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sø- & handelsrettens dombog

- alj udskrift af sø- & handelsrettens dombog ____________ kendelse afsagt den 6. november 2015 a-34-15 1) astrazeneca ab 2) astrazeneca a/s (advokat peter-ulrik plesner for begge) mod 1) orion corporation 2) orion pharma a/s (advokat johnny petersen for begge) sagens baggrund og parternes påstande denne sag om midlertidigt forbud og påbud i henhold til retsplejelovens kap. 40 angår navn- lig, om astrazeneca ab og astrazeneca a/s (herefter tilsammen astrazeneca) har godtgjort eller sandsynliggjort, at orion corporations og orion pharma a/s’ (herefter tilsammen ori-

  1. on)udbud m.v. i danmark af lægemidlet ketipinor depot udgør en krænkelse af astrazene- cas rettigheder til patent nr. dk/ep 0 907 364. -2- astrazeneca har nedlagt følgende påstande: 1. det forbydes orion corporation og orion pharma a/s i danmark at udbyde, bringe i omsætning eller anvende lægemidlet ketipinor, omhandlet af orion corporations mar- kedsføringstilladelse med d.sp.nr. 28855, jf. bilag 8, eller importere eller besidde det med et sådant formål. 2. det forbydes orion corporation og orion pharma a/s i danmark at udbyde, bringe i omsætning eller anvende lægemidlet ketipinor, omhandlet af orion corporations mar- kedsføringstilladelse med markedsføringstilladelsesnumrene 52703 (50 mg), 52704 (150 mg), 52705 (200 mg), 52706 (300
  2. mg)og 52707 (400 mg), jf. bilag 8, eller importere eller besidde det med et sådant formål. 3. det påbydes orion corporation og orion pharma a/s at tilbagekalde allerede skete leve- rancer af ketipinor, omhandlet af orion corporations markedsføringstilladelse med markedsføringstilladelsesnumrene 52703 (50 mg), 52704 (150 mg), 52705 (200 mg), 52706 (300
  3. mg)og 52707 (400 mg), jf. bilag 8, fra samtlige grossister og apoteker, hvortil leve- ring er foretaget af orion corporation og orion pharma a/s. 4. det påbydes orion corporation og orion pharma a/s at anmode sine distributører i danmark af ketipinor, omhandlet af orion corporations markedsføringstilladelse med markedsføringstilladelsesnumrene 52703 (50 mg), 52704 (150 mg), 52705 (200 mg), 52706 (300
  4. mg)og 52707 (400
  5. mg)jf. bilag 8, om at tilbagekalde og returnere til orion corpora- tion og orion pharma a/s de pågældendes leverancer af nævnte lægemiddel fra samtlige grossister og apoteker. 5. det påbydes orion corporation og orion pharma a/s omgående at afmelde markedsfø- ring af lægemidlet ketipinor omhandlet af orion corporations markedsføringstilladelse med markedsføringstilladelsesnumrene 52703 (50 mg), 52704 (150 mg), 52705 (200 mg), 52706 (300
  6. mg)og 52707 (400 mg), jf. bilag 8, hos sundhedsstyrelsen. -3- astrazeneca påstår de midlertidige forbud og påbud nedlagt, så længe astrazenecas patent nr. dk/ep 0 907 364 er i kraft i danmark. astrazeneca påstår subsidiært de midlertidige forbud og påbud nedlagt mod en af retten fastsat sikkerhed. orion har nedlagt påstand om, at begæringen om nedlæggelse af forbud og påbud nægtes fremme, subsidiært at forbud og påbud nedlægges mod en af retten fastsat sikkerhed. oplysningerne i sagen sagens parter astrazeneca-koncernen driver virksomhed globalt inden for forskning og udvikling af origi- nale lægemidler. astrazeneca ab har stået for udviklingen af det i sagen omhandlede læge- middel, seroquel prolong (også kaldet seroquel
  7. xl)(herefter seroquel prolong), og er inde- haver af patent nr. dk/ep 0 907 364 (herefter stridspatentet). astrazeneca a/s forestår mar- kedsføringen af seroquel prolong i danmark. orion-koncernen er en global virksomhed, der beskæftiger sig med produktion og markeds- føring af generiske lægemidler, bl.a. markedsføring af det i sagen omhandlede lægemiddel, ketipinor depot (herefter ketipinor). orion pharma a/s fungerer som orion corporations danske salgskanal. stridspatentet astrazeneca ab er som nævnt indehaver af stridspatentet dk/ep 0 907 364. stridspatentet er udstedt af epo (the european patent office) den 14. august 2002 og har prioritet fra den 31. maj 1996. stridspatentet er valideret i danmark. -4- i den danske oversættelse har stridspatentets krav 1 følgende ordlyd: ”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 farmaceu- tisk acceptabelt salt deraf sammen med en eller flere farmaceutisk acceptable exci- pienser.” 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. quetiapin eller quetiapinfumarat (dvs. et farmaceutisk acceptabelt salt af quetiapin) anvendes som læ- gemiddel 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 profy- laktisk, 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- 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, -5- 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.” ved opfindelsen i stridspatentet omfatter formuleringen med den langvarige frigivelse af quetiapin eller quetiapinfumarat et ”geleringsmiddel”. stridspatentets beskrivelse (den dan- ske oversættelse) indeholder bl.a. følgende omtale heraf: ”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.” som yderligere fortolkningsbidrag til forståelsen af begrebet ”gel” er der under sagen frem- lagt uddrag fra faglitteratur. af henning gjelstrup kristensens lærebog ”almen farmaci” (2. udgave, 2000) fremgår således bl.a.: ”6.4 geler en gel er et fast eller halvfast disperst system, bestående af mindst to komponenter; en geldannende komponent, der danner et sammenhængende netværk, og som inde- slutter en flydende komponent. < det tredimensionale polymernetværk i en hydrogel kan være dannet ved tværbin- ding af polymeren eller ved, at molekylerne holdes sammen af intermolekylære kræf- ter. tværbundne polymerer holdes sammen af kovalente bindinger. en sådan poly- mer kvælder, men kan ikke opløses i vand. de kaldes hydrogeler og betegnes under- tiden type i geler.” af ”compendium of chemical terminology” (gold book, version 2.3.3, 2014), som udgives af iupac (international union of pure and applied chemistry), fremgår bl.a. følgende defi- nitioner: ”gel non-fluid colloidal network or polymer network that is expanded throughout its whole volume by a fluid. notes: 1. a gel has a finite, usually rather small, yield stress. -6- 2. a gel can contain: < 2. a polymer network formed through the physical aggregation of polymer chains, caused by hydrogen bonds < the resulting swollen network may be termed a thermoreversible gel if the regions of local order are thermally revers- ible. < swelling < the increase in volume of a gel or solid associated with the uptake of a liquid or gas.” spørgsmålet om forståelsen af begreberne ”gel” og ”swelling” (på dansk: ”kvældning”) og sammenhængen mellem disse begreber er nærmere omtalt i visse af de til brug for sagen indhentede erklæringer samt under forklaringerne afgivet for retten. der er mellem parterne enighed om, at i hvert fald stoffet hydroxypropylmethylcellulose er et geleringsmiddel i stridspatentets forstand. det fremgår desuden af beskrivelsen i stridspa- tentet, at dette geleringsmiddel er den foretrukne udførelsesform af stridspatentet. hydro- xypropylmethylcellulose kendes også som ”hpmc”. om mængden af geleringsmidlet anføres i stridspatentets beskrivelse (den danske oversæt- telse) bl.a.: ”mængden af geleringsmiddel, fortrinsvis [hpmc], er fortrinsvis udvalgt sådan, at den aktive bestanddel frigives fra formuleringen på kontrolleret vis i løbet at en peri- ode på 4 h eller længere, fortrinsvis i løbet af en periode på 8 h eller længere og navn- lig i løbet at en periode på mellem 8 og 24 h, dvs. så mindst 60 % af den aktive be- standdel blevet frigivet ved slutningen af denne periode. geleringsmidlet, fortrinsvis [hpmc], er hensigtsmæssigt til stede som ca. 5-50 % (med hensyn til vægt), mere hensigtsmæssigt ca. 5-40 %, mest hensigtsmæssigt ca. 8- 35 % og navnlig ca. 10-35 %. det er generelt foretrukket, at geleringsmidlet, fortrins- vis [hpmc], er til stede som ca. 10-30 %, mere fortrinsvis ca. 15-30 %.” der er ikke mellem parterne enighed om, i hvilket omfang geleringsmidlet skal medvirke til den langvarige frigivelse af quetiapin/quetiapinfumarat i henhold til opfindelsen i stridspa- tentet. -7- orion har ikke under denne forbudssag gjort gældende, at stridspatentet er ugyldigt i dan- mark. astrazenecas lægemiddel seroquel prolong i danmark sælger astrazeneca quetiapin (som et quetiapinfumarat-salt) formuleret i hen- hold til stridspatentet under navnet seroquel prolong. astrazeneca fik første gang markeds- føringstilladelse til produktet den 10. januar 2008. seroquel prolong markedsføres i sammen- sætninger indeholdende 50 mg, 150 mg, 200 mg, 300 mg og 400 mg quetiapinfumarat. af produktresuméet for seroquel prolong fremgår bl.a., at produktet er godkendt til behand- ling af skizofreni, bipolar lidelse og depressive episoder hos patienter med unipolar depres- sion. grundet formuleringen med den langvarige frigivelse skal seroquel prolong kun tages en gang dagligt. udover selve aktivstoffet, quetiapinfumarat, indeholder seroquel prolong i tabletkernen bl.a. hpmc, hvilket er det stof, der som geleringsmiddel giver den forlængede frigivelse af que- tiapinfumarat. seroquel prolong er således udtryk for den foretrukne udførelsesform efter stridspatentet. det påståede krænkende produkt, ketipinor den 4. marts 2015 fik orion udstedt markedsføringstilladelse til lægemidlet ketipinor. mar- kedsføringstilladelsen har dansk specialitetsnummer 28855. orion corporation er registreret som indehaver af markedsføringstilladelsen, og orion pharma a/s er registreret som repræ- sentant. orion markedsfører ketipinor i sammensætninger indeholdende quetiapin (quetiapinfuma- rat) i doser på 50 mg (under markedsføringstilladelsesnr. 52703), 150 mg (under markedsfø- ringstilladelsesnr. 52704), 200 mg (under markedsføringstilladelsesnr. 52705), 300 mg (under markedsføringstilladelsesnr. 52706) samt 400 mg (under markedsføringstilladelsesnr. 52707). -8- af produktresuméet for ketipinor fremgår, at produktet er godkendt til behandling af de samme indikationer som seroquel prolong, og at ketipinor også kun tages en gang dagligt. der er mellem parterne enighed om, at ketipinor som nævnt indeholder aktivstoffet quetia- pin (som et quetiapinfumarat-salt). der er endvidere enighed om, at der er tale om en depot- tablet, dvs. en formulering med langvarig frigivelse af aktivstoffet. parterne er derimod ikke enige om, hvorvidt den langvarige frigivelse i ketipinor sker ved dannelsen af et gelerings- middel som foreskrevet i stridspatentet. af produktresuméet for ketipinor fremgår, at ketipinor anvender følgende hjælpestoffer: ”tabletkerne lactose, vandfri magnesiumstearat methacrylsyre – ethylacrylatcopolymer (1:1) type a maltose talkum tabletovertræk methacrylsyre – ethylacrylatcopolymer (1:1) type a triethylcitrat” methacrylsyre – ethylacrylatcopolymer (1:1) type a, som findes i både tabletkernen og tab- letovertrækket i ketipinor, er også kendt under navnet ”eudragit l 100-55”. tvisten mellem parterne går særligt på, om eudragit l 100-55 i stridspatentets forstand er et geleringsmid- del, der fører til den langvarige frigivelse af aktivstoffet. nærmere om eudragit l 100-55 producentens produktspecifikationer eudragit l 100-55 produceres af den tyske koncern, evonik industries. af en af producenten udsendt specifikation for eudragit l 100-55 fremgår om stoffets kemiske struktur bl.a.: -9- ”eudragit® l 100-55 contains an anionic copolymer based on methacrylic acid and ethyl acrylate. the ratio of the free carboxyl groups to the ester groups is approx. 1:1” om de nærmere karakteristika ved eudragit l 100-55 fremgår af en anden produktspecifika- tion bl.a: “product form: powder targeted drug release area: duodenum dissolution: above ph 5.5 characteristics:  effective and stable enteric coatings with a fast dissolution in the upper bo- wel  granulation of drug substances in powder form for controlled release” duodenum er den latinske betegnelse for tolvfingertarmen. pharmathens udviklingsrapport og patentansøgning orion har oplyst, at ketipinor er produceret af pharmathen s.a. (herefter pharmathen). ori- on har under sagen fremlagt uddrag af pharmathens udviklingsrapport vedrørende ketipi- nor. om eudragit l 100-55 og om stoffets virkningsfunktion for den langsomme frigivelse af quetiapinfumarat-saltet i ketipinor fremgår af udviklingsrapporten bl.a.: ”b. pharmathen’s quetiapine sustained release product – formulation technology pharmathen’s quetiapine sustained release product is dissolution/erosion-controlled matrix system also having ph-independent release properties. the development of the products is based on: - a core matrix consisting of water soluble (or conditionally water soluble) com- ponents including < eudragit l100-55, lactose (sd 250), maltose (advantose 100). - an enteric coating system consisting of < eudragit l30-d55. < eudragit l 100-55 and l 30 d-55 consist of linear polymeric chains. due to the absen- ce of any crosslinking entanglement between the polymer chains, eudragit l-55 tran- sits abruptly from non-soluble state to soluble state (by changing ph value) without any swelling. < - 10 - the ph-independent release of pharmathen’s quetiapine product is achieved not through the use of a buffer, as with astrazeneca seroquel, but through the opposing ph-dependent water solubility of the polymeric matrix-forming material eudragit l- 55 and quetiapine drug substance. eudragit l-55 contributes to the retardation of the drug release (acting as erosion-suppress agent) in the stomach because of its limited solubility in low ph values. at low ph quetiapine has a high solubility and whilst the erosion of the formulation is limited some of the quetiapine is able to diffuse from the matrix. on the contrary eudragit l-55 acts as erosion-inducing agent at higher ph values (in the intestine) and thus facilitates the drug release at these ph values by allowing the erosion of the matrix to occur speeding up release. at the same time at the higher ph the solubility of quetiapine is low thus less quetiapine diffuses from the matrix. thus the combined effects of the ph dependent solubility of the quetia- pine is counteracted by the ph dependent erosion of the matrix in the formulation.” det fremgår endvidere af udviklingsrapporten, at indholdsprocenten i ketipinor af eudragit l 100-55 er 12,377 %. det fremgår desuden, at 96,3 % af quetiapinfumarat-saltet vil være op- løst 12 timer efter indtagelsen af tabletten. orion har under sagen endvidere oplyst, at ketipinor er omfattet af pharmathens patentan- søgning wo 2014/037022, som blev indleveret den 10. september 2012. denne patentansøg- nings krav 1 har følgende ordlyd: ”1. an extended release pharmaceutical composition for oral administration compris- ing quetiapine or a pharmaceutical acceptable salt thereof, as an active ingredient and an effective amount of a matrix forming non-gelling, non-swellable, methacrylic acid-based enteric polymer.” af patentansøgningens beskrivelse fremgår om opfindelsens virkemekanisme bl.a.: ”several attempts have been made to overcome ph-dependent variability in sus- tained release formulations of weakly basic drugs. the present invention ensures pharmaceutical availability of quetiapine or pharmaceutical acceptable salt thereof from extended release dosage forms using micro-environmental ph modulators and/or materials with ph-dependent solubility, such as polymethacrylates, in order to create a system with ph-independent dissolution profile. these formulations pro- vide constant release of quetiapine during the transit through the gastro-intestinal tract in spite of the variation in ph values. enteric polymers or co-polymers, such as polymethacrylates, can contribute to the re- tardation of the release phenomenon in the stomach (by adjusting tablet’s micro- environmental
  8. ph)while acting as pore-forming agents at higher ph values (intes- tine). moreover, the same type of enteric polymers or copolymers can also be used as - 11 - coating agents to enhance ph-independent dissolution behaviour when the formula- tion is transferred from stomach to small intestine. < example 3 eudragit ll00-55 was selected instead of eudragit l100 for both tablet core and coat- ing layer. compared to eudragit l100, eudragit l100-55, which is also an anionic co- polymer, dissolves at a slightly lower ph value (about 5.5) and indicates a signifi- cantly higher dissolution rate in neutral and alkaline mediums. additionally, two sugar types was decided to be added in the core as water soluble non-gelling exci- pients in order to facilitate release of the active substance from the core at the initial acidic ph of the stomach. the first sugar type was decided to be lactose and the other one selected from maltose or dextrose. < all tested tablets showed extended release profiles of quetiapine. the profiles indi- cated a combination of two dissolution mechanisms depending on the ph of the dis- solution medium. in the acidic medium, where quetiapine indicates higher solubility as a weakly basic drug, tablets acted as reservoir type matrices (diffusion through the coating layer). the release of the drug through the enteric coating depended on the hydrophilicity of the core and the thickness of the coating layer. since the conditions and the weight gain of tablets during coating remained constant, differences between the dissolution profiles of the experiments were attributed to differences in the core. on the contrary, at higher ph values, where quetiapine indicates lower solubility and coating is freely soluble, erosion was the main release mechanism. the erosion rate of the matrix was mainly controlled by the solubility of the quetiapine and the hydrophilicity of the core excipients.” af patentansøgningen fremgår endvidere, at opfindelsen beskrevet som eksempel 3 består af 43,81 % quetiapinfumarat, 12,38 % eudragit l 100-55, 28,58 % maltose, 9,52 % lactose, 3,81 % talkum og 1,90 % magnesiumstearat. faglitteratur astrazeneca har under sagen fremlagt faglitteratur, som beskriver brugen af eudragit som gelformulering. astrazeneca har for det første fremlagt artiklen ”preparation and evaluation of eudragit gels. iii: rectal gel preparations for sustained release of pentoxifylline” af nak-seo kim m.fl.

