SD' 15193.45 SE q-62 8 3168.05 3956.40 GeoMean' 27724.63 30024.46 I 41 Io98 SD' 2 0.434 , 0.495 m lo4 SE~ I 0.094 0.103:;0.087 Min 7 I l i 2498.8 146]9.5 PC T/IB2012/002973 32248.48 I 43282.61 64001 6 j 64670.1 j 1 01394."-: Kxampje 1 TTS BnYjrans4l 6.7 7 7.10 Median' 66.00 Max' ' 72.00 Kxanglle I YYS jaxam~de 2 TTS nsOI4 O.tlI92 001'5 0.00, 9 0.0018 ~ajjia" 0.00, 0.044 j 11.04 j.

TxamPle jj TTS ' ll'xamT&je 2 TTS Mean'Il 3.68 3.36 i&)III l (3.73 Median Max'" 93, , 9 83.91 98.2'' n =-' Irulnllcr of sublccfs vvlth dafa Rvallablc jj non-zcI 0 values).

Mean —Br,thltlctlc Incan; thc sum of BH the values of atlons dlvrdc(1 bv the total numbcl. OEobservafions.

SD:-- standard deviation.

:'CT'eoPllcanSk -=' ard error, = geometric mean: the mean of the log transformed data backfransforlned to lhc Ol.lglnal scale. log SO -= rd dcvlatlon of the log Iransforlncd datB. ' log SJt' ""standal d error of thc log trallsformcd data. ,'h,Mln = mlnlnluln value, ' Median =- middle value vvhcn the list of vahles is ranked.

MRX = IIIBXInlurn VahlC.

PC T/IB2012/002973 ] Tahle 7m2 Statistical results for pl-.armacokinetic parameters (full analysis population): Comparative Example 5 TTS (6.75 mg / 15 cm ) relative to BuTrans (20 mg /25 cm ) Cmaa /~/ml) AUCt .kPÃ' ' Comp. BuTrans Comp. BuTrans ' Example 5 Example 5 TTS TTS 28 28 Me iin 27709.30 SO" 137.67 13213.42 19273.58 26.02 33.38 2497.10 t 'eo%'Iean' 258.05 25025.91 l&)g 0.484 0.467 0.456 lo~SE' 0.091 0.086 0.081 'M' 111.98 11539.6 1/4312 ] 254.25 ".". 6.74 24401.87 40866.',' 1 595.80 57931.7 100315.6 tmax ('hrl Comp. i a' i Comp. BuTrans Example 5 Example 5 '; TTS TTS 26 28 28850.38 451 .21 13805.37 38.02 2707.46 to 04 4 12".3.~4 NA log~SO 0.461 0 434 NA' NA' NA' lo~op SE 0.090 0.087 liI/lhn 11702.00 14619.5 48.OO 24.00 Median 25186.06 43282.61 96.00 72.00 60731.70 101394.2 169.00 ' 169.00 Lamb~daZ '1/hr) j tl/ZZ Comp. BuTrans Comp. BuTrans l Example 5 ' ',, Example 5 S TTS 6 26 0.0172 I 0 50.38 44.73 0.0090~0.0065 27.38 16,82 SE' 0018 5.37 &Iln 13.80 16.75 PC T/IB2012/002973 Median' 0.0157 I 0.0164 I 44.14 42.22 Max' 0.050', 0.041 ' 154.54 98.27 n = number of subjects with data available ero values).

" Mean = ar'thmetic mean; the sum of all the values of observations divided by the total number of observations.

'SD = rd deviation.

'GeoMeanSE = standard error. = ric mean; the mean of the log transformed data backtransformed to the original scale. log SD = rd deviation of the log transformed data. s log SE = standard en or of the log transformed data.

"Min = minimum value.

' Median = middle value when the list of values is ranked.

" Max = maximum value.

'NA = not applicable.

Table 7.3 Mean AUCt per area of release (pg. hr. 'ml-cm ) Example 1 I Kxample 2 Comparatrve l 8u I 1I"ans'x' TTS k;xarnple & 2690.49 2746.86 1668.39 1624.53 PC T/IB2012/002973 Table 7.4 y of mixed model' for pharmacokinetic parameters Cmax, AUCt, and AUCINF (full analysis population): Example 1 TI'S (12 mg) relative to BuTrans (20 mg) LS Mean' n d e 1 BuTrans Ratio 90% TTS Exampel 1 Confidence TTS/ Interval (%) BuTrans ( /0),:; Cmax 25 278.48 352.93 78.90' [66.65, 93.41] AUCt 25 27289.42 49 64.46 [55.05, 75.48] AUCINF 20 26968.66 40541.38 66.52 [58.09, 76.18] 'Data analysed using a mixed effects linear model with treatment, actual sequence and period as fixed effects and subject within sequence as random effect. The analyses only consider subjects who completed both periods of the respective treatment ison.

Least square mean; back-transformed from log scale to linear scale.

'Least square mean; back-transformed &om difference on log scale to ratio on linear scale. 'equivalentNumber of subjects with data for both Example 1 and BuTrans ble. i to relative Cmax ratio. equivalent to relative bioavailability.

PC T/IB2012/002973 ] Table 7.5 Summary of mixed model' for pharmacokinetic parameters Cmax, AUCt, and AUCINF (full analysis population): Example 2 TTS (12 mg) relative to BuTrans (20 mg) LS Mean Example2 i BuTrans Ratio 90'/, TTS Fxarapet 2 I' ontidenee TYS/ l Interval ("/o) BuTransOR (%) l Cmax 24 267.94 338.34 79.19' [69.03, 90.86] AUCt 28021.68 [61.99, 81.15] AUCINF, , 16 31910.44:,:42095.11 l 75.81 [62.53, 91.90] 'Data analysed using a mixed effects linear model with treatment, actual sequence and period as fixed effects and subject wi.hin sequence as random ,, . Tne es only consider subjects who completed both periods of the ' respective treatment comparison.

Least square mean; back-transformed from log scale to linear scale.

'Least square mean; back-transformed from difference on log scale to ratio on linear scale.

'Number of subjects with data for both e 2 and BuTrans available. equivalent to relative Cmax ratio. equivalent to relative bioavailability.

PC T/IB2012/002973 Table 7.6 Summary of mixed model' for pharmacokinetic parameters Cmax, AUCt, and AUCINF (full is population): Comparative Example 5 TTS (6.75 mg) relative to BuTrans (20 mg) LS Mean LS Mean' n Comp. BuTrans, Ratio Comp. ;', 90% e 5 Exampel 5 I Confidence TTS TTS/ BuTrans (%) Cmax 274.03 348.94 78.53' [65.43, 94.26j AUCt 2 26037.56 41121.8] 63.32 [52.64, 76.16] AUCINF 21 26782~27 41460.21 64.60 [51.62, 80.84] 'Data analysed using a mixed effects linear model with treatment, actual sequence and period as fixed s and t within sequence as random effect. The analyses only consider subjects who completed both periods of the respective treatment comparison.

"Least square mean; back-transformed from log scale to linear scale.

'Least square mean; ransformed from difference on log scale to ratio on linear scale.

Number of subjects with data for both Comparative Example 5 TTS and 'BuTrans available. equivalent to relative Cmax ratio. equivalent to relative bioavailabilih.

PC T/IB2012/002973 ] Table 7.7 y of mixed model' for pharmacokinetic parameter t1/2Z (full analysis population): Example 1 TTS (12 mg) relative to BuTrans (20 mg) LS Meanb : Example 1,,: BuTrans Exampel 1- 90% BuTrans Confidence Interval tl/2Z ~20 42.09 42.62 0.07 [-4.38, 4.53] 'Data analysed using a mixed effects linear model with treatment, actual sequence and period as fixed effects and subject within sequence as random effect. The analyses only consider subjects who ted both periods of the respective treatment comparison.

'NumberLeast square mean. of subjects with data for both Example 1 and BuTrans available.

Table 7.8 y of mixed model' for pharmacokinetic parameter tl/2Z (full analysis population): Example 2 TTS (12 mg) relative to BuTrans (20 mg) LS Mean" n' Example 2 BuTrans Exampel 2- 90% BuTrans Confidence Interval llnZ iS 43.16 -1.47 [-10.63, 7.70] I 44.63 'Data analysed using a mixed effects linear model with treatment actual sequence and period as fixed effects and subject within sequence as random . The es only consider subjects who completed both periods of the tive treatment compar'son.

Least square mean.

,;'Number of sub', ects with data for both Example 2 and BuTrans available, .

PC T/IB2012/002973 SUIIIB'18&'of IBIxcd BIodcl for pharnIacokutctIC pRI'RBIctcr t!/2Z(fi'Ill anal%'sIs popularIOB): Con1paratIvc LxMBplc 0 I ES (6,75 BIg) rclatIvc to BU l ransom@ (20 1.S Meam Comp Bm I I.ams'wI Comp. 90"/e Kxampk 5', , Kxamtple 5 COBMemce TTS TTS- Interval BUTrams~~~ tI/2Z 'Data ed using a BIixcd s! inear model with treatment, actual sequence and period as fIxed effects Rnd subject ~vithin sequence as random effect. Thc anal''scs oB!v consider subjects who completed both pcr ods of thc rcspccttvc 1L'Icatn1cnt arIson.

"Leasi. square mean. i "Yumb "r of sub1ects xvtth dlata for both Comparatrvc Example 5 TTS and BUTraps available.

Table 7 10 Bioequivalence assessment relative to BuTransCa3 for 8 36':4increase' in plasIBR conccnt18tIQBs foI' Example 2 T I S Ratio KxarmpeI 2 YTS/ g'0 /6 lemce BUYrams ("l!) 1mterval! (~/o) llm((. max) ICt) I82.07„'l E0.82' ' CalcUlatcd based oB tlIc Indtvidual subject data ot l-.'xan1p!c 2 TTS (l2 Ing), PC T/IB2012/002973 An increase of about 36 % in plasma trations for Example 2 TTS would be expected to render the TTS bioequivalent to BuTrans (20 mg /25 cm ), also known as Norspan, in a single dose study.

[00201] Table 7.11 Bioequivalence lrlent relative to BuTrans'R) for a 50% increase ln plasma col'lcentratlons for Conlpazatlve Exanlple 0 I 15 Ratio Comp. Kxampel 5 90'/o Confiidenee YI S/ Bn franst@~ (~/0) Interval ( A) ln(Cmax) 3„139.9 l ln(AUCt) ln(AU CIA) [85.04; 120.29'; 'Calculated based on the individual subject data of Comparative Example TTS (6.75 mg).

] Even an increase of about 50 % in plasma concentrations for Comparartive Example 5 TTS would not be expected to render the TTS bioequivalent to BuTrans (20 mg /25 cm ), also known as Norspan, in a single dose study.

