sign in sign up
<<
Home , Acrocinonide, Amebucort, Amflutizole, Ancarolol, Berefrine, Betamethasone acetate

US007 175854B2

(12) United States Patent (10) Patent No.: US 7,175,854 B2 Dietrich et al. (45) Date of Patent: Feb. 13, 2007

(54) PHARMACEUTICAL PREPARATION EP O 120 589 B1 10, 1984 COMPRISING AN ACTIVE DISPERSED ON A EP O 125 756 A2 11/1984 MATRIX EP O 165 545 A2 12/1985 EP 0 204 285 A1 12, 1986 EP O 228 006 A1 7, 1987 (75) Inventors: Rango Dietrich, Constance (DE); EP O 259 174 A1 3, 1988 Rudolf Linder, Constance (DE); EP O 261 912 A2 3, 1988 Hartmut Ney, Constance (DE) EP O 264 883 A2 4f1988 EP O 266 890 A1 5, 1988 (73) Assignee: Altana Pharma AG, Constance (DE) EP O 268989 B1 6, 1988 EP O 307 078 B1 3, 1989 (*) Notice: Subject to any disclaimer, the term of this EP O 3O8917 A2 3, 1989 patent is extended or adjusted under 35 EP O 330 485 A1 8, 1989 U.S.C. 154(b) by 426 days. EP O 368 158 A1 5, 1990 EP O 387 821 B1 9, 1990 (21) Appl. No.: 10/433,398 EP O 393 926 B1 10, 1990 EP O 399 267 A2 11/1990 (22) PCT Filed: Dec. 6, 2001 EP O 438 359 A1 7, 1991 EP O 509 974 B1 10, 1992 (86). PCT No.: PCT/EPO1/14307 EP O 535 529 B1 4f1993 EP O 537 532 B1 4f1993 S 371 (c)(1), JP 2-270873 11, 1990 (2), (4) Date: Sep. 11, 2003 JP 3-31280 2, 1991 JP 3-284622 12/1991 (87) PCT Pub. No.: WO02/45693 JP 3-284686 12/1991 JP 2000-865O2 3, 2000 PCT Pub. Date: Jun. 13, 2002 WO 89.00570 1, 1989 WO 91.14677 10, 1991 (65) Prior Publication Data WO 91f17164 11, 1991 WO 91f18887 12/1991 US 2004/0058896 A1 Mar. 25, 2004 WO 92.06979 4f1992 WO 92,12969 8, 1992 (30) Foreign Application Priority Data WO 92/21328 12/1992 Dec. 7, 2000 (EP) ...... OO 126847 WO 93,08190 4f1993 WO 93.12090 6, 1993 (51) Int. Cl. WO 93.15055 8, 1993 A6 IK 9/20 (2006.01) WO 93.15056 8, 1993 A6 IK 9/14 WO 93.15071 8, 1993 (2006.01) WO 94f14.795 T 1994 A6 IK 3/44 (2006.01) WO 94.24130 10, 1994 A6 IK 9/48 (2006.01) (52) U.S. Cl...... 424/464; 424/484; 424/489: 424/465; 424/469 (Continued) (58) Field of Classification Search ...... None OTHER PUBLICATIONS See application file for complete search history. Hafner et al. Additive effects of phosphodiesterase-4 inhibition on (56) References Cited effects of rSP-C surfactant, AM J Respir Crit Care Med. May 2000:161(5): 1495-500.* U.S. PATENT DOCUMENTS Primary Examiner Michael G. Hartley 3,065,142 A 11/1962 Antonides ...... 424/489 Assistant Examiner Jake M. Vu 4,006,227 A 2, 1977 Gallegos et al...... 424,764 4,464,372 A 8, 1984 Bristol et al. (74) Attorney, Agent, or Firm Nath & Associates PLLC; 4,833, 149 A 5, 1989 PreSS Joshua B. Goldberg; Sheldon M. McGee 5,041,442 A 8, 1991 Romero et al. 5,429,824. A 7, 1995 June ...... 424/489 (57) ABSTRACT 5,665,730 A 9/1997 Senn-Bilfinger et al. 5,677,302 A * 10, 1997 Karimian et al...... 514,233.2 The present invention relates to the field of pharmaceutical 5,719, 161 A 2f1998 Rainer technology and describes a novel advantageous preparation 6,114,537 A 9/2000 Karimian et al. for an active ingredient. The novel preparation is suitable for 6,124.313 A 9, 2000 Grundler et al. producing a large number of pharmaceutical dosage forms. FOREIGN PATENT DOCUMENTS In the new preparation an active ingredient is present essentially uniformly dispersed in an excipient matrix com DE 3O 11 490 A1 3, 1981 DE 36 22 O36 A1 1, 1987 posed of one or more excipients selected from the group of DE 39 17 232 A1 11, 1990 fatty , triglyceride, partial glyceride and DE 199 25 71.0 A1 12/2000 ester. EP O 033 094 B1 8, 1981 EP O 068 378 B1 1, 1983 14 Claims, No Drawings US 7,175,854 B2 Page 2

FOREIGN PATENT DOCUMENTS WO 99.63940 12/1999 WO OOf 10999 3, 2000 WO 95/27714 10, 1995 WO OOf 11000 3, 2000 W 3.76 SE WO OOf 17200 3, 2000 WO OO,26217 5, 2000 WO 98/427O7 10, 1998 WO OOf 63211 10, 2000 WO 98.54.188 12/1998 WO 00,74654 A1 12/2000 WO 99.29299 6, 1999 WO 99, 55705 11, 1999 WO 99.557O6 11, 1999 * cited by examiner US 7,175,854 B2 1. 2 PHARMACEUTICAL PREPARATION composed of the excipients of the invention (also referred to COMPRISING AN ACTIVE DISPERSED ON A as active ingredient units hereinafter). The active ingredient MATRIX is preferably essentially uniformly dispersed, in particular homogeneously dispersed or dissolved, in the excipient TECHNICAL FIELD matrix. A preparation preferably comprises microspheres. The present invention relates to the field of pharmaceu The preparations of the invention are distinguished in tical technology and describes a novel advantageous prepa particular by high stability, a release of active ingredient ration for an active ingredient. The novel preparation is which can be controlled by the particle size and composition Suitable for the production of a large number of pharmaceu 10 of the matrix, good flow characteristics, good compressibil tical dosage forms. ity and by a uniform delivery of active ingredient. In the case of acid-labile active ingredients it is moreover possible to BACKGROUND ART achieve, through choice of the matrix excipients, an acid resistance so that it is possible in the case of oral forms to In order to achieve particular properties of a dosage form, 15 dispense with an acid-resistant coating (enteric coating). In Such as, for example, taste masking in the case of active the case of active ingredients which have an unpleasant taste ingredients with an unpleasant taste, resistance to gastric or, for example, show a local effect in the mouth juice in the case of acid-labile active ingredients or con after administration, it has been observed that an unpleasant trolled release of an active ingredient, normally active taste of the active ingredient can be masked, and anesthetic ingredient pellets are provided with an appropriate func effects in the mouth can be avoided, by preparations of the tional coating. If such coated pellets are then further pro invention. It is particularly worthy of mention that the cessed to dosage forms, for example shaped to tablets by preparations of the invention can be further processed to a compression with excipients, there is a risk that the coating large number of pharmaceutical dosage forms without is damaged and thus the functionality is at least partly lost thereby losing a given functionality (such as taste masking, aga1n. 25 resistance to gastric juice, slowing of release). Thus, for DESCRIPTION OF THE INVENTION example, on compression of the active ingredient units of the invention no or negligible loss of functionality is observed It is an object of the present invention to provide a even if deformation of the active ingredient units occurs. In preparation for active ingredients which is able to retain a 30 contrast to this, with conventional pellets, which normally desired functionality and can be further processed to a large have a functional coating (such as taste masking, resistance number of pharmaceutical process forms with negligible to gastric juice, slowing of release), a certain degree of impairment of a given functionality. damage to the coating and thus to the functionality is It has now been found, Surprisingly, that this object is observed on further processing to dosage forms, for example achieved by a preparation in which an active ingredient is 35 on compression to tablets. This may also lead in Some cases essentially uniformly dispersed in an excipient matrix com to active ingredient being released in an unwanted way. posed of one or more excipients selected from the group of The particle size of the individual units is advantageously fatty alcohol, triglyceride, partial glyceride and fatty acid less than or equal to 2 mm, preferably 50–800 um, particu ester. larly preferably 50–700 um and very particularly preferably The invention therefore relates to a preparation in which 40 50–600 um. Preference is given to microsphers of a particle an active ingredient is essentially uniformly dispersed in an size of 50–500 um, particularly preferably of 50–400 um. excipient matrix composed of one or more excipients Particular preference is given to monomodal microspheres selected from the group of fatty alcohol, triglyceride, partial with a particle size of 50–400 um, particularly of 50–200 glyceride and fatty acid ester. lm. It has further been found that particularly advantageous 45 Active ingredients of the invention are, in particular, preparations can be obtained by adding Solid paraffin to the active pharmaceutical ingredients. Examples of active ingre excipient matrix. The invention therefore relates further to a dients which may form part of the preparations of the preparation in which an active ingredient is essentially invention are, in particular, the active pharmaceutical ingre uniformly dispersed in an excipient matrix composed of at dients mentioned below: least one solid paraffin together with one or more excipients 50 selected from the group of fatty alcohol, triglyceride, partial : glyceride and fatty acid ester. ; , ; ; The invention further relates to preparations in which an dipivefrin, ; ; esproquin; ; active ingredient is essentially uniformly dispersed i) in an hydroxyamphetamine; levonordefrin, ; norepi excipient matrix composed of a mixture comprising at least 55 nephrine; ; ; ; 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 Adrenocorticosteroids: excipient matrix composed of a mixture comprising at least ; desoxycorticosterone ; desoxycor one partial glyceride and at least one solid paraffin or iv) in 60 ticosterone pivalate; acetate; an excipient matrix composed of a mixture comprising at acetate; ; hemisuccinate; meth least one fatty acid ester and at least one solid paraffin. ylprednisolone hemisuccinate; ; ; Further subject matters are evident from the claims. acetate; . The preparations for the purpose of the invention prefer ably comprise numerous individual units in which at least 65 Agents to Prevent Alcohol Abuse: one active ingredient particle, preferably a large number of disulfiram, acamprosate, , fomepizole, laza active ingredient particles, is present in an excipient matrix bemide, nadide; nitrefazole; . US 7,175,854 B2 3 4 Antagonists: decanoate; phenpropionate; ; oxan canrenoate; ; ; meXrenoate; pro drolone; ; ; ; pras renoate; , epostane, ; Oxprenoate, terone; ; ; ; testosterone , , , . cypionate; ; testosterone ketolaurate; Amino Acids: testosterone phenylacetate; ; tres alanine; aspartic acid; ; histidine, isoleucine; leu tolone. cine; lysine; methionine; ; proline; serine; Anesthetic Additives: threonine; ; ; Valine. Sodium oxibate. Active Ingredients for Ammonium Detoxification: 10 (non-inhalation): arginine; arginine glutamate; arginine hydrochloride; alfaxalone; amolanone; etoxadrol; fentanyl. ; glutamic acid; levoxadrol; methitural; methohexital; midazolam; minax Anabolics: olone; propanidid; propoxate; pramoxine; propofol; remifentanyl; Sufentanyl; ; . , diproplonate; ; 15 undecylenate; ; bolnantalate; ethylestre Anesthetics (local): nol; acetate; ; ; ambucaine; amoxecaine; ; aptocaine; artic mesteronole; ; nandrolone; ; pras aine; benoximate; benzyl alcohol; ; betoxycaine; terone; stanozolone; ; ; ; biphenamine; bucricaine; bumecaine; ; nandrolone cyclotate; norbolethone; ; ; ; butanilicaine; carbizocaine; chlorop acetate; ; . rocaine clibucaine; clodacaine; ; dexivacaine; Analeptics: diamocaine; dibucaine: dyclonine; elucaine; ; ; ; endomide; ; fenoxypro euprocin, fexicaine; fomocaine; heptacaine; ; pazine; ; hexapradol; ; nicethamide. hydroxyprocaine; hydroxytetracaine; isobutamben; 25 ; leucinocaine; lidocalne, ; mepryl Analgesics: caine; octocalne; ; oxethacaine; oxybuprocaine; acetaminophen; alfentanil; aminobenzoate; aminoben parabutoxycalne, phenacaine; pinolcaine; ; piri Zoate; anidoxime; anileridine; anilleridine; anilopam; aniro docaine; polidocanol; pramocaine; ; ; pro lac; antipyrine; ; ; ; bici panocaine; propipocaine; ; ; fadine hydrochloride; brifentanil; brom adoline; : 30 pyrrocaine; quatacaine; quinisocaine; ; rodocaine; ; butacetn; butixirate; ; butorpha ; salicyl alcohol; Suicaine; ; trap nol; ; carbaspirin ; carbiphene; encaine; . carfentanil; ciprefadol Succinate; ciramadol; ciramadol; clonixeril; ; ; codeine phosphate; codeine Appetite Suppressants: Sulfate; conorphone; cyclazocine; dexoxadrol; dexpemed ; amfetamine; , ; olac, dezocine; ; ; dimefadane; 35 anisacril; benzfetamine; ; ; dipyrone; doXpicomine; drinidene; enadoline; epirizole; , ; ; dexamfetamine; dexfen ergo tamine tartrate; ethoxazene: ; eugenol; fluramine; difemetorex; efilamfetamine: etolorex; fen ; fenoprofen calcium; fentanyl citrate; floctafe butraZate; fencamfamiln; ; , fenpro nine; flufenisal; ; flunixin meglumine; ; porex; ; ; formetorex; : fluproduaZone; fluradoline; ; : 40 imanixil; .; levamfetamine; levofacetoperane; ibufenac; , ketazocine; ketorfanol, , levofenfluramine; levopropylhexedrine; ; mefeno letimide; levomethadyl acetate; levomethadyl acetate hydro rex: ; ; norpseudoephedrine; orl chloride; levonantradol; levorphanol; lofemizole; lofentanil istat; ; , , ; oxalate; lorcinadol; lomoxicarn; salicylate; ; , ; satietine; setaZin mefenamic add; menabitan; meperidine; meptazinol; metha 45 dol; ; triflorex; trifluorex. done; methadyl acetate; methopholine; methotrimeprazine; metkephamid acetate; mimbane; mirfentanil; molinaZone; : morphine Sulfate; ; nabitan; nalbuphine; ; ; albendazole oxide; amidantel; nalmexone; namoXyrate; nantradol; ; naproxen; amoScanate, antafenite; antazonite; anthelmycin; naproxol; ; nexeridine; noracymethadol; ocfentanil; 50 