(1991), hvoraf fremgår bl.a.: - 12 - ”eudragit l, eudragit s, and eudisperts are block copolymers of methacrylic acid and methyl methacrylate in ratios of —1:1, —1:2, and —7:3, respectively. < experimental section < hydrogel preparations — pentoxifylline was dissolved in purified water, and then eudragit l, eudragit s, and eudisperts were added in amounts that were 5-15 % (w/w) of the total weight. < results and discussion determination of amounts of naoh added for hydrogel formation of eudragit l, eudragit s, and eudisperts— < ranges between 3.0 and 3.5 meq naoh for eudra- git s, between 3.0 and 5.75 meq naoh for eudragit l, and between 4.0 and 7.5 meq naoh for eudisperts hv, mv, or lv are desirable. if a very small amount of naoh or no naoh is incorporated, no hydrogel will be produced. if more naoh is incorpo- rated, the hydrogel will be strongly alkaline and not suitable for use in a living body.” kim-artiklen nævner ikke specifikt eudragit l 100-55. astrazeneca har for det andet fremlagt artiklen ”hydrogels: a smart drug delivery system” af chauhan sandeep
(2012), hvoraf fremgår bl.a. (noter er udeladt): ”classification of hydrogels < hydrogels may also show a swelling behavior dependent on the external environ- ment. these polymers are physiologically-responsive hydrogels, where polymer complexes can be broken or the network can be swollen as a result of the changing external environment. these systems tend to show drastic changes in their swelling ratio as a result. some of the factors affecting the swelling of physiologically respon- sive hydrogels include ph, ionic strength, temperature and electromagnetic radia- tion. a list of few ph sensitive polymers is given in table 2 along with their corres- ponding threshold ph. < advantages of hydrogels hydrogels being three-dimensional, hydrophilic, polymeric networks capable of im- bibing large amounts of water or biological fluids may offer several advantages:
  1. sustained and prolonged action in comparison to conventional drug delivery sys- tems. - 13 -
  2. decreased dose of administration.” i tabel 2 i sandeep-artiklen nævnes eudragit l 100-55 udtrykkeligt, og det angives, at dette stofs ”threshold ph” er 5,
  3. astrazeneca har desuden fremlagt faglitteratur om polymeren carbomer, som i stridspaten- tets beskrivelse nævnes som eksempel på et muligt geleringsmiddel. det fremgår heraf, at carbomer, ligesom eudragit l 100-55, indeholder methacrylsyre, men at carbomer er ”cross- linked”. erklæringer der er afgivet en række skriftlige erklæringer til brug for sagen, herunder følgende: dr. shen yung luk har afgivet erklæring af
  4. maj 2014 (herefter luk 1). af erklæringen fremgår bl.a.: ”gelling characteristics of eudragit l100-55 < 1) i was asked by astrazeneca to determine whether eudragit l100-55 can form a gel in the context of european patent ep907364 [stridspatentet]. 2) eudragit l100-55 is copolymer comprised of methacrylic acid and ethylacrylate, with a range of methacrylic acid units between 46.0% to 50.6%. the material is supplied by evonik industries ag pharma polymers & services, kirschenallee, 64293 darmstadt, germany. i attach a copy of the specification and test methods documentation of eudragit l100-55 as appendix
  5. 3) according to appendix 1, a test solution is made by forming a 12.5% weight/volume solution, see page 2 [”a 12.5 % solution of the dry substance in iso- propyl alcohol/water is used for the test solution: a quantity of eudragit® l 100-55 corresponding to 12.5 g dry substance is dissolved in a mixture of 84.9 g isopropyl alcohol and 2.6 g water”.] 4) from this < solution a film can be prepared, see also page 2 *”when the test solu- tion is poured onto a glass plate, a clear film forms upon evaporation of the sol- vent”]. 5) in order to test whether a gel forms with eudragit l100-55, i prepared a film exact- ly according to the steps outlined in paragraph
(3)and
(4)to form a transparent - 14 - film, with the exception that i cast a film on a ptfe (polytetrafluroethylene) sub- strate. i cast a film onto ptfe to facilitate removal of the film so that i could sepa- rate the film from the supporting substrate. the film so prepared was brittle and rigid. i enclose a photograph of a film prepared in this manner in appendix
  1. in this image, the circular film was snapped into two halves, illustrating its brittle na- ture. 6) in order to determine whether this film forms a gel, i immersed this film into disso- lution media of ph 6.2 prepared according to ep907364 at page 5, lines 55-
  2. i per- formed this test on the two semi-circular films prepared and shown in appendix
  3. 7) when i immersed the film into ph 6.2 media, the film turned from a brittle and ri- gid film into a non-rigid, hydrated and pliant film. i enclose < photographs of the two films exposed to ph 6.2 in appendix
  4. 8) i subsequently weighed this film as a wet gel and also after drying the film at 105° c. the film exposed to ph 6.2 contained approximately 80% water by weight. i en- close an image of the film after removal of the aqueous phase in appendix
  5. 9) these results show that a eudragit l100-55 film prepared in accordance with the technical specification sheet of evonik, exposed to ph 6.2 (the dissolution media in ep907364) shows that the film swells in this media, absorbing approximately 5 ti- mes the films weight. this behaviour is indicative of a gel, and consequently eu- dragit l100-55 forms a gel when placed in ph 6.
  6. < appendix
  7. image of film prepared according to evonik specification sheet. appendix
  8. image of film prepared according to evonik specification sheet immersed in dissolu- tion media, ph 6.
  9. - 15 - appendix
  10. image of film prepared according to evonik specification sheet immersed in dissolu- tion media, ph 6.2 and dried at 105° c. <” - 16 - professor jukka seppälä har afgivet erklæring af
  11. december 2014 (herefter seppälä 1). af erklæringen fremgår bl.a.: ”expert statement on solubility properties of polymer eudra- git l 100-55 < background on polymer solubility properties polymers are by definition high molecular weight substances that dissolve somewhat differently in comparison to small molecules. basic chemical composition is a key pa- rameter to dictate the solubility of linear polymers into water. it is essential that the water molecules have the natural ability to penetrate among the polymer molecules and that the polymer molecules eventually transfer into the surrounding water pha- se. due to the large molecular size, the first temporary stage in this process is usually swelling. gel and its formation the swelling phenomenon in connection to dissolving polymer has to be differen- tiated from another phenomenon named gelling. gel has the following definition in polymer science: a gel is a substance composed of at least two components: 1) the first component, usually a polymer, forms a three dimensional network by virtue of covalent or non- covalent bonding; 2) the second component is liquid, e.g. water, which functions as a medium of the aforesaid network making it elastic. thus, a gel and a soluble polymer shall not be conceptually mixed with each other. in gel, the polymer absorbs the liquid, in this case water, but the molecular network structure prevents the polymer from dissolving. it is essential that the gel has a po- lymer network structure, it is non-creeping and it shows long standing stable shape which even recovers elastically after deformations. conclusion; eudragit l 100-55 is not a gelling agent polymer known with the trade name eudragit l 100-55 is an anionic copolymer ba- sed on methacrylic acid and ethylacrylate. it dissolves in neutral and basic aqueous conditions when the anionic carboxyl groups included in its chemical structure form a salt at ph values above 5.
  12. in evaluating the nature of the polymer, one has to consider the aforementioned scientific definition of polymeric gel stating that in gel, the polymer forms a three dimensional network. furthermore, one has to take into account the chemical compo- sition and the linear structure of eudragit l 100-55 which is not susceptible for such a network formation in water, and also the well-known polymer supplier’s specifica- tion (evonik <) stating fast dissolution in the upper bowl at ph over 5.
