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sø- & handelsrettens dombog

- lca udskrift af sø- & handelsrettens dombog ____________ dom afsagt den 17. juni 2016. t-2-12 1) astrazeneca ab 2) astrazeneca a/s (advokat peter-ulrik plesner for begge) mod teva denmark a/s (advokat klaus ewald madsen) og -2- t-20-13 1) astrazeneca ab 2) astrazeneca a/s (advokat peter-ulrik plesner for begge) mod accord healthcare ltd. (advokat nicolai lindgreen og advokat nicolaj bording) sagens baggrund og parternes påstande hovedspørgsmålet i nærværende dom, der er en delafgørelse, jf. retsplejelovens § 253, er, om astrazeneca abs patent dk/ep 0 907 364 (stridspatentet) er gyldigt, og om patentet, såfremt det erklæres ugyldigt i den udstedte form, kan opretholdes med begrænsende krav. dette spørgsmål er udskilt til særskilt behandling og afgørelse, således at behandlingen af parter- nes erstatningspåstande er udskudt til et senere tidspunkt. parterne er enige om, at der først træffes afgørelse om sagsomkostninger i forbindelse med afslutningen af sagerne, der be- handles i forening med hinanden. astrazeneca ab og astrazeneca a/s (herefter tilsammen astrazeneca) har under nærvæ- rende delforhandling nedlagt følgende endelige påstande mod teva denmark a/s (t-2-12): 1. det af fogedretten i lyngby ved kendelser af 13. april 2012 og 17. april 2012 nedlagte forbud og accessoriske forpligtelser i sag nr. fs 350-2728/2012 stadfæstes. 2. det forbydes sagsøgte, teva denmark a/s, i danmark at udbyde, bringe i omsæt- ning eller anvende lægemidlet quetiapin "teva" og quetiapine "teva", omhandlet af sagsøgtes markedsføringstilladelse med d.sp.nr. 25398 og markedsføringstilladel- ses-numre 47660 (50 mg), 47661 (200 mg), 47662 (300 mg), 47663 (400

  1. mg)og 50133 (150 mg), jf. bilag 3, bilag 3a og bilag 3b, (alle bilagslitereringer t-0002-12) eller im- -3- portere eller besidde det med et sådant formål, så længe patent nr. dk/ep 0 907 364 er i kraft i danmark. 3. den af sagsøgerne, astrazeneca, stillede sikkerhed i fogedsag fs 350 2728/2012 fri- gives. sagsøgte teva denmark a/s (herefter teva) har nedlagt påstand om frifindelse overfor astrazenecas påstande 1 og 2. overfor astrazenecas påstand 3 har teva nedlagt påstand om, at den af astrazeneca over for fogedretten i lyngby stillede sikkerhed på kr. 6.000.000 frigives, når astrazeneca har be- talt teva ethvert beløb, herunder sagsomkostninger, som astrazeneca måtte blive pålagt at betale til teva ved endelig upåankelig dom i nærværende sag. teva har endvidere nedlagt følgende selvstændige påstande: 1. patent dk/ep 0907364 erklæres ugyldigt i sin helhed. 2. rettens dom i nærværende sag, om ophævelse af forbuddet og tilknyttede accessoriske foranstaltninger pålagt teva, skal være eksigibel uanset om afgørelsen appelleres før fuldbyrdelsesfristens udløb. astrazeneca har overfor tevas selvstændige påstand 1 nedlagt følgende påstande: principalt: frifindelse. subsidiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 43, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et ge- leringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethyl]- 1-piperazinyl]dibenzo[b,f][1,4]thiazepin eller et farmaceu- tisk acceptabelt salt deraf sammen med en eller flere far- -4- maceutisk acceptable excipienser, hvori en af de en eller flere farmaceutiske acceptable excipienser er et ph- modificerende middel, der er natriumcitrat." mere subsidiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 44, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et ge- leringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethyl]-1- piperazinyl]dibenzo[b,f][1,4]thiazepin eller et farmaceu- tisk acceptabelt salt deraf sammen med en eller flere far- maceutisk acceptable excipienser, hvori geleringsmidlet er hydroxypropylmethylcellulose, og hvori en af de en eller flere farmaceutiske acceptable excipienser er et ph- modificerende middel, der er natriumcitrat." tertiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 80, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et ge- leringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethyl]-1- piperazinyl]dibenzo[b,f][1,4]thiazepin i form af et hemi- fumaratsalt sammen med en eller flere farmaceutisk accep- table excipienser, hvori en af de en eller flere farmaceuti- ske acceptable excipienser er et ph-modificerende middel, der er natriumcitrat." mest subsidiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 81, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et ge- leringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethyl]-1- piperazinyl]dibenzo[b,f][1,4]thiazepin i form af et hemi- fumaratsalt, hvori geleringsmidlet er hydroxypropyl- methylcellulose, og hvori en af de en eller flere farmaceu- tiske acceptable excipienser er et ph-modificerende mid- del, der er natriumcitrat." overfor tevas selvstændige påstand 2 har astrazeneca påstået frifindelse. -5- astrazeneca har nedlagt følgende påstande mod accord healthcare limited (t-20-13): 1. det forbydes sagsøgte, accord healthcare limited, i danmark at udbyde, bringe i omsætning eller anvende lægemidlet quetiapin "accord", omhandlet af accord healthcare limiteds markedsføringstilladelse med d.sp.nr. 26756, jf. bilag 5 (t-0020- 13), 34 (t-0002-12) og ai (t-0020-13), eller importere eller besidde det med et sådant formål, så længe patent nr. dk/ep 0 907 364 er i kraft i danmark med patentkrav som i bilag 1. 2. det forbydes sagsøgte, accord healthcare limited, i danmark at udbyde, bringe i omsætning eller anvende lægemidlet quetiapin "accord", omhandlet af accord healthcare limiteds markedsføringstilladelse med markedsføringstilladelsesnum- rene 46349 (200 mg), 46350 (300 mg), 46351 (400
  2. mg)og 50890 (50 mg), jf. bilag 5 (t0020-13), 34 (t0002-12) og ai (t0020-13), eller importere eller besidde det med et sådant formål, så længe patent nr. dk/ep 0 907 364 er i kraft i danmark med pa- tentkrav som i bilag 1. sagsøgte accord healthcare limited (herefter accord) har nedlagt påstand om frifindelse over for astrazenecas påstande 1 og 2. accord har endvidere nedlagt følgende endelige selvstændige påstande: 1. astrazenecas europæiske patent dk/ep 0 907 364 som udstedt for danmark ugyldig- gøres. 2. det midlertidige forbud udstedt af sø- og handelsretten i sagen a-0011-13 den 20. december 2013 bortfalder, også selv om afgørelsen i nærværende sag ankes inden udløbet af fuldbyrdelsesfristen. astrazeneca har over for accords selvstændige påstand 1 nedlagt følgende påstande: -6- principalt: frifindelse. subsidiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 43, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et gel e- ringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethy1]- 1-piperazinyl]dibenzo[b,f][1,4]thiazepin eller et farmaceutisk acceptabelt salt deraf sammen med en eller flere farmaceutisk acceptable excipienser, hvori en af de en eller flere farmaceuti- ske acceptable excipienser er et ph-modificerende middel, der er natriumcitrat." mere subsidiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 44, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et gel e- ringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethy1]-1- piperazinyl]dibenzo[b,f][1,4]thiazepin eller et farmaceutisk a c- ceptabelt salt deraf sammen med en eller flere farmaceutisk ac- ceptable excipienser, hvori geleringsmidlet er hydroxypropyl- methylcellulose, og hvori en af de en eller flere farmaceutiske acceptable excipienser er et ph-modificerende middel, der er natriumcitrat." tertiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 80, herunder følgende krav 1: "formulering med langvarig frigivelse, der omfatter et gel e- ringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethy1]-1- piperazinyl]dibenzo[b,f][1,4]thiazepin i form af et hemifumarat- salt sammen med en eller flere farmaceutisk acceptable exci- pienser, hvori en af de en eller flere farmaceutiske acceptable excipienser er et ph-modificerende middel, der er natriumcit- rat." mest subsidiært: patent nr. dk/ep 0 907 364 opretholdes med virkning for danmark med kravsæt som i bilag 81, herunder følgende krav 1: -7- "formulering med langvarig frigivelse, der omfatter et gel e- ringsmiddel og 11-[4-[2-(2-hydroxyethoxy)ethy1]-1- piperazinyl]dibenzo[b,f][1,4]thiazepin i form af et hemi fumarat- salt, hvori geleringsmidlet er hydroxypropylmethylcellulose, og hvori en af de en eller flere farmaceutiske acceptable excipienser er et ph-modificerende middel, der er natriumcitrat." over for accords selvstændige påstand 2 har astrazeneca påstået frifindelse. oplysningerne i sagen sagens parter astrazeneca-koncernen driver virksomhed globalt inden for forskning og udvikling af origi- nale lægemidler og er en af verdens største lægemiddelvirksomheder. astrazeneca ab har stået for udviklingen af det i sagen omhandlede lægemiddel, seroquel prolong (også kaldet seroquel
  3. xl)(herefter seroquel prolong) som indeholder stoffet quetiapin, og er indehaver af stridspatentet dk/ep 0 907 364. astrazeneca a/s forestår markedsføringen af seroquel prolong i danmark. koncernen har en omsætning på ca. 25 mia. usd årligt. teva er et helejet datterselskab af det israelske selskab teva pharmaceutical industries ltd. teva pharmaceutical industries ltd er et af verdens største farmaceutiske selskaber. hoved- vægten ligger på udvikling af generiske lægemidler, men virksomheden udvikler også origi- nale lægemidler. koncernen omsætter årligt for ca. 20 mia. usd. accord er en del af intas pharmaceuticals ltd, der er en global virksomhed med hovedsæde i indien, som primært beskæftiger sig med generiske lægemidler. baggrunden for sagen astrazeneca fik den 17. april 2012 nedlagt et fogedforbud mod teva, således at teva ikke kunne sælge produktet ‛quetiapin teva sr‛. astrazeneca indledte derefter nærværende sag mod teva (t-2-12). -8- som led i en processuel aftale mellem astrazeneca og accord blev der nedlagt et midlerti- digt forbud mod accords salg af produktet ‛quetiapin accord sr‛ den 20. december 2013, hvorefter nærværende sag (t-20-13) blev indledt. idet astrazenecas sager mod teva og accord har det samme materielle indhold, behandles sagerne sammen. nærmere afgrænsning af sagens hovedspørgsmål det er under sagerne ubestridt, at stridspatentet opfylder kravet om nyhed. teva og accord har imidlertid gjort gældende, at stridspatentets krav 1 (hovedkravet) er ugyldigt på grund af manglende opfindelseshøjde, idet løsningen med langvarig frigivelse (sr-formulering) ikke adskiller sig væsentligt fra den kendte teknik. astrazeneca har heroverfor gjort gældende, at stridspatentet har den fornødne opfindelses- højde, idet opfindelsen adskiller sig væsentligt fra den kendte teknik, og stridspatentet skal derfor opretholdes, enten som det er udstedt eller – subsidiært - i overensstemmelse med et af fire begrænsede krav. stridspatentet astrazeneca ab er som nævnt indehaver af stridspatentet dk/ep 0 907 364. stridspatentet er på grundlag af en ansøgning af 27. maj 1997 udstedt af epo (the european patent office) den 14. august 2002 og har prioritet fra den 31. maj 1996. stridspatentet er valideret i danmark. i den danske oversættelse har stridspatentets krav 1 m.fl. følgende ordlyd: ‛1. formulering med langvarig frigivelse, der omfatter et geleringsmiddel og 11-[4- [2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepin eller et farma- ceutisk acceptabelt salt deraf sammen med en eller flere farmaceutisk acceptable ex- cipienser.‛ ... 3. formulering med langvarig frigivelse ifølge krav 1 eller krav 2, hvori gelerings- midlet er hydroxypropylmethylcellulose. < -9- 12. formulering ifølge krav 1-11, hvori de en eller flere farmaceutisk acceptable exci- pienser er udvalgt fra gruppen, der består af mikrokrystallinsk cellulose, lactose, magnesiumstearat, natriumcitrat og povidon. < 14. formulering ifølge et hvilket som helst af kravene 1-13, hvori en eller flere farma- ceutisk acceptable excipienser er et ph-modificerende middel. 15. formulering ifølge krav 14, hvori det ph-modificerende middel er natriumcitrat. 16. formulering ifølge et hvilket som helst af kravene 1-15, hvori 11-[4-[2-(2- hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo-[b,f][1,4]thiazepin er i form af et hemi- fumaratsalt.‛ aktivstoffet 11-[4-[2-(2-hydroxyethoxy)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepin er og- så kendt under navnet ‛quetiapin‛. quetiapin var kendt forud for stridspatentet bl.a. fra astrazenecas ansøgning om patent på stoffet ep 0 240 228. quetiapin eller quetiapinfumarat (dvs. et farmaceutisk acceptabelt salt af quetiapin) anvendes som lægemiddel til behandling af forskellige former for psykiske lidelser, herunder skizofreni. opfindelsen i stridspatentet angår en formulering, der giver langvarig frigivelse af quetiapin eller quetiapinfumarat. om baggrunden herfor anføres i stridspatentets beskrivelse (den danske oversættelse) bl.a.: ‚< det er ønskeligt ved behandling at et antal sygdomme, både terapeutisk og profylak- tisk, at tilvejebringe den aktive farmaceutiske bestanddel i en form med langvarig frigivelse. den langvarige frigivelse tilvejebringer ønskeligt en generelt ensartet og konstant frigørelseshastighed i løbet af en længere tidsperiode, hvorved der opnås et stabilt og ønsket blod- (plasma-) niveau af aktiv bestanddel uden behov for hyppig indgivelse at medikamentet. medens der er talrige formuleringer med langvarig frigivelse kendt inden for faget, der gør anvendelse af geleringsmidler, såsom hydroxypropylmethylcelluloser, har det vist sig at være vanskeligt at formulere formuleringer med langvarig frigivelse af opløselige medikamenter og geldannende midler, såsom hydroxypropylmethylcellu- lose, af adskillige grunde. først og fremmest vil aktive bestanddele, der er opløselig i vand, have tendens til at danne et produkt med langvarig frigivelse, der er udsat for et fænomen kendt som dosisdumping. dvs. frigivelse af den aktive bestanddel er for- sinket en periode, men når frigivelsen begynder, er frigivelseshastigheden meget høj. endvidere er der tendens til fluktuationer i plasmakoncentrationer af den aktive be- standdel, hvilket forøger sandsynligheden for toksicitet. endvidere er der også blevet observeret nogen grad af daglig variation i plasmakoncentration af den aktive be- - 10 - standdel. endelig har det vist sig at være vanskeligt at opnå de ønskede fortyndings- profiler eller at kontrollere frigivelseshastigheden for det opløselige medikament. følgelig er der et behov for formuleringer med langvarig frigivelse af opløselige me- dikamenter, såsom [quetiapin] eller et farmaceutisk acceptabelt salt, hvilke formule- ringer overvinder, eller i det mindste letter, en eller flere af de ovenfor beskrevne be- sværligheder, og som endvidere tilvejebringer den fordelagtige egenskab at tillade det aktive medikament at indgives mindre hyppigt, for eksempel en gang dagligt, medens der opnås blod- (plasma) niveauer svarende til dem, der opnås ved indgivel- se af mindre doser af medikamentet oftere, for eksempel to eller flere gange dagligt. fig. 1 viser frigivelses- (opløsnings-) profiler for formuleringerne med langvarig fri- givelse ifølge eksempel 8, 9 og 10, hvilke profiler opnås ved at nedsænke en egnet tablet i 750 ml 0,1 n hcl i 2 h ved 37 ˚c og en hastighed af 100 rpm og derefter at til- sætte 250 ml 0,2 m natriumphosphatpuffer til opløsningsmedierne for at give en ph på 6,2. fig. 2 viser profiler for plasmakoncentration versus tid af den aktive bestanddel for formuleringerne med langvarig frigivelse ifølge eksempel 1 og 2 og formuleringen med umiddelbar frigivelse ifølge eksempel 