antholimine; bephenium hydroxynaphthoate; bidimazium octaZamide, olvanil; ; oxycodone; oxycodone; iodide; bisbendazole; bithionoloxide; bitoscanate; bromox oxycodone terephthalate; oxymorphone; pemedolac, penta anide; brotianide; bunamidine; butamisole; butonate; cam morphone; pentazocine; pentazocine; phenazopyridine; bendazole; carbantel; cidobendazole; clioxanide; closantel; phenyramidol; picenadol; pinadoline; pirfenidone; piroxi dexamisole; diamfenetide; ; : cam olamine; pravadoline; prodilidine; profadol; propiram; 55 dimantine; diphenan; ; dribendazole, eprinome propoxyphene; propoxyphene napsilate; proxazole; proXor cUn; ; etibendazole; febantel; ; phan; pyrroliphene; remifentanil; Salcolex; salethamide ; flurantel; ftalofyne; furodazole; haloxon; maleate; : Salicylate meglumine; ; sali hexylresorcinol; imcarbofos; ; kainic acid; cylate; spiradoline; Sufentanil; Sufentanil; talmetacin; talni ; ; metyridine; ; moxidec 60 tin, naftalofoS; netobimin; niclofolan; : nitrami flumate; talosalate; tazadolene; tebufelone; tetrydamine; Sole; nitrodan; ; nitroXinil; oltipraz: ontlanil, tifurac, tilidine; tiopinac; tonazocine; tramadol; trefentanil; ; ; oxyclozanide; par trolamine; Veradoline; verilopam; volazocine; Xorphanol: bendazole; peXantel; piperamide; adipate; pipera ; Zenazocine mesilate; : Sucapsaicin. Zine calcium edetate; piperamide ; proclonol; : 65 pamoate; pyrantel tartrate; pamoate; androstanolone; ; ; mester rafoxanide; resorantel; salantel; spirazine; stilbanzium olone; metandienone; ; nandrolone iodide; subendazole; tetramisole; thenium closilate; thio US 7,175,854 B2 5 6 furadene; ; ticarbodine; tioxidazole; tricla Alpha 1 Antagonists: bendazole; triclofenol piperazine; uredofos; Vincofos; Zilan , adoZelesin; ; ; benox tel. athian; : CI-926; DL017; dapiprazole; dihydroer gotamine mesilate: ; euigenodilol; ; therapeutics: GI-231818: GYKI-12743: GYKI-16084; indoramine; meta adapalene; adelmidrol; benzoyl peroxide; betacarotene; Zosin; MK-912; ; ; meldazosin; nesapidil; ; ; ; doretinel, erythromy ; ; peradoxime; peraquinsine; peral J cin Salnacedin, etretinate; fumaric acid; halofuginonen; Zole; perbufylline; phendioxan; ; phen acetate; isotretinoin, linolenic acid; ; tolamine; podilfen; : ; RS-97078; proroX masoprocol; ; motretinide; namirotene; rosterelone; 10 ane; ; SGB-1534; SL-89.0591; ; Sumarotene; tazarotene; tematotene; tioXolone; ; : ; tibalosin, ; ; trima tradecamide; tretinoin, triadimenol; ; Zeranol: Zosin; upidosin: ; ; Zollertine. Zimidoben. ACE Inhibitors: alacepril; benazepril; benazeprilat; BMS-189921; BRL : 15 36378; captopril; ceronapril; CGS-13928C; cilazapril; ; azaspirium chloride; ; ; cilaZaprilat, dehydrocaptopril; delapril; enalapril; enalapri bitoiterol; ; butaprost; ; cipamfylline; lat; EU4867; EXP-7711; fasidotril; fosinopril; fosinoprilat; : doxaprost: ; dyphylline; : idrapril; imidapril; imidaprilat; indolapril; libenzapril; lisi ephedrine; ; etanterol; fenspiride; flutropium bro nopril; mixanpril; moexipril; moexiprilat, moveltipril; oma mide; : guaithylline; : Hoku-81: patrilat, orbutopril; pentopril; perindopril; perindoprilat, hoquizil; imoxiterol, ipragratine; ipratroplum bromide; iso pivopril; quinapril; quinaprilat, ramipril; rentiapril; Sampat etharine; isoproterenol; ; : rilat; SCH-54470; spirapril; spiraprilat; temocapril; temoca meduitamium iodide; metaproterenol; mexafylline; narde prilat; teprotide; trandolapril; trandolaprilat; utibapril; terol; nestifylline; nisbuterol; picumeterol, piquizil; pir utibaprilat; Z-13752A; Zabicipril; zofenopril; Zofenoprilat. buterol; ; : RO-24-4736; quaZodine: 25 quinterenol; racepinephrine; reproterol: ; salbuta Renin Antagonists mol; , Saimeterol Xinafoate; sevitropium mesilate; CGP-38560; ciprokiren: CP-108671; enalkiren: ES-6864; soterenol; sulfonterol; Suloxifen; TA-2005; : FK-906; remikiren; terlakiren, Zankiren. ; theophylline ethylenediamine; tiaramide: Antiallergics such as PDE Inhibitors: tipetropium bromide; ; ; zindotrine; 30 arofylline; atizoram, AWD-12-281 (N-(3,5-dichloro-4- . pyridinyl)-2-1-(4-fluorobenzyl)-5-hydroxy-1H-in-dol-3- yl)-2-oxoacetamide); BAY-19-8004 (ethanesulfonic acid Beta-blockers: 2-(2,4-dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl acebunolol, ; ; ; alprenoXime; ester); benafentrine; CC-1088; CDC-801 (B-3-(cyclopenty , , ; ; ; benzo 35 loxy)4-methoxyphenyl-1,3-dihydro-1,3-dioxo-2H-isoin dioxine; ; ; ; bormetolol; dole-2-propanamide); CDC-998; CI-1018; cilomilast (cis ; bomaprolol; ; ; ; 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) buftiralol; ; bunolol; ; ; cyclohexane-1-carboxylic acid); ; cipamfylline ; burocrolol; , , ; (8-amino-1,3-bis(cyclopropylmethyl)): D-4396; , , , , ; 40 D-4418 N-(2,5-dichloro-3-pyridinyl)-8-methoxy-5-quino , ; ; dexpropranolol; linecarboxamide: darbufelone; denbufylline; ER-21355; ; dichlorisoproterenol; dilevalol; ; dro ; ; IC-485; indolidan; laprafylline; lixazi pranolol, , , , esatenolol, ; none; MESOPRAM (-)-(R)-5-(4-methoxy-3-propoxyphe ; fallintolol; fiestolol; ; hydroxycarteolol; nyl)-5-methyloxazolidin-2-one: nitraquaZone; NM-702; hydroxytertatolol ; ICI-118551; ; ; 45 olprinone; ORG-20241 (4-(3,4-dimethoxyphenyl)-N2-hy , ; isamoltan; ; ; droxythiazole-2-carboxamidine); piclaimilast; pumafentrine ; ; levocicloprolol; ; ((-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 10 ; mephenoxalone; ; metalol; metipra Ob-hexahydro-6-(4-diisopropylaminocarbonylphenyl) nolol; ; mindodilon; ; ; nadox benzoc 1.6-naphthyridine); ; RO-15-2041; rof olol, nafetolol, napitane; , neraminol; ; 50 lumilast (3-(cyclopropylmethoxy)-N-(3,5-dichloro-py nipradillol, oberadillol, Oxanamide; ; pacrinolol; ridyl)-4-(difluoromethoxy)-benzamide); ; SCH ; ; ; parodilol; ; 351591; SH-636; tibenelast (5,6-diethoxybenzob. penirolol; PHQA-33; ; pirepolol; ; prenal thiophene-2-carboxylic acid); tolafentrine; trequinsin; terol; , , pronetalol; ; pro V-11294A (3-3-(cyclopentyloxy)-4-methoxyphenylme pranolol, ; , ronactolol, ; 55 thyl-N-ethyl-8-(1-methylethyl)-3H-purin-6-); ; TA-2005; ; ; teoprolol; ; YM-58997 (4-(3-bromophenyl)-1-ethyl-7-methyl-1,8-naph terthianolol; ; ; ; ; tolam thyridin-2(1H)-one); YM-976 (4-(3-chlorophenyl)-1,7-di olol; ; tribendilol; trigevolol: : ; ethylpyrido 2,3-dipyrimidin-2(1H)-one); Zardaverine. Y-12541; ZAM1-1305. 60 Other Antiallergics for Treatment: : ablukast, atreleuton; bunaprolast, cinalukast, cromitrile; betanidine; tosilate; cromanidine; debriso cromolyn; FPL-55712; iralukast; isamoxole: ketoufen; quine; ethomoxane; guabenXan; , guanacline: L-648051; levcromakalim; ethyl: lodoxamide ; :guancidine:guanclofine; guanethi tromethamine; , oxarbazole; piriprost; ; dine::guanisoquine; , guanoctine; gua 65 pobilukast, , ritolukast, Sulukast; tiaramide; noXabenz, ; guanoxyfen; olmidine, ; Ubenelast; tomelukast; Verlukast; verofylline; ; pyroxamidine; Solypertine; spirgetine. . US 7,175,854 B2 7 8 Other Antiallergics (for example leukotriene antagonists): Antiarthritics: acitaZanolast; acrivastine; allinastine; altoqualine; amlex AI-200; auranofin; aurothioglucose, cipemastat; etaner anox; andolast; ; ataquimast; ; azelas cept; etebenecid; interleukin-6: leflunomide; lenercept; tine; bamipine; barmastine; batebulast; BAY-X-1005; BAY lobenzarit; lodelaben: M-5010; : ; X-7195; bepiastine; bepotastine; BIIL-284; bilastine; RS-130830; S-2474; TSA-234 ; binizolast; buclizine; bunaprolast; cabastine; carebastine; Antiatherosclerotics: cetirizine; CI-959; ciproxifan; clemastine; CMI-977; cro mogleic acid; cromolyn natrium; dametralast; ; H-327/86; mifobate; lodaZecar; riboflavin butyrate; time dlmenhydrinate; ; doqualast; dorastine; furone. E-4704; efietirizine; emedastine; enofelast; enoxamast; 10 Bacteriostatics: ebastine; eclaZolast; ; fexofenadine; flezelastine; acedapsone; acetosulfone sodium; alamecin; alexidine; HSR-609; KCA-757; ; levocetirizine; linetas amdinocillin; amdlnocillin pivoxil, amicycline; amifloxacin; tine; ; LY-293111; mapinastine; meduitamium amifloxacin mesilate; amikacin; amikacin Sulfate; ami iodide; meduitazin; minocromil, mizolastine: MK-886; nosalicyllic acid; aminosalicylate sodium; ; moXastine; moXilubant, ; nedocromil calcium; 15 amphomycin; amplicillin; amplicillin Sodium; apaicillin nedocromil Sodium; nivimedone; noberastine; norastemi Sodium: apramycin; aspartocin, astromicin Sulfate; avilamy Zole; octastine; ONO-4057; ontazolast; oxatomide; pemiro cin; avoparcin; azithromycin; aziocillin; aziocillin Sodium; last; pentigetide; perastine;piclopastine;picumast, pirquino bacampicillin hydrochloride; bacitracin; bacitracin methyl Zol; poisonoak extract; probicromil: proXicromil: quaZolast; ene disalicylate; bacitracin , bambermycins; benzoylpas ; quinotolast; raxofelast; repirinast; REV-5901 - calcium; berythromycin; betamicin Sulfate; biapenem: A: rocastine; : SKF-S-106203; sequifenadine: biniramycin; biphenamine hydrochloride; bispyrithione ; Sudexanox; tagorizine; talastine; taZanolast, tazi magSulfeX; butikacin; butirosin Sulfate; capreomycin Sul fylline; temelastine; ; tetrazolast; texacromil; thi fate; carbadox; carbenicillin disodium; carbenicillin indanyl aZinamium chloride; tiacrilast; tiprinast meglumine; tix Sodium; carbenicillin phenyl Sodium; carbenicillin; caru anox; tranilast; WY-50295; ZD-3523: Zepastine. 25 monam sodium, cefaclor, cefadroxil, cefamandole; cefa mandole nafate, cefamandole Sodium, cefaparole; cefatriz Amebicides: ine; cefazaflur Sodium, cefazolin, cefazolin Sodium; 1B-bisamidine; berythromycin; bialamicol; carbarsone; cefbuperaZone; cefdinir, cefepime; cefepime; cefetecol; chloroquine; chloroquine; clamoxyquin; ciloquinol; dehy cefixime; cefimenoxime; cefimetazole; cefimetazole Sodium; droemetine; difetarSone; diloxanide; emetime; etofamide; 30 cefonicid monosodium, cefonicid sodium, cefoperaZone iodoquinol; lachnumon: liroldine; paromomycin Sulfate; Sodium, ceforanide; cefotaxime Sodium, cefotetan, cefotetan pinafide; quinfamide: satranidazole; stevaladil; stirimazole; disodium; cefotiam; cefoxitin: cefoxitin sodium; cefpimi Symetine; teclozan, tetracycline; tilbroqulnol; Zole; ce?pimizole sodium, cefpiramide; ce?piramide Sodium; : cefpirome Sulfate; cefpodoxime proxetil, cefprozil; cefroxa 35 dine, cefsulodin sodium; ceftazidime; ceftibuten; cefti abiraterone; ; cioteronel, cyproterone; Zoxime Sodium, ceftriaxone sodium, cefuroxime; delanterone; delmadinone; ; : cefuroxime axetil: cefuroxime pivoxetil: cefuroxime inocoterone; L-654066; minamestane; ; osater Sodium; cephacetrile sodium; cephalexin; cephalexin; one; ; ; rosterellone; topterone; Zan cephaloglycin; cephaloridine; cephalothin Sodium; cephapi OterOne. 40 rin Sodium; cephradine; cetocycline; cetophenicol; chloram Antianemics: phenicol; chloramphenicol palmitate; chloramphenicol pan ancestim; diciferron; epoetin alfa: epoetin beta; epoetin tothenate complex; chloramphenicol Sodium Succinate; epsilon; epoetin gamma; epoetin omega; ferrous Sulfate, chlorhexidine phosphanilate; chloroxylenol; chlortetracy FK-352; folic acid; gleptoferron; glutathione monoisopropyl cline bisulfate; chlortetracycline; cinoxacin; ciprofloxacin; 45 ciprofloxacin; cirolemycin, ; clinafloxacin; ester; leucovorin calcium; tucaresol; TYB-5220; Velaresol; clindamycin; clindamycin; clindamycin palmitate; clinda : mycin phosphate; clofazimine; cloxacillin benzathine; clox alinidine; ; besylate; amlodipine acillin Sodium; cloxyquin; colistimethate Sodium; colistin maleate; azaclorzine; bamidipine; bertosamil; betaxolol; Sulfate; coumermycin; coumermycin Sodium: cyclacillin; bertosamil: bevantolol; ; butoprozine; carvedilol; 50 cycloserine; dalfopristin; dapsone; daptomycin; demeclocy CD832; CERM-11956: cinepazet maleate; crobenetine: cline; ; demecycline; denofungin; diaveri cyclovirubuxine-D; desocriptine; ; dopropidil; dine; dicloxacillin; dicloxacillin Sodium, dihydrostreptomy elgodipine; EMD-57283; eniporide; ethacizine; : cin Sulfate; dipyrithione; dirithromycin; doxycycline; FK-409; ; flosaudil; flosequinan; FR-46171; GP-1- doxycycline calcium, doxycycline fosfatex, doxycydine 468: GP-1-531; hyperin; ipramidil; isosorbide dinitrate; 55 hyclate; droxacin Sodium; enoxacin; epicillin; epitetracy ivabradine: KC-764; KRN-2391; KW-3635: ligustizine; lin cline; ; erythromycin acistrate; erythromycin sidomine; metoprolol Succinate; ; mildronate; estolate; erythromycin ethylsuccinate, erythromycin glu ; molsidomine; monatepil maleate; nafagrel; ceptate; erythromycin lactoblonate; erythromycin propi NK-341; OP-2000; pirsidomine; pivazide; ; onate; erythromycin Stearate; ethambutol; ethionamide; primidolol; ; SL-87.0495; ST-1324; tedisamil: 60 fleroxacin; floxacillin; fludalanine; flumequine; fosfomycin; tosifen; Vatanidipine; : Y-27152; Zatebradine. fosfomycin tromethamine; fumoxicillin; furazolium chlo ride; furazolium tartrate; fusidate Sodium; fusidic acid; gen : tamicin Sulfate; gloXimonam, gramicidin; haloprogin; het adatanserin; alpidem; binospirone mesilate; bretaZenil; acillin; hetacillin; hexedine; ibafloxacin; imipenem: glemanserin; ; mirisetron maleate; ocinaplon; 65 isoconazole; isepamicin; ; josamycin; kanamycin ondansetron; panadiplon; pancopride; paZinaclone; seraza Sulfate; kitasamycin; levofuraltadone; levopropylcillin; pine; citrate; Zalospirone. lexithromycin; lincomycin; lincomycin; lomefloxacin, lom US 7,175,854 B2 10 efloxacin, lomefloxacin mesilate; loracarbef mafenide; hydrobromide; tematroplum methylsulfate; tiquinamide; meclocycline; meclocycline