  13. - 17 - on the basis of the aforesaid, i consider to be clear that eudragit l 100-55 is a soluble polymer which does not fall within the category of polymers forming a gel when in contact with water.” dr. luk har afgivet supplerende erklæring af
  14. juni 2015 (herefter luk 2). af erklæringen fremgår bl.a.: “gelling characteristics of eudragit l100-55 < 1) i was asked by counsel for astrazeneca to provide my comments to the points rai- sed by orion in respect to [luk 1] and to the reports submitted by persons retained by orion. the initial testing described in [luk 1] < 3) as described in [luk 1], in order to test whether a gel forms with eudragit l100-55, i prepared a film exactly according to the steps outlined in paragraph
(6)and
(7)of the evonik specification sheet < to form a transparent film, with the exception that i cast a film on a ptfe (polytetrafluroethylene) substrate (the reason for mak- ing this exception – which did not have any impact on the result – is that the film prepared according to evonik is for identification by infrared spectroscopy which commonly uses a nacl crystal as an infrared transparent support. in my experi- ments i used a ptfe substrate for ease of delaminating the film so that i could per- form the test exposing the film to water solution). this is the manufacturer’s test that describes how to prepare a film. this allows a look into how the eudragit l100-55 functions in the dosage form, by forming a barrier layer, to control the re- lease of the active ingredient. 4) as further described in [luk 1], in order to determine whether this film forms a gel, i immersed the film into dissolution media of ph 6.2 prepared according to ep907364 at p. 5, ll. 55-
  1. the dissolution media has the same ph as the gastroin- testinal tract where the barrier layer will form and control the release of the active ingredient. 5) the purpose of the experiment was to determine whether eudragit l100-55 beha- ves as a gel in accordance with ep
  2. accordingly, the experiment was perfor- med using instructions from evonik industries in view of the dissolution testing described in ep907364 at p. 5, ll. 54-
  3. 6) the experiment definitively concluded that eudragit l100-55 forms a gel when in contact with water as can be seen by the pictures attached to my initial expert re- port (appendixes 2-4 to [luk 1]). in addition to my experiment, this conclusion is supported by the literature from the time of the invention. for example < [kim- artiklen] < manufactured drug containing hydrogels based on eudragit l as the gelling agent, for the purpose of controlled release formulation of that drug. eu- - 18 - dragit l is a methacrylic acid:ethyl acrylate copolymer, as referred to in the evonik literature < 7) thus, eudragit l100 55 can function as a gel that retards the release of drug. fur- thermore, eudragit l100-55 behaves in this manner because at a range physiologi- cal ph values (which is, through the intestine, approximately ph 7), there exists two functional groups, a carboxylic acid group which can form strong hydrogen bonds and is insoluble in water, and an ionized function group, which is water so- luble < however, in the presence of unionized carboxylic acid, a situation which exists at a ph of 6.2 (under which i performed my test and in accordance with the teachings of ep907364), the carboxylic acid groups present form h-bonded cross- links and therefore prevent or retard dissolution of the ionized carboxylic acid groups < collectively, this combination of carboxylic acid and carboxylate salt gives rise to a mixture of water soluble regions (in blue) and water insoluble re- gions (in red) which is represented schematically in figure
  4. this leads to the gel i observed in my experiment, and is also the basis of the gel based preparations re- ported by kim et al. this is also consistent with professor seppälä’s definition of a gel (although i disagree that such a narrow description is taught by the ep907364). < figure 3: schematic of hydrogel comprising hydrophilic carboxylate ion groups on polymer (----), insoluble carboxylic acid h-bonded cross-links (----) and water, hydra- ting carboxylic ion groups . <” dr. luk har endvidere afgivet supplerende erklæring af
  5. juli 2015 (herefter luk 4) (dr. luks tredje erklæring er ikke fremlagt under denne sag). af erklæringen fremgår bl.a.: ”final report: swelling tests of ketipinor <
  6. ketipinor, 200mg tablets
(100x), batch 1404835, expiry 11/2017 < swelling test in water (ph 5-7) the swelling in a neutral ph (ph 5-7) as demonstrated below is in accordance with the neutral conditions that is relevant for the small and large intestine where the re- lease and absorption of quetiapine occurs over a sustained time period. visual assessment (videography) of the swelling behaviour of the product following the below parameters (as outlined in ep 0 907 364 b1; pg 5, para 0036-0037, line 53 - 54) was performed. - 19 -
  1. i)dissolution media: ultra-pure water 900 ml apparatus: paddles speed: 100 rpm time period: 8 hours in the presence of ultra-pure water, the tablet swells markedly, in all directions, e.g. length, width and height. in my opinion, this behaviour is consistent with the formu- lation forming a hydrophilic matrix tablet, where the water soluble components (lac- tose, maltose and quetiapine fumarate) are contained within a hydrophilic gel. in this case, the gel can only have been formed from eudragit l100-55, which is present as a coating and also within the interior of the tablet. conclusion ketipinor is not immediately dissolved in the presence of water, but rather forms a hydrophilic matrix tablet, wherein the gelling agent is eudragit l100-55.” professor seppälä har afgivet supplerende erklæring af 20. august 2015 (herefter seppälä 2). af erklæringen fremgår bl.a.: ”dissolution tests of ketipinor and seroquel tablets a test run series was carried out to demonstrate ketipinor tablet behavior in condi- tions corresponding to stomach acidic conditions (0.1n hcl aqueous solution ph around 1), and corresponding to intestine conditions (buffered solution of ph 6.2). - 20 - experiment no. 1 a ketipinor tablet 200 mg (orion pharma) was immersed into 900 ml of 0.1 n hcl in a standard dissolution device vessel stirred with rotating paddle 50 rpm. rotation speed of 50rpm was used instead of 100rpm to avoid any disintegration of the tablets due to mechanical shearing. after 4 hours the tablet was removed, surface dried, weighted and photographed. initial weight: 518 mg weight after 4 hours in 0.1n hcl: 397 mg the experiment shows a 23 % weight reduction of the ketipinor tablet after 4 hours in around ph 1 (i.e. 0.1n hcl). no gel formation was observed at any stage of the experiment. figure 1 left: ketipinor tablet before (upper) and after (lower) 4 hours immersion in 0.1 n hcl. right: tablet cut after 4 hours immersion in 0.1 n hcl. experiment no. 2 ketipinor tablet 200 mg (orion oyj) was immersed into 900 ml of 0.1 n hcl in a stan- dard dissolution device vessel stirred with a rotating paddle 50 rpm. after 7.75 hours the tablet was removed, surface dried, weighted and photographed. initial weight: 525 mg weight after 7.75 hours in 0.1 n hcl: 397 mg the experiment shows a 24 % weight reduction of the ketipinor tablet after 7.75 hours in 0.1 n hcl. no gel formation was observed at any stage of the experiment. - 21 - figure 2. ketipinor tablet before (upper) and after (lower) 7.75 hours immersion in 0.1 n hcl. experiment no. 3 3.1 a ketipinor tablet 200 mg (orion oyj) was immersed into 900 ml of 0.1 n hcl in a standard dissolution device vessel stirred with a rotating paddle 50 rpm. after 2 hours the tablet was removed, surface dried, weighted and photographed. thereafter the same tablet was immersed into 900 ml ph 6.2 buffered aqueous solu- tion in a stirred vessel of the same kind. the tablet was removed and weighted at time points 1 hour and 4 hours from the time of immersion into ph 6.2. weight in change vs. initial milligrams weight initial weight 523 weight after 2 hours in 0.1 n hcl 489 -6.5 % weight after 1 hour in ph 6.2 424 -19 % weight after 4 hours in ph 6.2 232 -56 % the sample started to disintegrate in fifteen minutes after immersion into ph 6.2 and was significantly eroded after four hours in ph 6.2. the experiment shows a 56 % overall weight reduction of the ketipinor tablet. no gel formation was observed. 3.2 a seroquel prolong® tablet 200 mg (astrazeneca) was immersed into 900 ml of 0.1 n hcl in a standard dissolution device vessel stirred with a rotating paddle 50 rpm. af- ter 2 hours the tablet was removed, surface dried, weighted and photographed. thereafter the same tablet was immersed into 900 ml ph 6.2 buffered aqueous soluti- on in a stirred vessel of the same kind. the tablet was removed and weighted at time points 1 hour and 4 hours from the time of immersion into ph 6.2. weight in change vs. initial milligrams weight initial weight 627 weight after 2 hours in 0.1 n hcl 933 +49 % weight after 1 hour in ph 6.2 749 +19 % weight after 4 hours in ph 6.2 823 +31 % the seroquel sample retained the gelly structure over the entire experiment, and increased in the weight 19 – 49 %. - 22 - figure 3 left: ketipinor tablet before (upper) and after (lower) 2 hours immersion in 0.1 n hcl followed by 4 hours immersion in ph 6.2 buffered solution. right: seroquel tablet before (upper) and after (lower) 2 hours immersion in 0.1 n hcl fol- lowed by 4 hours immersion in ph 6.2 buffered solution. experiment no. 4 a ketipinor 200 mg tablet was weighted (520
  2. mg)and immersed into 900 ml of ion exchanged water, magnetic stirring at 37 °c. the tablet was removed from water after one hour time, surface dried and weighted. weight: 545 mg. no gel was observed (see figure 4). figure 4. left: ketipinor tablet after 1 hour immersion into ion-exchanged water for 1 hour. right: tablet after 1 hour, broken to two halves. conlusions experiment 1  after 4 hours immersion in 0.1 n hcl, a 23 % weight reduction was observed in the ketipinor tablet weight, which is not compatible with the idea of a gel. no gel formation was observed at any stage of the experiment. - 23 - experiment 2  after 7.75 hours immersion in 0.1n hcl, a 24 % weight reduction was ob- served in the ketipinor tablet, which is not compatible with the idea of a swel- ling gel. no gel formation was observed at any stage of the experiment. experiment 3  in the experiment where the ketipinor tablet was first exposed to acidic condi- tions for 2h, followed by ph 6.2 exposure for 4 h, an overall weight reduction of 56 % was measured in the ketipinor tablet. such weight reduction is not compatible with the idea of a swelling gel. no gel formation was observed at any stage of the experiment.  cutting of the ketipinor tablets showed powdery structure, no gel.  some apparent deformation of a tablet is not an indication of gel formation.  in the same conditions, the astrazeneca seroquel tablet swells (gains weight and increases in size in all dimensions) and the observations shows a wet, sticky and viscous material. these characteristics are consistent with the iu- pac definition of a gel. experiment 4  after 1 hours immersion into 900 ml of ion exchanged water, cutting of the ke- tipinor tablet showed a powdery core structure, no gel.  the tablet’s change in weight was less than 5 %. overall conclusion the observations as well as the weight measurements show that orion’s ketipinor tablet does not show any indications of gel formation when exposed to either ion ex- changed water, conditions corresponding to stomach ph or conditions correspond- ing to intestine ph.” professor sven frøkjær har afgivet erklæring af 20. august 2015 (herefter frøkjær 1). af den danske oversættelse af erklæringen fremgår bl.a.: ”det spørgsmål, som jeg er blevet bedt om at tage stilling til, er: om hvorvidt eudragit l 100-55 – som jeg forstår, er en ingrediens i kernen af orions ketipinor tabletter – danner en gel, når det bringes i kontakt med vand, som stridspa- tentet kræver (afsnit [0010]), og derfor kan betragtes som et ”geleringsmiddel” i en formulering med langvarig frigivelse ifølge krav 1 i patentet. i henhold til patentet [0010] betyder udtrykket geleringsmiddel et hvilket som helst stof, især et hydrofilt stof, som danner en gel, når det bringes i kontakt med vand, og omfatter følgelig sådanne stoffer som [hpmc] osv. - 24 - krav 1 i stridspatentet definerer en formulering med langvarig frigivelse, som omfat- ter et geleringsmiddel og [quetiapin] eller et farmaceutisk acceptabelt salt deraf sam- men med en eller flere farmaceutisk acceptable excipienser. smpc for ketipinor < angår quetiapinfumarat formuleret som en depottablet. exci- pienserne i tabletkernen omfatter lactose (anhydrat/vandfri), magnesiumstearat, methacrylsyre - ethylacrylat-copolymer (1:1) type a, maltose og talkum. tabletcoa- tingen omfatter methacrylsyre-ethylacrylat-copolymer (1:1) type a og triethylacetat. eudragit l 100-55 er en copolymer bestående af en methacrylsyre og ethylacrylat og opfylder specifikationen i overensstemmelse med ph.eur. monografien for metha- crylsyre - ethylacrylat-copolymer (1:1) type a. [luk 4] viser, at ketipinor ikke opløses med det samme eller desintegrerer ved tilste- deværelse af vand, men kvælder på en måde, der er i overensstemmelse med opførs- len af en hydrofil matrixtablet, som indeholder et geleringsmiddel som dem, der er beskrevet i stridspatentet. når man betragter listen af excipienser i tabletkernen, kan kvældningsadfærden kun tilskrives eudragit l 100-55 og dets interaktion med vand. en depotvirkning af en tabletformulering kan opnås på forskellige måder, f.eks. ved en coating, der kontrollerer frigivelsen af lægemiddelstoffet eller med en matrixstruk- tur, hvor frigivelsen af lægemiddelstoffet kontrolleres af diffusionen via matrixen. i ketipinor-depottabletten kan eudragit l 100-55-coatingen ikke virke som en frigi- velseskontrollerende coating, fordi tabletten kvælder op, hvilket vil medføre, at fil- men går i stykker – hvis den ikke allerede er opløst efter at have passeret maven – på grund af ændringen fra en sur ph til en ph på ca. 5,5. dette tyder stærkt på, at den kontrollerede frigivelse af quetiapinfumarat opnås på grund af matrixstrukturen af den kvældende/kvældede ketipinor-tablet. ... dette er < i overensstemmelse med definitionen [af en gel] i den danske lærebog ”almen farmaci” af henning gjelstrup kristensen < eudragit l 100-55 er en hydrofil polymer, hvor polymerkæderne kan bindes sammen via intermolekylære kræfter, f.eks. iontiltrækning og hydrogenbindinger. at dette faktisk finder sted i ketipinor-depotformuleringen, er tydeligt dokumenteret ved hjælp af det forsøg, som dr. luk har udført. skønt eudragit l 100-55 til sidst kan op- løses helt under passagen gennem mave-tarmkanalen, står det absolut klart for mig, at ketipinors egenskaber med hensyn til langvarig frigivelse må tilskrives matrix- strukturen (den kvældede tablet), og at matrixstrukturen er en hydrofil gel dannet af eudragit l 100-55 på grund af intermolekylære bindinger mellem polymerkæderne. konklusion: på grundlag af den dokumentation, jeg har modtaget, og min generelle ekspertise in- den for farmaceutiske formuleringer konkluderer jeg, at eudragit l 100-55 i kernen af ketipinor-depottabletten danner en gel, når det bringes i kontakt med vand eller et vandigt medium, såsom tarmvæsken, og følgelig er et geleringsmiddel som defineret i patent ep 0 907 364 b1 [0010].” - 25 - professorerne jukka seppälä og thomas rades har afgivet en fælles erklæring af 16. septem- ber 2015 (herefter seppälä/rades’ fælles erklæring). af erklæringen fremgår bl.a.: ”dissolution tests of ketipinor and seroquel tablets two test run series was carried out to demonstrate ketipinor tablet (orion pharma) behavior in various ph-conditions: experiment set no. 1: phosphate buffer ph 5.5, phosphate buffer ph 6.8, de-ionized water, experiment set no. 2: aqueous solution 0.1n hcl (ph1.2), phosphate buffer ph 5.5, phosphate buffer ph 5.8, phosphate buffer ph 6.2. seroquel tablets (astrazeneca) were used as comparative reference. experiment set no. 1 test 1a. a ketipinor tablet (orion pharma) and a seroquel tablet (astrazeneca) were im- mersed into 900 ml of phosphate buffer ph 5.5 in two separate standard dissolution device vessels stirred with rotating paddle 100 rpm, temperature 37°c. after 30min, 1h, 3,5h and 8hrs the tablets were removed, surface dried, evaluated in physical cha- racter, weighted and photographed. table 1. test run 1a in aqueous phosphate buffered solution ph 5.5. time ketipinor / orion seroquel / astrazeneca point/ weight physical appearance weight physical appearance hrs mg +/- mg +/- % % 0 526 622 0.5 540 +2.7 solid, dry surface 796 +28 wet, gelly, swollen 1 544 +3.4 dry, non-sticky surface 804 +29 sticky swollen 3.5 541 +2.8 non-sticky surface 684 +10 sticky swollen 8 470 -11 non-sticky surface. 