PC T/IB2012/002973 The invention relates in tsarrteutar to the toltosvtn further items: 1. Transdermal eutic system for the transdermal administration of buprenorphine, sing a buprenorphine-containing self-adhesive layer structure comprising A) a orphine-impermeable backing layer, and B) a buprenorphine-containing re-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, Rn RnalgesEcally cftcctEve RB'lomlt of buprcnog)lltnc base or a pharmaceuticaHy acceptable sallt thereof. and c) a yhc acid selected trom the group consisting of oleic acids linoleic acid. HEEolenic acid, levuhnic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amon»t of buprenorphine is soh1bilized therein to form a mixtures and the cal'boxyllc acid bupreBolphlnc B1Exturc forEYEs dlspc1s d deposits BE thc said plessure-sensitive adhesive, whcrcEB said buprcnoE+hutc-contaEBEBg prcssure-scnsltEvc adhesive layer Es the skin co1'ltRct. layer. 2. Transderrral therapeutic system in accordance with item 1, wherein said buprenorphine is present in the form of buprenorphine base. 3. Transdermal therapeutic system in accordance with item 1, n said ylic acid is levulinic acid, PC T/IB2012/002973 4. fr'Rnsdcr1nal cut1c systcn1 1B accordance w1th 1tcn1 1 s whcrc1B. sa1il buprc11orphiBc lls prcscnt ml thc Eorm of buprcnorpl11nc base ru1d sa1d carboxyl1c ac1d 1s lcvul1nic R.c1d. 5. crn181 thcrapcu11c systcn1 1n accordarlcc w 0th 1tcnt 1, wllcrc1B said Polymer-bstsed PrCSSurC-SCBS1t1VC RdhCS1VC 1S baSCd OB PolVS11OXstnes O1 po ly1sobuty le ncs. 6. Transdern-. al therapeutic system in accordance with item 1, wherein said r-based re-sensitive ve is based on polysiloxanes. 7. Transdermal therapeutic system in accordance with item 1, wherein said buprenorphine is present in the form of buprenorphine base, said carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes. 8. Transdermal therapeutic system in accordance with any one of items 1 to 7, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof. , or about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or about 11.5 mg to about 24 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

PC T/IB2012/002973 9. TFHBsdcfnERJ thcfapcBDC systcnl UE HccofdafEcc vvith Iten k 8, Ehc RIT!ount of sRKl 4Bpf'cBofphEnc coBERBlcd Bi thc tYHnsdcfinal E'hclapcUt ic systcPE FHTEglng YTQBI about l ing lo 84out 3.5 mg buprcnoE'phutc 48si" ol Mi cqBEBEQJRF RPEQBnt ot R pha"Pfaccutfcally Hccept84lc sRit Thcfcof QF about 3.5 mg I.o about 7 mg orphhie base or an equifrfolar amount of'a phRTFBacciltlcRHy acceptable sall thereof, of 840UE 6.5 Big to abou't l 4 BEg of ph Enc base 01 Rn cquiIBolRf RBIQBfit of 8 accutically acccptablc salt thcf'cof. QT 840Ut M'BQUBt of 8 1 1. i BIL- to R40Ut 2 l Blg 4Bpl'cnorphuic base QT an cqufmolar pharmaccutically acceptable saJt thereof„or about i 3 Pig to 840Bt:8 Ing bupfcnofphlnc base QI' an cqunnoiaf Hnloklnt ot 8. phafPEaceutica Jly able salt thercot, . i Tansdcf'fBRi thai'HpcUtlc n En accoTdHBcc vvlth Itcnf &8», thc HIBQBfi't of said 4upFcnolphfnc contRlncd IB thc transdcfmal therapeutic system Tanging Ifoni aboilt 1 frig to RboUt 3 Big buplcnofphlffc base of Hn equnnolar HBEQEEnt OCH phafnlaccuticRHy acceptable salt thereof, or a40ut 3,5 mg to about 6 mg buprenorphine base or an cquimo Jar amount of 8 pharniaccutlcRHy acceptable saJ't thereof, OI' R40lrt 6,5 fBg to R40Ut l ] Blg bupfcBQI'phlnc 48sc of an cqllhr»QJHF Hrnoufit of 8 8ccutlcHHy Hcccptablc sRlit thereof» of about 11.5 mg to abour 14 mg 4uprenorphine base or an oiar amount of a phRTIBHCCBtllCRHy RCCCptablC Salt thCTCot, OT 840Bt 1 5 lirig to 84olLlt. 24 Bfg 4UpFcBQTphuic 48sc QT an cqUBBolal MTEQUnt of R pharmaccutlcally2,Rcccptablc salt thereof.

Transdcrmal therapeutic system in accordance vvitll any one of items 1 to 10, tllc slzc of sMd ofphulc-containing pFcssulc"scnsltfvc Rdheslvc Jaycf providing thc area of lclcRsc fanglng ff'QBI about cIB to about '-'l,8 cnl 2 1 ,. Qr about 3 cfn to 840ut 9.5 cnl .

PC T/IB2012/002973 about 6 cm to about 19 cm, about 12 cm to about 28.5 cm, or about 16 cm to about 38 cm . 12. Transdermal therapeutic system in accordance with item 11,the size of said orphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.5 cm, or about 3 cm to about 9 cm, about 6 cm' to about 18 cm, about 12 cm to about 27 cm, or about 16 cm to about 35 cm . 13. Transdermal eutic system in accordance with item 11,the size of said orphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm to about 4 cm, about 5 cm to about 8 cm, about locm to about 16 cm, about 17cm to about23 cm, or about 2"=.5 cm to about 32 cm 14, Transdermal therapeutic system in ance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.8 cm and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

PC T/IB2012/002973 . Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm to about 9.5 cm, and the amount of said buprenorphine ned in the ermal therapeutic system ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a ceutically able salt thereof. 16. Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive ve layer providing the area of release ranging from about 6 cm to about 19 cm and the amount of said buprenorphine contained in the transdermal therapeutic system ranging fiom about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 17. Transdermal therapeutic system in accordance with any one of items to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer the area of release ranging from about 12 cm to about 28.5 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 18. Transdermal therapeutic system in ance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm to about 38 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from PC T/IB2012/002973 about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof. 19. 1 ransdermal thelapeutic system in accordance with any one of items 1 to '~ khc slzc of sREd buprcnorphknc colllfakBHlg prcssure-scnsltlvc adhcslvc Iavcl provldnlg thc RreR of c 1'RBgulg froHl about 1 cnl to about 4.5 CB'1 alld thc anlount ot said bllpl'cnorphUlc confMBcd 1B thc transdelmal eutic systclB lan~~lug 'lroB1 about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceuticRHy acceptable salk. thereof.

. Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm to about 9 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system g from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 21. Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of e ranging from about 6 cm to about 18 cm and the amount of said orphine contained in the transdermal therapeutic system ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 22. Transdermal eutic system in accordance with any one of items to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 27 cm . Rnd the PC T/IB2012/002973 amount of said buprenorphine contained in the ermal therapeutic system g from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 23. Transdermal therapeutic system in accordance with any one of items I to I, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm to about 35 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 24. Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing re-sensitive ve layer providing the area of release ranging from about 2.5 cm to about 4 cm and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof . Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive ve layer providing the area of release ranging from about 5 cm to about 8 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system g from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof. 26. Yransderrnal therapeutic system in accordance with any one of items PC T/IB2012/002973 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 10 cm' to about 16 cm and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 6.5 mg to about 11 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 27. ermal therapeutic system in accordance with any one of items 1 to 7, the size ot said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm to about 23 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 28. Transdermal therapeutic system in accordance with any one of items 1 to 7, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of e ranging from about 23.5 cm to about 32 cm, and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof. 29. Transdermal therapeutic system in accordance with any one of items 1 to 7, the amount of said buprenorphine contained in the ermal eutic system ranging from about about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

. Transdermal eutic system in ance with item 29„the amount of said buprenorpbine contained in the transdermal therapeutic system ranging from PC T/IB2012/002973 about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 31, Transdermal therapcufle system in accordance with item 29, the anlount of sRld buprcnolplnnc contained ln the transdcrnitalthci'apcullc systcnl rRngulg &om abou't 1 nlg fo about 3 IBg norpluBc base or Rn cqulinlolal' Rlnouilt of 8 ph8rlBRccilitlcally acceptable salt thereof. 32. Transdcr. nal therapeutic sysfenl ln Rccordanccwlfh. RBy onc of lfcfBs l 0 29 to 31, the size ot said buprenorphine-contamhig pressure-sensitive adhesive layer ding thc Rica of I'clcasc 1angn'lg from aboU't 1 cln to Rbout 4.&N cm . 33. ermal therapeutic system in accordance with item 32, the size of said buprenorphine-containing re-sensitive ve layer ing the area of l 5 release ranging from about 1 cm 2 to about 4.5 cm 2 . 34. Transdermal therapeutic system in accordance with item 32, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 2.5 cm 2 to about 4 cm 2 .

. Transdermal therapeutic system in accordance with any one of items 14, 19, 24, or 29 to 34, said transdermal therapeutic system providing a mean AUCt of more than 7,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a t population. 36. 1 ransdcrnlal thcI'Rpcut)c systcnl IB RccordRBcc with ltciH 35. said transdcrmal (hcrapcullc systcni providing 8 irlcan Aki(. t of Blorc than 8,000 pg. hr/1Hl ovcl' RboUt l 68 hour» of adIHinistration after a single-dose administration to 8 subject popUlRfloB, WO 88254 PC T/IB2012/002973 37. Transdermal therapeutic system in accordance with item 35, said transdermal therapeutic system providing a mean AUCt of from more than 8,000 pg.hr/ml to about 16,000 pg. hr/ml over about 168 hours of stration after a single-dose administration to a subject population. 38. Transdermal therapeutic system in ance with any one of items 14, 19, 24, or 29 to 37, wherein the ermal therapeutic system provides a nominal mean release rate of about 5 pg/hr over about 168 hours of administration. 39. Transdermal therapeutic system in accordance with any one of items 14, 19, 24, or 29 to 37, wherein the transdermal therapeutic system provides a mean release rate ranging from about 2.5 to about 7.5 pg/hr over about 168 hours of stration. 40. Trar-, sdermal therapeutic system in accordance with any one of items 14, 19, 24, or 29 to 39, wherein buprenorphine is present in the form of buprenorphine base and wherein the transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to the commercial product BuTrans having an area of release of 6.25 cm . 41. Transdermal therapeutic system in accordance with any one of items 1 to 7, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 3.5 mg to about 8 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 42. ermal therapeutic system in accordance with item 41, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

PC T/IB2012/002973 43. Transdermal therapeutic system in accordance wi~h item 41, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 3.5 mg to about 6 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt f. 44. Transdermal therapeutic system in accordance with any one of items 41 to 43, the size of said buprenorphine-containing pressure-sensitive adhesive layer ing the area of e ranging from about 3 cm to about 9.5 cm'. 45. Transdermal therapeutic system in accordance with item 44, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm to about 9 cm . 46. ermal therapeutic system in accordance with item 44, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release rangir;g from about 5 cm 2 to about 8 cm 2 . 47. Transdermal therapeutic system in accordance with any one of items 15, 20, , or 41 to 46, said transdermal therapeutic system providing a mean AUCt of more than 14,000 pg. hr/ml over about 168 hours of administration after a -dose administration to a subject population. 48. Transdermal therapeutic system in accordance with item 47, said transdermal therapeutic system providing a mean AUCt of more than 16,000 pg. hr/ml over about 168 hours of administration aAer a single-dose administration to a subject tion. 49. Transdermal therapeutic system in accordance with item 47, said transdermal therapeutic system providing a mean AUCt of from more than 16,000 pg. hr/ml to about 32,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population, PC T/IB2012/002973 50. Transdcrmal eutic sys'tcnl HI accordance w&th Bny onc of Items 15, 20, or 41 to 49 whcrcln thc trans(lcl mal thcI'Bpcutlc systcln provl(lcs B nominal meal l release ovcI' about ii ate of about 1 0 U pohr 1(&8 hollrs of lstratlon. 51. ermal therapeutic system in ance with any one of items 15, 20, , or 41 to 49, ~herein the transdermal therapeutic system provides a mean release rate ranging from about 8 to about 12 llg/hr over about 168 hours of administration. 52. Transdermal therapeutic system in accordance with any one of items 15, 20, 25, or 41 to 51, n buprenorphine is t in the form of buprenorphine base and wherein the ermal therapeutic system when tested in a comparative clinical study is bioequivalent to the commercial product BuTrans having an area of release of 12.5 cm ., 53. Transdermal therapeutic system in accordance with any one of items 1 to 7, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 6.5 mg to about 16 mg buprenorpl&inc base or an equimolar amount of a pharmaceutically acceptable salt thereof. 54. Transdermal therapeutic system in accordance with item 53, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 55. Transdermal therapeutic system in accordance with item 53, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 6.5 mg to about 11 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, 56,. Transderlnal therapeutic system in accordance with any one of items PC T/IB2012/002973 53 to 55, the size of sa)d buprenorphme-contamtno pressure-sens)tive ve layer providing the area of release ranging from about 6 cm to about 19 cm', 57. Transdermal therapeutic system in accordance with item 56, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm to about 18 cm . 58. Trarsdermal therapeutic system in accordance with item 56, the size of said orphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 10 cm to about 16 cm . 59. Transdermal therapeutic system in accordance with any one of iten:s 16, 21, 26, or 53 to 58, said transdermal eutic system providing a mean AUCt of more than 28,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject tion. 60. Transdermal therapeutic system in accordance with item 59, said transdermal therapeutic system providing a mean AUCt of more than 32,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 61. Transdermal therapeutic system in ance with item 59, said transdermal therapeutic system providing a mean AUCt of from more than 32,000 pg. hr/ml to about 64,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 62. Transdermal therapeutic system in ance with any one of items 16, 21, 26, or 53 to 61, wherein the transdermal therapeutic system provides a nominal mean re(ease rate of about 20 pg/hr over about 168 hours of administration.

