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`(19)United States
`
`
`(12)Patent Application Publication
`US 2004/0058896 Al
`
`(10)Pub. No.:
`(43)Pub. Date: Mar. 25, 2004
`
`Dietrich et al.
`
`US 20040058896Al
`
`(54)PHARMACEUTICAL PREPARATION
`
`
`
`COMPRISING AN ACTIVE DISPERSED ON A
`MATRIX
`
`(30)
`
`
`
`Foreign Application Priority Data
`
`
`
`
`
`Dec. 7, 2000 (EP) ........................................ 00126847.3
`
`
`
`Publication Classification
`
`(76)
`Inventors: Rango Dietrich, Konstanz (DE);
`
`
`
`
`Rudolf Linder, Kontanz (DE);
`(51)Int. Cl.7 ...................... A61K 31/56; A61K 31/4439
`
`
`Hartmut Ney, Konstanz (DE)
`
`
`
`
`(52)U.S. Cl. ........................... 514/171; 514/179; 514/338
`Correspondence Address:
`ABSTRACT
`(57)
`
`NATH & ASSOCIATES PLLC
`
`
`
`The present invention relates to the field of pharmaceutical
`
`1030 FIFTEENTH STREET, N.W.
`
`
`
`technology and describes a novel advantageous preparation
`SIXTH FLOOR
`
`for an active ingredient. The novel preparation is suitable for
`
`
`
`
`producing a large number of pharmaceutical dosage forms.
`
`
`
`
`In the new preparation an active ingredient is present
`
`
`
`
`
`essentially uniformly dispersed in an excipient matrix com­
`
`
`
`posed of one or more excipients selected from the group of
`
`
`
`fatty alcohol, triglyceride, partial glyceride and fatty acid
`ester.
`
`WASHINGTON, DC 20005 (US)
`
`Appl. No.: 10/433,398
`(21)
`
`
`(22)
`
`PCT Filed: Dec. 6, 2001
`
`
`
`(86) PCT No.:
`
`PCT/EPOl/14307
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2001
`Page 1
`
`

`

`US 2004/0058896 A1
`
`Mar. 25, 2004
`
`PHARMACEUTICAL PREPARATION
`COMPRISING AN ACTIVE DISPERSED ON A
`MATRIX
`
`TECHNICAL FIELD
`[0001] The present invention relates to the field of phar
`maceutical technology and describes a novel advantageous
`preparation for an active ingredient. The novel preparation is
`suitable for the production of a large number of pharmaceu
`tical dosage forms.
`
`BACKGROUND ART
`[0002] In order to achieve particular properties of a dosage
`form, such as, for example, taste masking in the case of
`active ingredients with an unpleasant taste, resistance to
`gastric juice in the case of acid-labile active ingredients or
`controlled release of an active ingredient, normally active
`ingredient pellets are provided with an appropriate func
`tional coating. If such coated pellets are then further pro
`cessed to dosage forms, for example shaped to tablets by
`compression with excipients, there is a risk that the coating
`is damaged and thus the functionality is at least partly lost
`again.
`
`DESCRIPTION OF THE INVENTION
`[0003] It is an object of the present invention to provide a
`preparation for active ingredients which is able to retain a
`desired functionality and can be further processed to a large
`number of pharmaceutical process forms with negligible
`impairment of a given functionality.
`[0004] It has now been found, surprisingly, that this object
`is achieved by a preparation in which an active ingredient is
`essentially uniformly dispersed in an excipient matrix com
`posed of one or more excipients selected from the group of
`fatty alcohol, triglyceride, partial glyceride and fatty acid
`eSter.
`[0005] The invention therefore relates to a preparation in
`which an active ingredient is essentially uniformly dispersed
`in an excipient matrix composed of one or more excipients
`selected from the group of fatty alcohol, triglyceride, partial
`glyceride and fatty acid ester.
`[0006] It has further been found that particularly advan
`tageous preparations can be obtained by adding solid par
`affin to the excipient matrix. The invention therefore relates
`further to a preparation in which an active ingredient is
`essentially uniformly dispersed in an excipient matrix com
`posed of at least one solid paraffin together with one or more
`excipients selected from the group of fatty alcohol, triglyc
`eride, partial glyceride and fatty acid ester.
`[0007] The invention further relates to preparations in
`which an active ingredient is essentially uniformly dispersed
`i) in an excipient matrix composed of a mixture comprising
`at least one fatty alcohol and at least one solid paraffin, ii) in
`an excipient matrix comprised of a mixture comprising at
`least one triglyceride and at least one solid paraffin, iii) In an
`excipient matrix composed of a mixture comprising at least
`one partial glyceride and at least one solid paraffin or iv) in
`an excipient matrix composed of a mixture comprising at
`least one fatty acid ester and at least one solid paraffin.
`
`[0008] Further subject matters are evident from the claims.
`[0009] The preparations for the purpose of the invention
`preferably comprise numerous individual units in which at
`least one active ingredient particle, preferably a large num
`ber of active ingredient particles, is present in an excipient
`matrix composed of the excipients of the invention (also
`referred to as active ingredient units hereinafter). The active
`ingredient is preferably essentially uniformly dispersed, in
`particular homogeneously dispersed or dissolved, in the
`excipient matrix. A preparation preferably comprises micro
`spheres.