236 -62 sticky swollen core: wet fine powder like ”wet sand” - 26 - figure 1. dissolution in ph 5.5 at time point 0.5 hour. left: ketipinor right: seroquel. figure 2. ph 5.5 at time point 3.5hrs. left: ketipinor right: seroquel. figure 3. ph 5.5 at time point 8hrs. left: ketipinor right: seroquel. figure 4 a. ketipinor after 8hrs at ph 5.5 after cutting, ”wet sand”. left before and right after standing in ambient conditions overnight. - 27 - figure 4 b. seroquel after 8hrs at ph 5.5. left before and right after standing in ambient condi- tions overnight. test 1b. a ketipinor tablet (orion pharma) was immersed into 900 ml of phosphate buffer ph 6.8 in a standard dissolution device vessels stirred with rotating paddle 100 rpm, temperature 37°c. after 30min, 1h, 3,5h and 8hrs the tablets were removed, surface dried, evaluated in physical character, weighted and photographed. table 2. test run 1b in aqueous phosphate buffered solution ph 6.8. time ketipinor / orion point/ hrs weight physical appearance mg +/- % 0 520 0.5 470 -10 solid, dry surface, starting to erode 1 309 -41 non-sticky surface, eroded 3.5 71 -86 largely eroded 8 - figure 5 ketipinor tablet at ph 6.8 after 1h. test 1c. a ketipinor tablet (orion pharma) and a seroquel tablet (astrazeneca) were immer- sed into 900 ml of de-ionized water in two separate standard dissolution device ves- sels stirred with rotating paddle 100 rpm, temperature 37°c. after 30min, 1h, 3,5h and 8hrs the tablets were removed, surface dried, evaluated in physical character, weighted and photographed. table 3. test run 1c de-ionized water. - 28 - time ketipinor / orion seroquel / astrazeneca point/ weight physical appearance weight physical appearance hrs mg +/- mg +/- % % 0 522 608 0.5 536 +2.7 solid, dry surface, text 780 +28 wet, swollen surface visible 1 518 -0.7 non-sticky surface 805 +32 swollen, sticky 3.5 494 -5.3 non-sticky surface 740 +22 swollen, sticky 8 386 -26 non-sticky surface, 187 -69 swollen, sticky core: grainy, ”wet sand” core: sticky, swollen like powdery figure 6. left: ketipinor tablet after 1h in deionized water. right: seroquel tablet after 1h in de-ionized water. figure 7. de-ionized water 3.5hrs. left: ketipinor. upper: intact reference. lower: sample. right: seroquel. upper: intact reference. lower: sample experiment set no. 2 test 2a a ketipinor tablet (orion pharma) was immersed into 900 ml of 0.1n hcl (ph 1.2) aqueous solution in a standard dissolution device vessel stirred with rotating paddle - 29 - 100 rpm, temperature 37°c. after 1h and 2hrs the tablets were removed, surface dried, evaluated in physical character, weighted and photographed. table 4. test run 2a 0.1n hcl aqueous solution ph 1.2. time ketipinor / orion point/ hrs weight physical appearance mg +/- % 0 518 1 488 -5.8 dry on touch, solid, mark visible 2 369 -29 dry non-sticky solid surface core: dry compressed tablet figure 8. ketipinor tablet in 0.1n hcl. left: 1h time point. right upper: 2 hrs time point. right lower: intact reference. test 2b a ketipinor tablet (orion pharma) and a seroquel tablet (astrazeneca) were immer- sed into 900 ml of phosphate buffer ph 5.5 in two separate standard dissolution de- vice vessels stirred with rotating paddle 100 rpm, temperature 37°c. after 1h and 2hrs the tablets were removed, surface dried, evaluated in physical character, weigh- ted and photographed. table 5. test run 2b phosphate buffer ph 5.5. time ketipinor / orion seroquel / astrazeneca point/ hrs weight physical appearance weight physical appearance mg +/- mg +/- % % 0 525 623 1 554 +5,5 dry solid, mark visible 823 +32 swollen, gelly surface, sticky 2 536 +2.1 dry non-sticky solid. 789 +27 gelly, sticky on the core: wet fine powder, surface ”wet sand” dry in the middle, gel on the skin - 30 - figure 9. dissolution test at ph 5.5 after 2hrs. left: ketipinor. right: seroquel. test 2c two ketipinor tablets (orion pharma, two parallel experiments) were immersed into 900 ml of phosphate buffer ph 5.8 in two separate standard dissolution device ves- sels stirred with rotating paddle 100 rpm, temperature 37°c. after 1hour and 2hours the tablets were removed, surface dried, evaluated in physical character, weighted and photographed. table 6. test run 2c phosphate buffer ph 5.8. two parallel samples of ketipinor. time ketipinor / orion seroquel / astrazeneca point/ weight physical appearance weight physical appearance hrs mg +/- mg +/- % % 0 521 518 1 539 +3,5 dry skin, mark visible 537 +3.7 dry solid, mark visible 2 464 -11 dry surface, solid, non- 474 -8.5 core: wet fine powder sticky ”wet sand” core: wet fine powder, ”wet sand” figure 10. dissolution test at ph 5.8 after 2hrs ketipinor tablet. - 31 - test 2d a ketipinor tablet (orion pharma) was immersed into 900 ml of phosphate buffer ph 6.2 in a standard dissolution device vessel stirred with rotating paddle 100 rpm, tem- perature 37°c. after 1h and 2hrs the tablet was removed, surface dried, evaluated in physical character, weighted and photographed. table 7. test run 2d phosphate buffer ph 6.2. time ketipinor / orion point/ hrs weight physical appearance mg +/- % 0 521 1 509 -2.3 dry, solid, mark visible 2 371 -29 solid, half eroded. dry on touch, non-sticky hard on touch core: wet fine powder ”wet sand” figure 11. ketipinor tablet after 2hrs in ph 6.2. conclusions experiment set no.1  clear qualitative difference in behavior is seen in weight and appearance be- tween ketipinor and seroquel tablets in dissolution in phosphate buffer solu- tions ph 5.5 and in purified water.  in purified water and in ph 5.5 seroquel tablets quite rapidly gained weight (approx. 30 %) and on the surface a gel had clearly formed.  in purified water and in ph 5.5 ketipinor tablets gained a little weight (<5%) to begin with. no indication of gel formation on the surface.  at ph 6.8 ketipinor tablets were largely eroded/dissolved after 3.5 hrs (>80%). at no time point did the tablet gain weight. < - 32 - experiment set no.2  clear qualitative difference in behavior is seen in weight and appearance be- tween ketipinor and seroquel tablets in phosphate buffer solution ph 5.5.  at ph 5.5 seroquel tablets quite rapidly gained weight (approx. 30 %) and on the surface a gel had clearly formed.  at ph 5.5 ketipinor tablets gained a little weight (up to approx. 5%) to begin with. no indication of gel formation on the surface.  at ph 5.8 the ketipinor tablet gained a little weight (3-4%) to begin with but after 2 hrs. the weight had decreased by approx. 10%. thus, the dissolution behavior clearly changes between ph 5.5 and 5.8. this trend was further reinforced at ph 6.2 where the weight of the kepitinor tablet had decreased by approx. 2% after 1h and by 29% after 2 hrs. at no time point was there any indication of gel formation. < overall conclusions: the experiments did not indicate any gel formation in ketipinor tablets and clearly the sustained release profile of ketipinor tablets is not achieved through gel forma- tion.” professor rades har afgivet en yderligere erklæring af 16. september 2015 (herefter rades 1). af erklæringen fremgår bl.a.: ”polymers and gelling agents 1. please provide your basic explanation about the role of a polymer in a pharma- ceutical formulation when it is acting: (
  3. a)as a binder in the core of a tablet or (
  4. b)as an enteric coating of a tablet binders are an essential part of a tablet formulation. the main role of a binder is to al- low tablets to be formed under the mechanical stress of tablet compaction and to keep their shape and compacted state after tableting. if granules are formed of a pow- der mix before tableting, binders are added to allow granule formation. polymers can be used for this purpose, either added to the powder mix as a solution (followed by drying of the granules) or as dry binders. depending on the concentration and nature of the binder used, these can affect the drug release from the tablet, with more hydro- philic, fast dissolving binders leading to a faster drug release than more hydrophobic, slowly dissolving binders. likewise, high concentrations of a binder may lead to slo- wer drug release. the main purpose of a polymer used in enteric coating is to protect the drug from the harsh environment of the stomach (or to protect the stomach form irritating effects of the drug) by forming a continuous layer on the surface of the tablet. polymers used for this purpose are ph sensitive, i.e. they are insoluble at the low ph conditions of - 33 - the stomach but soluble at the higher ph conditions of the small intestine. this ph dependence is achieved by the presence of free carboxylic acid groups in the polymer that are non-ionized in the stomach (the polymer thus has a comparatively low polar- ity and thus is insoluble in water) but get ionized in the intestinal ph conditions (high polarity, soluble). however, depending on the type of polymer used and the thickness of the coating layer, some water may enter the tablet and some drug release may occur also under gastric conditions. 2. is the definition of a gel (in a polymer) provided by professor seppälä [seppälä 1] consistent with the definition provided iupac? the definition of a gel, given by prof. seppälä is a short general definition of gels which, in my opinion, is consistent with the iupac definition. the iupac definition is more detailed, and lists possibilities of the nature of the gel forming interactions in a polymer network as well as other gel-formers than polymers. 3. is the fact that a polymer/tablet swells proof of polymer gelling? no. whilst gelling is accompanied by swelling, the opposite conclusion, i.e. that swelling is indicative of gelling is not necessarily true. swelling of a material is an increase in volume (through and increase in mass) by uptake of another material. polymers for example can swell through the uptake of moisture from the air or a liquid surroun- ding. especially amorphous (non-crystalline) polymers can take up moisture. these water molecules are usually hydrogen bonded to the polymer and since they add mass to the polymer, this will lead to some swelling as well as a lowering of the glass transition temperature (acting as a plasticizer). the amount of moisture taken up is usually limited to a few percent, but can, depending on the hygroscopicity of the po- lymer also be substantial. this process would not be defined as a gel formation. compacted powders, for example of a polymer (but not restricted to these), can also swell as a function of water uptake through for example capillary forces through gaps between the powder particles. moreover, if soluble components are present in a compacted powder, water entering the compact for example by capillary forces, may dissolve a part of the soluble components, creating a higher osmotic pressure inside the compact, leading to further water ingress into the compact, and thus to further swelling. this would not be regarded as a gelling process. in the case of coated tablets, the uptake of water (e.g. water entering the interior of the tablet through the coating surrounding the tablet) may also result in tablet swel- ling. as the tablet swells, the coating may be expanded until the swelling causes the coating to crack or break (depending e.g. on the plasticity of the coating). this pro- cess has nothing to do with gelling. 4. what is the typical scope of application for eudragit l100-55 according to text books and commercial materials, such as the evonik specification of eudragit l100-55? eudragit l100-55 is an anionic co-polymer of methacrylic acid and ethyl acrylate. since it contains (ionizable) free carboxylic acid groups, it is ph depended in its dis- - 34 - solution properties. eudragit l100-55 is insoluble in aqueous solutions at ph levels under 5.5, but becomes soluble at ph levels above 5.5. as such, eudragit l100-55 is usually used as a ph responsive coating on granules, pellets or tablets, to restrict drug release in the stomach (ph below 5.5) but to allow drug release in the small in- testine (ph levels above 5.5). the polymer may also be used as a binder in granulati- on and tableting processes. pharmaceutical formulations and sustained release 5. please briefly describe the most common mechanisms to obtain ”sustained re- lease” from pharmaceutical formulations? several mechanisms to achieve sustained release are listed in textbooks < excluding gastro retentive and bio-eroding polymer based systems (that are not of re- levance here), one can differentiate dissolution and diffusion based mechanisms. in dissolution rate limited sustained release processes, slow dissolution of the dosage form (or indeed the drug itself), is the main mechanism of sustaining drug release. this can be based on poor solubility of the materials (drug and/or excipient) under certain ph conditions. in contrast to dissolution rate limited sustained release, in diffusion based systems, the slow diffusion of the drug through, for example, a lipidic or polymer matrix (so called matrix systems) or a coating (so called reservoir systems) is the rate limiting step for drug release. release mechanism – seroquel® prolong vs. ketipinor® depot 6. please briefly describe the sustained release mechanism of astrazeneca’s sero- quel® prolong? the sustained release mechanism of astrazeneca’s seroquel® prolong is in my opi- nion based on a diffusion based mechanism, i.e. the slow diffusion of the drug through a gel formed by the polymer hydroxypropylmethylcellulose (hpmc). this gel formation is a largely ph independent process. however, since the solubility of the drug will be ph dependent, and higher at the low ph conditions of the stomach, the addition of a buffer (sodium citrate) may have been necessary to locally create a micro ph environment to affect the release of the drug. under acidic (gastric) condi- tions it will nevertheless be necessary for the gel to form quickly, since the drug has a higher solubility under these conditions than under less acidic or near neutral condi- tions (small intestine). 