Sulfosalicylate; megalomicin ; toguizine; triampyZine Sulfate; trihexyphenidyl; phosphate; medulidox; meropenem; methacycline; methacy . cline; methenamine; methenamine hippurate; methenamine Anticoagulants: mandelate; methicillin Sodium; metioprim; metronidazole; ancrod; ardeparin sodium; bivalirudin; bromindione; metronidazole phosphate; meZiocillin; meZiocillin Sodium; dalteparin Sodium; desirudin; dicumnarol; heparin calcium; minocycline; minocycline; mirincamycin; monensin; mon heparin Sodium; lyapolate sodium; nafamo.stat mesilate; ensin Sodium; nafeilin Sodium; nalidixate sodium; nalidixic phenprocoumon; tinzaparin Sodium; warfarin sodium. acid; natainycin; nebramycin; palmitate; neomy 10 : cin Sulfate; neomycin undecylenate; netilmicin Sulfate; neu albutoin: ameltolide; atolide; buramate; carbamazepine; tramycin; nifuiradene; nifuraldeZone; nifuratel; nifuratrone; cinromide; citenamide; clonazepam, cyheptamide; deZina nifurdazil; niftrimide; niflupirinol; nifurcquinazol; nifurthia mide; dimethadione; divalproex sodium; eterobarb; ethosux Zole; nitrocycline; nitrofurantoin: nitromlde; norfloxacin; imide; : flurazepam, fluzinamide; novobiocin Sodium; ofloxacin; onnetoprim; oxacillin 15 Sodium; , ilepcimide; ; magnesium Sodium; oximonam; oximonam Sodium; ; Sulfate; : mephobarbital; methetoin: methSuX oxytetracycline; oxytetracycline calcium; oxytetracycline; imide; millacemide: nabaZenil; nafimidone; nitrazepam, paldimycin; parachlorophenol; paulomycin; pefloxacin; ; phenobarbital; phenobarbital Sodium; phen pefloxacin mesilate; penamecillin; penicillin G benzathine; Suximide; : phenytoin Sodium; ; proga penicillin G., penicillin G procaine; penicillin G Sodium; bide; ralitoline; ; ropizine; sabeluzole; stiripen penicillin V: penicillin V benzathine; penicillin V hydrab tol; Sulthiame; thiopental sodium; tiletamine; ; amine; penicillin V: pentizidone sodium; phenyl aminosali ; Sodium; Valproic acid; vigabatrin; cylate; piperacillin Sodium; pirbenicillin Sodium; piridicillin ZonicleZole; . Sodium; pirlimycin; pivampicillin; pivampicillin pamoate; : pivampicillin probenate; polymyxin B sulfate; porfiromycin; 25 adatanserin; adinazolam; adinazolam mesilate; alapro propikacin; pyrazinamide; pyrithione Zinc, quindecamine clate; aletamine; amedalin; ; ; acetate; quinupristin; racephenicol; ramoplanin; ranimycin; maleate; azaloxan fumarate; ; relomycin; repromicin: rifabutin: rifametane; rifamexil; rifa ; bipenamol; ; butacetin; ; mide; rifampin: rifapentine; rifaximing rollitetracycline; roli ; ; ; ; tetracycline nitrate; rosaramicin; rosaramicin butyrate; rosa 30 mesilate; clodaZon; ; fumarate; ramicin propionate; rosaramicin Sodium phosphate: cyclindole; ; cyprolidol, cyproximide; daledalin rosaramicin stearate; rosoxacin; roXarsone; ; tosylate; dapoxetine, dazadrol maleate; dazepinil; sancycline; Sanfetrinem sodium; Sarmoxicillin; Sarpicillin; ; dexamisole; deximafen; ; dioxa scopafungin; sisomicin; Sisomicin Sulfate; sparfloxacin; drol; dothiepin: ; dulloxetine; eclanamine maleate; spectinomycin; spiramycin; stallimycin; Steflimycin; Strep 35 encyprate; ; fantridone; fehmetozole; fenmetra tomycin Sulfate; streptonicoZid; SulfabenZ: Sulfabenzamide; mide; fumarate; ; ; fluoxet Sulfacetamide; Sulfacetamide Sodium; Sulfacytine; Sulfadi ine; ; gamfexine; guanoxyfen Sulfate; imafen; azine; Sulfadiazine sodium; Sulfadoxine; Sulfalene, Sulfam , ; ; ; lprindole; erazine, Sulfameter, Sulfamethazine, Sulfamethizole; Sul ; ketipramine fumarate; ; lorta famethoxazole; Sulfamonomethoxine; Sulfamoxole; 40 lamine; ; maprotiline; ; millacemide; Sulfanilate Zinc, Sulfanitran; SulfaSalazine; Sulfasomizole; ; ; ; modaline Sulfate; Sulfathiazole; Sulfazamet; sulfisoxazole; sulfisoxazole napacitadine; napamezole; ; ; acetyl; Sulfisboxazole diolamine; Sulfomyxin; Sulopenem: nitrafudam; maleate; ; Sultarmicillin; Suncillin Sodium; talampicillin, telcoplanin; phosphate; , ; oxypertine; ; temafloxacin; temocillin, tetracycline; tetracycline; tetracy 45 pheneizine Sulfate; ; pizotyline; ; pro cline phosphate complex; tetroXoprim; ; lintane; ; quipazine maleate; rolicyprine; thiphencillin: ticarcillin cresyl sodium; ticarcillin disodium; ; ; Sibutramine; ; SuritoZole; ticarcillin monosodium, ticlatone; tiodonium chloride; ; fumarate; ; thiazesim: tobramycin; tobramycin Sulfate; toSufloxacin; trimethoprim; ; tomoxetine; ; trebenZomine; trimi trimethoprim Sulfate; trisulfapyrimidines; troleandomycin; 50 trospectomycin Sulfate; tyrothricin; Vancomycin; Vancomy pramine; maleate; ; ; cin; Virginiamycin; Zorbamycin. Zimeldine; Zometapine. Antidiabetics: : ; bimoclomol; BM-17.0249; buformin; alverine citrate; anisotropine methylbromide; ; 55 butoxamine; ; centpiperalone; ; atropine oxide; atropine Sulfate; belladonna; benapry Zine; clomoxir; etoformin: etomoxir; fenbutamide: GI-262.570; benzetimide; benzilonium bromide; biperiden; biperiden; gliamilide; ; ; glibutimine; glic biperiden lactate; clidinium bromide; ; dex aramide; glicetanile sodium; ; glicondamide; etimide; dicyclomine; dihexyverine; domaZoline fumarate; glidaZamide; gliflumide; ; glipalamide; glipiz elantrine; elucaine; ethybenztropine; eucatropine; glycopy 60 ide; ; glisamuride; glisentide; glisindamide; gliso rrolate; heteronium bromide; hydrobromide: lamide; ; glucagon; glyburide; glybuthiazol; gly homatropine methylbromide; hyoscyamine; hyoscyamine buzole; ; glycyclamide; glyhexamide; hydrobromide; hyoscyamine Sulfate; isopropamide iodide; glymidine Sodium; glyoctamide: glyparamide; glypinamide; mepenZolate bromide; methylatropine nitrate; metoquizine; glyprothiazol; glysobuzole; heptolamide: HMR-1964; insu oxybutynin chloride; parapenzolate bromide; pentapiperium 65 lin; insulin argine; insulin aspart; insulin dalanat; insulin methylsulfate; phencarbamide; poldine methylsulfate; pro defalan; insulin detemir; insulin glargine; insulin human; glumide; propantheline bromide; propenZolate: insulin human, isophane; insulin human Zinc, insulin human US 7,175,854 B2 11 12 Zinc, extended; insulin, isophane; insulin lispro; insulin, cin; Sanguinarium chloride; Saperconazole; scopafungin; neutral; insulin Zinc; insulin Zinc, extended; insulin Zinc; sulfide; sinefungin; Sulconazole nitrate; terbin isaglidole; JTT-501; JTT-608; mebenformin; : afine; terconazole; thiram; ticlatone; tioconazole; tolciclate; metfomin: methyl palmoxirate; ; midaglizole; tolindate; tolnaftate; triacetin; triafungin; ; ; ; NN-304; NVP-DPP-728; palmox viridofulvin, Zinc undecylenate; Zinoconazole. irate sodium; PNU-106817; pramlintide; proinsulin human; : seglitide acetate; tibeglisene; tiformin; ; tolbuta alprenoXime; colforsin; dapiprazole; diplivefrin, naboc mide; tolpyrramide; tate; pilocarpine; pimabine. Aldose Reductase Inhibitors: AD-5467; alrestatin; ciglitaZone; darglitaZone; englita 10 : Zone sodium; epalrestat; fidarestat; imirestat; linogliride; acrivastine; phosphate; astemizole; azatadine linogliride; MCC-555; minalrestat; NZ-314; pioglitazone: maleate; barmastine; bromodiphenhydramine; bromphe pirogliride; ponalrestat; Sorbinil; risarestat; rosiglitaZone; niramnine maleate; carbinoxamine maleate; cebrizine; chlo tendamistat, tolrestat; troglitaZone; Zenarestat; Zopolrestat. rpheniramine maleate; chlorpheniramine polistirex: cin 15 narizine; clemastine; clemastine fumarate; closiramine Alpha-glucosidase Inhibitors: aceturate; cycliramine maleate; cyclizine; ; acarbose; camiglibose; emiglitate; englitaZone; miglitol; dexbrompheniramnine maleate; dexchlorpheniramine male moranoline; Voglibose. ate; dimethindene maleate; diphenhydramine citrate; diphenhydramnine; dorastine: doxylamine Succinate; ebas Antidiarrheals: tine; levocabastine; loratadine; ; noberastine; rolgamidine, diphenoxylate (Lomotil), metronidazole citrate; pyrabrom, pyrilamine maleate; pyrox (Flagyl), (Medrol), sulfasalazine (AZu amnine maleate; rocastine; rotoxamine; taZifylline; temelas lfidine). tine; terfenadine, tripelennamine citrate; tripelennamine; Antidiuretics: triprolidine; Zolamine. argipressin tannate; desmopressin acetate; lypressin. 25 Lipid-lowering Agents: Antidotes: cholestyramine resin; clofibrate; colestipol; crilvastatin: dimercaprol; edrophonium chloride; fomepizole; leucov dalvastatin; dextrothyroxine sodium; fluvastatin Sodium; orin calcium; levoleucovorin calcium; ; gemfibrozil; lecimibide; lovastatin, ; pravastatin protamine Sulfate. 30 Sodium; probucol; simvastatin; tiqueside; Xenbucin; acifran; Antiemetics: beloxamide; bezafibrate; boxidine; butoxamine; cetaben alosetron; batanopride; bemesetron; benzcuinamide: sodium; ciprofibrate; gemcadiol; halofenate; ifibrate; meglu ; chlorpromazine; ; cyclizine; tol; nafenopin; pimetine; theofibrate; tibric acid; treloxinate. dimenhydrinate; diphenidol; diphenidol; diphenidol pamo Antihypertensives: ate; dolasetron mesilate; ; dronabinol; fluidorex; 35 alfuzosin; alipamide; althiazide; amidulinsin; amlodipine flumeridone; galdansetron; granisetron; granisetron; luro besylate; amlodipine maleate; anaritide acetate; setron mesilate; ; ; ; maleate; belfosdil; bemitradine; bendacalol mesilate; ben ondansetron; pancopride; ; prochlorpera droflumethiazide; benzthiazide; betaxolol; sul Zine edisylate; prochlorperazine maleate; ; thi fate; bevantolol; biclodil; bisoprolol; bisoprolol fumarate; ethylperazine; malate; thiethylperazine 40 ; bupicomide; buthiazide: candoXatril; candoxat maleate; ; Zacopride. rilat; captopril; carvedilol; ceronapril; Sodium; ; cilaZapril; ; clonidine; clopa Antiepileptics: mide; , ; ; debriso felbamate; loreclezole; tolgabide. quin Sulfate; delapril; diapamide; ; dilevalol, dilt (non-steroidal): 45 iazem malate; ditekiren, doxazosin mesilate; ecadotril; clometherone; , ; enalapril maleate; enalaprilat, enalkiren; endralazine mesi citrate; ; citrate; late; epithiazide, eprosartan; eprosartan mesilate; citrate; mesilate. mesilate; flavodilol maleate; flordipine; flose Antifibrinolytics: quinan; fosinopril Sodium; fosinoprilat, guanabenz, guana 50 benZ acetate; guanacline Sulfate; guanadrel Sulfate; guancy camo.stat; nafamo.stat mesilate. dine; monosulfate; guanethidine Sulfate; Fungistatics: guanfacine; guanisoquin Sulfate; guanoclor Sulfate; guanoc acrisorcin; ambruticin; amphotericin B; azaconazole; aza tine; , guanoxan Sulfate; guanoxyfen Sulfate; serine; basifungin: bifonazole; biphenamine; bispyrithione hydralazine; hydralazine polistirex: : magSulfeX; butoconazole nitrate; calcium undecylenate; 55 ; ; indolaprif ; indoramin; candicidin; carbol-fuchsin; chlordantoin: ciclopiroX, ciclo indorenate; ; leniquinsin; levcromakalim, lisino piroX olamine; cillofungin; cisconazole; clotrimazole; pril; ; losartan; losulazine; mebutamate; mecamy cuprimyxin; denofungin; dipyrithione; doconazole; econa lamine; medroxalol; medroxalol; methalthiazide; methy Zole; econazole nitrate; enilconazole; ethonam nitrate; fen clothiazide; ; methyidopate; ; ticonazole nitrate; filipin; fluconazole; flucytosine; fungimy 60 ; metoprolol fumarate; metoprolol Succinate; cin; griseofulvin, hamycin; isoconazole; itraconazole; metyrosine; ; monatepil maleate; ; kalafungin; ; lomofimgin; lydimycin; mepartri nebivolol; ; oftormine; ; paZoxide; pel cin; ; miconazole nitrate; monensin; monensin anserin; perindopril erbumine; phenoxybenzamine; pinaci Sodium; naftifine; neomycin undecylenate, nifuratel; nifur dil; pivopril; ; prazosin; primidolol; prizidilol; merone, nitralamine; nystatin; octanoic acid; orconazole 65 quinapril; quinaprilat, quinaZosin; ; ; nitrate; oxiconazole nitrate; oxifungin; parconazole; partri quinuclium bromide; ramipril; rauwolfia serpentina; reser cin; iodide; proclonol; pyrithione Zinc, pyrrolnitrin, rutamy pine; Saprisartan; Saralasin acetate; sodium nitroprusside; US 7,175,854 B2 13 14 ; tasosartan; teludipine; temocapril; teraZosin; ter froVatriptan; iprazochrome; IS-159; ; : lakiren, ; tiamenidine; ticrynafen; Unabinol; LY-334370; LY-53857; ; metergotamine; methy tiodaZosin; tipentosin; , ; tri sergide; naratriptan: ORG-GC94; oxetorone; pipethiadene: methaphan camsylate; trimoxamine; tripamide; ; ; propisergide; rizatriptan; Sergolexole; Sumatrip Zankiren, Zofenoprilat arginine. tan; tropanserin; tropoxin; UK-116044: valofane; Antihypotensives: Zatosetron; Zolmitriptan. ; . Active Ingredients for Sea Sickness and Vomiting: Antiinflammatory Agents: buclizine; cyclizine lactate: naboctate. ; dipropionate; algestone 10 acetonide; alpha amylase; , ; Cytostatics: Sodium; amiprilose; anakinra; anirolac, ; apa acivicin; aclarubicin; acodazole; acronine; adoZelesin; Zone; balsalazide disodium; , benoxaprofen; ben aldesleukin; altretamine; ambomycin; ametantrone acetate; Zydamine; bromelains; broperamole; ; ; ; amsacrine; anastrozole; anthramycin; cicloprofen; cintaZone; cliprofen; propionate; clo 15 asparaginase; asperlin; azacitidine; azetepa; azotomycin; betaSone butyrate; clopirac, proplonate; batimastat; benzodepa; ; bisantrene; bisnafide cormethasone acetate; cortodoxone; ; ; dimesilate; bizelesin; bleomycin Sulfate; brequinar Sodium; ; dexamethasone dipropionate; ; bropirimine; buSulfan, cactinomycin; ; carace diclofenac sodium; diacetate; diflumidone mide; carbetimer; carboplatin: carmustine; carubicin; carZe sodium; diflunisal; ; diftalone; dimethyl sul lesin, cedefingol; chlorambucil; cirolemycin; cisplatin: foxide; ; endry Sone; enlimomab, enolicam Sodium; epirizole; , etofenamate; ; fen cladribine; crisinatol mesilate; cyclophosphamide; cytara