`[0010] The preparations of the invention are distinguished
`in particular by high stability, a release of active ingredient
`which can be controlled by the particle size and composition
`of the matrix, good flow characteristics, good compressibil
`ity and by a uniform delivery of active ingredient. In the case
`of acid-labile active ingredients it is moreover possible to
`achieve, through choice of the matrix excipients, an acid
`resistance so that it is possible in the case of oral forms to
`dispense with an acid-resistant coating (enteric coating). In
`the case of active ingredients which have an unpleasant taste
`or, for example, show a local anesthetic effect in the mouth
`after administration, it has been observed that an unpleasant
`taste of the active ingredient can be masked, and anesthetic
`effects in the mouth can be avoided, by preparations of the
`invention. It is particularly worthy of mention that the
`preparations of the invention can be further processed to a
`large number of pharmaceutical dosage forms without
`thereby losing a given functionality (such as taste masking,
`resistance to gastric juice, slowing of release). Thus, for
`example, on compression of the active ingredient units of the
`invention no or negligible loss of functionality is observed
`even if deformation of the active ingredient units occurs. In
`contrast to this, with conventional pellets, which normally
`have a functional coating (such as taste masking, resistance
`to gastric juice, slowing of release), a certain degree of
`damage to the coating and thus to the functionality is
`observed on further processing to dosage forms, for example
`on compression to tablets. This may also lead in some cases
`to active ingredient being released in an unwanted way.
`[0011] The particle size of the individual units is advan
`tageously less than or equal to 2 mm, preferably 50-800 um,
`particularly preferably 50-700 um and very particularly
`preferably 50-600 um. Preference is given to microsphers of
`a particle size of 50-500 um, particularly preferably of
`50-400 um. Particular preference is given to monomodal
`microspheres with a particle size of 50-400 um, particularly
`of 50-200 um.
`[0012] Active ingredients of the invention are, in particu
`lar, active pharmaceutical ingredients. Examples of active
`ingredients which may form part of the preparations of the
`invention are, in particular, the active pharmaceutical ingre
`dients mentioned below:
`[0013] Adrenergics:
`dapiprazole;
`[0014] apraclonidine; brimonidine;
`deterenol; dipivefrin; dopamine; ephedrine; espro
`quin; etafedrine; hydroxyamphetamine; levonorde
`frin; metaraminol; norepinephrine; oxidopamine;
`phenylpropanolamine; prenalterol; propylhexedrine;
`pseudoephedrine.
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2001
`Page 2
`
`

`

`US 2004/0058896 A1
`
`Mar. 25, 2004
`
`[0015] Adrenocorticosteroids:
`[0016] ciprocinomide; desoxycorticosterone acetate;
`desoxycorticosterone
`pivalate;
`dexamethasone
`acetate; fludrocortisone acetate; flumoxonide; hydro
`cortisone
`hemisuccinate;
`methylprednisolone
`hemisuccinate; naflocort; procinonide; timobesone
`acetate; tipredane.
`[0017] Agents to prevent alcohol abuse:
`[0018] disulfiram, acamprosate, milmacipran, fome
`pizole, lazabemide, nadide; nitrefazole; sunepitron.
`[0019] Aldosterone antagonists:
`dicirenone;
`[0020) canrenoate;
`canremone;
`mexrenoate; prorenoate; spironolactone, epostane,
`mespirenone; Oxprenoate, spirorenone, Spiroxasone,
`prorenone, eplerenone.
`[0021] Amino acids:
`[0022] alanine; aspartic acid; cysteine; histidine; iso
`leucine; leucine; lysine; methionine; phenylalanine;
`proline; serine; threonine; tryptophan; tyrosine;
`valine.
`[0023] Active ingredients for ammonium detoxifica
`tion:
`[0024] arginine; arginine glutamate; arginine hydro
`chloride; glutamic acid;
`[0025] Anabolics:
`diproplonate;
`bolandiol
`[0026] androstanolone,
`bolasterone; boldenone undecylenate; bolenol; bol
`nantalate;
`ethylestrenol;
`metenolone acetate;
`metenolone enanthate; bolazine; mesteronole; met
`andienone; nandrolone; oxandrolone; prasterone;
`stanozolone; tionesterone; clostebol; mibolerone;
`nandrolone cyclotate; norbolethone; quinbolone;
`stenbolone acetate; tibolone; Zeranol.
`[0027] Analeptics:
`[0028] modafinil; amineptine; endomide; etamivan;
`fenoxypropazine; fenozolone; hexapradol; niala
`mide; nicethamide.