7. please briefly describe the sustained release mechanism of orion’s ketipinor ® depot? the sustained release mechanism in orion’s ketipinor® depot in my opinion is based on two effects: firstly, the enteric coating (a film formed by eudragit l100-55 that is insoluble at ph conditions such as in the stomach (lower than 5.5)). under these con- ditions the drug would be soluble, and, without the coating, would release fast. ho- wever, the insoluble polymer coating largely (but not completely) prevents this. in this sense the thin eudragit l100-55 coating can be regarded as a rate-limiting mem- - 35 - brane providing sustained release of the drug as in a reservoir system. some water may penetrate into the core of the tablet and dissolve a portion of the drug that is then released. secondly, once the higher ph conditions of the small intestine have been reached, the polymer coating will dissolve and the drug can be released directly from the interior of the tablet to the surroundings as the tablet slowly erodes or disin- tegrates. however, under these conditions the drug is poorly water soluble and thus will be released slowly (dissolution based sustained release) even without a coating. it is thus the poor dissolution of the drug under the ph conditions in the small in- testine that largely sustains the drug release. the composition of the core may, however, contribute to the release-rate of the drug by slowing down or increasing the release of drug over time, by aiding or decreasing the contact between the drug and the liquid surroundings. as stated in my above answer 1, high concentrations of a binder may lead to slower drug release, simply by limiting the contact between the drug and the liquid surroundings. fast dissolving binders will provide a faster drug release than slowly dissolving binders. 8. please explain major differences between seroquel ® prolong and ketipinor® de- pot in terms of their release mechanisms? the major differences in the release mechanisms of seroquel ® prolong and ketipi- nor® depot are that the former is in essence a diffusion controlled sustained release system whereas the latter is a diffusion controlled system at gastric ph conditions and a dissolution controlled sustained release system at intestinal ph conditions. gel formation is essential for the action of seroquel ® prolong but is not relevant for the action of ketipinor® depot. 9. is the fact that seroquel® prolong and ketipinor® depot are bioequivalent un- ambiguous proof that the two products possess the same sustained release me- chanisms? no. bioequivalence is determined based on the plasma concentration time curves of the drug being ”similar” between different products. however, these plasma concen- tration time curves of the drug can be achieved by using a range of formulation ap- proaches, for example diffusion and dissolution based sustained release systems but also others, such as erosion based systems etc. experimental evidence in the case 10. what may in your opinion be derived from [luk 4]? dr. shen yung luk's experiments described [luk 4] show swelling of ketipinor 200 mg tablets in water. the test is performed in water, but the exact ph conditions are not stated. in my opinion, the ph conditions should have been defined or at least recorded, as should have the time after immersion, when the tablet is removed from the aqueous environment. also, in dr. shen yung luk's experiments gel formation of the polymer is implied by the observed swelling of the tablet, but these two processes are not ne- cessarily the same. swelling can occur through ingress of water for example by capil- lary forces. moreover, rather than the volume, the weight gain of the tablets should - 36 - have been recorded. whilst there appears to be an increase in volume of the tablet, in my opinion, this does not allow the conclusion that a gel formation of the polymer eudragit l100-55 is responsible for this. 11. on 9 and 10 september 2015 you were present during dissolution experiments with respect to ketipinor® depot and seroquel® prolong tablets at orion’s pre- mises in finland [seppälä/rades’ fælles erklæring]. furthermore, you have read [seppälä 2] describing certain dissolution experiments with respect to dissolution of ketipinor depot and seroquel® prolong tablets. in your opinion what may be deducted from these experiments with regard to how sustained release is achieved in ketipinor tablets passing through the gastro-intestinal tract? no, or only a very small, weight gain of the ketipinor® depot tablets was found, and the texture of the tablets also does not indicate that any gel formation would have taken place. the opposite was true for the seroquel ® prolong tablets, with both sub- stantial weight gain and a sticky, gel-like appearance of the tablet. in my opinion these results do not support the idea that the polymer eudragit l100- 55 forms a hydrogel in the ketipinor® depot tablet in the investigated ph conditions (1.2, 5.5, 5.8, 6.2, 6.8, deionized water) but do support the idea that the polymer hpmc present in seroquel® prolong tablets does so. the experiments allow the conclusion that no gel formation takes place in ketipinor® depot tablets in any of the ph conditions tested and thus this cannot be the reason for the sustained release of the drug form these tablets. the opposite is true for sero- quel® prolong tablets.” dr. luk har ydermere afgivet supplerende erklæring af 22. september 2015 (herefter luk 5). af erklæringen fremgår bl.a.: ”gelling characteristics of eudragit l100-55 (part
  5. ii)and composition of eudragit l100-55 in ketipinor 200 mg quetiapine fumarate product. 1) < in this report i have addressed further comments raised by orion in respect of the gelling properties of eudragit l100-55 and furthermore provide chemical anal- ysis that in ketipinor’s product a eudragit l100-55 based gel is formed. 2) < as discussed in [luk 2], eudragit l100-55 forms a gel structure in water when it contains carboxylic acid groups (unionised and which act as a cross-linking agent) and carboxylate ions (which are the ionised form of carboxylic acid, and are so- luble). 3) in order to confirm that the chemical functional groups responsible for this me- chanism are present in the eudragit l100-55, i prepared a series of gels manufac- tured using the approach of kim and analysed these using infrared spectroscopy. infrared spectroscopy is particularly suited to the analysis of eudragit l100-55 gels since it is sensitive to the change in carboxylic acid groups to carboxylate ions. - 37 - 4) i prepared a series of gels using 1g of eudragit l100-55, to which i added 2 ml, 3 ml and 5 ml of water and sodium hydroxide (naoh) in a 20 ml scintillation vial. the sodium hydroxide was added at 1 meq, 2 meq, 3 meq and 10 meq naoh (1 meq naoh is 1 mm of naoh for each gram of eudragit l100-55). at the highest naoh concentration, the sodium hydroxide is present at a level which completely ionizes the carboxylic acid groups and therefore renders the eudragit l100-55 in a completely ionized state. 5) i calculated the ph of these gels. using a pka of polymethacrylic acid of 6, i input the three concentrations of 1 g of eudragit with the meq of naoh added into a standard ph calculation program (see http://www.chembuddy.com/?left=bate&- right=ph-calculator). the results are tabulated below; amount of eudragit l100- 1 meq 2 meq 3 meq 10 meq 55 / amount of water ml naoh naoh naoh naoh 1g / 2 ml 4.98 5.05 5.12 14 1g / 3 ml 5.19 5.31 5.43 14 1g / 5 ml 5.33 5.5 5.6 14 this shows that a gel is formed in the range between approximately ph 5 to 5.6 – a ph range that spans the ph of the media in the dissolution tests performed on the ketipinor tablets (see paragraph 16). 6) for the 1 meq, 2 meq and 3 meq naoh samples, the eudragit l100-55 forms a gel at all concentrations (ratio of eudragit to water) examined. in contrast, the 10 meq naoh sample was a viscous liquid. this shows that the gel formed at the lower naoh concentrations is related to the formation of cross-links due to residual car- boxylic acid groups as described by sandeep and also in [luk 2]. 7) for the samples prepared in 2 ml of water, the product was a solid rubbery mass which could be picked up with a pair of tweezers. figure 1: gel made from 2 ml water and 1 g of eudragit l100-55 with 1 meq naoh - 38 - figure 2: gel made from 2 ml water and 1 g of eudragit l100-55 with 2 meq naoh figure 3: gel made from 2 ml water and 1 g of eudragit l100-55 with 3 meq naoh 8) for the samples prepared in 3 ml of water, the gels exhibited zero flow when tilted to a horizontal position, whereas eudragit l100-55 to which 10 meq naoh was added exhibited flow. for the samples prepared in 5 ml of water, the gels exhibited deformation when tilted to horizontal, whereas eudragit l100-55 to which 10 meq naoh was added exhibited liquid flow, see attached video in electronic appendix 1 and also illustrated by the images below. figure 4: 1 g eudragit in 3 ml 1 vs 10 meq naoh. left- start in vertical position, right- after placing into horizontal position < - 39 - figure 5: 1 g eudragit in 3 ml 2 vs 10 meq naoh. left- start in vertical position, right- after placing into horizontal position < figure 6: 1 g eudragit in 3 ml 3 vs 10 meq naoh. left- start in vertical position, right- after placing into horizontal position < figure 7: 1 g eudragit in 5 ml 1 vs 10 meq naoh. left- start in vertical position, right- after placing into horizontal position < figure 8: 1 g eudragit in 5 ml 2 vs 10 meq naoh. left- start in vertical position, right- after placing into horizontal position < - 40 - figure 9: 1 g eudragit in 5 ml 3 vs 10 meq naoh. left- start in vertical position, right- after placing into horizontal position < 9) i analysed these samples using attenuated total reflectance infrared spectroscopy (atr-ir). the samples were placed onto the diamond crystal of a thermonicolet golden gate atr accessory, attached to a thermonicolet avatar spectrometer. data were acquired at a resolution of 4 cm-1 and averaged over 100 scans. data was then modified using advanced atr correction, with a reflection of 45° and a re- fractive index of 1.5 for diamond, to adjust for the optical effects of atr measure- ment. atr-ir measures the surface of a sample, in contact with the diamond. in this case, the sampling depth is approximately 5 μm. i also measured the eudragit l100-55 powder samples as they were received from the manufacturer. 10)i have plotted the atr-ir of the 2 ml compositions with different levels of naoh in figure 7 below. figure 7: atr-ir spectra of eudragit l100-55 at different levels of naoh, in 2 ml of water. as the naoh increases, the proportion of carboxylic acid converted to carboxylate increases. 11)the assignments are based on known spectra for identified functional groups as follows (
  6. a)peak 1740 – 1700 cm-1 = carbonyl due to carboxylic acid and ester (
  7. b)1640 cm-1 = water and (
  8. c)1560 cm-1 carboxylate group from ionized carbonyl. the graph shows that as the naoh level is increased, the carboxylate group increases reflecting the increased neutralisation of the carboxylic acid. 12)the spectra show that even at relatively low levels of meq naoh (1 meq) the car- boxylate ion can be detected. the 1 meq naoh forms a gel, as shown by the phys- ical characteristics observed for this level of naoh. the chemical composition of eudragit l100-55 on the surface of ketipinor 13)i then measured the surface of the ketipinor 200 mg tablet and also the core using atr-ir. the spectra are shown in figure 8 below. - 41 - figure 8: atr-ir of eudragit l100-55, the surface of ketipinor tablet, the core of ketipinor tablet. 14)it is evident that the surface of the ketipinor tablet contains quetiapine in addition to eudragit l100-55, which are indicated by peaks at ca. 1600 and 1570 cm-1. in or- der to remove this interference, i subtracted the spectrum of the core of the ketipi- nor tablet, which is predominantly quetiapine fumarate, to give a spectrum largely comprising the eudragit l100-55 coating. this is shown in figure 9 below. figure 9: atr-ir spectra of eudragit l100-55 and the surface of ketipinor tablet, after subtraction of quetiapine fumarate from the core of the tablet. the subtraction spectrum shows the presence of a peak at 1560 cm-1 assigned to carboxylate group, the water soluble part of eudragit l100-55 when a gel is formed in the presence of water. 15)i have subtracted out the quetiapine fumarate peaks at 1600 and 1570 cm -1 so that these are overcompensated (i.e. appear as negative peaks). in spite of this, there is a peak at ca. 1560 cm-1 which can be assigned to a carboxylate ion. based on the test results, eudragit l100-55 is present on the surface of the ketipinor tablets are only partially ionized and are therefore present in a state which can form a gel when in contact with water. the behaviour of ketipinor tablets in water in dissolution tests. - 42 - 16)i performed a dissolution test on ketipinor tablets in water using the same condi- tions as reported previously in my report dated 31 july 2015. in the current test, i made observations at 1 hour and 2 hour time points. i also measured the ph of the dissolution medium which was 5.6 at one hour and 5.5 at two hours. the ph of the dissolution medium is therefore at the value where the carboxylic acid in eudragit l100-55 would be only partially ionized. 17)at the 1 hour time point, i attempted to remove the tablet from the dissolution ves- sel. however, the surface of the ketipinor tablet in contact with the dissolution ves- sel remained adhered to the surface of the dissolution vessel. an image of this is shown below. figure 10: image of film adhered to bottom of dissolution vessel after dissolution test of ketipinor tablet in water. 