amole; , ; fenclorac, fendosal; fenpipa bine; dacarbazine; dactinomycin; daunorubicin; decitabine; lone; , flazalone; , ; flu dexormaplatin; deZaguanine; deZaguanine mesilate; diazi mizole; acetate; flunixin; flunixin meglumine; 25 quone; docetaxel, doxorubicin, doxonubicin; ; butyl; acetate; fluguaZone; flur droloxifene citrate; dromostanolone propionate; duaZomy biprofen; fluretofen; propionate; furaprofen; cin, edatrexate; eflomithine; elsamitrucin; enloplatin; enpro furobufen; ; halobetasol propionate; halopre mate; epipropidine; epirubicin; erbulozole; esorubicin; done acetate; ibufenac; , ibuprofen aluminum; ; Sodium; etanidazole; ibuprofen piconol; illonidap; indomethacin; indomethacin 30 ethiodized oil I 131: etoposide: etoposide phosphate: eto Sodium; indoprofen; indoxole; intrazole; prine; fadrozole; fazarabine; fenretinide; floxuridine; flu acetate; isoxepac; , ; lofemizole; darabine phosphate; fluorouracil; flurocitabine; fosquidone: lomoxicam, , etabonate; meclofe fostriecin Sodium; gemcitabine; gemcitabine; gold Au 198; namate sodium; ; dibutyrate; hydroxyurea; idarubicin; ifosfamide: ilmofosine; interferon ; mesalamine; meseclaZone; methylpred 35 alfa-2a: interferon alfa-2b; interferon alfa-n1; interferon nisolone Suleptanate; momiflumate, ; naproxen; alfa-n3; interferon beta-I a... interferon gamma-Ib; I propl naproxen Sodium; naproXol; nimaZone; olsalazine Sodium; atin: irinotecan; lanreotide acetate; letrozole; leuprolide orgotein; orpanoxin; , ; para acetate; liarozole; lometrexol Sodium, lomustine; losox nyline; pentosan polysulfate sodium; phenbutaZone sodium antrone; masoprocol; maytansine; mechlorethamine; mege glycerate; pirfenidone; , piroxicam cinnamate; 40 strol acetate; melengestrol acetate; melphalan; menogaril; piroXicam olamine; ; ; prifelone; pro mercaptopurine; ; methotrexate sodium; meto dolic acid; produaZone; proxazole; proxazole citrate; rimex prine; meturedepa; mitindomide; mitocarcin, mitocromin: olone; romazarit; Salcolex; salnacedin; Salsalate; sangui mitogillin, mitomalcin, mitomycin; mitosper, mitotane; narium chloride; seclaZone; sermetacin; Sudoxicam, mitoxantrone; ; nocodazole; nogalamy : ; talmetacin; talniflumate; talosalate; 45 cin; ormaplatin, oxisuran, paclitaxel; pegaspargase; pelio tebufelone; ; tenidap Sodium; , tesicam, mycin; pentamustine; peplomycin Sulfate; perfosfamide; tesimide; tetrydamine; tiopinac; pivalate; tol pipobroman; piposulfan, piroXantrone; plicamycin; plomes metin; Sodium; ; triflumidate; Zidometa tane; porfimer Sodium; porfiromycin; ; pro cin; Zomepirac sodium. carbazine; puromycin; puromycin; pyrazofurin: riboprine; 50 rogletimide; safmgol, Safingol; semustine; simtraZene; spar Antimalarials: fosate sodium, sparsomycin; spirogermanium; Spiromus acedapsone; amodiaquine; amduinate; arteflene; chloro tine; Spiroplatin; Streptonigrin: Streptozocin, strontium chlo quine; chloroquine; chloroquine phosphate, cycloguanil ride Sr 89: Sulofenur; talisomycin; taxane; taxold; tecogalan pamoate; enpiroline phosphate; halofantrine; hydroxychlo Sodium, tegafur, teloxantrone; temoporfin; teniposide; roquine Sulfate; ; menoctone; mirincamycin; pri 55 teroxirone; ; thiamiprine; thioguanine; thiotepa; maquine phosphate; pyrimethamine; quinine Sulfate; tebu tiazofurin; tirapazamine; topotecan; toremifene citrate; tre qu1ne. stolone acetate; triciribine phosphate; trimetrexate; trimetr Microbicides: exate glucuronate; triptorelin; tubulozole; mustard; aztreonam; chlorhexidine gluconate; imidurea: lyc uredepa; vapreotide; verteporfin; vinblastine sulfate; Vinc etamine; nibroxane: piraZmonam sodium; ; 60 ristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sul pyrithione sodium; Sanguinarium chloride; tigemonam fate; Vinglycinate sulfate; Vinleurosine sulfate; Vinorelbine dicholine. tartrate; Vinrosidine sulfate; Vinzolidine sulfate; Vorozole; Zeniplatin: Zinostatin; Zorubicin. Antimigraine Agents: almotriptan; alniditan; avitriptan; aZasetron; azatadine; 65 Active Ingredient for Combination Therapy with Cytostat bemesetron; BIBN4096BS; BMS-181885; : ics: dolasetron; donitriptan; ebalZotan; eletriptan; ; imipramine and desipramine. US 7,175,854 B2 15 16 Antiparkinson Agents: Antithrombotics: benztropine mesilate; biperiden; biperiden; biperiden lac ; anagrelide; bivalirudin; dalteparin Sodium; tate; carmantadine; , dopamantine; ethopropazine; domitroban; daltroban; danaparoid sodium; : ; levodopa, lometraline; mofegiline; naxagolide; E-3040; efegatran sulfate; enoxaparin sodium; : pareptide Sulfate; procyclidine; quinetorane; ; sel ifetroban sodium; KW-3635; LCB-2853; linotroban; mipi egiline; tolcapone; trihexyphenidyl; antiperistaltic; difenox troban; NM-702; : ; ridogrel; S-1452: imide; difenoxin; diphenoxylate; fluperamide; lidamidine; samixogrel; seratrodast; Sulotroban; ; Unzaparin ; malethamer; nufenoXole; paregoric. Sodium; trifenagrel.

Antiproliferative Active Ingredients: 10 Antitussives: piritreximisethionate. ; ; : brom Antiprotozoal Active Ingredients: hexine; citrate; butetamate; ciobutinol; chlo amodiaquine; azanidazole; bamnidazole; carnidazole; fedanol; codeine; codeine polistirex; codoxime; dex chlortetracycline bisulfate; chlortetracycline; flubendazole; tromethorphan; polistirex; 15 dihydrocodeine; ; ; drotebanol: flunidazole; halofuginone hydrobromide; imidocarb: ; ethyl ; ; gualapate; hydroc ipronidazole; metronidazole; misonidazole; moXnidazole; odone; polistirex, iquindamine; ; nitarSone; partricin; puromycin; puromycin; ronidazole; levdropropizine; napsylate; medaZo Sulnidazole; tinidazole. mide; ; moguisteine; ; ; Active Ingredients for Treating Pruritus: ; pemerid nitrate; ; ; cyproheptadine; ; methdilazine; trimeprazine picoperine; ; ; promolate; saredu tartrate. tant; sodium dibunate; SuXemerid Sulfate; ; tipepi Psoriasis Active Ingredients: dine; vadocaine; . acitretin; anthralin; azaribine; calcipotriene; cyclohexim Antiulcer Aents: ide; enaZadrem phosphate; etretinate; liaroZole fumarate; 25 histamine H2 antagonists lonapalene; . BL-6271; BL-6341A; BMY-25368; BRL-28390; cimeti Neuroleptics: dine; dalcotidine; donetidine; ebrotidine; etintidine; famoti maleate; hydrobromide; alper dine: ICI-162846; icotidine; IGN-2098; isotidulimide; lafu tine, ; batelapline maleate; ; benzin 30 tidine; lamtidine; ; ; mifentidine: dopyrline; brofbxine; ; bromperidol decanoate: ; ; osutidine; OXmetidine; pibubdine; ; ; butaperazine maleate; carphena pifatidine, ramixotidine; ; ranitidine bismuth cit Zine inaleate; carvotroline; chlorpromazine; chlorprom rate; ranitidine nitrate; roXatidine; ; TAS, tiotidine; azine; ; cinperene; cintriamide; comacran venritidine; WHR-2348; YM-14471; Zaltidine; Zolantidine. phosphate; ; ; clopipazan mesilate; 35 Proton Pump Inhibitors cloroperone; clothlapine; clothixamide maleate; ; disuprazole; : FPL-65372-XX: H-335/25; cyclophenazine; ; ; fenimide; ; H-405/02; HN-11203: IY-81149; ; leminopra ; fluiphenazine decanoate; fluiphenazine enan Zole; lucartamide: N-2220; NC-1300; nepaprazole; omepra thate; ; fluspiperone; ; flutroline; Zole; ; pantoprazole sodium; picartamide; pico ; halopemide; ; haloperidol 40 prazole; pumaprazole; ; saviprazole; SCH decanoate; illoperidone; imidoline; ; Succinate; ; mesoridazine besylate; ; 28080; SKF-95-601, SKF-96067; SKF-97574; T-330; milemperone; millipertine; ; ; neflumozide; T-776; ; ufiprazole: YH-1885; YM-19020. : ; oxiperomide; ; pentiap ine maleate; ; ; ; pipamper 45 arbaprostil; butaprost, deprostil; dimethyidinoprostone; one; ; painlitate; ; dimoxaprost, enisoprost; emprostil; mexiprostil; misopros prochlorperazine edisylate; prochlorperazine maleate; pro tol; nocloprost; ornoprostil, oxoprostol; remiprostol; rio mazine; ; remoxipride; rimcazole; Seperidol; prostil; rosaprostol; SC-30249; spiriprostli; TEI-1226; sertindole; setoperone; ; ; thioridazine; tiprostanide; trimoprostil; thiothixene; thiothixene; tioperidone; ; trifluop 50 erazine; ; ; triflupromazine: Other Antiulcer Agents . ; AD-1308; benexate; benzotript: beperidium iodide: ; BTM-1086; cadexomer Antirheumatics: iodine; ; CF-19415: CHINOIN-127; darenzepine: auranofin; aurothioglucose: bindarit; lobenzarit Sodium; 55 deboxamet; detralfate; DH-6615; dosmalfate; ecabapide: ; piraZolac, prinomide tromethamine; ecabet; esaprazole; espatropate, gefamate; irsogladine; seprilose. KW-5805; lactalfate; lozilurea: MAR-99; MCI-727; MDL Antischistosomal Agents: 201034; mezolidon; molfamate; nolinium bromide; nuven becanthone; hycanthone; lucanthone; ; oxam Zepine; octreotide; P-1100; pifamine: ; plauno niquine; pararosaniline pamoate; teroxalene. 60 tol; polaprezinc.; ; RGH-2961; rispenzepine; rotraxate; ; siltenZepine; ; ; Active Ingredients for Treating Seborrhea: Sucrosofate; Sulglicotide; ; ; chloroxine; piroctone; piroctone olamine; resorcinol ; tiopropamine; ; triletide; tritioZine; monoacetate. : UH-AH-37; Zolenzepine; . 65 Antispasmolytics: Agents for Treating Urolithiasis: stilonium iodide; . benzoic acid; cysteamine; cysteamine; tricitrates. US 7,175,854 B2 17 18 Virustatic Agents: Cardiotonics: abacavir, acemannan; aciclovir, adefovir, alovudine; acadesine; acetylidigitoxin; acetyldigoxin; acrihellin; alvircept Sudotox; atevirdine; , aranotin; aril actodigin; adibendan; ; amselamine; ; done; atevirdine; avridine: BW-935-U83; calanolide B: arpromidine: AWD-122-239; bemoradan; ; buto cidofovir, cipamfylline; cytarabine; DAPD; delavirdine: pamine; carbaZeran; cariporide; carperitide; carsatirin; CGS 13928C; cilobradine; CK-2 130; CK-2289; colforsin; desciclovir, didanosine; disoxaril; DPC-083; edoxudine; CV-6402; ; deslanoside; dexraZOxane; digitalis; , emivirine; enviradene; enviroxime; famciclovir, ; ; ; dobutamine; docarpamine; famotine; flacitabine; fialuridine; fosarilate; foscarnet domipizone: ; doridosine: doxaminol; DPI-201 sodium; fosfonet sodium; ganciclovir; GW-420867X; 10 106; draflazine; eniporide; ; ER-21355; evodi idoxuridine, kethoxal: L-697661; lamivudine; lobucavir, amine; falipamil: FK-664; fosfructose; FR-113453; memotine; methisazone; nevirapine; NSC-678323; penci FR-46171; gapromidine; gitaloxin; gitoformate; JP-1-468; clovir, pirodavir, ribavirin; : S-1153; saquinavir, GP-1-531; GP-668; ; ; : Somantadine, Sorivudine; statolon; stavudine; talviraline; imaZodan; indolidan; isamoltan; isomazole; levacecarnine; thioctic acid; tillorone; trifluridine; trovirdine; U-93923; val 15 levdobutamine; ; limaprost; linsidomine; lix aciclovir, Vidarabine; Vidarabine; Vidarabine; viroxime; Zal azinone; MCI-154; medorinone; meproscillarin; meriben citabine; Zidovudine; ZinviroXime. dan; metildigoxin; mildronate; ; mioflazine; mixi dine; MS-857; nanterinone; neraminol; NKH-477; Active Ingredients for Treating Benign Prostate Hyperpla olprinone; OPC-18750; otenzepad: Oxfenicine; peirinone; sia: pengitoxin; pentrinitrol; peruvosid; ; piroxi alfuzosin; CEP-701; doxazosin; ; FK-143; mone: pirsidomine; prinoXodan; prisotinol; propionylcam GI-231818: GYKI-16084; levormeloxifene: pirfenidone: itine; proscillaridin; quaZinone; quaZodine; quindonium bro RS-97078; tamsulosin; sitoglusid. mide; ramnodigin; revizinone; Saterinone; siguaZodan; simendan; Sulmazole; thevetosid; toborinone; ubide Active Ingredients for Treating : alendronic 25 carenone; ; VPA-985. acid; butedronic acid; clodronic acid; EB-1053; etidronic Choleretic Agents: acid; ibandronic acid; incadronic acid; medronic acid; mino alibendol; azintamide: boldine, cicloxilic acid, cinametic dronic acid; neridronic acid; olpadronic acid; oxidronic acid; acid; clanobutin, dehydrocholic acid; dibuprol; epomediol; pamidronic acid; piridironic acid; ranelic acid; risedronic exiproben; febuprol; fencibutirol; fenipentol; hexacyprone: acid; tiludronic acid; YM-529; Zoledronic acid. 30 hymecromone; menbutone; moduizone; piproZolin; proZap Carbonic Anhydrase Inhibitors: ine; sincalide; tenylidone; terbuprol; tocamphyl; trepibu ; AL4414A, diclofenamide; dorzolamide: tOne. methazolamide; seZolamide: Sulocarbilate. Cholinergic Agents: 35 acedidine; bethanechol chloride; ; demecarium Antiarrhythmics: bromide; dexpanthenol; echothiophate iodide; isoflurophate: abanoquil: ACC-9164, acecainide; actisomide; adenos methacholine chloride; neostigmine bromide; neostigmine ine; ; alinidine; ; alprafenone; methylsulfate; physostigmine; physosugmine salicylate; amafolone; ambasilide; ameltolide; amiodarone; ; physosugmine Sulfate; pilocarpine; pilocarpine; pilocarpine aprindine; artilide; asocainol; AWD-G-256; ; ben 40 nitrate; pyridostigmine bromide. derizine; benrixate; benzodioxine; berlafenone; bertosamil: Cholinergic Agonists: bidisomide; bisaramil: BRL-32042; bucainide; bucromar one; ; buquineran; butobendine; butoprozine; Xanomeline; Xanomeline tartrate. capobenic acid; carbizocaine; carcainium chloride; cari Cholinesterase Inhibitors: poride; carocainide; cercainide; cibenzoline; cifenline; 45 acetohydroxamic acid; DMPS; ; obidoxime ciprafamide: CL-284027; clamikalant; clofilium phosphate: chloride; pralidoxime chloride; pralidoxime iodide; prali CV-6402: CVT-510; cyclovirobuxine-D, D-230; detaJmium doXime mesilate. bitartrate; disobutamide: dexsotalol; dioxadilol; Coccidiostats: ; disobutamide; ; dofetilid; drobu aklomide; amidapsone; amprolium; arprinocid; bitipa line; ; droxicainide; E047/1, E-0747; E4031; 50 Zone; buquinolate; ciadox; claZuril; dopidol; decoquinate; edifolone; emilium tosilate; ; ; eproxin diciaZuril; dinitolamide; dinsed; halofluginone; letraZuril; dine; erocainide; ; fepromide; ; fluzo