12. forbindelsen 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo-[b,f][1,4] thia- zepin (se formel i herunder) og dens farmaceutisk acceptable salte udviser egnet an- tidopaminerg aktivitet og kan anvendes for eksempel som et antipsykotisk middel (for eksempel til kontrol af manifestationerne af psykotiske lidelser) eller som en be- handling for hyperaktivitet. < fremstilling af, de fysiske egenskaber for og de fordelagtige farmakologiske egen- skaber ved 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo-[b,f][1,4] thiaze- pin og dets farmaceutiske acceptable salte er beskrevet i offentliggjorte europæiske patenter ep 240 228 og 282 236 såvel som i u.s. patent 4 879 288. ifølge den foreliggende opfindelse tilvejebringes der en formulering med langvarig frigivelse, der omfatter et geleringsmiddel, fortrinsvis hydroxypropylmethylcellulo- se, og 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo-[b,f][1,4]thiazepin el- ler et farmaceutisk acceptabelt salt deraf sammen med en eller flere farmaceutisk ac- ceptable excipienser. fortrinsvis omfatter formuleringen med langvarig frigivelse med en hydrofil matrice, der omfatter et geleringsmiddel, fortrinsvis hydroxypro- pylmethylcellulose, og 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo- [b,f][1,4]thiazepin eller et farmaceutisk acceptabelt salt deraf sammen med en eller flere farmaceutisk acceptable excipienser. <‛ formuleringen med langvarig frigivelse af quetiapin eller quetiapinfumarat indeholder bl.a. et geleringsmiddel. stridspatentets beskrivelse (den danske oversættelse) indeholder bl.a. følgende omtale heraf: ‛< - 11 - udtrykket geleringsmiddel betyder, som det er anvendt heri, ethvert stof, navnlig et hydrofilt stof, der danner en gel, når det bringes i kontakt med vand, og indbefatter således sådanne stoffer som hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylethylcellulose, me- thylcellulose, ethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellu- lose, carbomer, natriumcarboxymethylcellulose, polyvinylpyrrolidon og lignende, el- ler blandinger deraf. geleringsmidlet er fortrinsvis hydroxypropylmethylcellulose. <‛ der står videre i beskrivelsen at: ‛< hydroxypropylmethylcellulosen kan indeholde mere end en kvalitet polymer og er kommercielt tilgængelig under adskillige varemærker, for eksempel methocel ® e, f, j oh k fra the dow chemical company, u.s.a., og methalose™ fra shin-etsu, ltd., japan<‛ derudover fremgår bl.a. følgende af beskrivelsen: ‛< formuleringen vil i almindelighed indeholde en eller flere excipienser. sådanne exci- pienser indbefatter < og ph-modificerende midler, som indbefatter egnede organiske syrer eller alkalimetal- (for eksempel lithium-, natrium-, eller kalium-) salte deraf, så- som benzoesyre, citronsyre, vinsyre, ravsyre, adipinsyre og lignende, eller de tilsva- rende alkalimetalsalte deraf, fortrinsvis alkalimetalsaltene af sådanne syrer og navnlig natriumsaltet af citronsyre (dvs. natriumcitrat). < ifølge den foreliggende opfindelse tilvejebringes der også en formulering med langva- rig frigivelse, der omfatter et geleringsmiddel, fortrinsvis hydroxypropylmethylcellu- lose, og 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo-[b,f][1,4]thiazepin el- ler et farmaceutisk acceptabelt salt deraf sammen med en eller flere farmaceutisk ac- ceptable excipienser, hvoraf en af excipienserne er et ph-modificerende middel. < i de ovenfor beskrevne formuleringer er 11-[4-[2-(2-hydroxyethoxy)ethyl]- 1piperazinyl1]-dibenzo-[b,f][1,4]thiazepinet fortrinsvis i form af et hemifumaratsalt, hvilken form har en ligevægtsopløselighed i vand ved 20°c på 3,29 mg/ml. < formuleringerne ifølge den foreliggende opfindelse kan fremstilles ved hjælp af tradi- tionel teknologi som velkendt for fagfolk, såsom vådgranulering, direkte kompression, tør komprimering (presning) og lignende. således blandes for eksempel den aktive be- standdel 11-[4-[2-(2-hydroxyethoxy)ethyl]-1piperazinyl1]-dibenzo-[b,f][1,4]thiazepin eller et farmaceutisk acceptabelt salt deraf, et geleringsmiddel, fortrinsvis hydroxypro- pylmethylcellulose, og andre excipienser sammen for at danne formuleringerne med langvarig frigivelse ifølge den foreliggende opfindelse< for at danne en blanding, der er egnet til komprimering i tabletter, hvilken blanding derefter komprimeres for at danne tabletter eller fyldes i kapsler. < formuleringen frigiver fortrinsvis den aktive bestanddel på kontrolleret vis i løbet af en periode på op til ca. 8 h eller længere. for eksempel frigav formuleringen beskrevet - 12 - i eksempel 2 herunder ca. 90 % af den aktive bestanddel i løbet af 16 h, og formulerin- gen beskrevet i eksempel 1 frigav ca. 90 % af den aktive bestanddel i løbet af en perio- de på 8 h. < opfindelsen illustreres yderligere af de følgende ikke-begrænsende eksempler, < eksempel 1 den følgende fremgangsmåde blev anvendt for at fremstille tabletter, der har sammen- sætningen defineret i tabel 1. < < profilen for plasmakoncentration af den aktive bestanddel over tid for formuleringen ifølge eksempel 1 er vist i fig. 2. eksempel 2 fremgangsmåden beskrevet i eksempel 1 blev gentaget ved anvendelse af metho- cel® e50lv og methocel® e4m i stedet for methocel® e50lv for at give tablet- ter med den følgende sammensætning. tabel 2 <‛ - 13 - eksemplerne 3-11 viser andre formuleringer med langvarig frigivelse. disse indeholder – i modsætning til eksempel 1 og 2 - alle natriumcitrat. af patentskriftets tabel 8 fremgår sam- mensætningen af tabletterne benævnt eksempel 8, 9 og 10: i eksempel 12 er beskrevet et præparat med umiddelbar frigivelse: - 14 - figur 1 i stridspatentet viser en sammenligning af frigivelsesprofiler over tid for formulerin- ger efter eksempel 8, 9 og 10, der alle indeholder blandt andet natriumcitrat. fig.1. figur 2 i stridspatentet illustrerer en sammenligning mellem profiler for plasmakoncentrati- oner over tid ifølge eksemplerne 1, 2 og 12. eksempel 1 og 2 er uden natriumcitrat og eksem- pel 12 er en formulering med øjeblikkelig frigivelse. - 15 - i forbindelse med behandlingen af patentansøgningen har epo i 1997 udarbejdet en ‛inter- national search report‛, hvori er nævnt to dokumenter, som er blevet anset for relevante i forhold til patentansøgningens krav 1-15. det ene dokument er stofpatentansøgningen ep 0 240 228 a fra 1987. begge dokumenter er blevet kategoriseret som ‚a‛ modhold, d.v.s ‛docu- ment defining the general state of the art which is not considered to be of particular relevance‛. skizofreni skizofreni er en psykisk lidelse, der rammer cirka 1 % af befolkningen. blandt symptomerne er hallucinationer, paranoia, vrangforestillinger og desorganiseret tænkning. patienter med skizofreni kan handle irrationelt og under akutte episoder blive aggressive og være til fare for sig selv og andre. ved behandling af akutte skizofreniepisoder er det vigtigt hurtigt at få patienten beroliget, særligt hvis patienten er ophidset eller voldelig, og at behandle det underliggende psykoti- ske forhold. skizofreni er en langvarig og kronisk sygdom, og det tager almindeligvis flere dage eller uger, før den antipsykotiske effekt af den medicinske behandling virker. udover antipsyko- tisk medicinering består behandlingen også af samtaleterapi. da skizofreni er en langvarig og kronisk sygdom, er der også tale om en langvarig medicinering. typiske og atypiske antipsykotika de første antipsykotiske lægemidler, 1. generations antipsykotika

(1g), blev introduceret i 1950’erne. lægemidlerne var begrænset til kun at have en virkning mod de ‛positive symp- tomer‛ på skizofreni (vrangforestillinger, hallucinationer, tankeforstyrrelser med videre). de havde derimod ikke effekt på de ‛negative symptomer‛ så som apati, manglende interesse i sociale interaktioner og manglende motivation. derudover havde de en række alvorlige bi- virkninger, hvoraf de væsentligste er ‛extrapyramidale symptomer‛ (eps), der blandt andet kommer til udtryk i form af muskelkramper og andre bevægelsesforstyrrelser. de første an- tipsykotika blev kendt som ‛typiske‛ antipsykotika. - 16 - der er efterfølgende udviklet en række antipsykotika, omtalt som 2. generations antipsykoti- ka, som er effektive mod både skizofrenis positive som negative symptomer og som resulte- rer i ingen eller væsentligt færre ekstrapyramidale symptomer (eps). disse antipsykotika benævnes ‛atypiske‛ antipsykotika. det første atypiske antipsykotika, som kom på markedet, var stoffet clozapin. clozapin blev udviklet i 1960’erne og anvendt som antipsykotisk lægemiddel siden 1970’erne. et senere an- tipsykotisk lægemiddel, der var kendt inden stridspatentets prioritetsdato, er risperidon. de nye atypiske lægemidler ændrede det kliniske landskab indenfor behandlingen af skizofreni. de bivirkninger, der kan være forbundet med clozapin, er agranulocytose, som medfører et meget lavt antal hvide blodlegemer, og forhøjet indhold af prolaktin i blodet, som kan føre til manglende fertilitet. lægemiddelindustrien har haft stor fokus på udvikling af ‛atypiske‛ antipsykotika som føl- ge af den dokumenterede effekt på såvel de positive som negative symptomer af skizofreni og som følge af færre eps. i 1996, efter prioritetsdatoen, blev lægemidlet ‛zyprexa‛ lanceret, og i 1997 blev ‛quetiapin‛ lanceret på markedet under navnet seroquel i en formulering til umiddelbar frigivelse. produkterne udviklede sig til de bedst sælgende lægemidler i verden. sr formuleringer lægemiddelformuleringer kan overordnet inddeles i to grupper. dels formuleringer, der fri- giver det aktive stof umiddelbart ved indtagelse af lægemidlet, kaldet formuleringer med umiddelbar frigivelse, ‛immediate release‛ eller ‛ir-formuleringer‛. dels formuleringer, som på en kontrolleret måde frigiver det aktive stof over en længere periode, kaldet formule- ringer med langvarig frigivelse, ‛sustained release‛ eller ‛sr-formuleringer‛. de to formuleringstyper giver forskellige frigivelsesprofiler. formuleringer med umiddelbar frigivelse giver normalt en højere maksimal plasmakoncentration (cmax), som aftager, mens lægemidlet nedbrydes eller udskilles fra kroppen. formuleringer med langvarig frigivelse - 17 - giver normalt en fladere frigivelsesprofil, der opretholder en jævn plasmakoncentration i en længere periode. formålet med en sr-formulering er at opnå en plasmakoncentration på et behandlingsmæs- sigt effektivt niveau i en længere periode end ir-formuleringer. sr-formuleringer og måder at fremstille dem på var velkendte før prioritetsdatoen den 31. maj 1996, hvilket er belyst i litteraturen og en række publikationer, samt i patentansøgninger og patentskrifter. af lærebogen ‛sustained and controlled release drug delivery systems‛ af j. r. robinson fra 1978 fremgår blandt andet følgende i kapitlet ‛properties influencing design‛: ‚< b. aqueous solubility the aqueous solubility of a drug is an extremely important consideration in its biological performance as well as in its incorporation into controlled drug delivery systems. eriksen [3] has commented that, in general, extremes in aqueous solubility are undesirable in the preparation of suitable sustained release drug products. < it has been claimed [12] that drugs with water solubility less than 0.1 mg/ml are apt to have reduced physiological availability in conventional oral dosage forms. furthermore, a drug with aqueous solubility less than 0.01 mg/ml would be considered relatively inso- luble [13] and would present problems in controlled release product design since the drug would probably manifest dissolution-limited availability and would be inherently sustained. indeed, preparing slightly soluble forms of a drug is one method for preparing prolonged action dosage forms. < finally, drugs exhibiting strong ph-dependent solubility characteristics, particularly in the physiological ph range of interest, would be poor candidates for oral sustained re- lease products. for example, testracycline dissolves to a greater externt in the stomach than in the intestine, in agreement with the fact that its aqueous solubility at ph 1-3 is about 100 times greater than that at ph 5-6. although it is best absorbed in the intestine, the amount ultimately absorbed is determined by the extent of dissolution in the stomach [14]. c. partition coefficient < c. metabolism metabolism of a drug can either inactivate an active drug or convert an inactive drug to an active metabolite. metabolic alteration of a drug can occur in a variety of tissues, some - 18 - of which are richer in enzymes than others. for example, the organ most responsible for metabolism is the liver and thus the greatest metabolic conversion occurs after a drug has been absorbed into the general circulation. it would thus appear that for optimal bioavai- lability the route of drug administration may be dictated by the drug’s metabolic pattern. metabolism of a drug will be reflected in the elimination constant of a drug or by the ap- pearance of metabolite. it is possible to incorporate this pharmacokinetic property into the design of a prolonged release product, provided that the rate and extent of metabol- ism are predictable and that the rate constant(
  1. s)for the process are not too large, al- though complex metabolic patterns make the design much more difficult, particularly when biological activity is due to a metabolite. < in addition, if there is a variable blood level of drug through either intestinal (or other tis- sue) metabolism or through a first-pass effect, this also will make preparation of a sus- tained release product difficult. since most of these processes can be saturable [32, 89], the fraction of drug lost would be dose-dependent and one would anticipate a significant reduction in bioavailability if the drug is slowly released over a period of time. < d. duration of action of the drug the biological half-life and hence the duration of action of a drug obviously play a major role in the process of considering a drug for controlled release. factors influencing the bi- ological half-life of a drug include its elimination, metabolism, and its distribution pat- terns [112]. < iv. conclusions in the past decade, the number of new drug entities appearing each year on the market has declined and manufacturers have a renewed interest in improving existing dosage forms and developing more sophisticated drug delivery systems, including those em- ploying the principles of controlled drug release. the need for a controlled release prepa- ration often arises as a result of drug properties, such as a short biological half-life, local irritation, or extensive metabolism, or perhaps through the nature of the disease state or for patient compliance reasons. in considering a drug for this mode of drug delivery, cer- tain criteria have to be examined and evaluated. these are the physicochemical, pharma- cokinetic, and biological, characteristics of the drug. with each drug property there is a range of values that lends itself to the design of sustained release products, and outside this range the design becomes more difficult or, in the extreme, prohibitive. extremes of aqueous solubility, oil/water partition coefficient, erratic absorption characteristics, mul- ticompartment distribution and binding, extensive metabolism/degradation of the drug during its transit from the point of drug delivery to the target area, and narrow therapeu- tic index are some of the limiting factors in formulating an effective sustained release product. theoretically, each of these limitations can be overcome and successful con- trolled drug delivery can be accomplished by using the physical, chemical, and