`[0029] Analgesics:
`[0030) acetaminophen; alfentanil; aminobenzoate;
`aminobenzoate; anidoxime; anileridine; anileridine;
`anilopam; anirolac; antipyrine; aspirin; benoxapro
`fen; benzydamine; bicifadine hydrochloride; brifen
`tanil; brom adoline; bromfenac; bupremorphine;
`butacetn; butixirate; butorphanol; butorphanol; car
`bamazepine; carbaspirin calcium; carbiphene;
`carfentanil; ciprefadol succinate; ciramadol; cirama
`dol; clonixeril; clonixin; codeine; codeine phos
`phate; codeine sulfate; conorphone; cyclazocine;
`dexoxadrol; dexpemedolac, dezocine; diflunisal;
`dihydrocodeine; dimefadane; dipyrone; doxpicom
`ine; drinidene; enadoline; epirizole; ergo tamine tar
`trate; ethoxazene; etofenamate; eugenol; fenoprofen;
`fenoprofen calcium; fentanyl citrate; floctafenine;
`flufenisal; flunixin; flunixin meglumine; flupirtine;
`fluproduazone; fluradoline; flurbiprofen; hydromor
`phone; ibufenac; indoprofen; ketazocine; ketorfanol;
`ketorolac,
`letimide;
`levomethadyl
`acetate;
`
`levomethadyl acetate hydrochloride; levonantradol;
`levorphanol; lofemizole; lofentanil oxalate; lorcina
`dol; lomoxicarn; magnesium salicylate; mefenamic
`add; menabitan; meperidine; meptazinol; metha
`done; methadyl acetate; methopholine; methotrime
`prazine; metkephamid acetate; mimbane; mirfenta
`nil; molinazone; morphine sulfate; moxazocine;
`nabitan; nalbuphine; nalmexone; namoxyrate; nant
`radol; naproxen; naproxen; naproxol; nefopam; nex
`eridine; noracymethadol; ocfentanil; octazamide;
`olvanil; oxetorone; oxycodone; oxycodone; oxyc
`odone terephthalate; oxymorphone; pemedolac, pen
`tamorphone; pentazocine; pentazocine; phenazopy
`ridine;
`phenyramidol; picenadol;
`pinadoline;
`pirfenidone; piroxicam olamine; pravadoline; prodi
`lidine; profadol; propiram; propoxyphene; pro
`poxyphene napsilate; proxazole; proxorphan; pyrro
`liphene; remifentanil; salcolex; salethamide maleate;
`salicylamide; salicylate meglumine; salsalate; sali
`cylate; spiradoline; sufentanil; sufentanil; talmeta
`cin; talniflumate; talosalate; tazadolene; tebufelone;
`tetrydamine; tifurac; tilidine; tiopinac; tonazocine;
`tramadol; treferitanil; trolamine; veradoline; verilo
`pam; volazocine; xorphanol; xylazine; zenazocine
`mesilate; Zomepirac, Sucapsaicin.
`[0031] Androgens:
`fluoxymesterone;
`[0032] androstanolone;
`mestanolone; mesterolone; metandienone; methylt
`estosterone; nandrolone decanoate; nandrolone
`phenpropionate; misterime; Oxandrolone; oxymester
`one; oxymetholone; penmesterol; prasterone; silan
`drone; stanozolol; testosterone; testosterone cypi
`Onate;
`teStoSterOne
`enanthate;
`teStoSterOne
`ketolaurate; testosterone phenylacetate; testosterone
`propionate; trestolone.
`[0033] Anesthetic additives:
`[0034] sodium oxibate.
`[0035] Anesthetics (non-inhalation):
`[0036] alfaxalone; amolanone; etoxadrol; fentanyl;
`ketamine; levoxadrol; methitural; methohexital;
`midazolam; minaxolone; propanidid; propoxate;
`pramoxine; propofol; remifentanyl; sufentanyl; tile
`tamine; Zolamine.
`[0037] Anesthetics (local):
`amylocaine;
`[0038] ambucaine;
`amoxecaine;
`aptocaine; articaine; benoximate; benzyl alcohol;
`benzocaine; betoxycaine; biphenamine; bucricaine;
`bumecaine; bupivacaine; butacaine; butamben; buta
`nilicaine; carbizocaine; chloroprocaine clibucaine;
`clodacaine; cocaine; dexivacaine; diamocaine;
`dibucaine; dyclonine; elucaine; etidocaine; euprocin;
`fexicaine; fomocaine; heptacaine; hexylcaine;
`hydroxyprocaine; hydroxytetracaine; isobutamben;
`ketocaine; leucinocaine; lidocalne; mepivacaine;
`meprylcaine; octocalne; orthocaine; oxethacaine;
`oxybuprocaine; parabutoxycalne; phenacaine; pinol
`caine;
`piperocaine;
`piridocaine;
`polidocanol;
`pramocaine; prilocaine; procaine; propanocaine;
`propipocaine; propoxycaine; proxymetacaine; pyr
`rocaine;
`quatacaine;
`quinisocaine;
`risocaine;
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2001
`Page 3
`
`

`

`US 2004/0058896 A1
`
`Mar. 25, 2004
`
`rodocaine; ropivacaine; salicyl alcohol; suicaine; tet
`racaine; trapencaine; trimecaine.