PC T/IB2012/002973 6'=. Transderma! therapeutic system in accordance with any one of items 16, 21, 26, or 53 to 61, wherein the transdermal therapeutic system provides a mean release rate ranging from about 15 to about 25 pg/hr over about 168 hours of administration. 64. Transdermal therapeutic system in accordance with any one of items 16, 21, 26, or 53 to 63, wherein buprenorphine is present in the form of buprenorphine base and wherein the ermal therapeutic system when tested in a comparative clinical study is ivalent to the commercial product BuTrans having an area of release of 25 cm . 65. Transdermal therapeutic system in accordance with any one of items 1 to 7, the amount of said orphine contained in the transdermal therapeutic system ranging from about 11.5 mg to about 24 mg buprenorphine base or an lar amount of a pl armaceutically acceptable salt thereof. 66. Transdermal eutic system in accordance with item 65, the amount of said buprenorphine contained in the transdermal therapeutic system g from about 11.5 mg to about 21 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 67. Transdermal therapeutic system in accordance with item 65, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 68. Transdermal therapeutic system in accordance with any one of items 65 to 67, the size of said orphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 28.5 cm, PC T/IB2012/002973 69. Transdermal therapeutic system in accordance with item 68, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 27 cm'. 70. Transdermal therapeutic system in accordance with item 68, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm to about 23 cm'. 71. Transdermal eutic system in accordance with any one of items 17, 22, 27, or 65 to 70, said transdermal therapeutic system providing a mean AUCt of more than 42,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 72. Transdermal eutic system in ance with item 71, said transdermal therapeutic system ing a mean AUCt of more than 48,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 73. ermal therapeutic system in accordance with item 71, said transdermai eutic system providing a mean AUCt of from more than 48,000 pg. hr/ml to about 96,000 pg.hr/m! over about 168 hours of administration after a single-dose administration to a subject population. 74. Transdermal therapeutic system in accordance with any one of items 17, 22, 27, or 65 to 73, wherein the transdermal therapeutic system provides a nominal mean release rate of about 30 pg/hr over about 168 hours of administration. 75. Transdermal therapeutic system in accordance with any one of items 17, 22, 27, or 65 to 73, wherein the transdermal therapeutic system provides a mean release rate g from about 26 to about 35 pg/hr over about 168 hours of administration, PC T/IB2012/002973 76. Transdermal therapeutic system in ance with any one of items 1 to 7, the amount of said orphine contained in the transdermal therapeutic system ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof. 77. Transdermal therapeutic system in accordance with item 76, the amount of said buprenorphine contained in the transdermal therapeutic system g from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof. 78. Transderhnal therapeutic system in accordance with item 76, the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, !9. I I'RBsdcrnhal thcrapcuthc systch'B hn accoI'dance whrl'I RBy oBc of Itcnhs /6 to 78„the size of said buprenorphinc-cohItaining pressure-sensitive ve layer front CIB2 provhdBIg thc RI'ca. of I'clcRsc Rbouh ) 6 to about 38 cm . h RBghng 80. Transdermal therapeutic system in accordance with item 79, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of e ranging from about 16 cm to about 35 cm'. 81. Transdermal therapeutic system in accordance with item 79, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 23.5 cm to about 32 cm, 82. Transdermal eutic system in accordance with any one of items 18, 23, 28, or 76 to 81, said transdermal therapeutic system providing a mean AUCt of more than 62,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population.

PC T/IB2012/002973 83. Transdermal therapeutic system in accordance with item 82, said transdermal therapeutic system providing a mean AUCt of more than 64,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 84. Transdermal therapeutic system in accordance with item 82, said transdermal therapeutic system providing a mean AUCt of from more than 64,000 pg. hr/ml to about 128,.000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population. 85. Transdermal therapeutic system in accordance with any one of items 18, 23, 28, or 76 to 84, wherein the transdermal therapeutic system provides a nominal mean release rate of about 40 pg/hr over about 168 hours of administration. 86. ermal therapeutic system in accordance with any one of items 18, 23, 28, or 76 to 84, wherein the transdermal therapeutic system provides a mean release rate ranging from about 36 to about 45 p,g/hr over about 168 hours of administration. 87. Transdermal therapeutic system in accordance with any one of items 1 to 86, said transdermal therapeutic system providing an arithmetic mean tmax of from about 60 hr to about 120 hr after a single-dose administration to a subject tion. 88. Transdermal therapeutic system in accordance with item 87, said ermal therapeutic system providing an etic mean tmax of from about 66 hr to less than 108 hr aAer a -dose administration to a subject population. 89. Transdermal therapeutic system in accordance with item 87, said transdermal eutic system providing an arithmetic mean tmax of from about 72 hr to about 96 hr aAer a -dose administration to a subject population.

PC T/IB2012/002973 90. Transdermal therapeutic system in accordance with any one of items 1 to 89, said transdermal eutic system providing a mean AUCt per area of release of more than 1,700 pg. hr/ml-cm over about 168 hours of administration after a single- dose administration to a subject population. 91. ern'Eall tl'EerapeutEc i En RccordaEEce wEth Etem 90, said transdertnal thcrRpeutEc systetn provtd333g B Eriean AUCt per BE'ea ok rejeRse of more than 1,900 pg. -cm' over about 168 hours of adEni3tistration after a single-dose BdmErEEsErBEE033 to B sub)ect population. 92. Transdermal therapeutic system in accordance with item 90, said transdermal therapeutic system providing a mean AUCt per area of release of more than 2,300 pg. hr/ml-cm over about 168 hours of administration after a single-dose administration to a subject population. 93. Transdermal therapeutic system in accordance with any one of items 1 to 92, said orphine-containing pressure-sensitive adhesive layer containing more than 0.55 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, 94. Transdermal therapeutic system in accordance with item 93, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 0.6 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f. 95. Transdermal therapeutic system in accordance with item 93, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 0.7 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

PC T/IB2012/002973 96. Transdermal therapeutic system in accordance with item 93, said orphine-containing re-sensitive adhesive layer containing more than 0.8 mg/cm of buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof, 97. TraBsdcrIBal thcrRpcutEc syst GE EB Rccol'dance wEIh Itcrn 93, said buprcnolphiEEc-coEEtaining re-sensitive Rclhcslvc laycl' confaullng Enorc th83I 0,9 IBg/cETE of bupY'cnorphlnc base o3' 838 cqhiiIInolar RIBOE3nt of 8 pharmacclltlcally 98. Transdermal therapeutic system in accordance with item 93, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 1 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 99. Transdermal therapeutic system in ance with item 93, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 1.1 mg/cm of orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 100. Transdermal therapeutic system in accordance with any one of items 1 to 92, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 0.55 mg/cm to about 2 mg/cm or from about 0.6 mg/cm to about 2 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 101. Transdermal therapeutic system in accordance with item 100, said buprenorphine-containing re-sensitive adhesive layer containing from about 0.7 mg/cm to about 2 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

WO 88254 PC T/IB2012/002973 102. Transdermal eutic system in accordance with item 100, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 0.8 mg/cm to about 2 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 103. Transdermal therapeutic system in accordance with item 100, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 0.9 mg/cm to about 2 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 104. ermal therapeutic system in accordance with item 100, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 1 mg/cm to about 2 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 105. Transdermal therapeutic system in accordance with item 100, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 1.1 mg/cm to about 2 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 106. ermal therapeutic system in accordance with any one of items 1 to 105, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 5% buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof. 107. Transdermal therapeutic system in accordance with item 106, said buprenorphine-containing pressure-sensitive ve layer containing more than 6% buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof, 108. ermal therapeutic system in accordance with item 106, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 7% PC T/IB2012/002973 buprenorphine base or an equirnolar amount ot a pharmaceutically acceptable salt ereof, 109. Transdermal therapeutic system in accordance with item 106, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 8% buprenorphine base or an equimolar amount of a phar~aceutically acceptable salt thereof. 110. Transdermal eutic system in accordance with item 106, said buprenorphine-containing re-sensitive adhesive layer containing more than 9% buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof, 111. Transdermal therapeutic system in accordance with any one of items 1 to 105, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 6% to about 20% buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof. 112. ermal therapeutic system in accordance with item id buprenorphine-containing pressure-sensitive adhesive layer containing from about 7% to about 20% buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, 113. Transdermal therapeutic system in accordance with item 111,said buprenorphine-containing pressure-sensitive adhesive layer containing from about 8% to about 20% orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 114. Transdermal therapeutic system in ance with item 111,said buprenorphine-containing pressure-sensitive adhesive layer containing from more than 9% to about 20% buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

PC T/IB2012/002973 115. Transdermal therapeutic system in accordance with any one of items 1 to 114, the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight of more than 6 mg/cm'. 116. Transdermal therapeutic system in accordance with item 115,the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight of more than 8 mg/cm . 117. Transdermal therapeutic system in accordance with item 115, the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight of more than 10 mg/cm . 118. Transdermal therapeutic system in accordance with any one of items 1 to 114, the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight ranging from 6 mg/cm to about 14 mg/cm, 119. ermal therapeutic system in accordance with item 118, the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight ranging from 8 mg/cm to about 14 mg/cm . 120. Transdermal therapeutic system in accordance with item 118,the buprenorphine-containing pressure-sensitive adhesive layer being coated at a dry weight ranging from 10 mg/cm to about 13 mg/cm, 121. ermal therapeutic system in accordance with item 118,the orphine-containing pressure-sensitive adhesive layer being coated at a dry weight ranging from 11.5 mg/cm to about 12.5 mg/cm . 122. Transdermal therapeutic system in accordance with any one of items 1 to 121, wherein the ylic acid is levulinic acid, said orphine-containing pressure-sensitive adhesive layer containing the same % amounts of levulinic acid and orphine, based on the % amount of buprenorphine base.