biomedi- cal engineering approaches, alone or in combination, as described in subsequent chap- ters. throughout this chapter, an attempt has been made to delineate the influence of drug properties on the design of sustained or controlled release drug delivery systems. infor- mation on the physicochemical properties of a new or existing drug is usually relatively abundant. in addition, with the increased application of pharmacokinetic analysis, there - 19 - is a steady growth in volume of information on the biological parameters of drug action, such as absorption rate constant, biological half-life, and volume of distribution, which also will be available to the formulator. < in the final analysis, a complete knowledge and understanding of the behavior of a drug, as well as judicious selection of the approach, is indispensable to the process of designing a useful controlled release product. < thus, the term controlled drug delivery is used in a rather loose sense. nevertheless, these types of products are a significant improvement over their nonsustained counter- parts in terms of temporal drug level control and patient compliance. on this basis, per- haps many more drugs should be placed in a sustained release dosage form. <‚ af artiklen ‚a review of cellulose ethers in hydrophilic matrices for oral controlled- re- lease dosage forms‛ skrevet af d.a. alderman i 1984 fremgår det blandt andet: ‚< pharmaceutical firms have found that the use of controlled- or sustained-release technol- ogy is increasingly important in the formulation of new drugs. improved patient com- pliance, often seen with longacting dosage forms, has provided an important impetus to this technology. < the hydrophilic matrix a matrix is defined as a well-mixed composite of ingredients fixed into a shape by tablet- ting or use of a hard shell-capsule. when a water-soluble polymer is used as a binder for the ingredients and the tablet is placed in a dissolution medium, a gelatinuous layer is formed at the tablet surface. the gel layer that forms is an aggregate mass of water- soluble polymer, drug, and excipients experiencing various degrees of hydration or solu- tion. (figure 1) the gel layer once formed contains regions which vary from 0 to 100% solids, (figure 2). in the area near 100% solids, the gel is a wetted mas of powders that have swollen. as water content of the wetted powder mass increases, the polymer becomes hydrated and takes on the characteristics of a true gel. at the outermost layer, the polymer is diluted to the point where it no longer has structural integrity and dissolves or wears away. this complex gelatinious layer controls the release of drugs by two mechanisms: (
  2. i)water-soluble drugs being released by diffusion out of the gelatinous layer. (
  3. ii)drugs may also be released by erosion of the gel regardless of the drug’s solubility in the dissolution media. a water-insoluble drug is exposed strictly through erosion. ...‚ artiklens tabel 1 indeholder en oversigt over de materialer, man har testet. under ‛poly- mers‛ er bl.a. nævnt hydroxypropylmethylcellulose (herefter hpmc). - 20 - i bogen fra 1987 ‚the theory and practice of industrial pharmacy‛ skrevet af lachman mfl. finder man en beskrivelse af 3 forskellige former for sr-systemer. der står blandt andet følgende: ‚< matrix tablets one of the least complicated approaches to the manufacture of sustained release dosage forms involves the direct compression of blends of drug, retardant material, and addi- tives to form a tablet in which drug is embedded in a matrix core of the retardant. < table 14-7 identifies examples of the three classes of retardant material used to formulate matrix tablets, each class demonstrating a different approach to the matrix concept. the first class consists of retardants that form insoluble or ‚skeleton‛ matrices; the second class represents water-insoluble materials that are potentially erodible; and the third class consists of polymers that form hydrophilic matrices. loading doses are best included as the second-layer of a two layer tablet or in a coating applied to the matrix core. <‛ i den omtalte tabel er der under ‚hydrophilic‛ bl.a. nævnt hpmc. der står videre i bogen om sr-formuleringer: ‚controlled release technology < controlled release technology implies a quantitative understanding of the physicochemi- cal mechanism of drug availability to the extent that the dosage form release rate can be specified. potential developments and new approaches to oral controlled release drug de- livery include hydrodynamic pressure controlled systems, intragastric floating tablets, transmucosal tablets, and microporous membrane coated tablets. one example of a dosage form design that illustrates the application of controlled release tech- nology to pharmaceutical formulation is the orally administered elementary osmotic pump shown in figure 14-14a< ‚ amerikansk patent nr. 4,389,393 udstedt i juni 1983 vedrører formuleringer med langvarig frigivelse baseret på hpmc med høj molekylær vægt. i patentskriftet er nævnt, at formule- ringen bl.a. kan anvendes i forbindelse med psykofarmaka. det fremgår endvidere af europæisk patentansøgning ep 0 156 592 fra 1985 med prioritet fra 1984, at: - 21 - ‚< the invention concerns gastrointestinal, ph-independent, sustained-release pharmaceut- ical unit dosage form comprising a non-compressed mixture of a therapeutic agent and from about 10 to about 60 per cent by weight of a high molecular weight hydroxypro- pylmethylcelluloses, and a method for production thereof in hard gelatin capsules. < the use of hydroxypropylmethylcelluloses as carrier bases in sustained action tablets has been well-established. for example, christensen et. al. (u.s. patent 3,065,143) < this invention provides a unit dosage form for administration of a therapeutic agent, which does not require expensive compression and granulation processing characteristic of the prior art sustained release tablets<‛ europæisk patentansøgning ep 0 177 893 fra 1985, publiceret i 1986, illustrerer, at hpmc er brugt i en sr-formulering, som bl.a. kan anvendes til psykofarmaka. der står bl.a.: ‚< a solid sustained release dosage form, including a transdermal dosage form, is disclosed compromising a gel matrix containing hpmc and a major amount of a plasticizer< sustained release or controlled release dosage forms are of interest because they can de- liver and maintain optimum therapeutic levels of a medicament for a longer period of time than a conventional dosage form. in addition, such dosage forms can often deliver the medicament without an initial release of a greater than a therapeutic amount thereof. an additional advantage is that by using a sustained release form, it is often possible to increase the time between successive administrations of the medicament, in effect reducing the frequency of administration. <‛ af us-patent nr. 4,695,591 fra 1987 med titlen ‚controlled release dosage forms compro- mising hydroxypropylmethylcellulose‛ fremgår bl.a. følgende: ‚< the present invention relates to controlled release solid dosage forms compromising a carrier base from which one or more therapeutically active medicaments may be slowly and regularly released upon administration. the carrier base of the present invention, the hydroxypropylmethylcellulose known as methocel e4m (trademark of the dow chemical co.) and further identified as hy- droxypropyl methylcellulose usp 2910 (hpmc usp 2910) comprises less than about one third of the weight of the unit dosage form and provides for release of the active ingre- dient(
  4. s)over a period of 2-14 hours. < the various advantages of controlled release dosage forms are well known to those skilled in the art, e.g., the therapeutic advantages of sustained blood levels and better pa- tient compliance, and the advantages of being able to use smaller dosage units and/or - 22 - higher dosages per unit which make the dosage forms easier to administer and more economical to manufacture. <‛ i bogen fra 1988 ‚the science of dosage form design‛ redigeret af michael aulton er de ge- nerelle fordele ved langvarig frigivelse i forbindelse med doseringsregimer blandt andet be- skrevet. s g proudfoot har i bogens kapitel 11 skrevet om doseringsregimer, herunder et af- snit om ‛maintenance of therapeutic drug levels by substained/controlled release peroral dosage forms‛, hvoraf følgende fremgår: ‚< however, there are a number of potential limitations associated with the repetitive ad- ministration of conventional dosage forms. 1 the concentration of drug in the plasma and hence at the site(
  5. s)of action of the drug fluctuates over successive dosing time intervals, even when so-called ‘steady state’ condi- tion is achieved. hence it is not possible to maintain a therapeutic concentration of drug which remains constant at the site(
  6. s)of action for the duration of drug treatment. at best, the mean value of the maximum and minimum plasma levels associated with each suc- cessive dose administered remains constant for the period of drug treatment. 2 the inevitable fluctuations in steady state concentrations of drug in the plasma and hence at the site(
  7. s)of action can lead to a patient being overmedicated or undermedicated for periods of time of the values of and rise or fall, respectively, beyond the the- rapeutic range of the drug. 3 for drugs with short biological half-lives, frequent administration of doses are required to maintain steady state plasma levels within the therapeutic range. for such drugs, the maintenance of therapeutic plasma levels is particularly susceptible to the consequence of forgotten doses and the overnight no dose period. lack of patient compliance, which is more likely in the case of dosage regimes requiring frequent administration of conven- tional dosage forms, is often an important reason for therapeutic inefficiency or failure. < the potential limitations of drug therapy based on the repetitive administration of con- ventional single dose, peroral dosage forms, particularly those containing drugs with short biological half-lives, has led to the development of a more specialized group of pe- roral dosage forms. such dosage forms are commonly referred to as sustained release do- sage forms (as for example by the british national formulary) but many other titles have been used to describe them over the years < consequently, depending on the degree of control over release (and consequently over drug absorption) that is achieved, peroral sustained release products are generally de- signed to provide either. 1 the prompt achievement of a plasma concentration of drug that remains essentially constant at a value within the therapeutic range of the drug for a satisfactory pro- longed period of time, or - 23 - 2 the prompt achievement of a plasma concentration of drug which, whilst not remain- ing constant, declines at such a sufficiently slow rate that the plasma concentration re- mains within the therapeutic range for a satisfactory prolonged period of time. < in practice, the design of an ideal sustained/controlled release product, which is capable of releasing the maintenance dose at a precise controlled rate that is in mass balance with the rate of drug elimination corresponding to the required therapeutic concentration of drug in the plasma, is difficult to achieve. < potential advantages of sustained release drug therapy over conventional drug therapy 1 improved control over the maintenance of therapeutic plasma levels of drugs permits (
  8. a)improved treatment of many chronic illnesses where symptom breakthrough oc- curs if the plasma level of drug drops below the minimum effective level, e.g. asthma, depressive illnesses, (
  9. b)maintenance of the therapeutic action of a drug during overnight no dose periods, e.g. overnight management of pain in terminally ill patients permits improved sleep, (
  10. c)reduction in the incidence and severity of untoward systemic side effects related to high peak plasma drug concentrations, (
  11. d)reduction in the total amount of drug administered over the period of drug treat- ment. this contributes to the reduced incidence of systemic and local side effects observed in the cases of many drugs administered in sustained release formula- tions. 2 improved patient compliance resulting from the reduction in the number and frequen- cy of doses required to maintain the desired therapeutic response, e.g. one peroral sus- tained release product every 12 hours, contributes to the improved control of therapeu- tic drug levels achieved with sustained release products. 3 there is a reduction in the incidence and severity of localized gastrointestinal side ef- fects produced by ‘dose dumping’ of irritant drugs from conventional dosage forms, e.g. potassium chloride. the more controlled, slower release of potassium chloride from its peroral sustained release formulations minimizes the buildup of localized irri- tant concentrations in the gastrointestinal tract. consequently potassium chloride is now administered perorally almost exclusively in sustained release form. 4 economic savings are claimed to be made from better disease management achieved with sustained release products. patients miss fewer working days and make fewer visits to hospitals and medical practitioners. potential limitations of peroral sustained release dosage forms 1 variable physiological factors such as gastrointestinal ph, enzyme activities, gastric and intestinal transit rates, food and severity of patient’s disease, which often influence drug bioavailability from conventional peroral dosage forms, may also interfere with the precision of control of release and absorption of drugs from peroral sustained re- lease dosage forms. the achievement and maintenance of prolonged drug action de- pends on such control. 2 the rate of transit of sustained release peroral products along the gastrointestinal tract limits the maximum period of time for which a therapeutic response can be maintained following administration of a ‘single dose’ to approximately 12 hours plus the length of - 24 - time that absorbed drug continues to exert its therapeutic activity. 3 sustained release products, which tend to remain intact, may become lodged at some site along the gastrointestinal tract. if this occurs, slow release of drug from the dosage form may produce a high localized concentration of drug which causes local irritation to the gastrointestinal mucosa. sustained release products which are formulated to disperse in the gastrointestinal fluids are less likely to cause such problems. 4 there are constraints placed on the types of drugs which are suitable candidates for incorporation into peroral sustained release formulations. for instance, drugs having biological half-lives of 1 hour or less are difficult to formulate as sustained release formulations. the high rates of elimination of such drugs from the body would mean that an extremely large maintenance dose would be required to provide 8-12 hours of continuous therapy following single administration of a sustained released product. apart from the potential hazards of administering such a large dose, the physical size of the sustained release dosage form could make it difficult to swallow. drugs having biological half-lives of between 4 and 6 hours make good candidates for inclusion in sustained release formulations. factors other than the biological half-life can preclude a drug from being formulated as a sustained release product. drugs which have specific requirements for their absorption from the gastrointestinal tract are poor candidates. in order to provide a satisfactory period of prolonged drug therapy, a drug is required to be well absorbed from all regions as the sustained release dosage form passes along the gastrointestinal tract. 