`[0039] Appetite suppressants:
`[0040] amfepramone; amfetamine; aminorex, amfe
`cloral; anisacril; benzfetamine; chlorphentermine;
`clobenzorex, cloforex, clominorex, clortermine;
`dexamfetamine; dexfenfluramine; difemetorex, efil
`amfetamine; etolorex, fenbutrazate; fencamfamln;
`fenfluramine; fenisorex, femproporex; fludorex, flu
`minorex; formetorex; furfenorex, imanixil; indan
`orex, levamfetamine; levofacetoperane; levofenflu
`ramine; levopropylhexedrine; mazindol; mefenorex,
`metamfepramone; morforex, norpseudoephedrine;
`orlistat; ortetamine; oxifentorex, pentorex, phen
`dimetrazine; phenmetrazine; phentermine; picilorex,
`satietine; setazindol; sibutramine; triflorex, trifluo
`I?èX.
`[0041] Anthelmintics:
`[0042] abamectin; albendazole; albendazole oxide;
`amidantel; amoscanate; antafenite;
`antazonite;
`anthelmycin; antholimine; bephenium hydroxynaph
`thoate; bidimazium iodide; bisbendazole; bithion
`oloxide; bitoscanate; bromoxanide; brotianide;
`bunamidine; butamisole; butonate; cambendazole;
`carbantel; cidobendazole; clioxanide; closantel; dex
`amisole; diamfenetide; dichlorvos; diethylcarbam
`azine; dimantine; diphenan; doramectin; dribenda
`zole; eprinomecun; epsiprantel; etibendazole;
`febantel; fenbendazole; flubendazole; flurantel; fta
`lofyne; furodazole; haloxon; hexylresorcinol; imcar
`bofos; ivermectin; kainic acid; mebendazole; metri
`fonate;
`metyridine;
`morantel;
`moxidectin;
`naftalofos; netobimin; niclofolan; niclosamide; nit
`ramisole; nitrodan; nitroscanate; nitroximil; oltipraz;
`ontlanil, oxantel oxfendazole; oxibendazole; oxyclo
`zanide; parbendazole; pexantel; piperamide; pipera
`zine adipate; piperazine calcium edetate; piperamide
`praziquantel; proclonol; pyrantel pamoate; pyrantel
`tartrate; pyrvinium pamoate; rafoxanide; resorantel;
`salantel; spirazine; stilbanzium iodide; subendazole;
`tetramisole; thenium closilate; thiofuradene; tia
`bendazole; ticarbodine; tioxidazole; triclabendazole;
`triclofenol piperazine; uredofos; vincofos; zilantel.
`[0043] Acne therapeutics:
`[0044] adapalene; adelmidrol; benzoyl peroxide;
`betacarotene; cioteronel; delanterone; cyproterone;
`doretinel; erythromycin salmacedin; etretinate;
`fumaric acid; halofuginonen; inocoterone acetate;
`isotretinoin; linolenic acid; manoalide; masoprocol;
`mitotane; motretinide; namirotene; rosterelone;
`Sumarotene; tazarotene; tematotene; tioxolone;
`topterone; tradecamide; tretinoin; triadimenol;
`zearalenone; Zeranol; zimidoben.
`[0045] Bronchodilators:
`[0046] acefylline; azaspirium chloride; bambuterol;
`bamifylline; bitoiterol; broxaterol; butaprost; car
`buterol; cipamfylline; colterol; doxaprost; doxofyl
`line; dyphylline; emprofylline; ephedrine; eprozinol;
`etanterol; fenspiride; flutropium bromide; formot
`erol;
`guaithylline;
`hexoprenaline;
`Hoku-81;
`
`hoquizil; imoxiterol; ipragratine; ipratroplum bro
`mide; isoetharine; isoproterenol; levosalbutamol;
`mabuterol; meduitamium iodide; metaproterenol;
`mexafylline; nardeterol; nestifylline; nisbuterol;
`picumeterol; piquizil; pirbuterol; procaterol; reprot
`erol; RO-24-4736; quazodine; quinterenol; racepi
`nephrine; reproterol; rimiterol; salbutamol; salme
`terol; saimeterol xinafoate; sevitropium mesilate;
`soterenol; sulfonterol; suloxifen; TA-2005; theo
`phylline; terbutaline; theophylline ethylenediamine;
`tiaramide;
`tipetropium
`bromide;
`tretoquinol;
`tulobuterol; zindotrine; Zinterol.