narasin; nequinate; nicarbazine; nifursemizone; ponaZuril; peride; gallanilide; glemanserin; guafecainol: GYKI-23107; produinolate; robenidine; semduramicin; SulaZuril; Sulfani GYKI-38233; heptacaine; hydroxyfenone; ibutiide: tran; tiaZuril; to Sulur. ; ipazilide; itrocainide; ketocainol; L-702958; 55 L-706000; levosemotiadil; ; lorcainide; meoben : tine; ; milacainide; modecainide; ; acetazolamide; acetothiazide, alipamide, ; moxaprindine; murocainide; nibentan; nicainoprol; nipekal amanozine; ; ambuside; ; aminome ant; nofecalnide; oxiramide: palatrigine; penticainide; pen tradine; amisometradine; ampyrimine; apaxifylline; tisomide; ; pirmenol; pirolaZamide; prajmalium 60 azolimine; ; bemetizide; bemitradine; bendroflu bitartrate; pranolium chloride; prifuroline; ; methiazide; ; benzolamide; benzthiazide; benzyl ; pyrinoline; quinacainol; quindonium bromide; ; besulpamide: besunide, brocrinat: ; recainam, riloZarone; risotilide; ronipamil; ropi ; butizide; ; carmetizide; chlora toin, sematilide. Sinomenine; Solpecainol; ; sti Zanil; chlorothiazide; chlorthalidone; cicletanine; cla rocainide; stobadine: SR47063; Sulamserod; Suricainide; 65 Zolimine; ; ; CVT-124; dicirenone; tedisamil: terikalant; tiracizine; ; tosifen, transcain disulfamide; ; ethacrynate sodium; ethacrynic ide; trecetilide; Zocainone. acid: etofylline: ; fenduizone; FK-352: FR-113453; US 7,175,854 B2 19 20 : hydrochlorothiazide; hydroflumethiazide; inda nate; ; , ; drocinonide; crinone; indapamide: isosorbide: KW-3902; lemidosul: FSDCICM; fluazacort; acetonide; flucloronide; ; ; ; methalthiazide; meth fludrocortisone; ; ; flumetasone aZolamide; methydothiazide; ; metolaZone; pivalate; flumoxonide; flunisolide; acetonide; muzolimine: niravoline; OPC-31260; oxprenoate; ozoli ; fluocortin; ; : none; paraflutizide; penflutizide; ; polythiazide; fluocortolone caproate; fluorometholone; flupamesone; flu canrenoate; propazolamide; prorenoate; prorenone; perolone acetate; ; ; flupred pytamine; quincarbate; : RPH-2823: S-8666: nisolone Valerate; flurandrenolide; fluticasone; fluticasone Sitalidone; spironolactone; spirorenone; spiroXasone; propionate; ; ; SR48692; sulciamide; sulicrinat: Sulocarbilate; Sulosemide: 10 GW-215864X ; GW-250945; halcinonide; halocortolone; Sumetizide, teclothiazide; tiamizide, ; torsemide; ; acetate; ; hydro ; trichlormethiazide; triflocin; tripamide: TRK ; ; hydrocortisone ace 820; ularitide; ; Xipamide. ponate; ; ; Ectoparasiticides: hydrocortisone enbutate; hydrocortisone sodium phosphate: 15 hydrocortisone sodium Succinate; ; carbaril; clidafidine, cypermethrin, ; fenclo enbutate; isoflupredone; ; itroci fos; fenvaierate; ivermectin; lindane; ; niflurid nonide; locicortolone; locicortolone dicibate; loteprednol ide; permethrin, temefos. etabonate; ; meclorisone; ; mepred Emetics: nisone; methylprednisolone; methylprednisolone acetate; . methylprednisoloXime sodium phosphate; methylpredniso Inhibitors: lone sodium Succinate; furoate, naflocort; niva acetohydroxamic acid; alrestatin Sodium; aprotinin; cortol; nivaZol; acetate; prednazate; predna benazepril; benazeprilat; benurestat; bromocriptine; bro Zoline; ; ; ; mocriptine mesilate; cilastatin Sodium; flurofamide; lergot ; prednisolone fameSylate; prednisolone 25 hemisuccinate; prednisolone sodium phosphate; predniso rile; mesilate; levcycloserine; libenzapril; pento lone sodium Succinate; ; ; pril; pepstatin; perindopril; polignate Sodium; sodium ; ; prednival; procinonide; reso amylosulfate; Sorbinil; spirapril; spiraprilat; ; tepro cortol; ; rofileponide; TBI-PAB; pro tide; tolfamide; Zofenopril calcium. pionate; timobesone; tipredane; tiXocortol; tixocortol piv : 30 alate; ; ; ; ; ; ; diethylstil triamcinolone acetonide Sodium; triamcinolone benetonide; bestrol diphosphate; ; ; ; estradiol ; ; triamci cypionate; estradiol enanthate; ; estra nolone hexacetonide; triclonide; . diol Valerate; hydrobromide; ; ; Hemostatics: estrogens, conjugated; estrogens, esterified; ; estropi 35 pate; ethinyl estradiol; ; ; nylestriol: aminocaproic acid; oXamarin; Sulmarin; thrombin; tran examic acid. Fibrinolytics: Hormones: diethylstilbestrol; progesterone; 17-hydroxy acexamic acid; amediplase; anistreplase; aprotinin; biso progesterone; medroxyprogesterone; ; norethyno 40 drel; estradiol; megestrol (Megace); norethindrone; brin lactate; brinase; brinolase; camoStat; fibrinolysin; ini ; ethyndiol; ethinyl estradiol; mestranol: carone; iduindamine; nattokinase; pamiteplase; picotamide; estrone; equilin; 17-alpha-dihydroequilin; ; 17 Staplabin; Streptokinase; taurine; tiZabrin; tranexamic acid; alpha dihydroequilenin; 17-alpha-estradiol; 17-beta-estra Free-radical Scavenger: diol; leuprolide (lupron); glucagon; testolactone; clomi pegorgotein. 45 phene; han memopausal ; human chorionic Motility-increasing Active Ingredients: ; urofollitropin; bromocriptine; gonadorelin; (Propulsid); metoclopramide (Reglan), hyos luteinizing hormone releasing hormone and analogs; gona cyamine (Levsin). dotropins; ; testosterone; ; ; dihydroestosterone; relaxin, oxytocin, Glucocorticosteroids: 50 vasopressin, folliculostatin; follicle regulatory protein; ; alclometaSone; algestone acetonide; gonadoctrinins; oocyte maturation inhibitor; insulin growth amcinafal, amcinafide; ; ; amelometa factor, follicle stimulating hormone; luteinizing hormone; Sone; beclomethasone dipropionate; bendazacort; tamoxifen, corticorelin ovine trifiutate; cosyntropin; ; ; betamethasone ben , pituitary, posterior, seractide acetate; somalapor; Zoate; betamethasone diproplonate; betamethasone sodium 55 Somatrem: Somatropin; somenopor; somidobove. phosphate; ; budesonide; ; butxocort propionate; CGP-13774; ; ciclometa HMG-CoA Reductase Inhibitors: Sone; ciprocinonide; clobetasol; clobetasol 17-propionate; lovastatin (Mevacor); simvastatin (Zocor); pravastatin ; acetate; ; (Pravachol); fluvasatin (Lescol). ; cloticaSone; cloticasone propionate; CMJ: 60 Immunomodulators: ; corticotropin; corticotropin; corticotropin Zinc dimepranol acedoben, imiquimod; interferon beta-lb., hydroxide; ; ; ; deflaza lisofylline; mycophenolate mofetil: prezatide copper cort, ; deprodone propionate; acetate. acetonide; desonide; desoximetasone; desoxycortone; dex amethasone; ; dexamethasone 65 Immunoregulators: sodium phosphate; ; ; diflo aZarole; mesilate; frentizole; oxamisole; ris rasone; ; diflucortolone pivalate; diflupred tianol phosphate; thymopentin; tilomisole. US 7,175,854 B2 21 22 Immunostimulants: Oxytocics: loxoribine; teceleukin. ; carboprost methyl; carboprost tromethamine; dinoprost, dinoprost tromethamine; dinoprostone; ergono Immunosuppressants: vine maleate; meteneprost; methylergonovine maleate; oxy ; azathioprine Sodium: cyclosporine; dal 5 tocin, Sparteine Sulfate. troban; gusperimus trihydrochloride; Sirolimus; tacrolimus. Plasminogen Activators: Active Ingredients for Treating Impotence: alteplase; urokinase. abanoquil; alprostadil; amlodipine; BMS-193884; PAF Antagonists: deleduanine, doxazosin, E-4010; trinitrate; 10 lexipafant. IC-351; melanotan II; minoxidil; nitraquaZone; ; phenoxybenzamine; praZosin; quinelorane; sildenafil; Aggregation Inhibitors: acadesine; ; beraprost sodium; ciprostene cal UK-1 14542; urapidil; Vardenafil; VIP; yohimbin; cium; itaZigrel, lifarizine; oxagrelate. LHRH Antagonists: 15 Progestins: deslorelin; goserelin; histrelin; lutrelin acetate; nafarelin algestone acetophenide; amadinone acetate; anagestone acetate. acetate; ; clingestol; clogestone acetate; clomegestone acetate; ; dimethisterone; Hepatoprotectant: dydrogesterone; ethynerone; ethynodiol diacetate; malotilate. ; flurogestone acetate; gestaclone; ; gestonorone caproate; ; haloprogesterone; Luteolytics: hydroxyprogesterone caproate; levonorgestrel; ; fenprostalene. ; medroxyprogesterone acetate; methynodiol Cerebrotonics: diacetate; norethindrone; norethindrone acetate; norethyno 25 drel; norgestimate; ; norgestrel; OXogestone aloracetam; alvameline; ; apaxifylline; apti phenproplonate; progesterone; acetate; ganel; azetirelin; brovincamine; ; cevimeline; ; tigestol. CI-844; CI-933; demiracetam; dimoxamine; donepezil; ; edaravone; ensaculin; ; FK-960; Prostate Growth Inhibitors: . gavestinel; igmesine; muracetam; IOS-11212; JTP4819; 30 KST-5410; leteprinim; ligustizine; ; MCI-225; Prothyrotropin: milameline; MKC-231; NDD-094; ; nicorac protirelin. etam; nizofenone; ONO-1603; OP-2507; OPC-141 17: , pikamilone; ; piraxelate; pirglu Psychotropic Agents: targine; ; ; quilostigmine; ribaminol; minaprine. rivastigmine; ; sabcomeline, sapropterin; SIB 35 1553A. sibopirdine: sipatrigine; SM-10888; SNK-882; Calcium Regulators: SR-46559-A: staco?ylline: T-588; T-82; TAK-147; talsacli alfacalcidol; calcifediol; calcipotriol; calcitonin; cal dine; taltirelin; tamitinol; tenilsetam; Vinconate; Vinpocet citriol: dihydrotachysterol: doxercalciferol: falecalcitriol: ine; xaliproden; Xanomeline: YM-796; YM-900: Z-321; lexacalcitol; maxacalcitol; Secalciferol; seocalcitol; tacalci Zifrosilone. 40 tol; Relaxants: Mucolytics: adiphenine; alcuronium chloride; ; ; adamexine; ; bencisteine; brom aZumolene Sodium; ; ; carisoprodol; hexine; brovanexine; carbocysteine; cartasteine; cistinexine; chlorphenesin carbamate; ; cinflumide: cin dacisteine; danosteine; dembrexine; ; ; 45 namedrine; clodanolene; cyclobenzapine; dantrolene; dant erythromycin Salnacedin; erythromycin Stinopate; guaime rolene sodium; femalamide; fenyripol; fetoxylate; flavoxate: sal; IDB-1031; isalsteine; ; ; ; fletazepam, flumetramide:-flurazepam, hexafluorenium bro midesteine; moguisteine; ; nesosteine; omonas mide; isomylamine; lorbamate; mebeverine; meSuprine; teine; OXabrexine; prenisteine; Salmisteine; ; tasul metaxalone; methocarbamol; methixene; nafomine malate; dine; taurosteine; telmesteine; tiopronin. 50 neleZaprine maleate; papaverine; pipoxolan, quinctolate; ; ritodrine; rolodine; theophylline Sodium glycinate; Mydriatics: thiphenamil: xilobam. . Scabicides: Neuroprotective Agents: 55 , crotamiton. maleate. Sclerosing Agents: NMDA Antagonists: clobenoside; ethanolamine oleate; morrhuate Sodium, ola ACPC; aptiganel: BMY-14802: CGP-37849; CP-101606: mine; tribenoside. dizocilpine; EAA-090; eliprodil; felbamate: FPL-12495; 60 Sedatives: gavestinel; harkoseride; HU-211; ipenoxazone: L-695902; . lanicemine; licostinel; ligustizine; midafotel; milnacipran; nebostinel; remacemide; selfotel; seratrodast; spermidine; Hypnotics/sedatives: spermine: UK-240255; ZD-9379. allobarbital; alonimid; alprazolam; amobarbital sodium; 65 bentazepam; brotizolam; butabarbital; butabarbital sodium; Nonhormonal Derivatives: butalbital; capuride; carbocloral; chloral betaine; chloral . hydrate; chlordiazepoxide; cloperidone; clorethate: US 7,175,854 B2 23 24 cyprazepam, dexclamol; diazepam, dichloralphenaZone; epinephrine; epinephrylborate; ; indanazoline; estazolam; ethchlorvynol: etomidate; fenobam; fluni ; ; ; metrafazoline; trazepam, fosazepam, glutethimide; halazepam, ; riemazoline; oxedrine; ; phe lormetazepam; mecloqualone; meprobamate; methaqua namaZoline; ; phenylpropanolamine polis lone; midaflur; paraldehyde; pentobarbital; pentobarbital tirex, tefazoline; tetry Zoline; tinazoline; , Xylom Sodium; ; prazepam; quazepam, reclazepam; role etazoline. tamide; secobarbital; secobarbital Sodium; Suproclone; tha lidomide; ; maleate; triazolam, triceta Vasodilators: mide; triclofos Sodium; trimetozine; uldazepam, Zaleplon; alprostadil; azaclorzine; bamethan sulfate; ; buter Zolazepam, Zolpidem tartrate. 10 izine; cetiedil citrate; chromonar, clonitrate; ; dipy ridamole; droprenilamine; erythrity1 tetranitrate; ; Selective Al Antagonists: ; ; ; niacinate; iproX apaxiylline amine; isosorbide dinitrate; isosorbide mononitrate; isoxSu Serotonin Antagonists: prine; ; mefenidil; mefenidil fumarate; mibefradil altanserin tartrate; , : , tro 15 dihydrochloride; mioflazine; mixidine; nafronyl oxalate: panserin ; nicergoline; ; nicotinyl alcohol; nife dipine; ; ; Oxfenicine; Oxprenolol; Serotonin Inhibitors: pentaerythritol tetranitrate; ; pentrinitrol; per cinanserin; ; fonazine mesilate; Xylamidine hexiline maleate; pindolol, pirsidomine; ; pro tosylate. patyl nitrate; suloctidil; ; tipropidil; tolazoline; : Xanthinol niacinate. ; Sulfate; ampyZine Sulfate; Active Ingredients for Wound Healing: arbutamine; azabon: ; ceruletide; ceruletide diethy erSofermin. lamine; cisapride; dazopride fumarate; ; dextroamphetamine Sulfate; difluanine; dimefline: 25 Xanthine Oxidase Inhibitors: apram; etryptamine acetate; ethamivan; ; fluba , oxypurinol nilate; ; histamine phosphate; indriline; mefexam In a preferred embodiment of the invention, the active ide; hydrochlo ride; ; ingredient is a PDE (phosphodiesterase) inhibitor, particu , : Xamoterol: Xamoterol fumarate. larly preferably PDE 4 inhibitor, especially N-(3,5-dichlo 30 ropyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy Suppressants: benzamide (INN: ) its N-oxide or a amflutizole; coxchicine; taZofelone. pharmacologically suitable salt of roflumilast or of its N-ox Active Ingredients for Treating Symptomatic Multiple Scle ide. The preparation of N-(3,5-dichloropyrid-4-yl)-3-cyclo rosis: propylmethoxy-4-difluoromethoxybenzamide, its pharma fampridine. 35 cologically Suitable salts and its N-oxide, and the use of these compounds as phosphodiesterase (PDE) 4 inhibitors is Synergistic Agents: described in the international application WO95/01338. In a . particularly preferred embodiment of the invention, the : active ingredient is a phosphodiesterase (PDE) 3/4 inhibitor, sodium; liothyronine sodium; liotrix. 