5 sustained release products normally contain a larger total amount of drug than the sin- gle dose normally administered in a conventional dosage form. there is the possibility of unsafe over-dosage if a sustained release product is improperly made and the total drug contained therein is released at one time or over too short a time interval. conse- quently, it may be unwise to include potent drugs in such formulations. 6 as a general rule, sustained release formulations cost more per unit dose than conven- tional dosage forms containing the same drug. however, fewer ‘unit doses’ of a sus- tained release formulation should be required. <‛ m.h. rubinstein har i samme bogs kapitel 18 skrevet om tabletter (‛drug delivery systems – tablets‛). heraf fremgår blandt andet følgende: ‚< tablets are now the most popular dosage form, accounting for some 70% of all ethical pharmaceutical preparations produced < sustained-release tablets (s. 315) advantages and disadvantages as a dosage form in recent years there has been a large increase in the development and use of sustained- release tablets which are designed to release the drug slowly after ingestion. the main factor in the more widespread use of these types of dosage forms is that patient com- pliance is improved, since only one or two tablets need to be taken daily. thus the fre- quency with which the patient has to take these tablets to obtain the desired effect is con- siderably reduced. in addition, the drug’s activity can be extended to take effect through- - 25 - out the night, so that the patient need not be awakened until morning. a single daily do- sage has advantages with psychiatric patients, since this patient group generally forgets to take their medication regularly, and for patients in hospital a decrease in the number of doses administered can result in a time saving for nurses. another advantage some- times expressed for sustained-release tablets is that this type of medication reduces the severity or frequency of untoward side effects< generally, a sustained-release tablet produces a more constant blood level of drug than repeated doses of a conventional tab- let and this may be clinically very significant. < the cost of prolonged action tablets is more per unit dose than conventional dosage forms< the physical size of the dosage form may present problems. some patients do experience difficulty in swallowing a 600-650 mg sustained-release tablet and it is often difficult to formulate the tablets so that the overall tablet weight is very much lower than this<variability of absorption can be a troublesome problem with sustained-release tab- lets< formulation factors affecting the release of a drug from tablets the effective surface area of the drug the dissolution rate of a drug is directly related to the surface area exposed to the disso- lution media< effect of binding agents <‛ det fremgår af publikationen ‚drug delivery to the central nervous system: general prin- ciples and relevance to therapy for infections of the central nervous system‛ af scheld fra 1989 bl.a. at: ‛drug delivery to the central nervous system (cns) is of vital concern to the therapy for primary cns disorders and the development of drug neurotoxicity. the factors influen- cing drug entry into the csf include the status of the blood–brain barrier (bbb) and lipid solubility, molecular weight, pka, proteinbinding, and removal of the drug from the csf by an exit pump in the choroid plexus< serum protein binding. only the free (non-protein-bound) portion of drug can enter csf readily under normal conditions [26-28]. in rabbits with experimental meningitis, high serum protein binding (>90%) markedly restricts entry of antibiotics into purulent cfs <‛ chang og robinson har i en bog fra 1990 skrevet følgende om ‛sustained drug release from tablets and particles through coating‛: ‛< - 26 - at the outset it may seem unnecessary to justify sustained-release products, but there are some who still view these products as convenience items that offer little clinical benefit to the patient. indeed the therapeutic advantages of sustained-release products over their nonsustained counterparts are well documented in the literature. some of these advan- tages are shown in table 1. aside from the enormous advantage of overcoming patient compliance problems, well-designed sustained-release dosage forms offer considerable potential in terms of the temporal and spatial delivery of drug and the resulting mainten- ance of drug levels in tissues of the body. this suggests that all drugs ought to be placed in a sustained-release form, but this is often not feasible and/or practical. < b. drug properties considerations there are a number of physical-chemical and derived biological properties of the drug that either preclude placement of the drug in a sustained-release system or have an ad- verse influence on product design and performance. some of these considerations are listed in table 2. with almost all of these properties we refer to them as restrictive factors, making formulation of a sustained-release system difficult, but not impossible. thus, by changing the type of sustaining mechanism, the dose, or the route of administration, it might be possible to generate a sustained-release system. frequently, a seeminly undesir- able property of a drug or dosage form can be overcome or minimized by placement of the drug in a sustained-release system. for example, low drug bioavailability due to in- stability may sometimes be overcome by placement in a sustained-release system. < table 2 drug properties adversely influencing a sustained-release dosage form property explanation physical-chemical properties dose size < aqueous solubility extremes in aqueous solubility are undesirable in the preparation of a sustained-release product. for drugs with low water solubility, they will be difficult to incorporate into a sus- tained-release mechanism. the lower limit on solubility for such product has been reported to me 0.1 mg/ml. drugs with great water solubility are equally difficult to incorporate into a sustained-release system. ph- dependent solubility, particularly in the physiological ph range, would be another problem because of the varia- tion in ph throughout the gi tract and hence variation in dissolution rate. partition coefficient < drug stability < biological properties absorption < distribution < metabolism sustained-release systems for drugs which are extensively metabolized is possible as long as the rate of meta- - 27 - bolism is not too great nor the meta- bolism variable with gi transit or oth- er routes. duration of action the biological half-life and hence the duration of action of a drug obviously plays a major role in considering a drug for sustained-release systems. drugs with short half-lives and high doses impose a constraint because of the dose size needed and those with long half-lives are inherently sus- tained. therapeutic drugs with a narrow therapeutic range require precise control over the blood levels of drug, placing a con- straint on sustained-release dosage forms. <‛ i en artikel af ranga rao mfl. publiceret i journal of controlled release i 1990 med overskriften ‛influcence of molecular size and water solubility of the solute on its re- lease from swelling and erosion controlled polymeric matrices‛ står der bl.a. følgende: ‚... the release of 23 drugs of various solubilities and molecular weights through matrices of hydroxypropylmethylcellulose(hpmc; matrix 1) and a mixture (1:1) of hpmc and so- dium carboxymethylcellulose (matrix
  12. ii)was studied. very soluble and soluble beta blockers and a freely soluble vitamin (thiamine hydrochloride) were released more slow- ly from matrix ii than from matrix i due to complex formation between the cationic drug and the anionic polymer. < when the release data (<60%) was fitted to the simple power law equation, the mode of drug release from matrix i and matrix ii was non-fickian and super case ii type, respec- tively, for sparingly soluble, slightly soluble and very slightly soluble drugs. the study revealed that drugs falling into this category can be released at nearly zero-order rate through hpmc matrices. since these matrices are prepared by direct compression, cellu- lose matrices may be preferred for oral controlled release formulations. <‛ i en artikel af tench m.fl. fra 1990 med overskriften ‛steady-state pharmacokinetics of con- trolled release and immediate release formulations of remoxipride in patients with chronic schizophrenia‛ står der bl.a. følgende: ‚< - 28 - most schizophrenics who are maintained successfully in the community require depot preparations because of poor compliance. remoxipride has a relatively short half-life of 4-7 h when given as an immediate release capsule (
  13. ir)and has to be administered either b.i.d. or t.i.d. a controlled release capsule (
  14. cr)formulation of remoxipride was devel- oped in order to be given once daily, since this may improve compliance and possibly could reduce adverse events that may be related to high peak plasma concentrations ... in conclusion, this study has demonstrated that the controlled-release formulation of re- moxipride shows a pharmacokinetic profile which is compatible with a once-daily ad- ministration. at a time when most schizophrenic patients are managed in the community it is essential to ensure good compliance with maintenance neuroleptic medication. once daily administration should enable patients who are sensitive to conventional depot neu- roleptics or who would not countenance parenteral administration of drugs to remain clinically stable.‛ i europæisk patentansøgning ep 0 413 061 a1, publiceret i 1991 indgivet af alza corpora- tion og vedrørende en sr-formulering indeholdende hpmc, står der bl.a. følgende: ‛controlled-release oral dosage forms comprising different cellulose ethers. < a dosage form is disclosed comprising a low number average molecular weight hydrox- ypropylmethylcellulose, a high number average molecular weight hydroxypropylme- thylcellulose and a beneficial drug. ...‛ fordelene ved langvarig frigivelse omtales ligeledes generelt i lærebogen ‛the science and practice of pharmacy‛ af remington fra 1995. i kapitel 94 om ‛sustained-release drug deli- very systems‛ af chou og robinson er følgende beskrevet: ‛< the goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve promptly, and then maintain, the desired drug concen- tration. that is, the drug-delivery system should deliver drug at a rate dictated by the needs of the body over the period of treatment. this idealized objective points to the two aspects most important to drug delivery, namely, spatial placement and temporal delivery of a drug. spatial placement relates to targeting a drug to a specific organ or tissue, while temporal delivery refers to controlling the rate of drug delivery to the target tissue. an appropriately designed sustained-release drug delivery system can be a major advance toward solving these two problems. it is for this reason that the science and technology responsible for development of sustained-release pharmaceuticals have been and contin- ue to be the focus of a great deal of attention in both industrial and academic laboratories. there currently exist numerous products on the market formulated for both oral and pa- renteral routes of administration that claim sustained or controlled drug delivery. the bulk of research has been directed at oral dosage forms that satisfy the temporal aspect of drug delivery, but many of the newer approaches under investigation may allow for spa- tial placement as well. this chapter will define and explain the nature of sustained- - 29 - release drug therapy, briefly outline relevant physicochemical and biological properties of a drug that affect sustained-release performance and review the more common types of oral and parenteral sustained-release dosage forms. in addition, a brief discussion of some methods currently being used to develop targeted delivery systems will be pre- sented. < potential advantages of sustained drug therapy < patient compliance has been recognized as a necessary and important component in the success of all self-administered drug therapy. minimizing or eliminating patient com- pliance problem is an obvious advantage of sustained-release therapy. because of the na- ture of its release kinetics, a sustained-release system should be able to use less total drug over the time course of therapy than a conventional preparation. the advantages of this are a decrease or elimination of both local and systemic side effects, less potentiation or reduction in drug activity with chronic use and minimization of drug accumulation in body tissues with chronic dosing. unquestionably the most important reason for sustained-drug therapy is improved effi- ciency in treatment, ie, optimized therapy. the result of obtaining constant drug blood levels from a sustained-release system is to achieve promptly the desired effect and main- tain it for an extended period of time. reduction or elimination of fluctuations in the drug blood level allows better disease state management. < table 1 – potential advantages of sustained drug therapy 1. avoid patient compliance problems 2. employ less total drug a. minimize or eliminate local side effects b. minimize or eliminate systemic side effects c. obtain less potentiation or reduction in drug activity with chronic use d. minimize drug accumulation with cronic dosing 3. improve efficiency in treatment a. cure or control condition more promptly b. improve control of condition, ie, reduce fluctuation in drug level c. improve bioavailability of some dugs d. make use of special effects, eg, sustaines-realease aspirin for morning relief of arthritis by dosing before bedtime < drug properties relevant to sustained-release formulation < physicochemical properties aqueous solubility and pka – it is well known that in order for a drug to be absorbed it first must dissolve in the aqueous phase surrounding the site of administration and then partition into the absorbing membrane. two of the most important physicochemical properties of a drug that influence its absorptive behavior are its aqueous solubility and, if it is a weak acid or base (as are most drugs), its pka. these properties play an influenti- al role in performance of nonsustained-release products; their role is even greater in sus- tained-release systems. < - 30 - partition coefficient – between the time that a drug is administered and the time it is eliminated from the body, it must diffuse through a variety of biological membranes which act primarily as lipid-like barriers. a major criterion in evaluation of the ability of a drug to penetrate these lipid membranes is its apparent oil/water partition coefficient, defined as k = c0/cw < drug stability < protein binding < thus, the protein binding characteristics of a drug can play a significant role in its thera- peutic effect, regardless of the type of dosage form. < absorption < distribution < metabolism < there are two factors associated with the metabolism of some drugs, however, that present problems for their use in sustained-release systems. one is the ability of the drug to induce or inhibit enzyme