18)i removed this and performed atr-ir analysis. the spectrum is shown below, compared to the 1 meq naoh eudragit l100-55 gel and the ketipinor core. this shows that the material adhered to the dissolution vessel contains water, quetia- pine and eudragit l100-55 in the partially ionized state at a similar level to the 1 meq naoh eudragit gel. figure 11: atr-ir spectra of eudragit l100-55 gel made from 1 g eudragit l100-55 / 3 ml water to which 1 meq naoh was added, middle-atr of film adhered to the - 43 - base of dissolution vessel and bottom atr-ir spectrum of ketipinor core (scaled so that peaks are at similar intensity to quetiapine fumarate found in adhered film). 19)at 2 hours, i observed that the tablet is still adhered to the bottom of the dissolu- tion vessel. this could not be readily removed. i enclose a video which shows the dissolution vessel inverted. the tablet remained fixed to the dissolution vessel. im- ages of this behaviour are shown below < figure 12: left ketipinor tablet after 2 hours dissolution in water; right – dissolu- tion vessel inverted showing adhesion of ketipinor tablet to bottom of vessel. 20)in summary, these experiments show that eudragit l100-55 is capable of forming a gel when partially ionized. the proposed mechanism, of partial cross-linking via unionized carboxylic acid groups, is consistent with the experimental observations adduced by infrared spectroscopy. furthermore, eudragit l100-55 in a partially ionized state is observed on the surface of the ketipinor tablet prior to exposure to water, suggesting that the eudragit l100-55 present on the surface of ketipinor ta- blets are in a state that can (and will) form a gel in the presence of water. after dis- solution tests in water, eudragit l100-55 was analysed by atr-ir and this confir- med that it was in partially ionized, hydrated and therefore present as a gel. physi- cally the eudragit l100-55 on the surface of ketipinor tablets is adhesive and sticks to the bottom of the dissolution vessel, consistent with the chemical analysis show- ing that eudragit l100-55 is present as a gel.” professor frøkjær har afgivet en supplerende erklæring af 22. september 2015 (herefter frøk- jær 2). af den danske oversættelse af erklæringen fremgår bl.a.: ”peter-ulrik plesner har nu bedt mig om at komme med en yderligere uddybning af min konklusion i [frøkjær 1] med hensyn til, om eudragit l 100-55 er et gele- ringsmiddel i stridspatentets forstand, under henvisning til yderligere testrappor- ter og litteratur, som jeg er blevet opmærksom på, siden jeg afgav min første er- klæring. iupac-definitionen af udtrykket ”gel” beskriver en struktur, som omfatter et ikke- flydende kolloidt netværk eller polymernetværk, som er ekspanderet gennem hele sit volumen med en væske. i henhold til produktspecifikationen fra evonik < er eudragit l 100-55 en methacryl- syre-ethylacrylat-co-polymer (1:1) type a. forholdet mellem frie carboxyl-grupper (fra methacrylsyreenheden) og estergrupperne (fra ethylacrylatenheden) er 1:1. - 44 - den gennemsnitlige molekylemasse (
  9. mw)er ca. 320,000 g/mol. stridspatentet angiver udtrykkeligt en liste af geleringsmidler som eksempler på ge- leringsmidler, der kan anvendes til at udøve opfindelsen. i denne liste nævner opfin- derne en strukturelt lignende polymer, carbomer, som i henhold til produktspecifika- tionen < er en tværbundet acrylsyrepolymer, som også har frie carboxylgrupper, men ingen estergrupper, eftersom den er en homopolymer, som et anvendeligt gele- ringsmiddel. i overensstemmelse hermed henviser produktspecifikationen til car- bomerer som værende i stand til at danne geler ved neutralisering af sure dispersio- ner. på grund af den strukturelle lighed med carbomer, især når det drejer sig om tilste- deværelsen af frie carboxylsyregrupper, ville jeg forvente, at eudragit l 100-55 også ville have iboende geldannende egenskaber og derfor ville være i overensstemmelse med de geleringsmidler, som er anført i stridspatentet. på grund af de frie carboxylgrupper i polymeren har eudragit l 100-55 ph-afhængi- ge opløselighedsegenskaber. i overensstemmelse med produktspecifikationen < op- løses polymeren over ph 5,5. den kan imidlertid danne en gel i ph-området, hvor carboxylsyregrupperne kun delvist er de-protoneret. den ph-afhængige deprotone- ring/ionisering af carboxylsyregrupperne i polymeren kontrolleres via pka-værdien for eudragit, som ikke er nævnt i produktspecifikationen. dannelsen af en gel er i overensstemmelse med sandeep et al. < side 606, som beskriver, hvordan eudragit l 100-55 danner en gel, og som anfører, at h-bundne hydrogeler kan tilvejebringes ved sænkning af ph'en af en vandig opløsning af polymer, der bærer carboxylgrupper, og sandeep et al. side 604, hvor eudragit l 100-55 er anført som en ph-følsom poly- mer, der kan danne hydrogeler over en tærskelværdi på ph 5,5. sandeep artiklen op- lyser, at en geldannelse faktisk også sker i et vandigt eudragit l 100-55-system. dette bekræftes af de eksperimenter, som er udført af dr. luk (”luk 5”) < dette betyder, at ændringen af ph i kernen af ketipinor-tabletten, når den udsættes for vand/mavetarmvæske, bliver en afgørende hovedfaktor for geldannelsen. på ba- sis af monografien for carbomer < forventes pka for carboxylgrupper i eudragit l 100-55 at være ca. 6 ±0,5, men sandsynligvis i den lave ende som følge af opløselig- hedsegenskaberne ved eudragit 100-55. imidlertid vil de andre bestanddele og pri- mært quetiapinfumaratet også bidrage til den lokale ph i tablettens kerne. i henhold til ”produktinformation – australien” < er quetiapinfumarat en svag syre (pka 3,3, 6,8) og vil følgelig bidrage til at opretholde et svagt surt miljø i tablettens kerne under frigivelsen af lægemiddelstoffet. derfor vil ph-værdien af quetiapinfumaratet i ker- nen bidrage til at opretholde et miljø, hvor eudragit l 100-55 kan danne en gel og derved kontrollere frigivelsesegenskaberne. denne geldannelse er i overensstemmelse med den almindeligt anerkendte forståelse af opløsningsprocessen for en polymer som belyst i ”almen farmaci” fig 6.2, side 61 < der trænger vand ind i polymeren, og der sker en kvældning (hvorved der dannes en hydratiseret polymer). i gellaget er vandmænget øget, og der dannes en gel, og til sidst dannes der en viskøs opløsning tæt ved den indtrængende vandfase. denne proces afhænger af den specifikke polymer og andre bestanddele i polymermatrixer og kan forsinkes af parametre, f.eks. en lokal ph i matrixen på grund af bevarelsen af intermolekylære kræfter (f.eks. h-bindinger) i gellaget. - 45 - hvad angår den specifikke geleringsproces for eudragit l 100-55, kan jeg også henvi- se til de test, der er foretaget af dr. luk i ”luk 1” < og diskuteret i ”luk 2” <, som er et yderligere bevis på, at eudragit l 100-55 fungerer som et geleringsmiddel. i ”luk 1” blev der fremstillet en film af eudragit l 100-55 i henhold til evonik- specifikationen < (som er producentens specifikation for sit eget produkt). for at fastslå, om hvorvidt denne film danner en gel, sænkede dr. luk filmen ned i opløs- ningsmedier på ph 6.2 i overensstemmelse med stridspatentet, side 5, linje 55-56. filmen blev omdannet til en hydratiseret og eftergivende film, som havde udseende af en våd gel med en vandoptagelse på 80 % som målt af dr. luk. denne opførsel er en indikation af en geldannelse. som dr luk forklarer i ”luk 2” <, afsnit 6, understøttes denne konklusion af kim et al. <, som fremstillede et lægemiddel, der indeholdt hydrogeler på basis af eudragit l som geleringsmidlet. i afsnit 7 forklarer d. luk mekanismen, ved hjælp af hvilken der dannes en gel som et resultat af h-binding mellem frie carboxylsyregrupper ved ph 6.2 anvendt i hans test. jeg er enig i denne forklaring. i ”luk 5” < fremstillede dr. luk en række geler ved at tilsætte en stigende mængde af naoh til et vandigt system, indeholdende eudragit l 100-55. atr-ir-spektrene viser, at mængden af deprotonerede (ioniserede) carboxylgrupper (carboxylatgrup- per) øges, når mængden af naoh (fig. 7) stiger. ved den højeste naoh- koncentration befinder eudragit l 100-55 sig i en fuldstændigt ioniseret tilstand. det fysiske udseende af den fuldstændigt ioniserede prøve var karakteriseret som en vi- skøs væske, hvorimod de andre prøver var geler (figur 4, 5, og 6). peter-ulrik plesner har endvidere bedt mig om min stillingtagen til det videnska- belige forhold mellem udtrykkene ”kvældning”, ”gelering” og ”gel”, som udtryk- kene er defineret af iupac … iupac-definitionen af udtrykket ”kvældning” beskriver en proces, hvorved en gel eller et fast stof undergår en volumenforøgelse ved optagelse af en væske eller en gas. iupac definerer ikke formelt udtrykket ”gelering”. jeg opfatter imidlertid udtrykket gelering som en proces, hvorved der dannes en gel. iupac-definitionen af udtrykket ”gel” beskriver en struktur, som omfatter et ikke- flydende kolloidt netværk eller polymernetværk, som er ekspanderet gennem hele sit volumen af en væske. efter min opfattelse angiver denne skelnen, som er foretaget i iupac-definitionen af ”kvældning”, at en allerede dannet gel, som er ekspanderet af en væske, kan kvælde yderligere ved optagelse af mere væske. som et andet alternativ kan et fast stof kvæl- de ved optagelse af væske. med hensyn til sidstnævnte, afhængigt af, om det faste stof kan danne et kolloidt eller et polymernetværk, kan kvældningen resultere i dan- nelsen af en gel. ”kvældning” og ”gelering” er således nært beslægtede udtryk og ikke er i uoverensstemmelse med hinanden. - 46 - en gel kan således dannes (”gelering”) på forskellig måde, f.eks. ved in situ-tværbin- ding af polymerkæder enten ved kovalente bindinger eller ved intermolekylære bin- dinger, indeholdende ion- og h-bindinger eller ved optagelse af en væske i en forud- formet struktur, der danner et molekylært netværk. optagelsen af en væske, f.eks. vand i en forudformet netværksstruktur associeres ofte med en kvældningsproces. i kernen af ketipinor-depottabletten må eudragit l 100-55 forventes at være fordelt ensartet og i stand til at danne molekylære polymere ikke-kovalent bundne netværk, som ved hydratisering forårsaget af tarmvæskerne kan danne en gel, dvs. en gele- ringsproces, som jeg har beskrevet ovenfor. ved at opsummere de ovenfor anførte observationer, er de efterfølgende punkter for mig en kraftig indikation af, at eudragit l 100-55 kan betragtes som et geleringsmid- del i stridspatentets forstand og desuden er i overensstemmelse med iupac-defini- tion af en gel:  den strukturelle lighed af eudragit l 100-55 – især hvad angår potentielt io- niserbare frie carboxylsyregrupper – med carbomer.  den ph-afhængige opløselighed af eudragit l 100-55, hvilket indikerer en ph-afhængig deprotonering af carboxylsyregruppen, hvorved der muliggø- res en geldannelse ved passende ph-værdier.  overensstemmelsen med forklaringerne i sandeep et al.  ”luk 4”-eksperimenterne, der viser en volumenforøgelse, som kun kan skyl- des kvældning af eudragit l 100-55, hvorved der dannes en gel.  de egnede ph-betingelser i ketipinor-kernen, når den bringes i kontakt med [tarmvæsker].  overensstemmelsen med den generelle opløsningsproces for polymerer be- skrevet i standardlærebogen ”almen farmaci”.  testene i ”luk 1” og forklaringerne i ”luk 2” under henvisning til testene i kim et al.  testene i ”luk 5” viser, at delvist deprotoneret eudragit l 100-55 danner en gel i vand. konklusion på grundlag af min generelle ekspertise inden for farmaceutiske formuleringer og den dokumentation, jeg har modtaget, konkluderer jeg, at eudragit l 100-55 i kernen af ketipinor-depottabletten danner en gel, når det bringes i kontakt med vand eller et vandigt medium, såsom tarmvæsken og følgelig er et geleringsmiddel som defineret i patent ep 0 907 364 b1. denne geldannelse er i overensstemmelse med iupac-defi- nitionen af en gel.” professorerne sven frøkjær og henning gjelstrup kristensen har afgivet en fælles erklæring af 24. september 2015 (herefter frøkjær/kristensens fælles erklæring). af den danske over- sættelse af erklæringen fremgår bl.a.: - 47 - ”1. de bedes beskrive, hvordan geldannelsen og den langvarige frigivelse af den aktive bestanddel fungerer i en matrixtablet. udtrykket ”matrixtablet” angår en tabletkerne, som indkapsler en aktiv farmaceutisk ingrediens (”api”) i en matrix af hjælpestoffer, omfattende f.eks. en uopløselig eller opløselig geldannende polymer. eksempler på sidstnævnte polymerer omfatter også både hydrofile og hydrofobe polymerer. matrixtabletten er en ikke-henfaldende en- hed, hvilket betyder, at tabletten ikke straks nedbrydes i sine enkelte bestanddele, kort tid efter den har været udsat for vand eller et vandigt medium såsom mave- tarm-væsker, selvom en matrixtablet kan eroderes over længere tid. når en matrixtablet, som indeholder et hydrofilt geleringsmiddel, f.eks. sænkes ned i vand eller en vandig væske såsom mave-tarm-væsker, vil polymeren opløses via en proces, som er illustreret på figur 1. vand polymer gel væskefront viskøs opløsning figur 1. opløsning af en hydrofil polymer. fra henning g. kristensen: almen farma- ci, 4th edition, academic books, copenhagen 2008 < det indtrængende vand frembringer typisk et infiltrationslag (benævnt som væske- front i figur 1) i grænsen til den tørre polymer. i denne væskefront bliver polymer- molekyler hydrateret. i det tilstødende gellag øges mængden af vand, og vandmole- kylerne er mere eller mindre mobile. gellaget fortyndes gradvis af det indkommende vand, så der dannes et viskøst diffusionslag i dets ydre del. afhængigt af opblandin- gen vil denne del af diffusionslaget blive yderligere fortyndet, og opløselige polymer- molekyler vil blive skyllet væk. api’en, som er dispergeret i den tørre polymer, oplø- ses i væskefronten og transporteres til tabletoverfladen ved diffusion af de opløste molekyler gennem gellaget. hydratering, geldannelse og opløsning af polymeren afhænger bl.a af molekylvægt og krystallinitet. diffusionshurtigheden afhænger stærkt af den vandige væskes vi- skositet. geler, der er dannet af hydrofile polymerer og vand (som ofte kaldes hydrogeler) be- står, som nævnt i iupac < af et ikke-flydende kolloidt netværk eller polymernet- værk, som er ekspanderet gennem hele sit volumen med en væske. gelen holdes sammen ved molekylære interaktioner såsom hydrogenbindinger eller van der waals-kræfter. vandmolekyler interagerer med polymermolekylerne gennem hydro- genbindinger. polymeropløsninger danner ofte geler ved koncentrationer på 5 % og derover. selvom det ikke er påkrævet for geleringsmidler, viser hydraterings- og opløsnings- processen, der er vist i figur 1, at der optages vand i det polymere netværk. dette be- tyder, at systemvolumenet øges, dvs. at der sker en kvældning. - 48 - når en matrixtablet udsættes for vand eller et vandigt medium, vædes tabletoverfla- den først, og dernæst trænger der vand ind i tabletkernen. en hydrofil opløselig po- lymer, som er indkapslet i matrixen, vil blive hydrateret og til sidst opløst som angi- vet i figur 1. den gelerede polymer virker som en barriere både for det indtrængende vand og for diffusionen af den opløste api ud af tabletten. frigivelseshastigheden påvirkes af mange faktorer, som er relateret til vandopløse- ligheden af api’en og dennes partikelstørrelse, den hydrofile polymers egenskaber og egenskaberne af de andre tabletbestanddele. desuden påvirkes frigivelseshastig- heden af den gradvise opløsning af polymeren og mekanisk erosion af gelen. 