40 in particular (-)-cis-9-ethoxy-8-methoxy-6-(4-diisopropy laminocarbonylphenyl)-2-methyl-1,2,3,4,4a, 10b-hexahy Thyroid Inhibitors: drobenzoc1.6naphthyridine (INN: pumafentrine). The methimazole; propyithiouracil. preparation of (-)-cis-9-ethoxy-8-methoxy-6-(4-disopropy Thyromimetics: laminocarbonylphenyl)-2-methyl-1,2,3,4,4a, 10b-hexahy thyromedan. 45 drobenzoc1.6naphthyridine and its pharmacologically Suitable salts, and the use of this compound as phosphodi Tranquilizers: esterase (PDE) 3/4 inhibitor is described in the International bromazepam, ; chlordiazepoxide; claZolam; application WO98/21208. clobaZam; cloraZepate dipotassium; cloraZepate monopotas sium; demoxepam; ; ; The matrix of the invention is outstandingly suitable as ; hydroxyphenamate; ; hydroxy Zine 50 dosage form for active ingredients from the class of Sub pamoate; ketazolam; , lorZafone; ; loX stances known as reversible H, K"-ATPase inhibitors, apine Succinate; medazepam, nabilone; nisobamate; which are also referred to as reversible proton pump inhibi oxazepam, pentabamate; piremperone; ripazepam, roliprarn, tors or APAS (acid pump antagonists). Reversible proton Sulazepam, taciamine; temazepam, triflubazam; tybamate; pump inhibitors or APAS are disclosed, for example, in the 55 patent document DE-A 3917232, EP-A-0399267, EP-A- Vainoctamide. 0387821, JP-A-3031280, JP-A-2270873, EP-A-0308917, Agent for Treating Cerebral Ischemia: EP-A-0268989, EP-A-0228006, EP-A-0204285, EP-A- . 0.165545, EP-A-0125756, EP-A-0120589, EP-A-0509974, DE-A3622036, EP-A-0537532, EP-A-0535529, JP-A- Agent for Treating Paget’s Disease: 60 3284686, JP-A-3284622, U.S. Pat. No. 4,833,149, EP-A- tiludronate disodium. 0261912, WO-A-9114677, WO-A-9315055, WO-A- UricoSuric Agents: 9315071, WO-A-9315056, WO-A-9312090, WO-A- ; irtemazole; probenecid; Sulfinpyrazone. 9212969, WO-A-9118887, EP-A-0393926, EP-A-0307078, U.S. Pat. No. 5,041,442, EP-A-0266890, WO-A-94.14795, Vasoconstrictors: 65 EP-A-0264883, EP-A-0033094, EP-A-025.9174, EP-A- adrenalone; amidefrine mesilate; angiotensin amide; caf 0330485, WO-A-8900570, EP-A-0368158, WO-A- aminol; cilutazolin; clonazoline; ; domazoline; 9117164, WO-A-9206979, WO-A-9312090, WO-A-

US 7,175,854 B2 29 30 In another preferred embodiment of the Invention, the acid esters which may be mentioned are cetyl palmitate, active ingredient is a glucocorticosterold, in particular which is commercially available for example under the ciclesonide. name Cutina R CP. It is also possible if desired for mixtures The active ingredients may, depending on the nature of of fatty acid esters to be present. the active ingredient, also be present in the preparations of 5 The solid paraffin is preferably paraffinum solidum (cer the invention in the form of a salt of the active ingredient. esin). It is also possible alternatively to use ozokerite, for Particular mention may be made of the pharmacologically example. It is also possible if desired to use mixtures. Suitable salts of the inorganic and organic acids normally The partial glyceride is according to the Invention glyc used in pharmaceutical technology. Suitable as such are, on erol in which one or two hydroxyl groups are esterified by the one hand, water-soluble and water-insoluble acid addi 10 carboxylic acids. The carboxylic acids are preferably tion salts with acids such as, for example, hydrochloric acid, monobasic carboxylic acids with 8 to 22 atoms, hydrobromic acid, phosphoric acid, nitric acid, Sulfuric acid, preferably naturally occurring carboxylic acids, in particular , citric acid, D-gluconic acid, benzoic acid, 2-(4- , palmitic acid and myristic acid. It is possible in hydroxybenzoyl)benzoic acid, butyric acid, sulfosalicylic this case for the carboxylic acids to be different or, prefer acid, maleic acid, lauric acid, malic acid, fumaric acid, 15 ably, the same. Examples which may be mentioned are Succinic acid, oxalic acid, tartaric acid, embonic acid, Stearic glycerol monostearate, glycerol distearate and glycerol acid, toluene Sulfonic acid, methanesulfonic acid or 3-hy monopalmitate, glycerol dipalmitate. It is also possible if droxy-2-naphthoic acid, the acids being employed for pre desired for mixtures of partial glycerides to be present. paring the salts in the equimolar ratio of amounts, or a ratio If desired, the mixtures in the individual active ingredient differing therefrom, depending on whether the acid is units may include one or more other pharmaceutically monobasic or polybasic and depending on which salt is suitable excipients. Other suitable excipients which may be required. mentioned by way of example are polymers, sterols and in On the other hand, salts with bases are also suitable. the case of acid-labile active ingredients—basic compounds. Examples of salts with bases which may be mentioned are Examples of polymers which may be mentioned are alkali metal (, Sodium, ) or calcium, alu 25 povidone (e.g. Kollidon(R) 17, 30 and 90 from BASF), minum, magnesium, titanium, ammonium, megiumine or vinylpyrrolidone/vinyl acetate copolymer and polyvinyl guanidinium salts, the bases being employed for preparing acetate. Others which may be mentioned are cellulose ethers the salts also in the equimolar ratio of amounts or in a ratio such as, for example, methylcellulose, ethylcellulose (Etho differing therefrom. cel(R) and hydroxypropylmethylcellulose, cellulose esters The skilled worker is aware that active ingredients and 30 such as cellulose acetate (CAP), cellulose acetate their salts may, if they are isolated, for example, in crystal trimellitate (CAT), hydroxypropylmethylcellulose phthalate line form, contain various amounts of solvents. The active (HP50 and HP55) or hydroxypropylmethylcellulose acetate ingredients will therefore also be present in the preparations succinate (HPMCAS), methacrylic acidimethyl methacry of the Invention in the form of solvates and, in particular, late copolymer or methacrylic acid/ethyl methacrylate hydrates, and in the form of Solvates and, in particular, also 35 copolymer (Eudragit(R) L). The polymer is preferably povi hydrates of the salts of the active ingredients. done or ethylcellulose. It is also possible if desired for The active ingredients may also be chiral compounds. It mixtures of polymers to be present. It is possible by adding is therefore also possible for the pure enantiomers of the Suitable polymers, for example, to influence the pharmaceu active ingredients and mixtures thereof in any mixing ratio tical properties of the individual active ingredient units (e.g. to be present in the preparations of the invention. 40 delivery of the active ingredient). Particularly preferred The fatty alcohol is preferably a linear, saturated or polymers according to the invention are povidone or ethyl unsaturated primary alcohol with 10–30 carbon atoms. It is cellulose. preferably a primary alcohol with 10 to 18 carbon atoms in The sterol is preferably a or a Zoosterol. linear chains. Examples of fatty alcohols which may be Examples of which may be mentioned are mentioned are cetyl alcohol, myristyl alcohol, lauryl alcohol 45 ergosterol, , sitosterol, brassicasterol and or stearyl alcohol, with preference for cetyl alcohol. It is also . Examples of Zoosterols which may be men possible if desired for mixtures of fatty alcohols to be tioned are and lanosterol. It is also possible if present. desired for mixtures of sterols to be present. The triglyceride is glycerol with its three hydroxyl groups Examples of Suitable basic compounds are inorganic basic esterified by carboxylic acids. The carboxylic acids are 50 salts such as ammonium carbonate and sodium carbonate, preferably monobasic carboxylic adds with 8 to 22 carbon salts of fatty acids such as sodium Stearate, Such as atoms, preferably naturally occurring carboxylic acids. It is meglumine, di-, triethylamine and TRIS(2-amino-2-hy possible in this case for the carboxylic acids to be different droxymethyl-1,3-propanediol) or fatty amines Such as or, preferably, identical. Examples which may be mentioned Stearylamine. Stearylamine and sodium Stearate may be are tristearate, tripalmitate and, particularly preferably, 55 mentioned as preferred. The addition of basic compounds to trimyristate (these triglycerides are commercially available the mixtures in the individual units results, in the case of under the name Dynasan 118, 116 and 114 respectively). It acid-labile active ingredients, in particularly stable prepara is also possible if desired for mixtures of triglycerides to be tions and prevents possible discolorations. present. The proportion (in percent by weight) of active ingredient The fatty acid ester is the ester of an alcohol with a fatty 60 in the individual active ingredient unit depends on the type acid. The alcohol in this case is preferably a linear, saturated of active ingredient and is advantageously 0.01-90%. The or unsaturated primary alcohol with 10–30, preferably with proportion of active ingredient is preferably 0.1–70%, par 12 to 18, carbon atoms. The fatty acid is preferably a ticularly preferably 5–40%, in particular 10–20%. The pro monobasic carboxylic acid with 8 to 22, in particular 12 to portion of fatty alcohol in the individual active ingredient 18, carbon atoms, preferably a naturally occurring carboxy 65 unit is advantageously 10–70%, preferably 20–70%, par lic acid. Fatty acid esters preferred according to the inven ticularly preferably 20–60% and in particular 30–60%. The tion have a melting point above 30° C. Examples of fatty proportion of triglyceride in the individual active ingredient US 7,175,854 B2 31 32 unit is advantageously 10–70%, preferably 20–70%, par Invention consist of 5–40% active ingredient, 20–60% fatty ticularly preferably 20–60% and in particular 30–60%. The alcohol, 10–60% solid paraffin, 1–15% polymer and 0.1–1% proportion of partial glyceride in the individual active ingre of a basic compound. Further particularly preferred indi dient unit is advantageously 10–70%, preferably 20–70%, vidual active ingredient units of the invention consist of particularly preferably 20–60% and in particular 30–60%. 5 5–40% active ingredient, 20–60% triglyceride, 10–60% The proport of fatty acid ester in the individual active solid paraffin, 1–15% polymer and 0.1–1% of a basic ingredient unit is advantageously 10–70%, preferably compound. Other particularly preferred individual active 20–70%, particularly preferably 20–60% and in particular ingredient units of the invention consist of 5–40% active 30-60%. The proportion of solid paraffin is advantageously ingredient, 20–60% fatty acid ester, 10–60% solid paraffin, 10–70%, preferably 20–60% and in particular 30–60%. If 10 1-15% polymer and 0.1–1% of a basic compound. present, the proportion of polymer in the individual active Examples of active ingredient units of the invention ingredient unit is expediently 1–25%, preferably 1–10%, contain 5-40% pantoprazole sodium sesquihydrate, 10–40% particularly preferably 5–10%. If present, the proportion of cetyl alcohol, 5-60% solid paraffin, 1-5% polymer and sterol is expediently 1–10%, preferably 1–5%. If present, the 0.1-0.2% of a basic compound. Further examples of active proportion of basic compound is 0.05–5%, preferably 15 ingredient units of the invention contain 540% pantoprazole O.1-1%. sodium sesquihydrate, 10 40% glyceryl tripalmitate, 5-60% Preferred individual active ingredient units of the inven solid paraffin, 1-5% polymer and 0.1-0.2% of a basic tion consist of 2 70% active ingredient, 10–60% fatty compound. Other examples of active ingredient units of the alcohol, 10–60% solid paraffin and 1–15% polymer. Further invention contain 5-40% pantoprazole Sodium sesqulhy preferred individual active ingredient units of the invention drate, 10–40% glyceryl tripalmitate, 5-60% solid paraffin, consist of 2 70% active ingredient, 10–60% triglyceride, 1–5% polymer and 0.1-0.2% of a basic compound. Still 10–60% solid paraffin, 1–15% polymer. Other preferred other examples of active ingredient units of the invention individual active ingredient units of the invention consist of contain 10–20% pantoprazole Sodium sesquihydrate, 2–70% active ingredient, 10–60% fatty acid ester, 10–60% 20-40% triglyceride, 40–70% solid paraffin, 1-5% sterol solid paraffin and 1–15% polymer. 25 and 0.05–0.1% of a basic compound. In one embodiment, the invention relates to a preparation The individual active ingredient units can be produced for in which an active ingredient is essentially uniformly dis example by spray drying or, preferably, by spray solidifica tributed in an excipient matrix composed of a mixture of at tion, in particular also by spray prilling. Production is least one solid paraffin, a fatty alcohol, a fatty acid ester and particularly preferably by prilling, in particular by vibration a partial glyceride or triglycedde. Such preparations prefer 30 prilling. ably consist of 0.05 to 25% active ingredient, 10 to 70% For the spray solidification or prilling expediently the solid paraffin, 5 to 80% fatty alcohol, 2 to 20% fatty acid matrix excipients are liquefied to give a melt. The active ester and 5 to 80% triglyceride or partial glyceride. Such ingredient is dissolved or dispersed in this solution, and the preparations consist, in particular, of 0.1 to 20% active resulting solution or dispersion is sprayed or, preferably, ingredient, 15 to 65% solid paraffin, 5 to 70% fatty alcohol, 35 prilled in a Suitable apparatus. A dispersion of the active 2 to 15% fatty acid ester and 5 to 20% 70% triglyceride or ingredient in a melt of the exciplents is preferably used. partial glyceride. Such preparations particularly preferably Spray Solidification takes place in a manner known perse. consist of 0.5 to 15% active ingredient, 15 to 60% solid A detailed description of this technique is to be found in P. paraffin, 5 to 50% fatty alcohol, 5 to 10% fatty acid ester and B. Deasy, Microencapsulation and Related Processes 10 to 50% triglyceride or partial glyceride. 