synthesis; this may result in a fluctuating drug blood level due to intestinal (or other tissue) metabolism or through a hepatic first-pass effect. < elimination and biological half-life < it is difficult to define precise upper and lower limits for the value of the half-life of a drug that best suits it for sustained-release formulation. in general, however, a drug with a half-life of less than 2 hours probably should not be used, since such systems will require unacceptably large release rates and large doses. at the other extreme, a drug with a half-life of greater than 8 hours also probably should not be used; in most in- stances, formulation of such a drug into a sustained-release system is unnecessary< side effects and safety considerations < dose size < oral dosage forms for sustained-release systems, the oral route of administration has, by far, received the most attention. this is, in part, because there is more flexibility in dosage-form design for the oral route than there is for the parenteral route. patient acceptance of the oral route is quite high. it is relatively safe route of administration, compared to most parenteral routes, and the constraints of sterility and potential damage at the site of administration are minimal. in this section, the more common methods that are used to achieve sus- tained release of orally administered drugs are discussed. < reservoir devices < - 31 - matrix devices < the three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers and fatty compounds. plastic matrices which have been investigated include methyl acrylate-methyl methacrylate, polyvinyl chloride and polye- thylene. the gradumet tablet (abbott) is an example of a dosage form using a plastic ma- trix. hydrophilic polymers include methylcellulose, hydroxypropylmethylcellulose, so- dium carboxymethylcellulose and carbopol 934< the most common method of preparation is to mix the drug with the matrix material and then compress the mixture into tablets<‛ i stridspatentet er nævnt, at geleringsmidlet fortrinsvis er hpmc. der er i den forbindelse fremlagt en brochure fra 1995 fra det amerikanske selskab dow chemical company, der igennem mange år har produceret hpmc. brochuren beskriver blandt andet, hvorfor hpmc ofte anvendes som ‚controlled release agent‛: ‚< the growing popularity of hydrophilic matrix systems for controlled release is easily un- derstood. first of all, tablet and capsule doses are by far the preferred drug form. second, matrix systems have been proven for over two decades. matrix tablets and cap- sules are highly resistant to release inconsistencies and drug ‚dumping‛ since they are relatively simple systems which are more forgiving of variations in ingredients, produc- tion methods, and end use conditions. < matrix systems are also relatively easy to formulate. the performance of many products is already well documented. so there is a body of data to reference and rely upon. this helps speed development work and, perhaps, approval times as well. equally important, matrix systems are easy to produce. tablets and capsules are manu- factures with existing, conventional equipment and processing methods. < finally, few approaches to sustained release are as economical as matrix systems. < in short compared to other controlled release drug forms, hydrophilic matrix systems of- fer the advantages of simplicity, familiarity, and economy. as a result, their number is expected to increase rapidly. < the widespread use of hydroxypropyl methylcellulose (hpmc) as a sustained release agent in matrix systems is easily understood as well. hpmc is a well-known excipient and all needed data are readily available. this can further speed developmental work. < fast gel formation to control initial release < strong, viscous gels control diffusion of water and drug release - 32 - < for these reasons, hpmc is very often the polymer of choice over other cellulosics. < understanding system variables and polymer effects < numerous other factors also affect the sensitivity of the matrix system to changes in po- lymer hydration rates. polymer concentration, polymer particle size, and type of drug or excipients must be considered. these will be discussed later. < effect of particle size < effect of polymer solution viscosity < effect of polymer concentration < viscosity-concentration relationships < effect of drug solubility hydrophilic matrices have been proven useful in the formulation of both very water- soluble drugs as well as insoluble drugs. it is important to note, however, that formula- tion of systems with very high soluble drugs and very soluble fillers can present a prob- lem because extremely fast polymer hydration is required. < effect of ph the viscosity of the gel which forms on the tablet surface and the rate of hydration are relatively independent of the ph environment. release rates of drugs will not be affected by ph unless drug solubility varies greatly over the normal ph range. it has also been reported that adding organic acids or buffers to the matrix can control the tablet’s ph environment through the gi tract. as a result, drugs with poor solubility at certain ph ranges can be formulated to optimize bioavailability. in conclusion, hydrophilic matrix tablets can exhibit good drug release uniformity in vivo even though transit times after ingestion will differ. clinical results experience in clinical trials involving hydrophilic matrix tablets containing methocel premium products has shown that acceptable correlations may be drawn to in vitro re- sults. further, mehtocel premium products have exhibited excellent bioavailability in commercial pharmaceutical products. < the costumer was able to determine that the three dosage forms were bioequivalent within statistical significance. the controlled release form prevented the high plasma drug concentration spike with more uniform drug release. <‛ - 33 - lærebogen ‚hydrogels in medicine and pharmacy, volume ii: polymers‛ af nicholas pap- pas fra 1987 beskriver bl.a. anvendelsen af polymerer som f.eks. hpmc, men også betydnin- gen af ph-afhængig opløselighed i sr-formuleringer. af kapitel 4 ‛water-swollen cellulose derivatives in pharmacy‛ skrevet af doelker, fremgår således bl.a. følgende: ‚< derivatives used today in pharmaceutical technology are essentially methylcellulose (
  15. mc)and the very similar product with a small amount of hydroxycthyl substitution, < (hemc)< (hpmc) < 3. modification of the micro-ph of the hydrated matrix drug release from nonionic cellulose derivative systems is known to be almost unaffected by the ph of the aqueous environment. this is true as long as the solubility of the drug is not ph dependent. in reality, many drugs are basic in nature and demonstrate reduced solubility at neutrality (owing to decreased ionization). dissolution rates of such drugs from hydrophilic matrices are very low. one way to counteract this effect and ensure complete release, even in the unfavorable intestinal medium, is to modify the ph of the hydrated matrix by incorporating an acid. this principle has first been applied to a poly- saccharide-based tablet containing the cerebral vasodilator vincamine hydrochloride. the solubility of this alkaloid at 37 °c is about 470-fold less at ph 7.5 than at ph 1.2 (0.034 and 15.9 g/dm3, respectively). the addition of some succinic acid to the matrix renders the release profile nearly independent of ph change. the applicability of this concept has been confirmed in vivo by administering the acidified matrix to human volunteers. the effect of the acid may be mainly attributed to the increased solubility of the alkaloid by acidification of the microenvironment inside the hydrated matrix. <‛ i bogen ‛controlled drug delivery‛ fra 1987 af robinson og lee beskrives i kapitel 9 ‛de- sign and fabrication of oral controlled release drug delivery systems‛ 7 forskellige former for systemer til opnåelse af ‛sustained release‛. af kapitlet fremgår, at oral administration af lægemidler længe har været det mest almindelige og mest bekvemme. af pkt. e ‛ph- independent formulations‛ fremgår desuden bl.a.: ‚< the ph dependency of drug release from sustained release formulations has been dem- onstrated < for instance, papaverine hydrochloride was preferentially released in the gastric region than in the intestine because its higher solubility in the upper part of the gi tract. however, buffers can be added to the formulation to help maintain a constant ph thereby rendering ph-independent drug release < to this end, salts of amino acids, citric acid, phthalic acid, phosphoric acid or tartaric acid are commonly used because of their physiological acceptability. <‛ - 34 - pagay har i en artikel trykt i ‛drug development and industrial pharmacy‛ i 1988 beskrevet brugen af puffere i kapselformuleringer. han har bl.a. skrevet følgende: ‚< abstract relatively few reports have appeared in the literature on the formulation of the hydro- philic matrix capsule as compared to the matrix tablet. this study was concerned with the development of a matrix capsule formulation to control the release rate of the drug specifically through the incorporation of buffers. one of the characteristics of hydrophilic matrix drug delivery systems is that the initial rate of release is high. the release rate is gradually brought under control as the diffusional barrier of hydrating polymers is estab- lished. many weak bases are more soluble at a gastric ph than at neutrality. such drugs are generally unsuitable for matrix systems since constant rates of drug release under the dynamic conditions of increasing ph make release rate control difficult. however, by us- ing an appropriate buffer system it was possible to suppress the initial release in acid by decreasing the solubility of the drug within the environment of the capsule matrix there- by controlling the rate of drug release. < introduction an investigational drug (compound
  16. i)has a short biological half life and targeted for a long term treatment. to reduce the dosing frequency of the drug, it was necessary to de- velop a prolonged release oral solid dosage formulation (e.g. matrix capsule) which could be processed on conventional manufacturing equipment. hydroxypropyl methyl cellulose (hpmc) polymers of different viscosities and chemi- stries are commonly used as matrices and were, therefore, considered as possible candi- dates for this formulation. the sustained release mechanism of matrix systems is depen- dent upon many variables, for instance, rate and extent of moisture permeation into the matrix, rate of gelation of the polymer and the dissolution and diffusion rate of the drug. in addition, the drug may be released after matrix erosion. < compound i is a weakly basic drug and both the solubility and the release rate are great- er in an acid medium (e.g. gastric fluid) than in a neutral one (e.g. intestinal fluid), result- ing in an increased release rate initially. since the release rate is influenced partly by the environmental ph as well as by the formulation, it is difficult to achieve a near constant release rate throughout the gi tract for a controlled release product. however, by adding an appropriate buffer to the formulation, it should be possible to control the release rate from a matrix. < a. matrix formulation the formulations were developed using usp/nf excipients. hpmc (methocel®) less than 80 mesh was the major component of each of the formulae. magnesium hydroxide and citrate buffer were selected in an attempt to control the ph of the cellulosic gel ma- trix. < results and discussion the major problem encountered during the development of a matrix drug delivery sys- tem stems from the initial high release rate of the drug. the initial release rate is depen- dent upon the rate of polymer hydration needed to form the gel and the solubility of the - 35 - drug. with this in mind, methocel k was selected for this study, because it has the fastest hydration rate of all the methocel chemistries. < < the ph solubility profile of a drug is a factor that can dramatically influence its release rate through the matrix system. for example, compound i has a pka at 4.1 and 8.3, and its solubility is 40 times greater at ph 1.5 than it is at ph 7, as shown in figure 1. this in- creased solubility also favors a rapid initial release rate in the acidic ph of the gastric en- vironment. this study shows how the release rate can be controlled by the addition of an appropriate buffer into matrix formulation. < - 36 - < buffered matrix capsule formula 2, shown in table 1, differed from formula 1, by the addition of an antacid (90 mg of magnesium hydroxide per capsule). the magnesium hydroxide provided a means of controlling th ph of the matrix when it was exposed to an acidic environment. formu- la 1 had no magnesium hydroxide and contained lactose as a filler. figure 2 compares the release rates of these two matrix capsules. the dissolution test was performed according to method i. the buffered matrix capsule, formula 2, released 19% (s.d. 0.6) drug in one hour compared to 38% (s.d. 1.6) for formula 1 during the same time period. therefore, by using an antacid, the initial release rate of the drug was de- creased by 50%. < - 37 - < release rate modification < upon exposure to an environment of ph 7.5, the magnesium hydroxide in formulae 3 and 4, like formula 2, is expected to have little control over the release rate since the drug is least soluble at that ph. when a buffer such as citrate is used; the release rate of the drug can be controlled both in an acidic and in a neutral ph environment. use of a citrate buffer will control the solubility of the drug within the matrix between ph 1.5 – 7.5. modifications of the ph caused by the gastrointestinal transit of the matrix capsule should not affect the release rate of the drug in this matrix, since the matrix ph can be controlled by the formulation itself and not by the ph of the gastrointestinal fluid. the buffer capacity of the matrix should, however, be greater than that of the gastrointestinal fluid. < citric acid-sodium citrate is a useful buffering agent in a ph range of 3 to 6. based upon the ph solubility profile of compound i (shown in figure 1), the solubility of the drug at ph 3 was found to be 10 mg/ml and at ph 5 was 1 mg/ml. matrix capsule formulations were developed using citrate buffer to achieve a ph of 5 (formula 5) and 3 (formula 6) in solution. these formulations are also described in table 1. < - 38 - ... summary 1) using hpmc matrix with appropriate buffers and antacids, formulations with differ- ent release rates were developed. 2) the cmax of the buffered matrix capsule was decreased by a factor of 5 from that of the conventional capsule; and the tmax was prolonged by a factor of 3. this shows that drug release from the buffered matrix capsule can be controlled over a prolonged period of time. < 5) it was shown empirically that the release rates from hpmc matrix formulations were controlled by the presence of the buffering agent and not by the ph of the dissolution test medium. <‛ artiklen af melia fra 1991, med titlen ‛hydrophilic matrix sustained release systems based on polysaccharide carriers‛ nævner hpmc og brugen af ph-modificerende midler og be- skriver blandt andet forskellige matrix-systemer og deres fordele: ‚< vi. formulation approaches to modifying drug-release profiles < c. ph modification of the gel layer hm devices employing macromolecular acids, such as cmc or alginates, or their salts possess an intrinsic buffering action, and release rates of drugs with ph-dependent solu- bility may be further modulated by adding excipients or buffers to control the ph of the - 39 - gel layer. for example, inclusion of succinic and tartaric acids has been shown to enhance the release of weak bases such as vincamine from hmpc matrices. unfortunately, in us- ing acids such as these, there is a potential for polysaccharide hydrolysis on prolonged storage, and this approach may introduce problems of long-term stability. more recently, the use of an alkali (magnesium hydroxide) to suppress the initial surge of weakly basic drugs from hpmc capsules in gastric fluid has been reported. relative to the unbuffered capsule, a more uniform and sustained drug-release profile was obtained in vitro and in vivo, and peak plasma concentrations were reduced by a factor of 5. in a floating capsule formulation, increased bicarbonate content reduced the rate of chlorpheniramine release, ostensibly via the influence of the bicarbonate on the solubility of the drug. suppression of the rapid release of weak bases in the stomach has also been achieved by adding a ph- dependent polysaccharide such as nacmc or sodium alginate to an hpmc carrier. in this case, the increased solubility of the drug is offset by decreased solubili- ty/permeability of the polymer. <‛ af bogen ‛pharmaceutics-drug delivery and targeting‛ fra 2010 af perrie og rades fremgår de forskellige sr-systemer i skematisk form, hvor blandt andet hpmc fremgår under ‛hy- drophilic matrix formers‛: ‛< <‛ - 40 - af udateret beskrivelse af astra zenecas produkt seroquel xr (bilag 87) udarbejdet til brug for ansøgning om markedsføringstilladelse i usa fremgår følgende om tilsætning af natri- umcitrat til sr-formuleringen: ‛< buffering agent (50