PC T/IB2012/002973 123. Transdermal therapeutic system in accordance with any one of items 1 to 121, wherein the carboxylic acid is levulinic acid, said buprenorphine-containing re-sensitive adhesive layer containing less % amounts of levulinic acid than % amounts of buprenorphine, based on the % amount of buprenorphine base. l 24. Transdermal therapeutic system in accordance with any one of items 1 to 123, wherein the carboxylic acid is levulinic acid, said buprenorphine-containing re-sensitive adhesive layer containing more than 5 % levulinic acid. 125. Transdermal therapeutic system in accordance with item 124, said buprenorphine-containing re-sensitive adhesive layer containing more than 6% levulinic acid. 126. Transdermal therapeutic system in accordance with item 124, said buprenorphine-containing pressure-sensitive adhesive layer containing more than 7% levulrmc acti, 127. Transdermal eutic system in accordance with item 124, said buprenorphine-containirg pressure-sensitive adhesive layer containing more than 8% levulinic acid. 128. Transdermal therapeutic system in accordance with item 124, said buprenorphine-containing pressure-sensitive adhesive layer ning more than 9% levulinic acid. 129. Transdermal therapeutic system in accordance with any one of items 1 to 78, wherein the carboxylic acid is levulinic acid, said buprenorphine-containing re-sensitive ve layer containing f;-om about 6% to about 20% levulinic acid.

PC T/IB2012/002973 130. Transdermal therapeutic system in accordance with item 129, said buprenorphine-containing pressure-sensitive adhesive layer containing from about 7% to about 20% levulinic acid. 131. Transdermal therapeutic system in accordance with item 129, said buprenorphine-containing re-sensitive ve layer containing from about 6% to about 9% levulinic acid. 132. Transdermal therapeutic system in ance with item 129, said orphine-containing re-sensitive adhesive layer containing from more than 9% to about 15% levulinic acid. 133. Transdermal therapeutic system in accordance with item 129, said buprenorphine-containing pressure-sensitive adhesive layer containing from more than 9% to about 15% buprenorphine base and form about 6% to about 9% levulinic ac&d. 134. Transdermal therapeutic system in accordance with item 129, said buprenorphine-containing pressure-sensitive adhesive layer containing from more than 9% to about 15% buprenorphine base and from more than 9% to about 15% levulinic acid. 135. Transdermal therapeutic system in accordance with any one of items 1 to 134, the pressure-sensitive adhesive layer being coated at a dry weight of about 12 , and n said buprenorphine is present in the form ofbuprenorphine base and the dry pressure-sensitive adhesive layer contains about 10% buprenorphine base, and wherein the carboxylic acid is levulinic acid the dry pressure-sensitive adhesive layer contains about 7% levulinic acid. 136. Transdermal therapeutic system in accordance with any one of items 1 to 134, the pressure-sensitive adhesive layer being coated at a dry weight of about 12 mg/cm ., and wherein said buprenorphine is present in the form of buprenorphine WO 88254 PC T/IB2012/002973 base HBd thc drv picssurc-sensitive adhesive lager contains about 10.&o blipf'cBQYphlnc base„afid M:hcr EB thc caiboxylic acid ls li.vulln!c acid thc dfy pf'cssurc-scnsitlvc Rdhcslvc 1Rycr coiltRlns RboUt 10/o lcv'Ulliilc Rcld. ct of tive different trans(icrfrlR1 pc'linc svstcfns kn Record(Ence v;Etli RBV one of items 1 to 136, wherein the first transdcrmal therapeutic system provides a size of said buprenorphwic- coEitRinhIg prcssul'c-scnsl'tive Rdhcslvc lavcr plovidiEIg thi. Rrca of c raEIging trorn about 1.5 cm" to.c about 5.5 ckn2 andi contains an amouiit of said buprenorphine t ofn HboUit' 1 rng to Hbouk 4.o I'ng bkfpreilorphlflc II3asc or RB equkinolar HEBQU.'it of 8. pharknaceukkcally Hi. ccptablc salt. thereof: the second transdcimal therapeutic system provides a size of said buprcnorphine- contaliiiflg pl'cssu! c-sekisitivc adhesive lRycr providing th - area of rclcasc rakiging EI'Qni about 3 cffi EQ about 9 cfn affd contaiiiis Ril'I anfount Qt said bUprcriorphli'lc from about 4 fng to about 9m' iok1lhkkie base or an equiknolar amount of a pharmaceutically acceptable salt thereof; Rfid the third transdefnial therap utiic systefn provides a siz" of said buprekkorphiEIC- ainukg prcsslirc-scnsluvc adhesive 1EE jcr plovEdlng thc Rf'ca Qf rclcasc rRBguig Frofn ibout 6 cEIE lo about 14 cfn Hnd coBtains Hn aknount of sRid buprcnokphiBc tiQEB HbQ'ut 8 to about 14 I'ng buprcnolphcnc base of' Hn Eolkir HBIQunk Qi 8 frig pharmaceutically acccptabic salt thereof; and Ehc toukth Erakksdcrmal thcrapckitkc syslcffk proviidcs 8 size of sRid buplcnolpiiimc- contaiEIing pressure-sckksitive adhesive layer providUEg Nkc RrcR ot Yclcasc ranging from Rbout 13 ci.''I to Hibout 1 / cni Rnd ifEs EEB HIBQUnt of said bUprcfiolphnkc from about 15 mg to about 20 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing re-sensitive adhesive layer providing the area of release ranging from about 16 cm to about 24 cm and ".ontains an amount of said buprenorphine PC T/IB2012/002973 from about 20 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, 138. A set of five different ermal therapeutic systems in ance with any one of items 1 to 136, wherein the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about2 cm to about4cm and contains an amount ofsaid buprenorphine from about 2 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; the second ermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 4.5 cm to about 7.5 cm and contains an amount of said orphine from about 5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 8 cm to about 12 cm and contains an amount of said buprenorphine from about 10 mg to about 14 mg orphine base or an equimolar amount of a ceutically acceptable salt thereof; and the fourth transdermal therapeutic system provides a size of said orphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about13 cm to about16cm and contains anamountofsaidbuprenorphine from about 16 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 17 cm to about 22 cm and contains an amount of said buprenorphine from about 21 mg to about 26 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

PC T/IB2012/002973 139. A set of five different transdermal therapeutic systems in ance with any one of items 1 to 136, wherein the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 2 cm to about 3 cm and contains an amount of said buprenorphine from about 2.5 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof; the second transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e g from about 4.5 cm 2 to about 6 cm 2 and contains an amount of said buprenorphine from about 5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 9 cm to about 11 cm and contains an amount of said buprenorphine from about 11 mg to about 13 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fourth transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging from about 14 cm to about 16 cm and contains an amount of said buprenorphine from about 17 mg to about 19 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 18 cm to about 21 cm and contains an amount of said buprenorphine trom about 22 mg to about 25 mg buprenorphine base or an equimolar amount of a ceutically acceptable salt thereof, PC T/IB2012/002973 i 40. Transderlnal therapeutic system in accordance with any one of items 1 to 139, said buprcnorphule-contaiinirlg self-adhesive layer structure being attached to H second larger active agent-frcc self-adhesive layer' strucQJrc fol lnl& thc adhesive ties of the overall transdermal therapeutic system. 141. Transdermal eutic system in accordance with item 140, said second actiivc-FTce self-adhesive layer structure comprishlg a backing layer and Hn active agent-free pressurc-sensitive adhesive layer OF'pressure-sensitive adhesive based on po lyac ry 1Rlcs. 142. Transderlnal therapelltic system in accordance with item 140, said second active-Free self:adhesive layer structure sing a g layer and rn actiive agent-Free prcssure-sensitive adhesive layer ot prcssure-scBslt lv'c vc based on polysiioxane, 143. ermal therapeutic system in accordance with any one of items 1 to 140, said polymer-based pressure-sensitive adhesive is based on polysiloxane in the buprenorphine-containing pressure-sensitive adhesive layer and/or in the active agent-free pressure-sensitive adhesive layer being amine-resistant. 144. Transdcrnlal thelapeulic system in accordance with any one of itelns l. to 14., whcrcin tbc polynlcr-based l'c-scnsltlvc Rdi&csivc ls based on polysiloxanc Rnd tbc poivslioxaBc ls Rirlinc-resistant being R product of tlte condcnsa lion reaction of siiaBol cndblockcd polyduncthvisiloxanc with a silica rcslB and thc residual silailoi functlonahty bclng capped with trinlcthyLsiloxy groups, 145. Transdermal therapeutic system in accordance with anyone of items 1 to 144, wherein the polymer-based pressure-sensitive adhesive is based on polysiloxane and wherein for the production of the buprenorphine-containing and the active agent-free PC T/IB2012/002973 pressure-sensitive adhesive layer an adhesive composition of the re-sensitive adhesive based on polysiloxane in heptane is used. 146. TransdeI anal rheIRpcutilc system IB ance v'Ith RBy onc ot Iten'Ls I to 145, whcrcm tlIc polyrBcr-based pressure-scnsItIvc RdhcsIvc Is based oB polysIlloxaric and is cl'IarRctcfIzcd by R solution ity Rt 25 C and 60 % solids content IB heptane ot more than about 150 rnPa s. 147. Transdermal therapeutic system in accordance with item 146, the polymer- based pressure-sensitive adhesive is based on polysiloxane and is characterized by a solution viscosity at 25'C 60 % solids content in heptane of from about 200 mPa s to about 700 mPa s. 148. Transdermal therapeutic system in accordance with item 146, the polymer- based pressure-sensitive ve is based on polysiloxane and is characterized by a solution viscosity at 25'C and 60 % solids content in heptane of from about 350 mPa s to about 600 mPa s. 149. Transdermal therapeutic system in accordance with item 146, wherein the polymer-based pressure-sensitive adhesive is based on polysiloxane and is terized by a solution viscosity at 25'C and 60 % solids content in e of from 480 mPa s to about 550 mPa s or alternatively from about 400 to less than 480 mPa s. 150. Transdermal therapeutic system in accordance items 146, wherein the polymer-based re-sensitive adhesive is based on polysiloxane is characterized by a solution viscosity at 25'C and 60 % solids content in heptane of about 500 mPa s or alternatively of about 450 mPa s.

PC T/IB2012/002973 151. Transdermal eutic system in accordance with any one of items 1 to 150, the polymer-based pressure-sensitive adhesive in the buprenorphine-containing layer and in the active agent-free layer being an amine-resistant pressure-sensitive adhesive based on loxane and the polysiloxane being a product of the sation reaction of silanol endblocked polydimethylsiloxane with a silica resin and the residual silanol functionality being capped with trimethylsiloxy groups and characterized by a solution viscosity at 25'C and 60 % solids content in heptane of more than 400 mPa s, and the buprenorphine-containing pressure-sensitive adhesive layer being coated at a coating dry weight of about 12 mg/cm and containing about 10% orphine base and about 10% levulinic acid. 152. Transdermal therapeutic system in accordance with any one of items 1 to 151, n buprenorphine is present in the form of buprenorphine base and providing a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 pg/cm -hr over a 168 hours test. 153. Transdermal therapeutic system in accordance with item 152, providing a mean cumulative skin permeation rate measured in a Franz diffusion ce!1with dermatomed human skin of more than 1.5 pg/cm -hr over a 168 hours test. 154. Transdermal therapeutic system in accordance with item 152, providing a mean tive skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 1.7 pg/cm -hr over a 168 hours test. 155. Transdermal therapeutic system in accordance with item 152, providing a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 2 pg/cm -hr over a 168 hours test, PC T/IB2012/002973 156. Transdermal therapeutic system in ance with item 152, providing a mean cumulative skin permeation rate measured in a Franz diffusion cell with omed human skin of more than 2.5 pg/cm -hr over a 168 hours test. 157. ermal therapeutic system in accordance with item 152, providing a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 3 pg/cm -hr over a 168 hours test. 158. Transdermal therapeutic system in accordance with any one of items 1 to 151, wherein buprenorphine is present in the form of buprenorphine base and providing a mean cumulative skin permeation rate measured in a Franz diffusion cell with omed human skin from about 1.3 pg/cm -hr to about 4 pg/cm'-hr over a 168 hours test. 159. Transdcrntal thcrapcutlc systcln ln accordance with ltcrn 158, providing a mean cumuhtive skin pelmeation rate measured in a Franz diffllsion ceH with dcxmatorncd hunlan skin fronl about 1.7 ug/cm -hl' to about 4 ug, cln -hr over a 168 llours test. 160. Transdermal therapeutic system in accordance with item 158, providing a mean cumulative skin permeation rate measured in a Franz diffusion cell with dermatomed human skin from about 2 pg/cm -hr to about 4 pg/cm -hr over a 1 08 hours test. 161. Transdermal eutic system in accordance with item 158, providing a mean cumulative skin permeation rate measured in a Franz ion cell with dermatomed human skin from about 2.5 pg/cm -hr to about 4 pg/cm -hr over a 168 hours test.