40 (1984). In another embodiment, the invention relates to a prepa The individual active ingredient units are particularly ration in which an active ingredient is essentially uniformly preferably produced by solidification from liquid phase by dispersed in an excipient matrix composed of at least one generating drops by means of vibrating nozzles and by fatty alcohol together with at least one excipient selected solidifying the drops which are formed, after they have from the group of solid paraffin or polymer. The polymer is 45 stabilized, by drying or cooling in a suitable medium (pref preferably ethylcellulose or povidones. Such preparations erably gaseous or liquid). The Suitable medium may be, for preferably consist of 0.05 to 25% active ingredient, 20 to example, cooled gas such as air or nitrogen. Processes of this 90% fatty alcohol, 10 to 80% solid paraffin and/or 0.05 to type and corresponding apparatuses are disclosed in DE 27 2% ethylcellulose. Such preparations consist in particular of 25924, EP 0467 221, WO99/33555 and WO00/24382. 0.1 to 20% active ingredient, 25 to 80% fatty alcohol, 10 to 50 It is particularly preferred according to the invention in 70% solid paraffin and/or 0.1 to 1.5% ethylcellulose. Such the prilling process for the liquid phase flowing to the nozzle preparations particularly preferably consist of 0.5 to 15% to be kept at a constant temperature. The Solidification active ingredient, 25 to 70% fatty alcohol, 10 to 60% solid preferably takes place by instantaneous cooling in a Suitable paraffin and/or 0.2 to 1% ethylcellulose. cooling medium. In prilling, moreover, it is preferred for the In the case of acid-labile active ingredients, in particular 55 liquid phase flowing to the nozzle, the vibrating nozzle and the acid-labile proton pump inhibitors, preferred individual the drops formed by prilling to be kept at a constant active ingredient units of the invention consist of 2–70% temperature until their spherical shape has stabilized, and for active ingredient, 10–60% fatty alcohol, 10–60% solid par the solidification of the drops after their stabilization to be affin, 1–15% polymer and 0.1–2% of a basic compound. carried out instantaneously by cooling with a gaseous or Further preferred individual active ingredient units of the 60 liquid cooling medium. Systems suitable for prilling by invention consist of 2–70% active ingredient, 10–60% trig means of vibrating nozzles are marketed, for example, by lyceide, 10–60% solid paraffin, 1–15% polymer and 0.1–2% Brace GmbH, Alzenau, Germany. It is possible by means of of a basic compound. Other preferred individual active prilling using vibrating nozzles to obtain the individual ingredient units of the Invention consist of 2 70% active active ingredient units in the form of microspheres with a ingredient, 10–60% fatty acid ester, 10–60% solid paraffin, 65 narrow monomodal particle size spectrum in the particle size 1-15% polymer and 0.1–2% of a basic compound. Particu range from 50 um to 2 mm. The narrow monomodal particle larly preferred individual active ingredient units of the size spectrum and the uniform spherical shape of the micro US 7,175,854 B2 33 34 spheres obtained in this way are expected to result in a ylcellulose, and starches able to carry out the uniformly smooth surface, a uniform, defined delivery of function of a disintegrant (e.g. Starch 1500). Suitable lubri active ingredient and, in relation to passage through the cants which may be mentioned are sodium Stearyl fumarate, stomach in the case of oral dosage forms (owing to the Small magnesium Stearate, calcium Stearate, Stearic acid, talc and particles), a behavior like that of a solution. The micro highly disperse silica (Aerosil). Suitable surfac-active sub spheres of the invention are distinguished in particular by stances which may be mentioned are sodium lauryl Sulfate high stability, a release of active ingredient which can be or Tween(R) 20, 60 or 80. Binders suitable according to the controlled via the particle size and composition of the Invention are polyvinylpyrrolidone (PVP, Poly Vidon R. K25, matrix, good flow characteristics, good compressibility and 90) or mixtures of PVP with polyvinyl acetate (e.g. Kolli a uniform delivery of active ingredient. It is particularly 10 don R. 64), gelatin, corn starch mucilage, preswollen Starches worthy of mention that the microspheres can be further (Starch 1500), hydroxypropylmethylcellulose (HPMC) or processed to a large number of pharmaceutical dosage forms hydroxypropyl-cellulose (L-HPC). without thereby losing a given functionality (Such as taste The proportion (in percent by weight based on the fin masking, resistance to gastric juice, slowing of release). ished tablet) of filler in the rapidly disintegrating tablet is The microspheres are preferably monomodal micro 15 advantageously from 1 to 99% by weight. The proportion of spheres with a particle size range of 50–800 um, preferably filler is preferably from 30 to 95% by weight, and the 50–500 um, particularly preferably 50–400 um, in particular proportion is very particularly preferably from 60 to 85% by 50–200 um. weight. The particle size of the active ingredient employed in the The proportion (in percent by weight based on the fin spray drying or spray Solidification, prilling or vibration ished tablet) of disintegrant in the rapidly disintegrating prilling is advantageously less than or equal to 100 um, in tablet is usually from 1 to 30% by weight. The proportion of particular less than 40 um. The particle size is preferably in disintegrant is preferably from 2 to 15% by weight. The the range 1–20 um, particularly preferably in the range 3–15 proportion of disintegrant is particularly preferably from 5 to um. Such a particle size can be achieved, for example, by 10% by weight. grinding the active ingredient in a suitable mill. 25 The proportion (in percent by weight based on the fin The individual active ingredient units (preparations) of ished tablet) of lubricant in the rapidly disintegrating tablet the invention can then be used as basis for producing the is usually from 0.1 to 5% by weight. The proportion of dosage forms of the invention. Examples which may be lubricant is preferably from 0.3 to 3% by weight. The mentioned are dosage forms of the invention, to which the proportion of lubricant is particularly preferably from 0.5 to preparations can be processed, as Suspensions, gels, tablets, 30 2% by weight. coated tablets, multicomponent tablets, effervescent tablets, The proportion (in percent by weight based on the fin rapidly disintegrating tablets, powders in sachets, coated ished tablet) of individual active ingredient units in the tablets, capsules, solutions or else Suppositories. Preferred rapidly disintegrating tablet is usually from 1 to 90% by dosage forms in this connection are oral dosage forms, in weight. The proportion of individual active ingredient units particular tablets. Particular preference is given to rapidly 35 is preferably up to 70% by weight, in particular from 10 to disintegrating tablets and effervescent tablets. The excipi 50% by weight. The proportion is very particularly prefer ents suitable for the desired dosage forms are familiar to the ably from 15 to 25% by weight. skilled worker on the basis of his expert knowledge. In the The proportion (in percent by weight based on the fin case of oral dosage forms it is Surprisingly possible to ished tablet) of binder can be up to 10% by weight, and it can dispense with the enteric coating. 40 preferably be up to 5% by weight. In the case of rapidly disintegrating tablets, Suitable If desired, one or more flavoring Substances (e.g. flavors excipients are, in particular, those excipients which on oral or Sweeteners) can additionally be present in the rapidly intake of the tablet bring about rapid disintegration of the disintegrating tablet. This makes it possible, for example, to tablets. Excipents which on oral intake of the tablet bring achieve an improvement of the taste of the rapidly disinte about rapid disintegration of the tablet preferably comprise 45 grating tablet. These Substances are added in conventional one or more substances selected from the group of fillers and amountS. disintegrants. One or more other excipients from the group The rapidly disintegrating tablet is produced by processes of lubricants, flavors, flavoring Substances and Surface known to the skilled worker. The rapidly disintegrating active Substances are preferably present in the rapidly dis tablet is preferably produced by integrating dosage form of the invention. Binders can also be 50 i) dry mixing of filler and/or disintegrant; present if desired. The rapidly disintegrating dosage form ii) production of granules of filler and binder and mixing of particularly preferably comprises a mixture of at least one the granules with a disintegrant or filler, one disintegrant and one lubricant. Fillers suitable iii) dry granulation (briqueting or compacting) of one or according to the invention are, in particular, basic fillers such more excipient components. as calcium carbonate (e.g. MagGran R. CC or DestabR 95) 55 The individual active ingredient units ar Subsequently and sodium carbonate, Sugar alcohols such as mannitol (e.g. admixed to the mixtures obtained in i), ii) or iii) and then, if Pearlitol(R) or Parteck R. M), sorbitol (e.g. Karion(R), xylitol desired, flavors/flavoring Substances and finally also one or or maltitol, Starches such as corn starch, potato starch and more lubricants are admixed. The mixture obtained in this wheat starch, microcrystalline cellulose, Saccharides such as way can be compressed in a tablet press under conventional glucose, lactose, levulose. Sucrose and dextrose. In a pre 60 conditions. ferred development of the invention, the rapidly disintegrat Rapid disintegration of the tablet means according to the ing dosage form of the invention comprises as filler a Invention disintegration of the tablet in about 60 seconds or mixture of a basic filler (in particular calcium carbonate) and less when the tablet is Subjected to a disintegration test as a Sugar alcohol (in particular Sorbitol or mannitol). Disin described in the European Pharmacopoeia (3rd edition, tegrants Suitable according to the invention are, in particular, 65 1997) 2.9.1 disintegration time of tablets and capsules. insoluble polyvinylpyrrolidone (insoluble PVP, crospovi In the case of Solutions and Suspensions, Suitable excipi done), Sodium carboxymethylstarch, sodium carboxymeth ents are, in particular, those excipients which are normally US 7,175,854 B2 35 36 used to produce solutions or Suspensions. Particularly Suit powdered mixture for reconstitution is then mixed with a able according to the invention are excipients with which it suitable amount of water immediately before administration. is possible to produce a thickened base, such as thickeners. Solution or Suspension ready for use is normally produced Examples of thickeners of the invention are Xanthan, Sub by introducing the individual active ingredient units into a stituted celluloses, polyvinylpyrrolidone (poly Vidone types), 5 dispersion of the thickener and, where appropriate, of addi sheet silicates, alginates or alginic acids. Also possible if tives in water or, alternatively, by introducing the thickener desired is a mixture of two or more different thickeners. The into a dispersion of the individual active ingredient units in proportion of thickener depends on the desired viscosity or Water. consistency intended for the solution or Suspension ready for In a preferred embodiment, the invention relates to rap use. A Solution or Suspension with a viscosity of less than 10 idly disintegrating tablets or solutions or Suspension which 500 mPa.s (determined with a rotational viscometer) is comprise preparations of the invention with PDE inhibitors particularly preferred. The proportion of Xanthan, based on as active ingredients. Preferred PDE inhibitors in this case the Solution or Suspension ready for use, is usually from 0.1 are roflumilast and pumafentrine. to 1% by weight. The proportion of substituted celluloses The dosage forms of the invention can be employed for depends on the viscosity levels of the celluloses and is 15 the treatment and prevention of all diseases which are usually from 0.1 to 10% by weight based on the solution or regarded as treatable or preventable by use of the particular Suspension ready for use. Examples of Substituted celluloses active ingredient. The dosage forms contain the particular of the invention which may be mentioned are carboxymeth active ingredient in