  17. mg)due to the smaller amount of active agent present in the formulation a study was con- ducted to examine the effects of sodium citrate concentration in the range of 2% to 12.5%. the effect of sodium citrate concentration on drug release is shown, see figure b6. these formulations contained a fixed ratio of hypromellose 100:4000 cp at 25:5. as the concen- tration of sodium citrate goes down the dissolution gets faster due to increased drug so- lubility. the optimum drug release profile is batch st72040-048-fa01 which contained 7.2% sodium citrate. … method b details < the dissolution method is performed using the basket apparatus at a rotation speed of 200 rpm. initially, 900 ml of dissolution medium consisting of 0.05 m sodium citrate and 0.09 n sodium hydroxide are placed in each vessel. the ph of this medium is 4.8. at 5 hours, 100 ml of a medium consisting of 0.05 m sodium phosphate and 0.46 n sodium hydroxide are added to each vessel to bring the ph of the medium to 6.6 for the final du- ration of the dissolution analysis. samples are withdrawn over a 20 hour time-period and analysed for quetiapine using ultraviolet spectrophotometric detection at 290 mm. <‛ patientefterlevelse/compliance en af fordelene ved en sr-formulering er, at doseringshyppigheden bliver nedsat, hvilket forbedrer patientefterlevelsen. dette gælder særligt i relation til psykiatriske patienter. - 41 - i en review artikel om ‛treatment adherence‛ i ‚the british journal of psychiatry‛ fra 1976 skrevet af blackwell gennemgår forfatteren en lang række artikler om patientefterlevelse. af det samlede antal artikler, som blackwell havde kendskab til, omhandlede 17 % compliance i en psykiatrisk kontekst og de udfordringer, der er forbundet med at få psykiatriske patienter til at tage deres medicin. følgende fremgår bl.a. af artiklen: ‚< a large part of medical practice is complicated by two problems; the degree to which treatments are specific (the placebo problem) and the extent to which they are imple- mented (the adherence problem). depending on setting and circumstance, up to half of the benefits of treatment are either non-specific or never obtained. this review considers the problem of adherence in the context of use of medication in psychiatry. < risk factors contributing to non-adherence < 2. the illness < in psychiatric patients, capacity to cooperate may be impaired by the illness as well as by attitudes toward health and treatment. renton et al
(1963), found that non-adherence was highest in schizophrenics who were the most ill at the time of discharge, but found it dif- ficult to disentangle the question whether this was the cause or result of further deteri- oration. those who were less ill attended out-patient clinics and adhered to medication more faithfully. among the more common symptoms which alter adherence in psychia- tric practice are the paranoid delusions which cause the schizophrenic to equate drugs with poison. < 5. medication a number of features associated with medication may affect adherence. (a) therapeutic regimen a study of parental compliance with recommendations for re- tarded children showed that two-thirds of those receiving one or two recommendations followed them all, whereas only a fourth of the group receiving three or more did so (wilder and stoycheff, 1974). the same considerations apply to complexity of medication regimens. there is clear evidence that adherence is adversely affected when multiple me- dications are prescribed or drugs are given in frequent divided doses. *<+. these obser- vations and increasing knowledge about the metabolism of psychotropic drugs has led to the widespread popularity of once daily therapeutic regimens as a means of improving adherence. < one consequence of the recognition of the adherence problem in schizophrenic patients has been the development of the long-acting intramuscular neuroleptics. based on over three years of experience with more than 200 patients, freeman
(1973)suggested that ad- herence can be significantly improved in schizophrenic out-patients. in a follow-up pe- riod of thirteen months, he reported that only 16 per cent of patients discontinued long acting injections, compared to a figure of up to 50 per cent recorded in the literature for similar patients taking oral medication. it is possible that the high adherence rates in this - 42 - clinic were contributed to by attention to the adherence issue and careful follow up of non-attenders and not only to the route of administration of medication. < management of adherence problems <
  1. medication regimen the medication itself plays an obvious part in management. the complexity of the regi- men should be kept to a minimum by prescribing the least possible number of medica- tions and daily dosages. <‛ i en artikel af seltzer og hoffman fra 1980 med titlen ‛drug compliance of the psy- chiatric patient‛ står der bl.a. følgende: ‚< summary non-compliance is one of the commonest causes of therapeutic failure in both medicine and psychiatry. with psychiatric patients the factors contributing to non-compliance are related to: illness variables (schizophrenia, mania, paranoia, chronicity), patient variables (inappropriate health beliefs, need to rebel against authority, a wish to remain sick, defec- tive memory), medication variables (inefficient and ineffective regimnes, side effects) and patient-therapist variables (degree of supervision, trust and information). treatment must consist of constant vigilance, health teaching-both verbal and written- enlisting the help of family and community to provide supervision, simplification of drug regimens, frequent examination and vigorous treatment of side effects, and improving the patient-therapist interaction. < compliance among medical patients is poor despite serious life-threatening and chronic physical illnesses. non-compliance rates with longterm treatments for conditions such as rheumatic fever and glaucoma have varied from 15-80%. it is not surprising that non- compliance is even higher among psychiatric patients especially on an outpatient basis where the non-compliance rate has been shown to average 50%. < despite the difficulty in measuring compliance, both the literature and clinical experience tell us that noncompliance is exceedingly common, and is a major cause of rehospitaliza- tion of those who suffer from the schizophrenias or the affective disorders. for many psychiatric patients, medication will mean the difference between control of illness, and active illness and hospitalization. < psychiatric outpatients with a diagnosis of schizophrenia have the highest non- compliance rates. < characteristics of the non-compliant patient it is difficult to know who will and who will not comply with the drug regimen; com- pliance can never be assumed. < it is clear that compliance among psychiatric patients is extremely poor and that the wide range of non-compliance rates depends upon a number of variables. although there is no - 43 - single or simple explanation for noncompliant behavior, it is correlated with a number of factors. sackett and haynes described the factors associated with non-compliance:
  2. psychiatric diagnosis
  3. complicated, longterm, or complex drug regiments
  4. inadequate and inconvenient clinics
  5. patient dissatisfaction with therapist and inadequate supervision
  6. patient characteristics such as previous non-compliant behavior, difficulty with author- ity figures, lack of understanding of prophylaxis, and a wish to remain sick.‛ < what can be done to increase compliance? < the physician can also consider the use of injectables, which clearly decreases the relapse rate and need for rehospitalization. the physician should always prescribe the most sim- ple regimen. only one neuroleptic or antidepressant at a time is usually indicated, and this can almost always be given once daily at bed time to incorporate the drug taking procedure to the activities of daily living. <‛ i en artikel af greenberg fra 1984 med titlen ‛overview of patient compliance with medica- tion dosing‛ står der bl.a. følgende om sammenhængen mellem doseringshyppighed og pa- tientefterlevelse: ‚< abstract the literature was reviewed in an effort to relate frequency of dosing and other influ- ences with patient compliance in medication taking. once-a-day and twice-a-day regi- mens were associated with significantly better compliance (73% and 70%, respectively) than were three-times-daily (52%) and four-times-daily (42%) regimens. compliance is not related to income, social class, occupation, or educational background, and it cannot be accurately predicted by physicians. unintentional errors in taking medication are made by 50% to 90% of patients. < this review strongly suggests that attempts to reduce dosage schedules to no more than bid[to gange dagligt] will significantly improve compliance rates<it appears that selec- tion of pharmacological agents that can be prescribed once or twice a day will improve patient compliance...‚ i en artikel af fenton et al. fra 1997 med titlen ‛determinants of medication compliance in schizohprenia: empirical and clinical findings‛, er følgende beskrevet: ‚< abstract advances in psychopharmacology have produced medications with substantial efficacy in the treatment of positive and negative symptoms of schizophrenia and the prevention - 44 - of relapse or symptom exacerbation after an acute episode. in the clinical setting, the in- dividual patient's acceptance or rejection of prescribed pharmacological regimens is often the single greatest determinant of these treatments' effectiveness. for this reason, an un- derstanding of factors that impede and promote patient collaboration with prescribed acute and maintenance treatment should inform both pharmacological and psychosocial treatment planning. we review the substantive literature on medication adherence in schizophrenia and describe a modified health belief model within which empirical find- ings can be understood. in addition to factors intrinsic to schizophrenia psychopathology, medication-related factors, available social support, substance abuse comorbidity, and the quality of the therapeutic alliance each affect adherence and offer potential points of intervention to improve the likelihood of collaboration. because noncompliance as a clin- ical problem is multidetermined, an individualized approach to assessment and treat- ment, which is often best developed in the context of an ongoing physician-patient rela- tionship, is optimal. the differential diagnosis of noncompliance should lead to interven- tions that target specific causal factors thought to be operative in the individual patient. < compliance is difficult to quantify and study for several reasons. clinicians' ability to identify which patients do not take medicine is limited (mcclellan and cowan 1970; no- rell 1981). other measures of adherence include patient or relative self-report, prescrip- tion renewals and pill counts, saliva and urine screens, or steady-state serum determina- tions. concordance across different measures of compliance is often low, although self- reported noncompliance is corroborated more often than is self-reported adherence (rickels and briscoe 1970; gordis 1976; boczkowski et al. 1985). measurement is further complicated because compliance is rarely an all-or-none phenomenon, but may include errors of omission, mistakes in dosage and timing, and taking medications that are not prescribed (blackwell 1976). a 1986 review of 26 studies using a variety of definitions and detection methods to assess medication use among outpatients with schizophrenia reported a median default rate of 41 percent (range, 10% to 76%) with oral medications and 25 percent (range, 14% to 36%) with depot injections over time periods up to 1 year (young et al. 1986). < the belief that noncompliance is a direct result of disease processes in schizophrenia do- minates the clinical perception of noncompliance for these patients. reported noncom- pliance rates for schizophrenia, however, are in the middle range of those reported for other common medical disorders. medication noncompliance rates of 55 to 71 percent have been reported for patients with arthritis (berg et al. 1993), 54 to 82 percent for pa- tients with seizure disorders (shope 1988), 20 to 57 percent for patients with bipolar affec- tive disorder (elixhauser et al. 1990), and 19 to 80 percent for patients with diabetes (friedman 1988). half of patients with hypertension drop out of care within 1 year, and only two-thirds of those who remain take adequate medication (eraker et al. 1984). < medication-related factors side effects<between one-quarter and two-thirds of patients who unilaterally disconti- nue prescribed neuroleptic medicines cite side effects as their primary reason for non- compliance< route<although long-acting phenothiazine injections do not ensure medication com- pliance because they must be administered by a treatment provider, noncompliance with this type of treatment can be detected quickly and with certainty. such noncompliance al- - 45 - lows an assessment of clinical impact for the individual patient and may trigger assertive interventions. for this reason, the major advantage of depot neuroleptics may be the abil- ity to eliminate covert noncompliance as a cause of clinical decompensation (schooler and keith 1993). complexity of regimen. although the complexity of a medication regimen is associated with compliance across a broad range of medical disorders (haynes 1976), only one (ra- zali and yahya 1995) of four empirical studies that focused exclusively on schizophrenia identified a statistically significant association between complexity of regimen and com- pliance. hoffman et al.