2. gælder ovennævnte beskrivelse også for ketipinor-tabletten? i henhold til produktresumeet <, pkt. 6.1, er ketipinor en tablet med langvarig frigi- velse (i europa går den almindeligvis under synonymet prolonged release tablet, dansk: depottablet). foruden api’en quetiapinfumarat indeholder tabletkernen to vandopløselige sukkerarter, vandfri lactose og maltose, glittemidlerne talkum og magnesiumstearat og et polymethacrylat, der går under produktnavnet eudragit l 100-55. tabletten er forsynet med et overtræk (”coating”) af eudragit l 100-55 med tilsat triethylcitrat som blødgører. i den farmaceutiske litteratur nævnes det, at polymethacrylater er blevet anvendt til gelformuleringer beregnet til rektal formulering. et eksempel herpå er at finde i pub- likationen af kim et al. <, som viser de geldannende egenskaber ved eudragit l. en europæisk patentansøgning [ep 0 386 688 a1; ikke medtaget i sagsfremstillingen], angiver en fremgangsmåde til fremstilling af geler fra polymethacrylater, herunder eudragit l, som vist i eksempel 5. eudragit l er en copolymer af methacrylsyre og methylmethacrylat 1:1, sandsynligvis anvendt i de to referencer i form af eudragit l 100. eudragit l 100-55 er et redispergerbart tørt pulver. det er en 1:1 copolymer af metha- crylsyre og ethylacrylat. forskellen mellem eudragit l 100 og eudragit l 100-55 (methylmethacrylat og ethylmethacrylat) bidrager til forskellige ph-opløseligheds- profiler. hvad angår de geldannende egenskaber, er der næppe forskelle bortset fra en mulig mindre indvirkning på det optimale ph-område for geleringen. dr. luk har især i bilag 32 påvist geleringsegenskaberne for eudragit l 100-55. eftersom eudragit l 100-55 er en gel-dannende polymer, passer den generelle be- skrivelse af matrixtabletter med langvarig frigivelse, som er givet i vores svar på spørgsmål 1, også på ketipinor-tabletter med langvarig frigivelse. 3. forklar, hvad der menes med udtrykket ”bindemiddel” ved tabletformulering? der anvendes bindemidler ved formuleringen af tabletter for at fremme den tekniske proces, hvor en pulverblanding eller et granulat komprimeres til en mekanisk be- standig tablet. i vådgranuleringsprocesser vædes blandingen af pulverformede bestanddele med en opløsning af bindemidlet ved mekanisk omrøring, hvilket fører til dannelsen af ag- glomererede partikler, som efter tørring omdannes til et fritflydende, ikke-støvende - 49 - granulat. det tørre granulat blandes almindeligvis med glittemidler såsom talkum og magnesiumstearat og komprimeres til sidst til tabletter. i en direkte komprimeringsproces komprimeres den fritflydende blanding af pulver- formede bestanddele direkte til tabletter. bindemidlet har en dobbeltfunktion. i vådgranuleringsprocessen anvendes binde- midlet til at binde partiklerne sammen og derved tilvejebringe et ikke-støvende og mekanisk bestandigt granulat. i komprimeringstrinnet ved både vådgranulering og direkte komprimering kan mange bindemidler også bidrage til blødgøring af massen under komprimeringen. tabletkomprimering betyder, at partiklerne af pulverblandingen eller granulatet sammenpresses ved et meget højt tryk, således at der dannes en binding, især ved van der waals kræfter, i kontaktområderne mellem partiklerne. hvis den komprime- rede masse udviser nogen elasticitet, vil kontaktområdet mellem partiklerne blive re- duceret som følge af elastisk recovery, når trykket aflastes. resultatet af dette er en tablet, som er mindre mekanisk bestandig end nødvendigt for at modstå yderligere behandling og håndtering af den færdigbehandlede tablet. bindemidlets funktion er at reducere tabletmassens elasticitet og forbedre dens plastiske deformation under tryk. bindemidler til tabletformuleringer omfatter en mangfoldighed af materialer. de ind- befatter sukkerarter såsom saccharose og sorbitol, produkter af naturlig oprindelse såsom gelatine, stivelser, natriumalginat og semisyntetiske eller syntetiske polymerer såsom povidon (pvp), methylcellulose og hypromellose (hpmc). det bemærkes, at hjælpestoffer kan have forskellige funktioner afhængigt af den tilsatte mængde, hvor- når de tilsættes, og hvordan de tilsættes en bestemt formulering. de syntetiske mate- rialer foretrækkes normalt ved tabletformulering, fordi de har forudsigelige egenska- ber, og fordi de har gode bindingsegenskaber til granulater såvel som ved tablet- komprimering. valget af bindemiddel kan også dikteres af ønsket om at påvirke frigivelseskarakteri- stikkerne. povidon, der anvendes i form af en vandig opløsning under vådgranule- ring, kan øge tablettens hydrofilicitet og således fremme befugtning og henfald, når tabletten udsættes for vandig væske. ethylcellulose, der anvendes i form af en etha- nol-/vandopløsning i vådgranuleringsprocessen, kan forsinke tablettens opløsnings- hastighed. 4. kan en polymer have mere end én funktion i tabletformuleringer, f.eks. både som bindemiddel og som geleringsmiddel? det korte svar er ja. mange farmaceutiske polymerer er multifunktionelle. som et ek- sempel kan man tage anvendelsen af povidon (pvp). det er et af de geleringsmidler, der er nævnt i [stridspatentet] side 4 linje 13, hvor det går under navnet polyvinyl- pyrrolidon. det kan således anvendes som et geleringsmiddel. det anvendes også hyppigt som et tabletbindemiddel, og som nævnt ovenfor kan det forbedre befugt- ningen af tabletmassen. ketipinor-tabletten med langvarig frigivelse er fremstillet ved en vådgranulerings- proces som beskrevet i [pharmathens patentansøgning], krav 10. eudragit l 100-55 - 50 - blandes med to vandopløselige sukkerarter, og blandingen vådgranuleres så med vand. efter tørring tilsættes glittemidlerne, og der komprimeres til sidst til tabletker- ner. vi er overhovedet ikke i tvivl om, at en del af de to sukkerarter opløses under våd- granuleringen (benævnt som æltning af den vædede masse i [pharmathens patentan- søgning]). det opløste sukker vil blive udskilt under tørringsfasen og derved virke som et bindemiddel i det tørrede granulat. derimod er det tvivlsomt, hvorvidt eudragit l 100-55-partiklerne opløses delvis under vådgranuleringsprocessen. que- tiapinfumarat og de to sukkerarter er neutrale eller en smule sure, mens eudragit l 100-55 er surt. således vil granuleringsvæskens ph ikke understøtte opløsning af eudragit l 100-55. et andet spørgsmål er, hvorvidt eudragit l 100-55 kan virke som et tabletbindemid- del i komprimeringstrinnet. vi skal tage egenskaberne ved termoplastiske polymerer med i betragtning, og et eksempel herpå er eudragit l. termoplastiske polymerer er karakteriseret ved at være hårde og skrøbelige materia- ler ved lave temperaturer. når temperaturen øges over en bestemt grænse, kaldet blødgøringspunktet eller glasovergangstemperaturen, bliver polymeren blød og flek- sibel. i litteraturen kan der findes flere værdier for blødgøringspunktet for eudragit l på grund af forskellige måleteknikker og på grund af varierende fugtindhold. der er fundet værdier over 100 °c, og der er ingen tvivl om, at blødgøringspunktet er langt over rumtemperatur. luk angiver i [luk 1], at den udvalgte film af eudragit l 100-55 er skrøbelig og stiv. dette er grunden til, at der tilsættes triethylcitrat til eudragit l 100-55-coatingen på ketipinor-tabletten. triethylcitrat virker som en blødgører, der sænker glasovergangstemperaturen for eudragit-coatingen. det er således vanskeligt at se, hvordan eudragit l 100-55-partikler kan virke som et bindemiddel i ketipinor-tabletten med langvarig frigivelse, eftersom partiklerne ikke har sådanne egenskaber, som kan bidrage til tabletmassens plasticitet. det bemærkes, at en af de sukkerarter, der er anvendt i formuleringen, vandfri lacto- se, har fremragende komprimeringsegenskaber. lactose eller kombinationen af lacto- se og maltose kan bibringe tabletmassen de ønskede komprimeringsegenskaber. 5. beskriver [pharmathens patentansøgning], at eudragit l 100-55 anvendes som et bindemiddel, og/eller at der anvendes et bindemiddel som et middel til at tilveje- bringe en langvarig frigivelse? i [pharmathens patentansøgning], side 4 linje 29–31, anføres det, at enteriske polyme- rer og copolymerer såsom polymethacrylater kan bidrage til at forsinke frigivelses- fænomenet i maven (ved justering af tablettens mikro-miljø-ph), mens de virker som pore-dannende midler ved højere ph-værdier (i tarmen). på side 5, linje 23-29, anføres det, at frigivelsesmatrixen ifølge opfindelsen desuden kan omfatte yderligere hjælpestoffer, der kan virke som pore-dannere, der muliggør dannelsen af kanaler i matrixen, hvorved man øger hastigheden af diffusionen af den aktive bestanddel fra matrixen ved den første sure ph. eksempler er forskellige suk- kerarter, herunder lactose og maltose. - 51 - på side 5, linje 35-39, anføres det: ”desuden kan de farmaceutiske præparater ifølge den foreliggende opfindelse også indeholde en eller flere yderligere formulerings- hjælpestoffer, såsom fortyndingsmidler, opløsningsmidler, bindemidler, smøremid- ler, glittemidler og smagstoffer”. [pharmathens patentansøgning] beskriver således anvendelsen af eudragit l 100-55 som et middel til at kontrollere frigivelsen af quetiapin ved en sur ph og som en po- re-danner ved højere ph-værdier. den mulige anvendelse af et bindemiddel nævnes som et middel ud over anvendelserne af eudragit l 100-55 og sukkerarterne. der fin- des ingen yderligere kommentarer i teksten vedrørende valget af bindemiddel og andre virkninger af bindemidlet. vi afviser derfor, at [pharmathens patentansøgning] beskriver, at eudragit l 100-55 anvendes som et bindemiddel, og at der anvendes et bindemiddel som et middel til tilvejebringelse af en langvarig frigivelse. 6. kan man udlede af [seppälä/rades’ fælles erklæring], at eudragit l 100-55 ikke gelerer i ketipinor-tabletten med langvarig frigivelse? *seppälä/rades’ fælles erklæring] er en rapport om det fysiske udseende og adfærd af ketipinor-tabletter og seroquel-tabletter under opløsningstest op til 8 timer under anvendelse af farmakopéens paddle metode. i forskellige test er vægtforøgelsen eller -tabet og det fysiske udseende blevet registreret. i forsøgsserie nr. 1 er der anvendt phosphatbuffer ph 5,5, phosphatbuffer ph 6,8 og renset (deioniseret) vand som op- løsningsmedium. i forsøgsserie nr. 2 er der anvendt saltsyre ph 1,2, phosphatbuffer ph 5,5, phosphatbuffer ph 5,8 og phosphatbuffer ph 6,2 som opløsningsmedium. der er ikke registeret opløselighedsprofiler i eksperimenterne. resultatet af eksperi- menterne er sammenfattet på side 10 og 11. med hensyn til forsøgsserie nr. 1 konkluderes det på side 10, at seroquel-tabletter i deioniseret vand og phosphatbuffer ph 5,5 ret hurtigt øgede vægten (30 %), og der blev dannet en gel på tabletoverfladen. til gengæld har ketipinor-tabletterne, testet i deioniseret vand og phosphatbuffer ph 5,5, i begyndelsen kun forøget deres vægt en smule (< 5 %). der er ingen indikation af en geldannelse på overfladen. da ketipinor- tabletten blev testet ved ph 6,8, blev den i det store og hele eroderet/opløst efter 3,5 timer, og på intet tidspunktet forøgede tabletten sin vægt. *seppälä/rades’ fælles erklæring] beskriver overfladen af ketipinor-tabletterne som ikke-klæbrige, når tabletterne testes i deioniseret vand og buffer ved ph 5,5. eudragit l 100-55 synes at holde tabletten sammen i deioniseret vand og befinder sig på græn- sen for opløselighed ved ph 5,5. under testningen i ph 6,8 bufferen, hvor eudragit l 100-55 opløses, henfalder tabletten i det store og hele på 3,5 timer, idet alle bestand- delene, herunder geleringsmidlet, bortset fra glittemidlerne i tabletkernen er opløse- lige ved denne ph. tabletoverfladen er ikke-klæbrig, idet eudragit l 100-55 opløses. ketipinor-tabletten viser i begyndelsen en let vægtforøgelse, hvilket viser, at noget vand optages af tabletten, og derefter et vægttab. det er på baggrund af disse testre- sultater umuligt at vurdere den præcise årsag til vægtforøgelsen, eftersom de opløse- lige sukkerarter i tabletkernen opløses og er diffunderet ud fra kernen som beskrevet i [pharmathens patentansøgning]. - 52 - med hensyn til forsøgsserie nr. 2 konkluderes det på side 11, at testningen af ketipi- nor-tabletter ved ph 5,8 viser en lille vægtforøgelse i begyndelsen (3-4 %) og derefter et vægttab på 2 timer. det konkluderes, at opløsningsadfærden tydeligt ændres mel- lem ph 5,5 og 5,8. når der testes ved ph 6,2, er der et hurtigt vægttab. desuden kan vægttabet, som er observeret ved testningen af ketipinor-tabletter, igen forklares ved opløsningen af to sukkerarter indeholdt i kernen og selvfølgelig tabet af quetiapin- fumarat. hvad angår kvældning og vægtforøgelse associeret med geldannelse, er det ikke mu- ligt at konkludere noget som helst ud fra dataene i *seppälä/rades’ fælles erklæring+, idet tabletternes vægtændring overlejres af tabet af de vandopløselige hjælpestoffer. vi noterer os ud fra *seppälä/rades’ fælles erklæring+ og også fra [luk 4], som viser fotografier på side 3 og 4 af den kvældede ketipinor-tablet, at der sker en vis grad af kvældning, og mens kvældning i sig selv ikke er et bevis på en geldannelse, er den i overensstemmelse med en gel, som danner et barrierelag og optager vand for be- stemte geleringsmidlers vedkommende (f.eks. hydrogeler). kvældning og gelering kan være beslægtet med hinanden, men er ikke nødvendigvis det samme. i nærvæ- rende sammenhæng er kvældning en kraftig indikation af en geldannelse. vi noterer os fra fotografierne, som er vist i [luk 4] og *seppälä/rades’ fælles erklæ- ring], at ketipinor forbliver mere eller mindre intakt – bortset fra en let kvældning – når det udsættes for vandige medier. i henhold til [pharmathens patentansøgning] frigives sukkerindholdene delvis ved en sur ph, og både sukkerarter og eudragit l 100-55 frigives delvis ved den højere ph i tarmen. når der optages vand i en kom- pakt enhed af partikler, vil vandet svække bindingskræfterne mellem partiklerne. vi vil derfor forvente, at tabletkernen nedbrydes, selv hvis der ikke er et sprængmiddel til stede. da vi ved, at eudragit l 100-55 er en gel-dannende polymer, jf. vores svar på spørgs- mål 2, er vi af den opfattelse, at den gel, der dannes af eudragit 100-55 inden i matrix- tabletten, bidrager til at bibeholde det fysiske udseende af tabletten under frigivelsen i medier med ph i det fysiologiske område. det er vores vurdering, at forsøgsresultaterne, der er vist i *seppälä/rades’ fælles er- klæring], ikke tillader den konklusion, at eudragit l 100-55, som er indeholdt i keti- pinor-tabletten med langvarig frigivelse, ikke udviser nogen geldannelse. 