PC T/IB2012/002973 162. Transdermal therapeutic system in accordance with item 158, providing a mean cumulative skin tion rate measured in a Franz diffusion cell with dermatomed human skin from about 3 N, g/cm -hr to about 4 pg/cm -hr over a 168 hours test. 163. Transder nal therapeutic system in accordance with any one of items 1 to 162, wherein buprenorphine is present in the form of buprenorphine base and providing a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 220 pg/cm to 640 N, g/cm over a time period of 168 hours. 164. ermal therapeutic system in accordance with item 163, providing a cumulative e of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 390 pg/cm to 640 pg/cm over a time period of 168 hours. 165. Transdermal therapeutic system in accordance with item 163, providing a tive release of buprenorphine base as measured in a Fr anz diffusion cell with dermatomed human skin of about 400 pg/cm to about 640 lj,g/cm over a time period of 168 hours. 166. Transdermal therapeutic system in accordance with item 163, ing a cumulative release of buprenorphine base as measured in a Franz diffusion cell with omed human skin of about 450 pg/cm to about 640 pg/cm over a time period of 168 hours. 167. Transdermal therapeutic system in accordance with item 163, providing a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of about 500 pg/cm to about 640 pg/cm over a time period of 168 hours, PC T/IB2012/002973 168. Transdermal therapeutic system in accordance with item 163, providing a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of about 600 pg/cm to about 640 pg/cm over a time period of 168 hours. 169. Transdermal therapeutic system in accordance with any one of items 1 to 168, wherein buprenorphine is t in the form of buprenorphine base and providing a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 pg/cm to 10 pg/cm in the first 8 hours, p, g/cm to 80 p.g/cm' from hour 8 to hour 24, pg/cm to 80 pg/cm from hour 24 to hour 32, pg/cm to 120 pg/cm from hour 32 to hour 48, 40 pg/cm to 150 pg/cn from hour 48 to hour 72, 100 pg/cm to 300 pg/cm from hour 72 to hour 144, and pg/cm to 100 pg/cm from hour 144 to hour 168. 170. Transdermal therapeutic system in accordance with item 169, wherein buprenorphine is present in the form of orphine base and ing a non- cumulative release of buprenorphine base as measured in a Franz diffusion cell with omed human skin of 2 pg/cm to 6 pg/cm in the first 8 hours, lig/cm to 60 pg/cm from hour 8 to hour 24, 25 pg/cm'to 60 pg/cm from hour 24 to hour 32, 40 pg/cm to 100 pg/cm from hour 32 to hour 48, 50 pg/cm to 140 pg/cm from hour 48 to hour 72, 100 pg/cm to 280 N, g/cm from hour 72 to hour 144, and pg/cm to 100 Ng/cm from hour 144 to hour 168.

PC T/IB2012/002973 171. Transdermal therapeutic system in accordance with item 169, wherein buprenorphine is present in the form of buprenorphine base and providing a non- tive release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 3 pg/cm to 6 pg/cm in the first 8 hours, pg/cm to 50 pg/cm from hour 8 to hour 24, ug/cm to 50 pg/cm from hour 24 to hour 32, 60 pg/cm to 90 Ng/cm from hour 32 to hour 48, 100 pg/cm to 130 pg/cm from hour 48 to hour 72, 200 pg/cm to 280 pg/cm from hour 72 to hour 144, and 60 pg/cm to 100 pg/cm from hour 144 to hour 168. 172. A set of two to five different transdermal therapeutic systems each in accordance with any one of items 1 to 171, wherein the first transdermal eutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer ing the area of release ranging from about 1 cm' to about 4.8 cm and contains an amount of said buprenorphine from about 1 mg to about 4 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof; the second ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging &om about 3 crr. to about 9.5 cm and contains an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 6 cm to about 19 cm and ns an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and PC T/IB2012/002973 the fourth transdermal eutic system provides a size of said buprenorphine- containing pressure-sensitive ve layer providing the area of release ranging from about 12 cm' to about 28.5 cm and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fifth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm to about 38 cm and contains an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof 173. A set of two to five ent transdermal therapeutic systems each in ance with any one of items 1 to 171,wherein the first transdermal therapeutic system provides a size of said buprenoxphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm to about 4.5 cm and contains an amount of said orphine from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; the second transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive ive layer providing the area of release ranging from about3 cm to about9 cm and contains anamountofsaidbuprenorphine from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic system provides a size of said buprenorphine- containing re-sensitive adhesive layer providing the area of release ranging from about 6 cm to about 18 cm and contains an amount of said buprenorphine from about 6.5 mg to about 14 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fourth transdermal therapeutic system provides a size of said buprenorphine- ning pressure-sensitive adhesive layer providing the area of release ranging PC T/IB2012/002973 froin about 12 cm' to about 27 cm and contains Rn amount of said buprenorphinc ffoEYI about 1 1.5 B1g to Rbi)UE: 1 Erig bupIcnofphIBC base 01 RB cquiniolar RBIount ot 8. pharinaceuticRHy acceptable salt thereof„and thc tifth transdcfinai EhcfapcUtic syslcni provides 8 sIzc of said bupI'cnofphmc- coniREBIBg pi'cssurc-sefisEtivc adhesive Ilaycr pfovidiEEg thc al ca of c I'RnglBg lfonl about I 6 CIB to Rbout 35 CIB RBd contRBis RIE RIBQUBI of said norphlnc troni Rboul. 1 5 Big to Rbouli' 28 IBg buprcnofpliinc base of an cquiniolaf RBIQUBt of 8 pharmaceuiicallv acceptable salt thereof. 174. A set of two to five different tfansdermal therapeutic systems each in ance with any one of items 1 to 171,wherein the first ermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of e ranging from about 2.5 cm to about 4 cm and contains an amount of said buIErenorphine J. 5 from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of 8 pharmaceutically acceptable salt thereof; the second transdermal therapeutic system provides a size of said buprenorphine- containing re-sensitive adhesive layer providing the area of e ranging from about 5 cm to about 8 cm and contains an amount of said buprenorphine from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and thc Ehii'd transdci IIER1 thcrapcUtic svstcHE provides 8 size ot said bupfciiorphiiic- ning pi'essure-sensitive ve layer providing the area ofrelease ranging tforn about I 0 cni Eo RboUt 16 ciri and contaEns Rn RIBount of saK1 bUpi'cnofphuic 23 troin about 6,3 Big to about 11 1ng bUprcnoiphinc base 01' BB cqUEBloliif aniount 0'f8, plianIiaccuticallv acceptable sRlt th-rcof: RIEd thc fouith tfaEEsdcfITE81'EhcfapcutIc sysicni provides 8 $1zc' of said bUpI'cnoiphinc- cQBtainu'1g pi'cssurc-scnsitivc Rdlicsivc laycf providiBg thc Rfca of Iclcasc g fL'QBI RboUt 17 cni to about: 3 cirl Rnd coBtauis RH amount ot said bupfcBQE7!Einc PC T/IB2012/002973 from about 11.5 mg to about 14 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof; and the fifth ermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 23.5 cm to about 32 cm and contains an amount of said buprenorphine from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 175. Transdermal therapeutic system ed from a set in accordance with any one of items 172 to 174, wherein buprenorphine is present in the form of buprenorphine base and wherein the first transdermal therapeutic system when tested in a comparative clinical study is ivalent to a reference product having an area of release of about 6.25 cm and providing a nominal mean release rate of about 5 pg/hr over about 168 hours of administration, the second transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 12.5 cm and providing a nominal mean e rate of about 10 pg/hr over about 168 hours of administration, the third trarsdermal eutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 25 cm and providing a nominal mean release rate of about 20 pg/hr over about 168 hours of administration, the fourth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product havirg an area of release of about 37.5 cm and providing a nominal mean release rate of about 30 pg/hr over about 168 hours of administration, the fifth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 50 cm and WO 88254 PC T/IB2012/002973 providing a nominal mean release rate of about 40 pg/hr over about 168 hours of administration, wherein the reference product is prepared by the following steps: 1. homogenizing of 1,139 g of a 47.83 % polyacrylate solution of a self- crosslinked acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate:heptanes:isopropanol:toluene:acetylacetonate in the ratio of 37:26:26:4:1),100 g of levulinic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100 g of buprenorphine base to provide a mixture; 2. ng the mixture of step 1 for about 2 hours and controlling the dissolution of all solids ly whereas comrolling the evaporation loss by reweighing and replenishing the possible solvent loss by ethyl acetate; 3. subsequently ng the mixture on a transparent polyester film in such a manner that the mass per unit area of the dry adhesive layer amounts to about 80 g/m n the ter film is rendered removable by means of siliconization and serves as protective layer; 4. removing the solvents of the mixture applied on a transparent ter film in step 3 by drying with heated air which is led over a moist lane resulting in evaporation of the solvents, but also in melting of the levulinic acid and covering the adhesive film with a polyester foil; . punching the area of e of 6.25 cm, 12.5 cm, 25 cm', 37.5 cm and 50 cm', respectively, by means of suitable cutting tools and removing the edges left between the individual systems. 176. Transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected from: a first transdermal therapeutic system providing a size of the area ot release ranging from about 1 cm 2 to about 4.8 cm 2 and ning an amount of said buprenorphine from 1 mg to about 4 mg buprenorphine base or an equimolar amount of a PC T/IB2012/002973 pharmaceutically acceptable salt thereof and providing a mean AUCt of more than 7,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; a second transdermal therapeutic system providing a size ofthe area of release ranging from about 3 cm to about 9.5 cm and ning an amount of said buprenorphine from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and ing a mean AUCt of more than 14,000 pg. hr/ml over about 168 hours of administration after a single-dose stration to a subject tion; and a third transdermal therapeutic system providing a size of the area of release ranging from about 6 cm to about 19 cm and containing an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a mean AUCt of more than 28,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a fourth transdermal therapeutic system providing a size of the area of e ranging horn about 12 cm to about 28.5 cm and containing an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and ing a mean AUCt of more than 42,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and a fifth transdermal therapeutic system providing a size ofthe area of release ranging from about 16 cm to about 38 cm and containing an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a mean AUCt of more than 62,000 pg. hr/ml over about 168 hours of administration after a single-dose adrniriistration to a subject population. 1.'7, Yransdermal eutic system in accordance with item. 1 '6. &vhereiri PC T/IB2012/002973 the first transdermal therapeutic system contains an amount of said buprenorphine g fiom about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a ceutically able salt thereof and provides a size of the area of release ranging from about 1 cm to about 4.5 cm; and the second transdermal therapeutic system contains an amount of said orphine ranging from about 3.5 mg to about 7 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 3 cm to about 9 cm; and the third transdermal therapeutic system contains an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 6 cm to about 18 cm; and the tourth ermal therapeutic system contains an amount of said buprenorphine ranging from about 11.5 mg to about 21 mg orphine base or an equimolar amount of a ceutically acceptable salt thereof and provides a size of the area of release ranging about 12 cm' to about 27 cm; and the fifth transdermal therapeutic system contains an amount of said orphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 16 cm to about 35 cm . 178. Transdermal therapeutic system in accordance with item 176, wherein the first transdermal therapeutic system contains an amount of said buprenorphine ranging from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 2.5 cm to about 4 cm; and the second transdermal therapeutic system contains an amount of said orphine ranging from about 3.5 mg to about 6 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 5 cm to about 8 cm:,. and PC T/IB2012/002973 the third transdermal therapeutic system ns an amount of said buprenorphine ranging from about 6.5 mg to about 11 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and es a size of the area of release ranging from about 10 cm to about 16 cm; and the fourth transdermal therapeutic system ns an amount of said buprenorphine ranging from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a phaimaceutically acceptable salt thereof and provides a size of the area of release ranging about 17 cm to about 23 cm; and the fifth ermal therapeutic system contains an amount of said buprenorphine ranging from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 23.5 cm to about 32 cm . 179. Transdermal therapeutic system in accordance with any one of items 176 to 178, wherein the first transdermal therapeutic system provides a mean AUCt of more than 8,000 pg. hr/rr 1 over about 168 hours of stration after a single-dose administration to a subject population; and the second transdermal therapeutic system provides a mean AUCt of more than 16,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the third eimal therapeutic system provides a mean AUCt of more than 32,000 pg. hr/ml over about 168 hours of administration after a single-dose administration to a subject population; and the fourth transdermal therapeutic system provides a mean AUCt of more than 48,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject tion; and the fiAh transdermal therapeutic system provides a mean AUCt of more than 64,000 pg. hr/ml over about 168 hours of stration after a single-dose administration to a subject population.