(1974), hogan et al.
(1983), and buchanan
(1992)found no such association. < discussion … new neuroleptics versus depot preparations. because of their reduced extrapyramidal side effects and greater efficacy against positive and negative symptoms, new neurolep- tics, such as clozapine, risperidone, olanzapine, and sertindole, should provide greater patient benefits at a reduced perceived cost. depot preparations have the advantage of eliminating covert noncompliance and maximizing the likelihood of steady-state neuro- leptic blood levels in patients with cognitive disorganization, memory disturbance, or motivational deficits. although an empirical basis for choosing among these two phar- macological interventions is not available, the full range of factors associated with non- compliance might be considered clinically relevant. patients with good insight and a good therapeutic alliance but who report intolerable side effects are likely the best candi- dates for a trial of a new agent. patients with poor insight, grandiosity, or other psychotic symptoms or those with memory, motivational, or cognitive deficits might also benefit from a trial of a new agent in the absence of comorbid substance abuse and the presence of either a good therapeutic alliance or adequate family or other supervision to ensure regular adherence. poor insight and severe psychopathology in the absence of sufficient supervision favor the use of depot agents. weiden
(1995)has suggested that family fac- tors may also have a bearing on the decision between atypical depot agents: family con- cern over akinesia or other side effects favors a trial of a new agent, whereas chronic fam- ily conflict over taking oral medications favors depot preparations. it is useful to reassess the decision between depot and new neuroleptics periodically. some patients, for exam- ple, may require a considerable period of depot treatment to attain a level of clinical sta- bility, therapeutic alliance, and insight sufficient to render a trial of a new agent feasible. …‛ i den seneste udgave af lærebogen ‛almen farmaci‛ fra 2008 skrevet af henning gjelstrup kristensen står der følgende om parenterale depotformuleringer: ‚< ved langtidsterapi tilstræber man generelt at undgå parenteral administration, men så- fremt dette ikke er muligt, søger man at opnå en virkningsvarighed på mindst et døgn pr. injektion. < med henblik på at opnå virkningstider af størrelsesorden uger eller måneder er parente- rale depotformuleringer eneste mulighed. - 46 - < parenterale depotformuleringer, der er fremstillet som opløsning i olie, er afhængig af den valgte olie og den hastighed, hvormed olien nedbrydes på administrationsstedet. < depotvirkningen af neuroleptika er opnået ved at fremstille fedtsyreestere af lægemid- delstoffet og opløse disse i olievehikler. <‛ i en tidligere udgave af samme bog fra 1991 fremgik de to første sætninger gengivet ovenfor også. clozapin clozapin anvendes til behandling af behandlingsresistente psykoser og var det første atypi- ske antipsykotikum på markedet. i bogen ‛synopsis of psychiatry‛ af kaplan og sadocks fra 1994, står der bl.a. følgende om clozapin: ‚< the lack of effects in those animal models is consistent with the low potency of clozapine as a d2 receptor antagonist. clozapine has a much higher potency as an antagonist at d 1, serotonin type 2 (5-ht2), and noradrenergic alpha receptors (especially a1). clozapine al- so has antagonist activity at muscarinic and histamine type 1(h 1) receptors. recently, it was reported that clozapine has a high affinity for the dopamine type 4 (d4) receptor. the diversity of receptor effects has led to three major hypotheses regarding the pharmaco- logical basis for the efficacy of clozapine and to new hypotheses regarding the pathophy- siology of schizophrenia. ... third, the discovery that clozapine has a high binding affinity for the d4 receptor has led to the hypothesis that a non-d2 dopamine receptor may be the most effective target for antipsychotic drugs, thus leading to research on additional d4 and d2 antagonist drugs. ... pharmacological actions pharmacokinetics although the pharmacokinetic properties of the antipsychotics vary widely (for example, their half-lives range from 10 to 20 hours), the most important clinical generalization is that all the antipsychotics currently available in the united states (with the exception of clozapine) can be given in one daily oral dose once the patient is in a stable condition and has adjusted to any adverse effects. most antipsychotics are incompletely absorbed after oral administration, although liquid preparations are absorbed more efficiently than are other forms. many antipsychotics are also available in parenteral forms that can be given intramuscularly in emergency situations, resulting in a more rapid and more reliable at- tainment of therapeutic plasma concentrations than is possible with oral administration. - 47 - ... in the united states, two antipsychotics, haloperidol and fluphenazine, are available in long-acting depot [hereafter udeladt pga. manglende læsbarhed] < pharmacodynamics < although the dopamine hypothesis holds for all drugs discussed here, it does not hold for clozapine, which apparently has a different mechanism of action, perhaps involving the d2 receptor or the 5-ht2 receptor or both. although d2 receptor antagonism is thought to be central to the therapeutic effects of both risperidone and remoxipride, it has been hypothesized that the additional antagonist activities of those drugs at the 5-ht2 re- ceptor for risperidone and the sigma receptor for remoxipride explain, at least in part, their favorable side-effect profiles. <‛ i ‛handbook of clinical pharmacokinetic data‛ af jack fra 1994, fremgår det af følgende skema over antipsykotiske stoffer, at clozapin og haloperidol har en relativ høj halverings- tid: ‛< <‛ i en artikel af nordström mfl. fra 1995 med titlen: ‛d1, d2, and 5-ht2 receptor occupancy in relation to clozapine serum concentration: a pet study of schizophrenic patients‛, er der beskrevet en undersøgelse af, hvordan clozapin binder til forskellige dopamine receptorer: - 48 - ‛< objective: central d1, d2, and 5-ht2 receptor occupancy in schizophrenic patients treated with clozapine was determined and related to clozapine serum concentrations. < results: d2 receptor occupancy (20%-67%) was lower than that previously determined in patients treated with classical neuroleptics (70%-90%). d1 receptor occupancy (36%-59%) was higher than that induced by classical neuroleptics (0%-44%). 5-ht2 receptor occu- pancy was very high (84%-95%), even at low clozapine doses. despite a 20-fold range in clozapine serum concentration (105-2121 ng/ml) at the time of pet examination, d2 recep- tor occupancy was low in all patients and was not described by the curvilinear relation- ship between serum drug concentration and receptor occupancy that has been demon- strated for classical antipsychotics. conclusions: the results confirm in an extended series of patients that clozapine is atypi- cal with regard to degree of d2 receptor occupancy, a finding that may explain the lack of extra-pyramidal side effects. the combination of relatively high d1, low d2, and very high 5-ht2 receptor occupancy values is unique to clozapine. clozapine serum concentrations have not been unequivocally shown to predict clinical effects. in this study, concentra- tions did not predict degree of occupancy in brain. thus, careful clinical titration cannot be replaced by monitoring of drug concentrations for optimization of clozapine treatment in individual patients. < differentiation of the mechanism of action of atypical antipsychotics from that of classical neuroleptics may provide guidelines for the development of new antipsychotic drugs and for clarification of the pathophysiology of schizophrenia. clozapine is the prototype atypical antipsychotic drug. the frequency of extrapyramidal side effects during cloza- pine treatment is low
(1), and clozapine is efficacious in some patients who do not re- spond to classical neuroleptics. < several receptors other than the d2 receptor subtype have been suggested as being in- volved in the mechanism of action of clozapine. < discussion in all 16 patients treated with 125-600 mg/day of clozapine, the d2 receptor occupancy (20%-67%) was lower than that previously found in patients treated with conventional doses of classical neuroleptics (70%-89%). < a simplistic explanation for the lack of extrapyramidal side effects during clozapine treatment is that the d2 receptor occupancy induced by clinical doses is too low (20%- 67%) to induce extrapyramidal side effects. < on the basis of the finding of a relatively low degree of d2 receptor occupancy it can be speculated that d2 receptor occupancy per se is not the mechanism of action of clozapine. it has been suggested that the mechanism of action of clozapine includes involvement of the d1 dopamine receptor. < other authors have claimed that the atypical effects of clozapine are related to a com- bined effect on d2 dopamine and 5-ht2 receptors. a consistent finding in the present study was a very high 5-ht2 receptor occupancy (>80%) even at low serum concentra- tions, when the d2 receptor occupancy was only 20%. <‛ - 49 - seeman har i bogen ‛psychopharmacology‛ fra 1995 skrevet om ‛dopamine receptors, cli- nical correlates‛, herunder blandt andet om clozapin, skizofreni og dopamine receptorer. heraf fremgår bl.a.: ‛< schizophrenia, clozapine and dopamine receptors the dopamine hypothesis of schizophrenia proposes that brain dopamine synapses are overactive in schizophrenia (see references in ref. 47). this overactivity may stem from ei- ther an excess release of dopamine or an overactive response by the dopamine receptors. most evidence for the hypothesis of dopamine overactivity in schizophrenia relies on the fact that neuroleptics block dopamine d2 receptors in direct relation to their clinical anti- psychotic potencies. < up to now, however, clozapine had been an exception to this rule, because clozapine blocks dopamine d2 receptors at concentrations which are 20 times higher than the con- centration range of 10-20 nm found in the spinal fluid of clozapine-treated patients(data of j. lieberman et al., 1991<). < relation between clinical signs and d2 blockade as a result of many studies using positron emission tomography to measure the occu- pancy of d2 receptors in neuroleptic-treated patients (1,9 ,18,19,21,39,43), there is a clear relation between clinical signs and d2 block. akathisia occurs at around 60-65% d2 blockade, anti-psychotic action occurs at about 65-75% d2 block, and extrapyramidal parkinsonian signs occur at approcimately 90% block of d2 receptors, as summarized in fig. 5. < conclusion practical benefits are emerging from the dopamine hypothesis and from the cloning strategies. as just noted above, there is a clear relation between clinical signs and d2 re- ceptor blockade. hence, the art of psychiatry is rapidly becoming the quantitative science of psychiatry. in addition, with the discoveries that clozapine targets to the dopamine d4 receptor and that dopamine d4 receptors are markedly elevated in schizophrenia, the development of new clozapine-like neuroleptics (which do not cause parkinsonism and do not cause tardive dyskinesia) is desirable and possible. a new generation of selective neuropsychopharmacology is on the horizon. <‛ quetiapin stoffet quetiapin blev udviklet af astrazeneca i 1985 og blev første gang beskrevet i europæ- isk patentansøgning ep 0 240 228 a1, som blev publiceret den 7. oktober 1987. af det parallelle danske stofpatent dk 174618 b1, som blev publiceret den 28. september 1987 fremgår følgende: - 50 - ‛< den foreliggende opfindelse angår en hidtil ukendt dibenzothiazepinforbindelse med den i krav 1 viste formel (