`[0047] Beta-blockers:
`[0048] acebunolol; adaprolol; afurolol; alprenolol;
`alprenoxime; ancarolol; arnolol; arotinolol; atenolol;
`befunolol; benzodioxine; betaxolol; bevantolol;
`bisoprolol; bormetolol; bopindolol; bomaprolol; bre
`fonalol; bucumolol; bufetolol; buftiralol; bunitrolol;
`bunolol; bupranolol; butaxamine; butidrine; buro
`crolol; butofilolol; carazolol; carteolol; carvedilol;
`celiprolol; cetamolol; cicloprolol; cinamolol; clo
`ranolol; cyanopindolol; dalbraminol; dexpropra
`nolol; diacetolol; dichlorisoproterenol; dilevalol;
`draquinolol; dropranolol, ecastolol; epanolol; eri
`colol; esatenolol; esmolol; exaprolol, falintolol; fies
`tolol; flusoxolol; hydroxycarteolol; hydroxyterta
`tolol
`;
`ICI-118551; idropranolol;
`indenolol;
`indopanolol; iprocrolol; isamoltan; labetalol; landi
`olol; levobetaxolol; levobunolol; levocicloprolol;
`levomoprolol; medroxalol; mephenoxalone; mepin
`dolol; metalol; metipranolol; metoprolol; mind
`odilon; moprolol; nadolol; nadoxolol; nafetolol;
`napitane; nebivolol; neraminol; nifemalol; nipradilol;
`oberadilol, oxanamide; oxprenolol; pacrinolol;
`pafenolol; pamatolol; pargolol; parodilol; penb
`utolol; penirolol; PHQA-33; pindolol; pirepolol;
`practolol; prenalterol; primidolol; procinolol; pron
`etalol; propacetamol; propranolol; ractopamine;
`ridazolol; romactolol; soduinolol; sotalol; TA-2005;
`talinolol, tazolol; teoprolol; tertatolol; terthianolol;
`tienoxolol; tilisolol; timolol; tiprenolol; tolamolol;
`toliprolol;
`tribendilol;
`trigevolol;
`xamoterol;
`xibenolol; Y-12541; ZAM1-1305.
`[0049] Adrenergic agonists:
`[0050] betanidine; bretylium tosilate; cromanidine;
`debrisoquine; ethomoxane; guabenxan; guanabenz;
`guanacline; guanadrel; guanazodine; guancidine;
`guanclofine; guanethidine; guanfacine; guaniso
`quine; guanoclor; guanoctine; guanoxabenz, guan
`oxan; guanoxyfen; olmidine; piperoxan; pyroxami
`dine; solypertine; spirgetine.
`[0051] Alpha 1 antagonists:
`[0052] abanoquil; adozelesin; alfuzosin; amosulalol;
`benoxathian; bunazosin; CI-926; DL017; dapipra
`zole; dihydroergotamine mesilate; doxazosin;
`euigenodilol; fenspiride; GI-231818; GYKI-12743;
`GYKI-16084; indoramine; metazosin; MK-912;
`monatepil; naftopidil; meldazosin; nesapidil; nicer
`goline; pelanserin; peradoxime; peraquinsine; per
`auzole; perbufylline; phendioxan; phenoxyben
`zamine;
`phentolamine;
`podilfen;
`prazosin;
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2001
`Page 4
`
`

`

`US 2004/0058896 A1
`
`Mar. 25, 2004
`
`quinazosin; RS-97078; proroxane; sertindole; SGB
`1534; SL-89.0591; tamsulosin; tedisamil; terazosin;
`tibalosin; tiodazosin; tolazoline; trimazosin; upid
`osin; urapidil; yohimbine; Zolertine.
`[0053] ACE inhibitors:
`benazeprilat;
`benazepril;
`[0054] alacepril;
`BMS-189921; BRL-36378; captopril; ceronapril;
`CGS-13928C; cilazapril; cilazaprilat; dehydrocapto
`pril; delapril; enalapril; enalaprilat; EU4867; EXP
`7711; fasidotril; fosinopril; fosinoprilat; idrapril;
`imidapril; imidaprilat; indolapril; libenzapril; lisino
`pril; mixanpril; moexipril; moexiprilat; moveltipril;
`omapatrilat; orbutopril; pentopril; perindopril; per
`indoprilat, pivopril; quinapril; quinaprilat; ramipril;
`rentiapril; sampatrilat; SCH-54470; spirapril; spira
`prilat; temocapril; temocaprilat; teprotide; trandola
`pril; trandolaprilat; utibapril; utibaprilat; Z-13752A;
`Zabicipril; zofenopril; zofenoprilat.
`[0055] Renin antagonists
`CP-108671;
`ciprokiren;
`[0056] CGP-38560;
`enalkiren; ES-6864; FK-906; remikiren; terlakiren;
`Zankiren.