PC T/IB2012/002973 180. Transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine selected fron:: a first transdermal eutic system providing a size of the area of release ranging &omabout cm 2 1 t4. 8cm 2 andcontaininganamountofsaidbuprenorphine from 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 5 pg/hr over about 168 hours of administration; a second transdermal therapeutic system providing a size of the area of e ranging from about 3 cm to about 9.5 cm and containing an amount of said buprenorphine from about "-.5 mg to about 8 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 10 pg/hr over about 168 hours of administration; and a third transdermal therapeutic system providing a size ofthe area of release ranging from about 6 cm to about 19 cm and ning an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean e rate of about 20 pg/hr over about 168 hours of administration; and a fourth transdermal therapeutic, system providing a size of the area of release ranging t'rom about 12 cm to about 28.5 cm and containing an amount of said buprenorphine from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean release rate of about 30 pg/hr over about 168 hours of administration; ",5 a fifth transdermal therapeutic system ing a size ofthe area of release ranging from about 16 cm to about 38 cm and containing an amount of said buprerorphine from about 15 mg to about 32 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof and providing a nominal mean e rate of about 40 pg/hr over about 168 hours of administration.

PC T/IB2012/002973 181. Transdermal therapeutic system in accordance with item 180, wherein the first transdermal therapeutic system contains an amount of said buprenorphine ranging from about 1 mg to about 3.5 mg buprenorphine base or an equimolar amount of a pharmaceutically able salt thereof and provides a size of the area of release g from about 1 cm to about 4.5 cm; and the second transdermal therapeutic system contains an amount of said buprenorphine ranging from about 3.5 mg to about 7 mg buprenorphire base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 3 cm to about 9 cm; and the third transdermal therapeutic system contains an amount of said buprenorphine ranging from about 6.5 mg to about 14 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 6 cm to about 18 cm; and the fourth transdermal therapeutic system contains an amount of said buprenorphine g from about 11.5 mg to about 21 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of e ranging about 12 cm to about 27 cm; and the fifth transdermal therapeutic system contains an amount of said buprenorphine ranging from about 15 mg to about 28 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release g from about 16 cm to about 35 cm . 182. Transdermal therapeutic system ir. accordance with item 180, wherein the first transderma! eutic system contains an amount of said buprenorphine ranging from about 1 mg to about 3 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 2.5 cm to about 4 cm; and the second transdermal therapeutic system ns an amount of said buprenorphine ranging from about 3,5 mg to about 6 mg buprenorphine base or an equimolar PC T/IB2012/002973 amount of a ceutically acceptable salt thereof and provides a size of the area of e g f:om about 5 cm to about 8 cm; and the third transdermal therapeutic system contains an amount of said buprenorphine ranging from about 6.5 mg to about 11 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 10 cm to about 16 cm; and the fourth transdermal therapeutic system ns an amount of said buprenorphine ranging from about 11.5 mg to about 14 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging about 17 cm to about 23 cm; and the fifth transdermal therapeutic system contains an amount of said orphine ranging from about 15 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof and provides a size of the area of release ranging from about 23.5 cm to about 32 cm . 183. Transdermal therapeutic system in accordance with any one of items 176 to 182, wherein buprenorphine is present in the form of buprenorphine base and providing a non-cumulative release of buprenorphine base as ed in a Franz diffusion cell with dermatomed human skin of 2 pg/cm to 10 pg/cm in the first 8 hours, pg/cm to 80 pg/cm from hour 8 to hour 24, pg/cm to 80 pg/cm from hour 24 to hour 32, lig/cm to 120 pg/cm from hour 32 to hour 48, 40 pg/cm to 150 pg/cm from hour 48 to hour 72, 100 pg/cm to 300 pg/cm from hour 72 to hour 144, and pg/cm to 100 pg/cm from hour 144 to hour 168. 184. Transdermal therapeutic system in accordance with item 183, wherein buprenorphine is present in the form of buprenorphine base and providing a non- PC T/IB2012/002973 cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 pg/cm to 6 pg/c, m in the first 8 hours, pg/cm to 60 pg/cm from hour 8 to hour 24, pg'cm' to 60 pg'cm' froni hour 24 to hour 32. 40 lig/cm to 100 u~~'cm t'rom hoiir 32 to hour 48, pg,'cm' to l. 40 I.i@I/cm' trois hour 48 to houi. '72 100 lig/cm ro 280 ug/cm from hour 72 to hour 144, and ~0 pg/cm to 100 pg/cm irom hour & 44 to hour 1 o8 185. Transdermal therapeutic system in accordance with item 183, wherein buprenorphine is present in the form of buprenorphine base and providing a non- cumulative release of orphine base as measured in a Franz diffusion cell with dermatomed human skin of 3 pg/cm to 6 pg/cm in the first 8 hours, pg/cm to 50 pg/cm from hour 8 to hour 24, li, g/cm to 50 pg/cm from hour 24 to hour 32, 60 pg/cm to 90 pg/cm &om hour 32 to hour 48, 100 pg/cm to 130 pg/cm from hour 48 to hour 72, 200 pg/cm to 280 pg/cm trom hour 72 to hour 144, and 60 pg/cm to 100 pg/cm from hour 144 to hour 168. 186. A set of transdermal therapeutic systems including at least two ermal eutic s selected from the first, second, third, fourth and fifth transdermal therapeutic system in accordance with any one of items 176 to 185. 187. Transdermal therapeutic system comprising buprenorphine for the transdermal administration of buprenorphine, wherein buprenorphine is present in the form of buprenorphine base and ing a non-cumulative release of PC 12/002973 buprenorphine base as measured in a Franz ion cell with dermatomed human skin of 2 pg/cm to 10 pg/cm in the first 8 hours, pg/cm to 80 pg/cm from hour 8 to hour 24, 20 pg/cm to 80 ug/cm &omhour24to hour 32, pg/cm to 120 pg/cm from hour 32 to hour 48, 40 pg/cm to 150 pg/cm from hour 48 to hour 72, 100 pg/cm to 300 ug/cm from hour 72 to hour 144, and pg/cm to 100 pg/cm from hour 144 to hour 168. 188. Transdermal therapeutic system in accordance with item 187, comprising a orphine base-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, and b) an analgesically effective lt ot buprenorphine base, wherein said bupieiiorphine base-containing pressure-sensitive adhesive layer is the skin contact layei'. 189. Transdermal eutic system comprising buprenorphine for the ermal administration of buprenorphine, wherein buprenorphine is present in the form of buprenorphine base and providing a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 pg/cm to 10 pg/cm in the first 8 hours, N, g/cm to 80 pg/cm from hour 8 tohour24, pg/cm to 80 pg/cm from hour 24 to hour 32, PC T/IB2012/002973 ij,g/cm to 120 Ng/cm fiom hour 32 to hour 48, 40 pg/cm to 150 pg/cm from hour 48 to hour 72, 100 pg/cm to 300 pg/cm' from hour 72 to hour 144, and pg/cm to 100 pg/cm from hour 144 to hour 168, and comprising a buprenorphine base-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable backing layer, the ve layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base, and c) a carboxylic acid selected from tl e group consisting of oleic acid, linoleic acid, linolenic acid, nic acid and mixtures f, in an amount sufficient so that said sically effective amount of orphine base is solubilized therein to form a e, and the carboxylic acid buprenorphine base solution forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer. 190. TransdellTlaJ. therapeutrc system 1n accordance with any one of items 1 to 189 for use m a method of treat&ng pam. 191. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a transdermal therapeutic system for more than 96 hours on the skin of a patient.

PC T/IB2012/002973 192. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a transdermal therapeutic system for more than 4 days on the skin of a patient. 19'-. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a transdermal therapeutic system for about 120 hours on the skin of a patient. 194. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of ng pain by applying a t ansdermal therapeutic system for days on the skin of a patient. 195. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a transdermal therapeutic system for about 144 hours on the skin of a patient. 196. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by ng a ermal therapeutic system for 6 days on the skin of a patient. 197. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a ermal therapeutic system for about 168 hours on the skin of a patient. 198. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a transdermal eutic system for 7 days on the skin of a patient.

PC 12/002973 199. Transdermal therapeutic system in accordance with any one of items 1 to 189 for use in a method of treating pain by applying a transdermal eutic system for a week on the skin of a patient. 200. Method of treating pain in a t by applying a transdermal therapeutic system in accordance with any one of items 1 to 189 for more than 96 hours on the skin of a patient. 201. K)ethod of treating pain in a patient by ng a transdermal therapeutic system in accordance with any one of items 1 to 189 for more than 4 days on the skin of a patient. 202. Method of treating pain in a patient by applying a transdermal therapeutic system in accordance with any one of items 1 to 189 for about 120 hours on the skin of a patient. 203. Method of treating pain in a patient by applying a transdeI-mal eutic system in accordance with any one of items 1 to 189 for 5 days on the skin of a patient. 204. Method of treating pain in a patient by applying a transdermal therapeutic system in accordance with any one of items 1 to 189 for about 144 hours on the skin of a patient. 205. Method of treating pain in a patient by applying a transdermal therapeutic system in accordance with any one of items 1 to 189 for 6 days on the skin of a patient.