  1. ii)eller et salt deraf. forbindelsen er anvendelig på grund af dens antidopaminerge virkning, f.eks. som et antipsykotisk meddel eller neuroleptisk middel< en sådan forbindelse er anvendelig på grund af dens antidopaminerge virkning, f.eks. som et antipsykotisk middel eller som en behandling for hyperaktivitet. en sådan forbin- delse har endnu større interesse, fordi den kan anvendes som et antipsykotisk middel med en væsentlig reduktion i muligheden for at forårsage bivirkninger såsom akut dystoni, akut dyskinesi, pseudo-parkinsonisme såvel som tardiv dyskinesi, som kan være et resultat fra anvendelsen af andre antipsykotiske midler eller neuroleptiske midler. < et foretrukket salt er hemi-fumaratsaltet. < den hidtil ukendte forbindelse ifølge opfindelsen er en centralnervesystemdepressant og kan anvendes som et beroligende middel til dæmpningen af hyperaktivitetstilstande. < til dette formål kan en forbindelse med formlen ii eller ikke-toksiske, fysiologisk accep- table syreadditionssalte deraf administreres oralt eller parenteralt i en hensigtsmæssig dosisform, såsom en tablet, pille, kapsel, injektionspræparat eller lignende. < en minimal effektiv dosis af en forbindelse med formel ii vil være mindst ca. 1,0 mg/kg legemsvægt pr. dag for pattedyr med en maksimal dosis til et lille pattedyr, såsom en hund, på ca. 200 mg/kg pr. dag. for mennesker vil en dosis på ca. 1,0 til 40 mg/kg være effektiv, f.eks. ca. 50 til 2000 mg/dag til en gennemsnitsperson. dosisen kan gives en gang dagligt eller i delte doser, f.eks. 2 til 4 doser dagligt og vil således afhænge af virknings- varigheden og det maksimale aktivitetsniveau af en bestemt forbindelse. dosisen kan hensigtsmæssigt formuleres i en oral eller parenteral dosisform ved at sammensætte ca. 25 til 500 mg. pr. enhedsdosis af konventionel bærer, excipiens, bindemiddel, konserve- ringsmiddel, stabiliseringsmiddel, smagsstof eller lignende. < patentkrav 1. dibenzothiazepinforbindelse, kendetegnet ved formlen (
  2. ii)eller et salt deraf. 2. forbindelse ifølge krav 1, kendetegnet ved, at den er i form af et farmaceutisk accepta- belt salt. 3. forbindelse ifølge krav 1, kendetegnet ved, at den er i form af et hemifumaratsalt. 4. forbindelse ifølge krav 1, kendetegnet ved, at den er i form af et hydrochloridsalt - 51 - <‛ der blev først gang givet markedsføringstilladelse for quetiapin som lægemiddel i danmark den 31. juli 1997. patentbeskyttelsen for stofpatentet udløb i 2012. wetzel har i en artikel udgivet i 1995 beskrevet seroquel som et formodet atypisk antipsyko- tikum i skizofreni. artiklen har overskriften: ‚seroquel (ici 204 636), a putative atypical an- tipsychotic, in schizophrenia with positive symptomatology: results of an open clinical trial and changes of neuroendocrinological and eeg parameters‛. af artiklen fremgår bl.a.: ‛< in the present study 12 patients suffering from schizophrenia or schizophreniform dis- order with predominatly positive symptomatology were treated in an open clinical trial for 4 weeks with seroquel at a maxium dosage of 750 mg/day. the drug was generally well tolerated, and virtually no adverse extrapyramidal side effects such as acute dysto- nia, parkinsonism or akathisia were observed. < introduction there are three main reasons to develop new antipsychotic drugs: first, a substantial number of schizophrenic patients will not respond sufficiently to neuroleptic treatment; second, beneficial effects of conventionnal antipsychotic drugs on negative symptoms may be less pronounced than on positive schizophrenic symptomatology; third, conven- tional neuroleptic drugs cause typical extrapyramidal side effects, of which tardive dyskinesia is still a major restriction to the long term administration of neuroleptics. compared to typica1‛ neuroleptics, the ‚atypical‛ antipsychotic drug clozapine causes only minimal, if any, extrapyramidal side effects, as illustrated by several double-blind controlled studies (baldessarini and frankenburg 1991). moreover, clozapine has been reported to be more efficient than the reference drug chlorpromazine in neuroleptic- refractory schizophrenic patients (kane et al. 1988). due to serious adverse effects, espe- cially agranulocytosis, the clinical use of clozapine is subject to some limitations (andermaun and griffith 1977). the cumulative risk for agranulocytosis in 1 year of treatment has been calculated to be as high as 1-2% (krupp and barnes 1989). moreover, clozapine has strong anticholinergic and antiadrenergic properties that are likely to be re- sponsible for the induction of delirious states and orthostatic hypotension, respectively. in a recent study, akathisia has been reported in a substantial number of patients under clozapine treatment (cohen et al. 1991). < from these preclinical findings, it was suspected that seroquel could possess an ‚atypi- cal‛ neuroleptic response pattern. .. (dansk oversættelse) med hensyn til farmakokinetiske parametre havde seroquel i dyreforsøg en lav biotil- gængelighed på 5-15% med en eliminationshalveringstid på 1-3 t. seroquel gennemgår omfattende first-pass metabolisering via ring hydroxylering, sulfoxidering, n- og o- - 52 - dealkylering og sidekædeoxidering. antageligvis er mindst den 7-hydroxylerede farma- kologisk aktiv og kan medvirke til seroquel’s kliniske effekter. lægemiddelinducerede ændringer i eeg kan til en vis grad forudsige de adfærdsmæssi- ge effekter af et stof og kan også guide den klinisk-farmakologiske søgning efter den pas- sende dosis (fink 1969). da seroquel bærer en vis lighed med clozapin med dets velkend- te effekter på cerebral elektrisk aktivitet (haller og binder 1990), blev eeg effekterne tæt overvåget i seroquelpatienter. for at vurdere virkningsgraden og tolerabiliteten af seroquel i skizofrene patienter med overvejende positiv symptomatologi, blev et åbent klinisk forsøg udført. ydermere skulle eeg profilen af det nye stof undersøges ved at sammenligne eeg profilerne fra pilotfor- søget med optagelser fra en historisk sammenligningsgruppe, som var blevet behandlet med en regelmæssig medicinering med clozapin. < with regard to side effects, seroquel was well tolerated and generally did not cause any untoward extrapyramidal symptoms, with the possible exception of one patient (no. 9) presenting with intermittent motor restlessness (table 2). in any patient, no anticholiner- gic medication was needed. < discussion in an open clinical trial, the antipsychotic properties and extrapyramidal side effect liabil- ity of seroquel, a putative atypical antipsychotic, was assessed. < with respect to seroquel’s antipsychotic effects, it is obvious that definitive conclusions cannot be drawn from a small open study. < it should be mentioned, however; that most patients received the maximal seroquel do- sage of 750 mg/day only for a relatively short time interval, and that antipsychotic effects might have been more pronounced if dosage had been increased more quickly and max- imum dosage could have been given for a longer time period. < our result of a modest antipsychotic response rate of about 33—40% under seroquel i in contrast to the report of fabre et al.
(1990), who treated eight mild to moderately ill schi- zophrenic patients in a small placebo-controlled double-blind study with seroquel in es- calating doses up to 250 mg/day, observing a 35% or greater drop in bprs total scores in all patients receiving verum medication. in order properly to estimate seroquel’s antipsy- chotic properties, it should be mentioned that four out of seven seroquel non-responders did not show a sufficient response to clozapine follow-up treatment for at least 4 weeks either. therefore, it should be considered that our patient population might have represented a clinical sample that was primarily unresponsive to atypical antipsychotics like clozapine or possibly seroquel. < however for seroquel our preliminary observations of virtually no extrapyramidal side effects should be interpreted with some caution due to the drug’s low bioavailability. in further clinical trials, plasma levels of seroquel and presumably active metabolites should be determined in order to exclude low systemic bioavailability as a reason for treatment non-response and/or lack of untoward extrapyramidal symptoms. < (dansk oversættelse) - 53 - som konklusion, eftersom der ikke observeredes nogle klare extrapyramidale bivirknin- ger under behandlingen med seroquel, så viser vore data, at dette nye antipsykotikum toleres godt og kunne vise nogen antipsykotisk virkningsgrad ved behandling af skizo- frene patienter. de antipsykotiske virkninger i doser på op til 750 mg/dag var imidlertid endnu ikke fuldt tilfredsstillende. ved fremtidige kliniske forsøg bør højere doser indgi- ves for yderligere at undersøge seroquels antipsykotiske potentiale. monitorering af plasmaniveauer for udgangslægemidlet og aktive metabolitter vil være af yderste vigtig- hed for at kunne undersøge biotilgængelighedsparametre in relation til behandlingsre- sultatet og extrapyramidale bivirkninger. for så vidt angår neuroendokrinologiske og pharmaco-eeg resultater, blev der ikke set ændringer i prolactin og tsh niveau eller tegn på paroxymal eeg aktivitet under seroquelbehandling. <‛ i et abstract fra en konference ved european college of neuropsychopharmacology i sep- tember-oktober 1995 har gefvert m.fl. beskrevet et forsøg, hvor skizofrene patienter fik dose- ret 150 mg seroquel tre gange dagligt. abstractet lyder som følger i dansk oversættelse: - 54 - - 55 - den
  1. oktober 1995 udsendte firmaet eurand følgende pressemeddelelse vedrørende et samarbejde med astrazeneca om seroquel: - 56 - astrazeneca udsendte, ligeledes i oktober 1995, følgende pressemeddelelse: ‚important results presented today from the first major phase iii clinical trial of ‛sero- quel‛ confirm that this new ‛atypical‛ antipsychotic beding developed by zeneca phar- maceuticals should offer substantial benefits in the management of schizophrenia. a convenient, twice daily dosing regime of ‚seroqeul‛ offers effective management of both the ‚positive and negative‛ symptoms of schizophrenia and fewer of the disturbing side-effects associated with current antipsychotic drugs. movement disorders (so-called extrapyramidal side effects) with ‚seroquel‛ have been no greater than those shown with placebo – a feature which helps to confirm its profile as an ‚atypical‛ antipsychotic.‛ the world market for the pharmaceutical treatment of psychotic disorders is currently valued at approximately gbp one billion p.a. and schizophrenia occurs in about one per cent of the population. psychosocial disabilities can place a major economic burden on society and studies from different countries have estimated that the cost of mental health treatment worldwide accounts for up to ten per cent of healthcare budgets. ‘seroquel’ represents a potentially important part of zeneca’s future product portfolio and these important results mark the completion of the first major study from the phase iii clinical trial programme. the safari** study results were presented at the 8th european college of neuropsycho- pharmacology congress (ecnp) in venice, by professor wolfgang fleischhacker of the department of psychiatry, innsbruck university clinics. the study involved 618 patients and results indicate that ‘seroquel’ was effective and well tolerated with a convenient twice daily dosage. professor fleishhacker said: ‚patient compliance is tremendously important in schizoph- renia. part of this illness is being out of touch with reality. patients have lost insight and may not even accept that they are ill – under such circumstances it can be difficult to get them to take their medication.‛ commenting on ‘seroquel’ trial results to date, zeneca pharmaceuticals chief executive officer, dr tom mckillop, said ‚the safari data confirms previous trial results which show ‘seroquel’ to be clinically superior to placebo and comparable to chlorpromazine – a standard treatment for schizophrenia. patients and their carers often complain that the side effects of existing medication can be more problematic than the disease itself. this latest data adds to our growing confidence that ‘seroquel’ should be an important addi- tion to treatment in this area of high unmet medical need. ‚ ‘seroquel’ displays other advantages over existing treatments in that it has no adverse ef- fect on prolactin levels and no cases of agranulocytosis have been reported. regulatory fillings for ‘seroquel’ are anticipated during the first quarter of
  2. background information < - 57 - clozapine, a newer antipsychotic offering advantage over traditional drugs has been li- mited in widespread usage because of its potential to cause agranulocytosis, a potentially fatal reduction in the number of white blood cells.‛ af materi

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