`[0057] Antiallergics such as PDE inhibitors:
`[0058] arofylline; atizoram, AWD-12-281 (N-(3,5
`dichloro-4-pyridinyl)-2-[1-(4-fluorobenzyl)-5-hy
`droxy-1H-indol-3-yl)-2-oxoacetamide);
`BAY-19
`8004
`(ethanesulfonic
`acid
`2-(2,4
`dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl
`ester); benafentrine; CC-1088; CDC-801 (B-[3-(cy
`clopentyloxy)4-methoxyphenyl]-1,3-dihydro-1,3-di
`oxo-2H-isoindole-2-propanamide);
`CDC-998;
`CI-1018; cilomilast (cis-[4-cyano-4-(3-cyclopenty
`loxy-4-methoxyphenyl)cyclohexane-1-carboxylic
`acid); cilostazol; cipamfylline (8-amino-1,3-bis(cy
`clopropylmethyl)xanthine); D-4396; D-4418 [N-(2,
`5-dichloro-3-pyridinyl)-8-methoxy-5-quinolinecar
`boxamidel; darbufelone; denbufylline; ER-21355;
`filaminast; ibudilast; IC-485; indolidan; laprafylline;
`lixazinone; MESOPRAM [(–)-(R)-5-(4-methoxy-3
`propoxyphenyl)-5-methyloxazolidin-2-one];
`nitraquazone; NM-702; olprinone; ORG-20241
`(4-(3,4-dimethoxyphenyl)-N2-hydroxythiazole-2
`carboxamidine); piclamilast; pumafentrine ((-)-cis
`9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10
`Ob-hexahydro-6-(4-diisopropylaminocarbonylphe
`nyl)benzo[c][1,6]-naphthyridine);
`quazinone;
`RO-15-2041; roflumilast (3-(cyclopropylmethoxy)
`N-(3,5-dichloro-pyridyl)-4-(difluoromethoxy)-ben
`zamide); rolipram; SCH-351591; SH-636; tibenelast
`(5,6-diethoxybenzo[b]thiophene-2-carboxylic acid);
`tolafentrine; trequinsin; V-11294A (3-[[3-(cyclopen
`tyloxy)-4-methoxyphenyl]methyl]-N-ethyl-8-(1-me
`thylethyl)-3H-purin-6-amine); YM-58997 (4-(3-bro
`mophenyl)-1-ethyl-7-methyl-1,8-naphthyridin
`2(1H)-one); YM-976 (4-(3-chlorophenyl)-1,7
`diethylpyrido[2,3-d]pyrimidin-2(1H)-one);
`Zardaverine.
`[0059] Other antiallergics for asthma treatment:
`[0060] ablukast; atreleuton; bunaprolast; cinalukast;
`cromitrile; cromolyn; FPL-55712; iralukast; isamox-
`
`ole; ketoufen; L-648051; levcromakalim; lodoxam
`ide ethyl; lodoxamide tromethamine; montelukast;
`oxarbazole; piriprost; pirolate; pobilukast; pran
`lukast; ritolukast; sulukast; tiaramide; Ubenelast;
`tomelukast; verlukast; verofylline; Zafirlukast; zileu
`ton.
`[0061] Other antiallergics (for example leukotriene
`antagonists):
`[0062] acitazanolast; acrivastine; alinastine; altoqua
`line; amlexanox; andolast; astemizole; ataquimast;
`azatadine; azelastine; bamipine; barmastine; batebu
`last; BAY-X-1005; BAY-X-7195; bepiastine; bepo
`tastine; BIIL-284; bilastine; binizolast; buclizine;
`bunaprolast; cabastine; carebastine; cetirizine;
`CI-959; ciproxifan; clemastine; CMI-977; cro
`mogleic acid; cromolyn matrium; dametralast; deslo
`ratadine;
`dlmenhydrinate;
`diphenhydramine;
`dogualast; dorastine; E-4704; efietirizine; emedas
`time; enofelast; enoxamast; ebastine; eclazolast; epi
`nastine; fexofenadine; flezelastine; HSR-609; KCA
`757; levocabastine; levocetirizine;
`linetastine;
`loratadine; LY-293111; mapinastine; meduitamium
`iodide;
`meguitazin; minocromil, mizolastine;
`MK-886; moxastine; moxilubant; nedocromil;
`nedocromil calcium; nedocromil sodium; nivine
`done; noberastine; norastemizole; octastine; ONO
`4057; ontazolast; oxatomide; pemirolast; pentiget
`ide; perastine; piclopastine; picumast; pirquinozol;
`poisonoak extract; probicromil; proxicromil; quazo
`last; quifenadine; quinotolast; raxofelast; repirinast;
`REV-5901-A, rocastine; rupatadine; SKF-S-106203;
`sequifenadine; setastine; sudexanox; tagorizine;
`talastine; tazanolast; tazifylline; temelastine; terfema
`dine; tetrazolast; texacromil; thiazinamium chloride;
`tiacrilast; tiprinast meglumine; tixanox; tranilast;
`WY-50295; ZD-3523; zepastine.
`[0063] Amebicides:
`[0064] 1 B-bisamidine; berythromycin; bialamicol;
`carbarsone; chloroquine; chloroquine; clamoxyquin;
`ciloquinol; dehydroemetime; difetarSone; diloxanide;
`emetime; etofamide; iodoquinol; lachnumon; lirol
`dine; paromomycin sulfate; pinafide; quinfamide;
`satranidazole; stevaladil; stirimazole; symetime;
`teclozan; tetracycline; tilbroqulmol;
`[0065] Antiandrogens:
`[0066] abiraterone; benorterone; cioteronel; cyprot
`erone; delanterone; delmadinone; drospirenone; epi
`tiostanol; inocoterone; L-654066; minamestane;
`norgestimate; osaterone; oxendolone; progesterone;
`rosterelone; topterone; Zanoterone.