PC T/IB2012/002973 206. Method of treating pain in a patient by ng a transdermal therapeutic system in accordance with any one of items 1 to 189 for about 168 hours on the skin of a patient. 207. Method of treating pain in a patient by applying a transdermal therapeutic system in accordance with any one of items 1 to 189 for 7 days on the skin of a 208. Method of treating pain in a t by applying a transdermal therapeutic system in accordance with any one of items 1 to 189 for a week on the skin of a patient. 209. Use of a transdermal therapeutic system in accordance with any one of items 1 to 199 for the manufacture of a medicament for the treatment of pain. 210. Use of a transdermal therapeutic system for the manufacture of a medicament in a method of treating pain in accordance with any one of claims 200 to 208. 211. Method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine in accordance with any one of items 1 to 199, comprising the steps of 1. providing a buprenorphine-containing adhesive mixture or solution comprising a) buprenorphine base or a pharmaceutically acceptable salt thereof b) a carboxylic acid, c) a polymer-based re-sensitive adhesive, and d) solvent 2. coating said buprenorphine-containing adhesive mixture or solution on a film in an amount to provide the desired coating dry weight, PC T/IB2012/002973 3. drying said coated buprenorphine-containing adhesive mixture or solution to provide a orphine-containing adhesive layer with the desired coating dry weight, 4. laminating said buprenorphine-containing adhesive layer to a backing layer to provide an buprenorphine-containing self-adhesive layer structure, . punching the individual systems from the buprenorphine-containing self- adhesive layer structure with the desired area of release, and 6. optionally adhering to the individual systems an active-free self-adhesive layer structure 'sing also a backing layer and an active agent-free pressure-sensitive adhesive layer and which is larger than the individual systems of buprenorphine-containing self-adhesive layer ure. 212. Method in accordance with item 211, wherein in step 1 buprenorphine is t in the form of buprenorphine base and the carboxylic acid is levulinic acid and are ded in ethanol and subsequently combined with a polymer-based pressure-sensitive adhesive based on loxane in heptane to e the buprenorphine-containing adhesive mixture or on. 213. Method of treating pain in a patient by applying for about 168 hours on the skin of a patient a transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable g layer, the adhesive layer comprising a) at least one polynter-based pressure-senslttve adhesive, b) an analgesically efiective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and PC T/IB2012/002973 c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid and linolenic acid, levulinic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of orphine is solubilized therein to form a e, and the carboxylic acid buprenorphine mixture forms dispersed ts in the saK1 prcssure-scnsltlvc adhesive. whcrclrl saKI bupl cnorphlnc-contalnulg prcssure-scBsltlvc adhcslvc layer Is thc skin coBtact Iavcl'. 214. Transdermal therapeutic system for administration of buprenorphine, comprising a buprenorphine-containing dhesive layer structure comprising A) a buprenorphine-impermeable g layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one r-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected trom the group ting ot oleic acid, llnolcrc acid, llnolcnlc acid, lcvullBlc acid and Bllxtur'cs thereof. 1B arl amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the sa!d pressure-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer for use in a method of treating pain by applying said ermal therapeutic system for about 168 hours on the skin of a patient.

WO 88254 PC T/IB2012/002973 215. Transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure sing A) a buprenorphine base-impermeable backing layer, and B) 8 buprcnorphinc base-coiiltRinlBg prcssure-scnsftlvc vc 1Rycr oB said buprcnorphiBc base-impcrmcabfc backing 1avcr, thc Rdhcslvc 1aycil' colBpris B.lg 8) at 1cRst onc pl'cssUrc-scnsltivc adhesive based on pofysi1oxanc, b) Rxl RBR1gcslc811y cffcctlvc anlount of huprcnorphiBc base, Rnd c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base mixture for ns dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer. 216. Method of treating pain in a t by applying to the skin of said t for about 168 hours a transdermal therapeutic system, comprising a buprenorphine base- containing dhesive layer structure comprising A) a buprenorphine base-impermeable backir-;g layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buplenorphine base-impermeab1e backing layer, the adhesive 1ayer comprkslBg 8') at 1east one pressure-serislrive adhesive based on po1vsii1oxane. b) Rn RBR1gcsic811y ive amount of bUplcnolphmc base„and PC T/IB2012/002973 c) levulinic acid, in an amount sufficient so that said sically effective amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, vvhcrcut sard orphutc base-contauung prcssure-scnsIttvc adhesive lavcr ts thc skm contact layer. 217. Transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backirg layer, and B) a buprenorphine base-containing pressure-sensitive ve layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprtsing a) at least one prcssure-sensitive adhesive based on polysHoxanc, b) an analgesically effective amount of orphine base, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is lized therein to form a mixture, and the levulinic acid buprenorphine base mixture forms dispersed deposits in the said re-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer for use in a method of treating pain by applymg said crmal Lhcrapcutic s~ sicnt for about 168 hours on thc skin of a patient. 218. Transdermal therapeutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprcnorphine-impermeable backing layer, and PC T/IB2012/002973 B) a orphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, b) an analgesically effective amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, nic acid and mixtures thereof, in an amount sufficient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine solution forms dispersed deposits in the said pressure-sensitive adhesive, vvherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 mg/cm of buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 219. Method of treating pain in a patient by applying to the skin of said patient for about 168 hours a transdermal eutic system for the transdermal administration of buprenorphine, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer sing a) at least one r-based pressure-sensitive adhesive, b) an sically ive amount of buprenorphine base or a ceutically acceptable salt thereof, . and PC T/IB2012/002973 c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount ient so that said sically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine solution forms dispersed deposits in the said re-sensitive adhesive, wherein said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 mg/cm of buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof. 220. Transdermal therapeutic system for the transdermal administration of buprenorphire, comprising a buprenorphine-containing self-adhesive layer structure comprising A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable backing layer, the adhesive layer comprising a) at least one polymer-based re-sensitive adhesive, b) an analgesically ive amount of buprenorphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group consisting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in an amount ient so that said analgesically effective amount of buprenorphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine solution forms dispersed deposits in the said pressure-sensitive adhesive, n said buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 mg/cm of PC T/IB2012/002973 orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof for use in a method of t;eating pain by applying said transdermal eutic system for about 168 hours on the skin of a patient. 221. Transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive ve layer on said orphine base-impermeable backing layer, the adhesive layer comprising a) at least one pressure-sensitive adhesive based on polysiloxanes, b) an analgesically effective amount of buprenorphine base, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid orphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more tha-. 0.6 mg/cm of buprenorphine base. 222. Method of treating pain in a t by applying to the skin of said patient for about 168 hours a transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a orphine base-containing self-adhesive layer structure comprising A) a buprenorphine base-impermeable backing layer, and PC T/IB2012/002973 B) a orphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeable g layer, the adhesive layer comprising a) at least one pressure-sensitive adhesive based on polysiloxanes, b) an analgesically effective amount of buprenorphine base, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein said buprenorphine ontaining pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 mg/cm of buprenorphine base. 223. Transdermal therapeutic system for the transdermal administration of buprenorphine base, comprising a buprenorphine base-containing self-adhesive layer structure comprising A) a orphine base-impermeable backing layer, and B) a orphine base-containing pressure-sensitive ve layer on said buprenorphine base-impermeable backing layer, the adhesive layer comprising a) at least one pressure-sensitive adhesive based on polysiloxanes, b) an sically ive amount of buprenorphine base, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount ofbuprenorphine base is solubilized therein to form a mixture, and the levulinic acid buprenorphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, PC 12/002973 wherein said buprenorphine base-containing pressure-sensitive adhesive layer is the skin contact layer and contains more than about 0.55 mg/cm or more than 0.6 mg/cm of buprenorphine base for use in a method of treating pain by applying said transdermal therapeutic system for about 168 hours on the skin of a patient. 224. A set of two to five different transdermal therapeutic systems for the transdermal administration of buprenorphine base selected from five ent transdermal therapeutic systems, a first, a second, a third, a forth and a fifth transdermal therapeutic system, each of the five different transdermal therapeutic systems comprising a buprenorphine-containing self-adhesive layer ure comprising A) a buprenorphine base-impermeable backing layer, and B) a buprenorphine base-containing pressure-sensitive adhesive layer on said buprenorphine base-impermeab!e backing layer, the adhesive layer comprising a) at least one pressure-sensitive adhesive based on loxanes, b) an analgesically effective amount of buprenorphine base, and c) levulinic acid, in an amount sufficient so that said analgesically effective amount of buprenorphine base is solubilized therein to form a mixture, and the nic acid buprenorphine base mixture forms dispersed deposits in the said pressure-sensitive adhesive, wherein, the first transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer ing the area of release ranging from about 1 cm to about 4.8 cm and ns from about 1 mg to about 4 mg buprenorphine base; the second transdermal eutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging PC 12/002973 from about 3 cm to about 9.5 cm and contains from about 3.5 mg to about 8 mg buprenorphine base; and the third transdermal therapeutic system provides a size of said buprenorphine- ning pressure-sensitive adhesive layer providing the area of e ranging from about 6 cm to about 19 cm and contains from about 6.5 mg to about 16 mg buprenorphine base; and the fourth transdermal therapeutic system provides a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 12 cm to about 28.5 cm and contains from about 11.5 mg to about 24 mg buprenorphine base; and the fifth transdermal therapeutic system es a size of said buprenorphine- containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm to about 38 cm from about 15 mg to about 32 mg buprenorphine base, wherein the five different transdermal therapeutic systems have increasing areas of release and amounts of buprenorphine from the first to the fifth transdermal therapeutic system for use in method of ng pair-, by applying one of said transdermal therapeutic systems for about 168 hours on the skin of a patient.

Claims

We Claim:

1. Use of a transdermal eutic system for the transdermal administration of buprenorphine, said system sing a buprenorphine-containing self-adhesive layer structure comprising 5 A) a buprenorphine-impermeable backing layer, and B) a buprenorphine-containing pressure-sensitive adhesive layer on said buprenorphine-impermeable g layer, the adhesive layer comprising a) at least one polymer-based pressure-sensitive adhesive, wherein said r-based pressure-sensitive adhesive is based on 10 polysiloxanes or polyisobutylenes, b) an sically effective amount of orphine base or a pharmaceutically acceptable salt thereof, and c) a carboxylic acid selected from the group ting of oleic acid, linoleic acid, linolenic acid, levulinic acid and mixtures thereof, in 15 an amount sufficient so that said analgesically effective amount of orphine is solubilized therein to form a mixture, and the carboxylic acid buprenorphine mixture forms dispersed deposits in the said pressure-sensitive adhesive, for the manufacture of a medicament for the treatment of pain, wherein said 20 buprenorphine-containing pressure-sensitive adhesive layer is the skin contact layer, and wherein the transdermal therapeutic system is for application to the skin for about 168h.

2. The use in accordance with claim 1, wherein said buprenorphine is present in the form of buprenorphine base and/or said carboxylic acid is levulinic acid.

3. The use in accordance with claims 1 or claim 2, wherein said buprenorphine is 25 present in the form of buprenorphine base, said carboxylic acid is levulinic acid and the polymer-based pressure-sensitive adhesive is based on polysiloxanes.