7. hvilke bemærkninger har de til [rades 1]? < i sit svar på spørgsmål 7 (mekanismen for langvarig frigivelse i orion’s ketipinorde- pottablet) beskriver rades to mekanismer, én ved en sur ph og én ved en ph, som er højere end 5,5, som er den rapporterede opløselighed for eudragit l 100-55-polymer. vi er enige i hans præsentation af den langsomme frigivelse gennem den intakte coa- ting baseret på eudragit l 100-55. forsøgsdataene om vægttabet hos ketipinor- tabletter tilvejebragt af rades i *seppälä/rades’ fælles erklæring+ understøtter, at vand passerer gennem membranen og transporterer en del af det vandopløselige ind- hold ved diffusion gennem laget og ud af tabletten. med hensyn til mekanismen ved en højere ph har vi indvendinger. rades antyder, at frigivelsen kontrolleres ved ero- sion og nedbrydelse af kernen og opløsning af det tungtopløselige (”poorly soluble”) - 53 - quetiapinfumarat. dette er ikke i overensstemmelse med de opløselighedsdata, som er rapporteret for quetiapin som nævnt nedenfor. vandopløseligheden af quetiapinfumarat er 3,29 mg/ml ved 25 °c, jf. den australske produktinformation < quetiapinfumarat er en svag syre, som udviser moderat ph- afhængig opløselighed (94,3 mg/ml til 2,37 mg/ml ved ph-værdier fra 1 til 9). que- tiapinfumarat er således langt fra at være et tungt opløseligt stof. tværtimod ville en 50 mg tablet i henhold til det biofarmaceutiske klassifikationsskema blive klassifice- ret som let opløselig, når opløseligheden i ph-området 1-8 er mindst 0,2 mg/ml. udtrykket ”tungtopløselig” (”poorly soluble”) angår generelt stoffer, hvis opløsning fra tabletterne kontrolleres af deres iboende opløsningshastighed. dette kan være til- fældet for stoffer med en vandopløselighed under 0,1 mg/ml. baseret på denne in- formation ville frigivelsen af quetiapinfumarat fra tabletkernen forløbe hurtigt på grund af stoffets opløselighed, medmindre der er en hastighedsbegrænsende meka- nisme, som er inkorporeret i tabletkernen. vi er derfor uenige med rades’ beskrivelse af frigivelsesmekanismen. i sit svar på spørgsmål 7 hævder rades i sidste afsnit, at en høj koncentration af et bindemiddel kan føre til en langsommere frigivelse af et lægemiddel. dette kan være rigtigt for nogle bindemidler, som let kan opløses i vand, men det er ikke relevant for frigivelsen fra ketipinor-tabletten, idet der ikke er noget tabletbindemiddel til stede i formuleringen. som nævnt i vores svar på spørgsmål 3, er vi ikke enige i, at eudragit l 100-55 skulle have bindingsegenskaber i den tørre tabletkerne. i sit svar på spørgsmål 8 gentager rades, at frigivelsen fra ketipinor-tabletten under tarm-ph-forhold er opløsningskontrolleret. som angivet ovenfor er vi ikke enige i denne udtalelse. rades mener, at geldannelsen er væsentlig for virkningen af sero- quel-tabletten, men ikke relevant for virkningen af ketipinor-tabletten. igen er vi uenige baseret på de grunde, der er angivet ovenfor. konklusioner den vigtigste konklusion, som skal drages, er, at vi har fremlagt bevismateriale i vo- res svar på spørgsmål 2 på, at eudragit l 100-55 er en gel-dannende polymer. som nævnt i vores svar på spørgsmål 7 er vi enige i, at den langvarige frigivelse fra ketipinor-tabletten under sure betingelser, dvs. ph under 5,5, kontrolleres af en dif- fusion gennem den coating, der påføres tabletten. det bør tilføjes, at coatingen skal være en meget tynd membran. vi har forklaret, at frigivelsen ved ph-værdier over 5,5 må være kontrolleret af tilste- deværelsen af eudragit l 100-55. vi er uenige i, at eudragit l 100-55 kun virker som et bindemiddel i tabletkernen. det er vores konklusion, at forsinkelsen af frigivelsen fra kernen skyldes gelen, der dannes af eudragit l 100-55 i tabletten. dette ville også forklare, hvor ketipinor-tabletten bibeholder sit fysiske udseende under opløsnings- testen. de andre bestanddele af tabletkernen er vandopløselige og opløses i det ind- trængende vand, så de kan ikke bidrage til det bibeholdte tabletudseende. den eksperimentelle sandsynliggørelse, som er fremlagt i [seppälä/rades’ fælles er- klæring], kan ikke understøtte den påstand, at der ikke er nogen kvældning associe- - 54 - ret med den foreslåede gelering af eudragit l 100-55. parallelt med kvældningen, mi- ster tabletkernen vægt grundet tabet af både quetiapinfumarat, lactose og maltose. registreringer af vægttab er således ikke noget bevis for fraværet af kvældning. afslutningsvis er det vores opfattelse, at matrixtabletten, som er repræsenteret af ke- tipinor-tabletten med langvarig frigivelse, har en frigivelsesmekanisme baseret på diffusion kontrolleret af tablettens coating ved ph-værdier under 5,5 og kontrolleret af polymethacrylatgelen ved ph-værdier over 5,5, hvor coatingen er opløst.” professor seppälä har ydermere afgivet en supplerende erklæring af 2. oktober 2015 (herefter seppälä 3). af denne erklæring fremgår bl.a.: ”dissolution tests of ketipinor tablets in water a test run was carried out to demonstrate ketipinor depot tablet’s (orion pharma) behavior in plain water: dissolution in ion-exchanged water for 8 hours time. experimental conditions: standard dissolution test device with blade mixers. mixing speed 100rpm. temperature 37°c. three parallel samples. test procedure and results three ketipinor tablets 200mg (orion pharma) were immersed into 900 ml of ion-ex- changed water in three separate standard dissolution device vessels stirred with ro- tating paddle 100 rpm in temperature of 37°c. the tablets did not adhere on the ves- sel walls. after 8 hours the tablets were removed, surface dried by gently rolling on tissue paper, the physical character was evaluated. in addition the samples were pho- tographed. table 1 presents the obtained results. table 1. test run of ketipinor depot tablets in ion-exchanged water dissolution experiments. ketipinor / orion physical appearance time sample 1 8h ph5.6 visually moderately swollen, coated film on surface remaining, soft, non-sticky and dry on surface on touch. non-adhering on nature. sample 2 8h ph5.5 visually moderately swollen, coated film on surface remaining, soft, non-sticky and dry on surface on touch. non-adhering on nature. sample 3 8h ph5.6 visually moderately swollen, coated film on surface remaining, soft, non-sticky and dry on surface on touch. non-adhering on nature. - 55 - figure 1. dissolution in ion-exchanged water at time point 8 hours. ketipinor depot tablet 200mg. the samples were cut with knife. the inside of the tablets after dissolution was wet and powdery. no gel was observed. when touched the powdery nature was confir- med. figure 2. dissolution in ion-exchanged water at time point 8 hours, ketipinor depot tablet 200mg. sample after cutting. conclusions  after 8 hours in ion-exchanged water the ketipinor tablets had the skin coat- ing left and were non-sticky on surface.  after 8 hours in ion-exchanged water the ketipinor tablets were powdery in the core, when cut with knife.  no gel formation was observed.” professor rades har afgivet en supplerende erklæring af 5. oktober 2015 (herefter rades 2). af erklæringen fremgår bl.a.: ”polymers and gelling agents 1. please explain your views on the general dissolution mechanism of polymers, as shown in figure 1 of [frøkjær/kristensens fælles erklæring]? - 56 - < figure 1 in [frøkjær/kristensens fælles erklæring] shows the dissolution process when polymers dissolve on contact with water. the figure may be divided into 3 ”states” with respect to the polymer;
  10. i)a first solid state wherein the polymer is in its solid form (designated ”polymer”),
  11. ii)a second intermediate state, wherein the po- lymer has taken up water (designated ”væskefront” and ”gel”), and a third dis- solved state wherein the polymer is in solution (designated ”viskøs opløsning”). < i completely agree that the figure is correct in its general assessment of the presence of these three states, i.e. a solid state, an intermediate state and a dissolved state, however, in my opinion, the designation of the intermediate state as a ”gel” is very generalized and does not apply universally to all polymers and certainly not to all polymers under all conditions. in my opinion, certain polymers may under certain conditions transit abruptly from a solid state to a dissolved state, while others may do so through a state wherein the polymer swell without forming a ”gel”. thus, in my opinion, the designation ”gel” is not universally applicable to all poly- mers under all conditions. even further, some polymers (e.g. the polymer carbomer) may be practically unable to reach the state of a viscous solution and may newer reach the ”dissolved state”. i have tried to illustrate some theoretical situations below: < situation 4, a polymer with a practically no swelling/gelling capacity (e.g. eudragit l- 100 55): solid state intermediate state dissolved state 2. please explain the mechanism of dissolution of eudragit l-100 55 in connection with figure 1 of [frøkjær/kristensens fælles erklæring]? eudragit l-100 55 is a linear polymer with a highly ph dependent solubility. the po- lymer transists abruptly from a solid state to a dissolved state at a ph of 5.5, making it an ideal polymer for enteric coating of pharmaceutical formulations for delivery of the active ingredient in the duodenum (immediately after passage of the hostile envi- ronment of the stomach). in contrast, hereto, a range of other polymers have a practically ph-independent (within specified ph values) solubility range. such polymers are used e.g. for provi- ding diffusion-barriers (through gel-layers) to pharmaceutical formulations for deli- very of the active ingredient at a constant rate over the gastro-intestinal system. - 57 - i have tried to illustrate some theoretical situations below: < situation 3, a polymer having ph dependent solubility (e.g. eudragit l-110 55): 1 increasing ph 9 in general, in my opinion, polymers having a solubility characteristic of abrupt tran- sit from solid state to dissolved state will, in their respective “intermediate states”, have the least tendency to form ”gels” even though some ”swelling” may occur. 3. please comment on [luk 5] and on the relations (if any) to example 5 in ep 386 688? in [luk 5], dr. shen yung luk has experimentally determined the conditions most favorable for formation of eudragit l-100 55 in its ”intermediate state”. dr. shen yung luk has experimentally determined that the addition of naoh to solu- tions/dispersions of eudragit l-100 55 producing a ph of between (approximately) 5 and 5.5 are the most favorable conditions. i am not, based on the information i have received so far, capable of assessing whe- ther or not the produced states of the eudragit l-100 55 solution are to be characte- rized as ”solid swells”, ”gels”, or ”viscous solutions/dispersions”. the experiments by dr. shen yung luk are similar to the experiment described in example 5 in ep 386 688, however, in example 5 in ep 386 688, another polymer has been used. 4. please comment on the mechanism of dissolution of carbomer (carbopol ® poly- mers) in connection with figure 1 of [frøkjær/kristensens fælles erklæring]? carbomers are covalently cross-linked polymer that are known for having high swel- ling and gelling capacity and to have gelling properties over a range of different ph values. it is, in my opinion, debatable if carbomer polymers are able to dissolve at all. < ketipinor® depot 5. in answers 7 and 8 in [rades 1] you elaborate on the sustained release mechan- ism of ketipinor® depot. are your views consistent with the mechanism of ac- tion documented in the development report from pharmathen? in my answers 7 and 8 i state that in my opinion, the sustained release mechanism in orion’s ketipinor® depot is based on two effects: - 58 - firstly, under the ph conditions of the stomach, the enteric coating (a film formed by eudragit l100-55 that is insoluble at ph conditions such as in the stomach (lower than 5.5)), will prevent quetiapine from releasing too fast from ketipinor® depot. under these conditions, the thin eudragit l100-55 coating can be regarded as a rate- limiting membrane providing sustained release of the drug as in a reservoir system. accordingly, in the stomach, ketipinor® depot may be characterized as a diffusion- controlled reservoir system, as described in the textbook reference referred to in an- swer 5 of my previous statement. secondly, once the higher ph conditions of the small intestine have been reached, the polymer coating will dissolve and the drug can be released directly from the interior of the tablet to the surroundings as the tablet slowly erodes or disintegrates. under these conditions, however, due to
  12. i)the composition of the core (which contri- butes to the release-rate of the drug by decreasing the contact between the drug and the liquid surroundings), and
  13. ii)the marked reduction in the solubility of the drug, the dissolution rate from the slowly eroding tablet will be main determinant of the re- lease rate of quetiapine. under these conditions, the system should therefore, in my opinion, be characterized as a dissolution controlled matrix system. i find my proposed explanations to be in perfect accordance with the mechanism of action proposed in the parts of the development report from pharmathen that i have been provided with. 6. please explain your views on the release mechanism of ketipinor® depot when situated in an environment where the ph is above 5.5. in this respect please also include your comments to the views expressed in answer 7 in [frøkjær/kristen- sens fælles erklæring]. first of all, i note that professor sven frøkjær and professor henning gjelstrup kris- tensen agree to my proposed ” first” mechanism of action of ketipinor. however, professor sven frøkjær and professor henning gjelstrup kristensen ex- press objections to my second proposed mechanism of action. specifically, the objec- tions seem to be related to the solubility characteristics of quetiapine. these objections are, in my opinion, not applicable. as i shall explain below, the so- lubility characteristics of quetiapine is not – in itself – determinative of the success of the proposed system. the relevant parameter is the dissolution rate. the dissolution rate of a given particle of api is, however, related to the solubility of the substance through the noyes whitney equation < to phrase this differently, the dissolution rate of a given api – such as quetiapine in ketipinor will decrease proportionally to the decrease in solubility of quetiapine, when situated in different ph environments. - 59 - accordingly, if the decrease in solubility following a change in environment is suffi- cie

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