`[0067] Antianemics:
`[0068] ancestim; diciferron; epoetin alfa, epoetin
`beta; epoetin epsilon; epoetin gamma; epoetin
`omega; ferrous sulfate, FK-352; folic acid; gleptof
`erron; glutathione monoisopropyl ester; leucovorin
`calcium; tucaresol; TYB-5220; velaresol;
`[0069] Antianginals:
`[0070] alinidine; amiodarone; amlodipine besylate;
`amlodipine maleate; azaclorzine; bamidipine; ber
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2001
`Page 5
`
`

`

`US 2004/0058896 A1
`
`Mar. 25, 2004
`
`bevantolol;
`bertosamil;
`betaxolol;
`tosamil;
`bimakalim; butoprozine;
`carvedilol; CD832;
`CERM-11956; cinepazet maleate; crobenetime;
`cyclovirubuxine-D; desocriptine;
`diproteverine;
`dopropidil; elgodipine; EMD-57283; eniporide;
`ethacizine; fantofarone; FK-409; flestolol; flosaudil;
`flosequinan; FR-46171; GP-1-468; GP-1-531;
`hyperin; ipramidil; isosorbide dinitrate; ivabradine;
`KC-764; KRN-2391; KW-3635; ligustizine; linsi
`domine; metoprolol succinate; mibefradil; mildr
`onate; mivazerol; molsidomine; monatepil maleate;
`nafagrel; NK-341; OP-2000; pirsidomine; pivazide;
`pranidipine; primidolol; ranolazine; SL-87.0495;
`ST-1324; tedisamil; tosifen; vatanidipine; verapamil;
`Y-27152; zatebradine.
`[0071] Anxiolytics:
`[0072] adatanserin; alpidem; binospirone mesilate;
`bretazenil; glemanserin; ipsapirone; mirisetron
`maleate; ocinaplon; ondansetron; panadiplon; pan
`copride; pazinaclone; serazapine; tandospirone cit
`rate; zalospirone.
`[0073] Antiarthritics:
`[0074] AI-200; auranofin; aurothioglucose; cipemas
`tat; etanercept; etebenecid; interleukin-6; lefluno
`mide; lenercept; lobenzarit; lodelaben; M-5010;
`parecoxib;
`rofecoxib;
`RS-130830;
`S-2474;
`TSA-234; valdecoxib;
`[0075] Antiatherosclerotics:
`[0076] H-327/86; mi?obate; lodazecar; riboflavin
`butyrate; timefurone.
`[0077] Bacteriostatics:
`[0078] acedapsone; acetosulfone sodium; alamecin;
`alexidine; amdinocillin; amdlnocillin pivoxil, ami
`cycline; amifloxacin; amifloxacin mesilate; amika
`cin; amikacin sulfate; aminosalicyllc acid; ami
`nosalicylate sodium; amoxicillin; amphomycin;
`ampicillin; ampicillin sodium; apaicillin sodium;
`apramycin; aspartocin; astromicin sulfate; avilamy
`cin; avoparcin; azithromycin; aziocillin; aziocillin
`sodium; bacampicillin hydrochloride; bacitracin;
`bacitracin methylene disalicylate; bacitracin zinc;
`bambermycins; benzoylpas calcium; berythromycin;
`betamicin sulfate; biapenem; biniramycin; biphe
`namine hydrochloride; bispyrithione magsulfex,
`butikacin; butirosin sulfate; capreomycin sulfate;
`carbadox; carbenicillin disodium; carbenicillin inda
`nyl sodium; carbenicillin phenyl sodium; carbenicil
`lin; carumonam sodium; cefaclor, cefadroxil, cefa
`mandole; cefamandole nafate; cefamandole sodium;
`cefaparole; cefatrizine; cefazafiur sodium; cefazolin;
`cefazolin
`sodium;
`cefbuperazone;
`cefdinir;
`cefepime; cefepime; cefetecol; cefixime; cef
`menoxime; cefnmetazole; cefnmetazole sodium;
`cefonicid monosodium; cefonicid sodium; cefopera
`zone sodium; ceforanide; cefotaxime sodium;
`cefotetan; cefotetan disodium; cefotiam; cefoxitin;
`cefoxitin sodium; cefpimizole; cefpimizole sodium;
`cefpiramide; cefpiramide sodium; cefpirome sulfate;
`cefpodoxime proxetil, cefprozil; cefroxadine; cefsu
`lodin sodium; ceftazidime; ceftibuten; ceftizoxime
`
`cefuroxime;
`sodium;
`ceftriaxone
`sodium;
`cefuroxime axetil, cefuroxime pivoxetil, cefuroxime
`sodium; cephacetrile sodium; cephalexin; cephal
`exin; cephaloglycin; cephaloridine; cephalothin
`sodium; cephapirin sodium; cephradine; cetocycline;
`cetophenicol; chloramphenicol; chloramphenicol
`palmitate; chloramphenicol pantothenate complex;
`chloramphenicol sodium succinate; chlorhexidine
`phosphanilate;
`chloroxylenol;
`chlortetracycline
`bisulfate; chlortetracycline; cinoxacin; ciprofloxa
`cin; ciprofloxacin; cirolemycin; clarithromycin;
`clinafloxacin; clindamycin; clindamycin; clindamy
`cin palmitate; clindamycin phosphate; clofazimine;
`cloxacillin benzathine; cloxacillin sodium; clox