4. The use in accordance with any one of claims 1 to 3, the amount of said buprenorphine contained in the transdermal therapeutic system g from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a 30 pharmaceutically acceptable salt thereof, or about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt f, or (11591431_1):KZA about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof, or about 11.5 mg to about 24 mg buprenorphine base or an lar amount of a pharmaceutically acceptable salt thereof, or 5 about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

5. The use in accordance with any one of claims 1 to 4, the size of said buprenorphine-containing pressure-sensitive ve layer providing the area of e ranging from 10 about 1 cm2 to about 4.8 cm2, or about 3 cm2 to about 9.5 cm2, or about 6 cm2 to about 19 cm2, or about 12 cm2 to about 28.5 cm2, or about 16 cm2 to about 38 cm2. 15

6. The use in accordance with any one of claims 1 to 3, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 1 cm2 to about 4.8 cm2 and the amount of said buprenorphine ned in the transdermal therapeutic system ranging from about 1 mg to about 4 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 20

7. The use in accordance with claim 6, said transdermal therapeutic system ing a mean AUCt of more than 7,000 pg.hr/ml, or of more than 8,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population, and/or wherein the transdermal therapeutic system es a nominal mean release rate of about 5 µg/hr over about 168 hours of administration. 25

8. The use in accordance with any one of claims 1 to 3, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 3 cm2 to about 9.5 cm2, and the amount of said buprenorphine contained in the transdermal therapeutic system ranging from about 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 30

9. The use in accordance with claim 8, said transdermal therapeutic system providing a mean AUCt of more than 14,000 pg.hr/ml, or of more than 16,000 pg.hr/ml over about 168 hours of stration after a single-dose administration to a t (11591431_1):KZA population, and/or wherein the transdermal therapeutic system provides a nominal mean release rate of about 10 µg/hr over about 168 hours of administration.

10. The use in accordance with any one of claims 1 to 3, the size of said buprenorphine-containing pressure-sensitive adhesive layer ing the area of release 5 ranging from about 6 cm2 to about 19 cm2 and the amount of said buprenorphine ned in the transdermal therapeutic system ranging from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

11. The use in accordance with claim 10, said transdermal therapeutic system 10 providing a mean AUCt of more than 28,000 pg.hr/ml, or of more than 32,000 pg.hr/ml over about 168 hours of administration after a single-dose administration to a subject population, and/or wherein the transdermal therapeutic system provides a nominal mean e rate of about 20 µg/hr over about 168 hours of administration.

12. The use in accordance with any one of claims 1 to 3, the size of said 15 orphine-containing re-sensitive adhesive layer providing the area of release ranging from about 12 cm2 to about 28.5 cm2, and the amount of said buprenorphine contained in the transdermal therapeutic system g from about 11.5 mg to about 24 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 20

13. The use in accordance with claim 12, said transdermal therapeutic system providing a mean AUCt of more than 42,000 pg.hr/ml, or of more than 48,000 pg.hr/ml over about 168 hours of stration after a single-dose administration to a subject population, and/or wherein the transdermal therapeutic system provides a nominal mean release rate of about 30 µg/hr over about 168 hours of administration. 25

14. The use in ance with any one of claims 1 to 3, the size of said buprenorphine-containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm2 to about 38 cm2, and the amount of said buprenorphine contained in the ermal therapeutic system ranging from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof. 30

15. The use in ance with claim 14, said transdermal therapeutic system providing a mean AUCt of more than 62,000 pg.hr/ml, or of more than 64,000 pg.hr/ml (11591431_1):KZA over about 168 hours of administration after a single-dose administration to a subject population, and/or n the transdermal therapeutic system es a nominal mean release rate of about 40 µg/hr over about 168 hours of administration.

16. The use in accordance with any one of claims 1 to 15, said transdermal 5 therapeutic system providing an arithmetic mean tmax of from about 60 hr to about 120 hr, or from about 66 hr to less than about 108 hr after a single-dose administration to a subject population.

17. The use in accordance with any one of claims 1 to 16, said transdermal therapeutic system providing a mean AUCt per area of e of more than 1,700 10 pg.hr/ml-cm2 over about 168 hours of administration after a single-dose administration to a subject population.

18. The use in accordance with any one of claims 1 to 17, said buprenorphinecontaining pressure-sensitive adhesive layer containing more than 0.55 mg/cm2, or more than 0.6 mg/cm2 of buprenorphine base or an equimolar amount of a pharmaceutically 15 acceptable salt thereof.

19. The use in accordance with any one of claims 1 to 18, the orphinecontaining pressure-sensitive adhesive layer being coated at a dry weight of more than 6 , or of more than 8 mg/cm2.

20. The use in accordance with any one of claims 1 to 19, wherein the carboxylic 20 acid is levulinic acid, said buprenorphine-containing pressure-sensitive adhesive layer containing the same % amounts of levulinic acid and buprenorphine, based on the % amount of buprenorphine base, or n said buprenorphine-containing pressuresensitive adhesive layer containing less % amounts of levulinic acid than % amounts of buprenorphine, based on the % amount of buprenorphine base. 25

21. The use in accordance with any one of claims 1 to 20, said buprenorphinecontaining self-adhesive layer structure being ed to a second larger active agent-free self-adhesive layer ure for enhancing the adhesive properties of the overall transdermal therapeutic system. (11591431_1):KZA

22. The use in accordance with claim 21, said second active-free self-adhesive layer structure comprising a backing layer and an active agent-free pressure-sensitive adhesive layer of pressure-sensitive adhesive based on polyacrylates or polysiloxane.

23. The use in accordance with any one of claims 1 to 22, wherein buprenorphine is 5 present in the form of buprenorphine base and ing a mean tive skin permeation rate measured in a Franz diffusion cell with dermatomed human skin of more than 1.3 µg/cm2-hr over a 168 hours test, and/or providing a cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 220 µg/cm2 to 640 µg/cm2 over a time period of 168 hours. 10

24. The use in accordance with any one of claims 1 to 23, wherein buprenorphine is present in the form of buprenorphine base and providing a non-cumulative release of buprenorphine base as measured in a Franz diffusion cell with dermatomed human skin of 2 µg/cm2 to 10 µg/cm2 in the first 8 hours, 20 µg/cm2 to 80 µg/cm2 from hour 8 to hour 24, 15 20 µg/cm2 to 80 µg/cm2 from hour 24 to hour 32, 30 µg/cm2 to 120 µg/cm2 from hour 32 to hour 48, 40 µg/cm2 to 150 µg/cm2 from hour 48 to hour 72, 100 µg/cm2 to 300 µg/cm2 from hour 72 to hour 144, and 30 µg/cm2 to 100 µg/cm2 from hour 144 to hour 168. 20

25. The use according to claim 1, wherein the medicament is a set of two to five different transdermal eutic systems, wherein the first ermal therapeutic system provides a size of said buprenorphinecontaining re-sensitive adhesive layer providing the area of release ranging from about 1 cm2 to about 4.8 cm2 and contains an amount of said buprenorphine from about 1 25 mg to about 4 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; the second transdermal therapeutic system es a size of said buprenorphinecontaining re-sensitive adhesive layer providing the area of release ranging from about 3 cm2 to about 9.5 cm2 and contains an amount of said orphine from about 30 3.5 mg to about 8 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the third transdermal therapeutic system provides a size of said buprenorphinecontaining pressure-sensitive adhesive layer providing the area of release ranging from (11591431_1):KZA about 6 cm2 to about 19 cm2 and contains an amount of said buprenorphine from about 6.5 mg to about 16 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fourth ermal therapeutic system provides a size of said buprenorphine- 5 containing pressure-sensitive adhesive layer providing the area of e ranging from about 12 cm2 to about 28.5 cm2 and contains an amount of said buprenorphine from about 11.5 mg to about 24 mg orphine base or an equimolar amount of a pharmaceutically acceptable salt thereof; and the fifth transdermal therapeutic system es a size of said buprenorphine- 10 containing pressure-sensitive adhesive layer providing the area of release ranging from about 16 cm2 to about 38 cm2 and contains an amount of said buprenorphine from about 15 mg to about 32 mg buprenorphine base or an equimolar amount of a pharmaceutically acceptable salt thereof.

26. The use in accordance with claim 25, wherein orphine is present in the 15 form of buprenorphine base and wherein the first transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference t having an area of release of about 6.25 cm2 and providing a nominal mean e rate of about 5 µg/hr over about 168 hours of administration, 20 the second transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 12.5 cm2 and providing a nominal mean release rate of about 10 µg/hr over about 168 hours of administration, the third transdermal therapeutic system when tested in a comparative clinical 25 study is bioequivalent to a reference product having an area of release of about 25 cm2 and providing a nominal mean release rate of about 20 µg/hr over about 168 hours of administration, the fourth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference product having an area of release of about 37.5 cm2 30 and ing a nominal mean release rate of about 30 µg/hr over about 168 hours of administration, the fifth transdermal therapeutic system when tested in a comparative clinical study is bioequivalent to a reference t having an area of release of about 50 cm2 (11591431_1):KZA and providing a l mean release rate of about 40 µg/hr over about 168 hours of administration, wherein the reference product is prepared by the following steps:

1. homogenizing of 1,139 g of a 47.83 % polyacrylate solution of a selfcrosslinked acrylate copolymer of 2-ethylhexyl acrylate, vinyl acetate, acrylic acid (solvent: ethyl acetate:heptanes:isopropanol:toluene:acetylacetonate in the ratio of 37:26:26:4:1), 100 g of levulinic acid, 150 g of oleyl oleate, 100 g of polyvinylpyrrolidone, 150 g of ethanol, 200 g of ethyl acetate, and 100 g of orphine base to provide a mixture;

2. stirring the e of step 1 for about 2 hours and controlling the dissolution of all solids visually whereas controlling the evaporation loss by reweighing and replenishing the possible t loss by ethyl e;

3. subsequently applying the mixture on a transparent polyester film in such a manner that the mass per unit area of the dry adhesive layer amounts to about 80 g/m2 wherein the polyester film is rendered removable by means of siliconization and serves as protective layer;

4. removing the solvents of the mixture applied on a transparent polyester film in step 3 by drying with heated air which is led over a moist lane resulting in evaporation of the solvents, but also in melting of the levulinic acid and covering the adhesive film with a polyester foil;

5. punching the area of release of 6.25 cm2, 12.5 cm2, 25 cm2, 37.5 cm2 and 50 cm2, respectively, by means of le cutting tools and removing the edges left between the individual systems.

27. Method of manufacture of a transdermal therapeutic system for the transdermal administration of buprenorphine, said system being as bed in any one of claims 1 to 26 comprising the steps of

1. providing a orphine-containing adhesive mixture or solution sing a) buprenorphine base or a pharmaceutically acceptable salt thereof b) a ylic acid, c) a polymer-based pressure-sensitive adhesive, wherein said polymer-based pressure sensitive adhesive is based on polysiloxanes or polyisobutylenes, and d) solvent,

2. coating said buprenorphine-containing adhesive mixture or solution on a film in an amount to provide the desired g dry weight, AH26(12048217_1):JIN

3. drying said coated buprenorphine-containing adhesive mixture or solution to provide a buprenorphine-containing adhesive layer with the d coating dry weight,

4. laminating said buprenorphine-containing adhesive layer to a g 5 layer to provide an buprenorphine-containing self-adhesive layer ure,

5. punching the individual s from the buprenorphine-containing self-adhesive layer structure with the desired area of release, and

6. optionally adhering to the individual systems an active-free selfadhesive layer structure comprising also a backing layer and an active agent-free 10 pressure-sensitive adhesive layer and which is larger than the dual systems of buprenorphine-containing self-adhesive layer structure.

28. Method in accordance with claim 27, wherein in step 1 buprenorphine is present in the form of buprenorphine base and the carboxylic acid is levulinic acid and are ded in ethanol and subsequently combined with a polymer-based pressure-sensitive 15 adhesive based on polysiloxane in heptane to provide the buprenorphine-containing ve mixture or solution.