`yguin; colistimethate sodium; colistin sulfate;
`coumermycin; coumermycin sodium; cyclacillin;
`cycloserine; dalfopristin; dapsone; daptomycin;
`demeclocycline;
`demeclocycline;
`demecycline;
`denofungin; diaveridine; dicloxacillin; dicloxacillin
`sodium; dihydrostreptomycin sulfate; dipyrithione;
`dirithromycin; doxycycline; doxycycline calcium;
`doxycycline fosfatex, doxycydine hyclate; droxacin
`sodium; enoxacin; epicillin; epitetracycline; erythro
`mycin; erythromycin acistrate; erythromycin esto
`late; erythromycin ethylsuccinate; erythromycin glu
`ceptate; erythromycin lactoblonate; erythromycin
`propionate; erythromycin stearate; ethambutol;
`ethionamide; fleroxacin; floxacillin; fludalanine;
`flumequine; fosfomycin; fosfomycin tromethamine;
`fumoxicillin; furazolium chloride; furazolium tar
`trate; fusidate sodium; fusidic acid; gentamicin sul
`fate; gloximonam; gramicidin; haloprogin; hetacil
`lin; hetacillin; hexedine; ibafloxacin; imipenem;
`isoconazole; isepamicin; isoniazid; josamycin; kana
`mycin sulfate; kitasamycin; levofuraltadone; levo
`propylcillin; lexithromycin; lincomycin; lincomycin;
`lomefloxacin; lomefloxacin; lomefloxacin mesilate;
`loracarbef, mafenide; meclocycline; meclocycline
`sulfosalicylate; megalomicin phosphate; meduidox;
`meropenem; methacycline; methacycline; meth
`enamine; methenamine hippurate; methenamine
`mandelate; methicillin sodium; metioprim; metron
`idazole; metronidazole phosphate; meziocillin;
`meziocillin sodium; minocycline; minocycline; mir
`incamycin; monensin; monensin sodium; nafcilin
`sodium; nalidixate sodium; nalidixic acid; natainy
`cin; nebramycin; neomycin palmitate; neomycin sul
`fate; neomycin undecylenate; netilmicin sulfate;
`neutramycin; nifuiradene; nifuraldezone; nifuratel;
`nifuratrone; nifurdazil; niftrimide; niflupirinol;
`nifurquinazol; nifurthiazole; nitrocycline; nitro
`furantoin;
`nitromlde;
`norfloxacin; novobiocin
`sodium; of oxacin; onnetoprim; oxacillin sodium;
`oximonam; oximonam sodium; oxolinic acid;
`oxytetracycline; oxytetracycline calcium; oxytetra
`cycline; paldimycin; parachlorophenol; paulomycin;
`pefloxacin; pefloxacin mesilate; penamecillin; peni
`cillin G benzathine; penicillin G; penicillin G
`procaine; penicillin G sodium; penicillin V; penicil
`lin V benzathine; penicillin V hydrabamine; penicil
`lin V; pentizidone sodium; phenyl aminosalicylate;
`piperacillin sodium; pirbenicillin sodium; piridicillin
`sodium; pirlimycin; pivampicillin; pivampicillin
`pamoate; pivampicillin probenate; polymyxin B sul
`
`UCB Biopharma SPRL (IPR2019-00400)
`Exhibit 2001
`Page 6
`
`

`

`US 2004/0058896 A1
`
`Mar. 25, 2004
`
`porfiromycin; propikacin; pyrazinamide;
`fate;
`pyrithione zinc, quindecamine acetate; quinupristin;
`racephenicol; ramoplanin; ranimycin; relomycin;
`repromicin; rifabutin; rifametane; rifamexil; rifa
`mide; rifampin; rifapentine; rifaximin; rolitetracy
`cline; rolitetracycline nitrate; rosaramicin; rosarami
`cin butyrate; rosaramicin propionate; rosaramicin
`sodium phosphate; rosaramicin stearate; rosoxacin;
`roxarsone; roxithromycin; sancycline; sanfetrinem
`sodium; Sarmoxicillin; sarpicillin; scopafungin; siso
`micin; sisomicin sulfate; sparfloxacin; spectinomy
`cin; spiramycin; stallimycin; Steffimycin; streptomy
`cin
`sulfate;
`streptonicozid;
`sulfabenz;
`sulfabenzamide;
`sulfacetamide;
`sulfacetamide
`sodium; sulfacytine; sulfadiazine; sulfadiazine
`sodium; sulfadoxine; sulfalene; sulfamerazine; sul
`fameter; sulfamethazine; sulfamethizole; sul
`famethoxazole; sulfamonomethoxine; sulfamoxole;
`sulfanilate zinc, sulfanitran; sulfasalazine; sulfa
`somizole; sulfathiazole; sulfazamet; sulfisoxazole;
`sulfisoxazole acetyl; sulfisboxazole diolamine; sul
`fomyxin; sulopenem; sultarmicillin;
`suncillin
`sodium; talampicillin; telcoplanin; temafloxacin;
`temocillin; tetracycline; tetracycline; tetracycline
`phosphate complex; tetroxoprim; thiamphenicol;
`thiphencillin; ticarcillin cresyl sodium; ticarcillin
`disodium; ticarcillin monosodium; ticlatone; tiodo
`nium chlor