the dose usual for treating the particular ylcellulose, ethylcellulose or methylcellulose or hydrox disease. ypropylcellulose. The proportion of polyvinylpyrrolidone The production of dosage forms and preparations of the (polyvidone types) is normally from 0.1 to 10% by weight invention is described by way of example below. The based on the Solution or Suspension ready for use. Sheet following examples illustrate the invention in detail without silicates Such as the Veegum or bentonites can be employed restricting it. alone or in combination with water-soluble thickeners. The total proportion of thickener is then advantageously from 0.1 25 EXAMPLES to 7% by weight based on the solution or suspension ready for use. Alginates and alginic acid are usually added in a Production of the Preparations proportion of from 0.1 to 10% by weight based on the (Active Ingredient Units) Solution or Suspension ready for use. Further pharmaceutical excipients preferably employed are insoluble, crosslinked 30 Example 1 polyvinylpyrrolidone (crospovidones) and microcrystalline cellulose. It is observed in this case that a loose sediment 50 g of solid paraffin, 34.9 g of cetyl alcohol and 0.1 g of forms and prevents agglomeration of the individual active Stearylamine are converted into a clear melt. 5.0 g of ingredient units. The ratio of crospovidones to the individual povidone is dissolved in the clear melt. At a temperature active ingredient units is advantageously from 1:1 to 0.5:1 35 between 56–60° C., 10.0 g of pantoprazole sodium ses (based on weight). Microcrystalline cellulose, which is quihydrate is added and Suspended homogeneously. The normally employed in a proportion of from 0.5 to 5% by Suspension is prilled in the molten state, and the drops thus weight based on the Solution or Suspension ready for use, is produced are solidified in a cooling Zone. likewise suitable for this purpose. The proportion of indi vidual active ingredient units in the solution or Suspension 40 Example 2 ready for use is usually according to the invention from 1 to 20% by weight based on the solution or suspension ready for 55 g of solid paraffin, 30.9 g of cetyl alcohol and 0.1 g of use, preferably 1 to 15% by weight and very preferably 5 to Stearylamine are converted into a clear melt. 4.0 g of 10%. Water is preferably used as solvent or dispersant for povidone is dissolved in the clear melt. At a temperature the solution or Suspension. 45 between 56–60° C., 10.0 g of pantoprazole magnesium is Other suitable excipients which may be present in the added and Suspended homogeneously. The Suspension is Solution or Suspension of the invention are, for example, prilled in the molten state, and the drops thus produced are flavoring Substances (such as flavors and Sweeteners), buffer Solidified in a cooling Zone. Substances, preservatives or else emulsifiers. Flavors are usually added in a proportion of from 0.05 to 1% by weight. 50 Example 3 Other flavoring Substances by way of example are acids Such as citric acid, Sweeteners such as saccharin, aspartame, 45.0 g of solid paraffin, 33.8 g of cetyl alcohol, 1.0 g of cyclamate Sodium or maltol, which are added according to B-sitosterol and 0.2 g of Stearylamine are converted into a the desired result. Examples of emulsifiers are lecithins, clear melt. 1.0 g of povidone and 4.0 g of ethylcellulose are sodium lauryl sulfate, Tweens(R or Spans, which are nor 55 dissolved in the clear melt. At a temperature between 56–60° mally added in a proportion of from 0.01 to 1% by weight. C., 15.0 g of pantoprazole sodium sesquihydrate is added Preservatives such as benzoic acid, salts of benzoic acid, and Suspended homogeneously. The Suspension is prilled in methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, Sor the molten state, and the drops thus produced are solidified bic acid or salts thereof are preferably also added. The in a cooling Zone. proportion depends on the preservative used and is normally 60 from 0.1 to 4% by weight based on the solution or suspen Example 4 sion ready for use. The Solution or Suspension of the invention is produced 52.0 g of solid paraffin, 30.3 g of cetyl alcohol and 0.2g by techniques known to the skilled worker. If a powder for of stearylamine are converted into a clear melt. 5.0 g of reconstitution is to be produced, preferably a mixture of the 65 povidone is dissolved in the clear melt. At a temperature individual active ingredient units with the thickener and, between 56–60° C., 12.5 g of pantoprazole sodium ses where appropriate, further excipients is produced. This quihydrate is added and Suspended homogeneously. The US 7,175,854 B2 37 38 Suspension is prilled in the molten state, and the drops thus state in a prilling unit (from Brace) with vibrating nozzles, produced are solidified in a cooling Zone. and the resulting drops are solidified in a cooling Zone. Example 5 Example 11 77.2 g of cetyl alcohol and 0.3 g of stearylamine are converted into a clear melt. 10.0 g of povidone is dissolved 50 g of solid paraffin and 40g of cetyl palmitate (Cutina(R) in the clear melt. At a temperature between 56–60° C., 12.5 CP) are converted into a clear melt at 100° C. The dear melt g of pantoprazole Sodium sesquihydrate is added and Sus is cooled to 50–60° C. 10 g of pantoprazole sodium ses pended homogeneously. The Suspension is prilled in the 10 quihydrate are introduced and Suspended homogeneously. molten state, and the drops thus produced are solidified in a The Suspension is prilled in the molten state in a prilling unit cooling Zone. (from Brace) with vibrating nozzles (200 um nozzle), and the resulting drops are solidified in a cooling Zone. Example 6 15 Example 12 47 g of Solid paraffin, 40 g of glyceryltripalmitate (Dyna san 116, from Hills) and 3 g of sitosterol ar converted into 50 g of solid paraffin and 40 g of cetyl alcohol are a clear melt at 100° C. and cooled to 55–60° C. 10 g of converted into a clear melt at 100° C. The clear melt is lansoprazole are added and Suspended homogeneously. The cooled to 50–60° C. 10 g of pantoprazole sodium sesquihy Suspension is put in the feed container of a prilling unit drate are introduced and Suspended homogeneously. The (from Brace) and prilled from a 200 um nozzle at about 0.1 bar. A periodic vibration with a frequency of about 390 HZ Suspension is prilled in the molten state in a prilling unit is transmitted to the nozzle head during this. The resulting (from Brace) with vibrating nozzles (200 um nozzle), and drops are solidified in a cooling Zone with air at a tempera the resulting drops are solidified in a cooling Zone. ture of -30° C. 25 Example 13 Example 7 50 g of solid paraffin and 40g of glyceryl trimyristate are 15 g of glyceryl trimyristate (Dynasan 114), 15 grams of converted into a clear melt at 100° C. The clear melt is glyceryl tripalmitate (Dynasan 116), 50 grams of solid 30 cooled to 50–60° C. 10 g of pantoprazole sodium sesquihy paraffin and 5 g of cholesterol are converted into a clear melt drate are introduced and Suspended homogeneously. The at about 100° C. The clear melt is cooled to about 55–65° C. Suspension is prilled in the molten state in a prilling unit 15 g of rabeprazole are added, the active ingredient is (from Brace) with vibrating nozzles (200 um nozzle), and uniformly dispersed, and the homogeneous Suspension is the resulting drops are solidified in a cooling Zone. priled as in example 6. 35 Example 14 Example 8 47 g of Solid paraffin, 40 g of glyceryl tripalmitate 10 g of glyceryl tripalmitate (Dynasan 116), 209 of (Dynasan 116, from Huls) and 3 g of sitosterol are converted glyceryl trimyristate (Dynasan 114), 529 of solid paraffin 40 into a clear melt at 100° C. and cooled to 55–60° C. 10 g of and 3 g of sitosterol are converted into a clear melt at about lansoprazole are added and Suspended homogeneously. The 100° C. The clear melt is cooled to 55–65° C. 15 g of Suspension is put into the feed container of a prilling unit Mg are added and Suspended homogeneously. (from Brace) and prilled from a 200 um nozzle at about 0.1 The Suspension is put in the feed container of a prilling unit bar. A periodic vibration with a frequency of about 390 HZ (from Brace) and prilled through a 200 um nozzle at 90 45 is transmitted to the nozzle head during this. The resulting mbar. A periodic vibration with a frequency of about 400 Hz drops are solidified in a cooling Zone with air at a tempera is transmitted to the nozzle head during this. The resulting ture of -30° C. drops are solidified with air at a temperature of -30°C. in a cooling Zone. Example 15 50 Example 9 30g of tristearin, 60 g of solid paraffin and 4 g of sitosterol 18 g of tristearin, 60 g of solid paraffin and 5 g of and 0.07 gstearylamine are converted into a clear melt. The cholesterol are converted into a clear melt. The clear melt is clear melt is cooled to 56–60° C. 15 g of pantoprazole cooled to 56–60° C. 10 g of pantoprazole sodium sesquihy 55 Sodium sesquihydrate are introduced and homogeneously drate are introduced and homogeneously dispersed. The dispersed. The Suspension is prilled in the molten state in Suspension is prilled in the molten state in a prilling unit prilling unit (from Brace) with vibrating nozzles, and the (from Brace) with vibrating nozzles, and the resulting drops resulting drops are solidified in a cooling Zone. are solidified in a cooling Zone. 60 Example 16 Example 10 17.5 g of glyceryl trimyristate (Dynasan 114), 67.59 of 18 g of cetyl palmitate, 40 g of Solid paraffin and 2 g of solid paraffin and 5 g of cholesterol are converted into a clear cholesterol are converted into a clear melt. The clear melt is melt at about 100° C. The clear melt is cooled to about cooled to 56–60° C. 10 g of pantoprazole sodium sesquihy 65 55–65° C. 10 g of pantoprazole are added, and the active drate are introduced and homogenized until a uniform ingredient is uniformly dispersed, and the homogeneous Suspension results. The Suspension is prilled in the molten Suspension is prilled as in example 6. US 7,175,854 B2 39 40 Example 17 Example 24 98 g of cetyl alcohol and 1 g of solid paraffin are 70 g of cetyl alcohol and 29.5g of paraffin are converted converted into a clear melt at about 90° C. 1 g of roflumilast into a clear melt at about 90° C. 0.5g of roflumilast is added, is added, and the mixture is stirred until it is a clear Solution. and the mixture is stirred until it is a clear solution. The clear The clear melt is prilled at about 70° C. in a suitable melt is prilled at about 75 to 80°C. in a suitable vibration vibration prilling unit (conditions: 200 or 350 um nozzle, prilling unit (conditions: 200 or 350 um nozzle, pressure 100 pressure 100 to 170 mbar, frequency about 1 kHz). to 170 mbar, frequency about 1 kHz). Example 18 10 Example 25 90 g of glyceryl monostearate are converted into a clear 97.7 g of cetyl alcohol and 0.3 g of ethylcellulose are melt at about 90° C. 10 g of roflumilast is added, and the converted into a clear melt at about 90° C. 2 g of pumafen mixture is stirred until it is a clear solution. The clear melt 15 trine is added, and the mixture is stirred until it is a clear is prilled at about 70° C. in a suitable vibration prilling unit solution. The clear melt is prilled at about 75 to 80° C. in a (conditions: 200 or 350 um nozzle, pressure 100 to 170 suitable vibration prilling unit (conditions: 200 or 350 um mbar, frequency about 1 kHz). nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). Example 19 Example 26 88 g of glyceryl myristate and 11.2 g of paraffin are 69 g of cetyl alcohol, 5 g of cetyl palmitate, 10 g of converted into a clear melt at about 90° C. 0.8 g of glyceryl tristearate and 15 g of paraffin are converted into a roflumilast is added, and the mixture is stirred until it is a 25 clear melt at about 90° C. 1 g of pumafentrine is added, and clear solution. The clear melt is prilled at about 70° C. in a the mixture is stirred until it is a clear solution. The clear suitable vibration prilling unit (conditions: 200 or 350 um melt is prilled at about 70° C. in a suitable vibration prilling nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). unit (conditions: 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). Example 20 30 Example 27 96 g of cetyl alcohol and 2 g of ethylcellulose are converted into a clear melt at about 90° C. 2 g of roflumilast 40 g of cetyl alcohol. 7 g of cetyl palmitate, 33 g of is added, and the mixture is stirred until it is a clear Solution. glyceryl tristearate and 15 g of paraffin are converted into a The clear melt is prilled at about 70° C. in a suitable 35 clear melt at about 90° C. 5g of (7R,8R,9R)-2,3-dimethyl vibration prilling unit (conditions: 200 or 350 um nozzle, 8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahy pressure 100 to 170 mbar, frequency about 1 kHz). droimidazo 1.2-h1.7naphthyridine are added, and the Example 21 mixture is stirred until it is a clear solution. The clear melt 40 is prilled at about 70° C. in a suitable vibration prilling unit 84 g of glyceryl monostearate and 8 g of paraffin are (conditions: 200 or 350 um nozzle, pressure 100 to 170 converted into a clear melt at about 90° C. 8 g of roflumilast mbar, frequency about 1 kHz). is added, and the mixture is stirred until it is a clear Solution. The clear melt is prilled at about 70° C. In a suitable Example 28 vibration prilling unit (conditions: 200 or 350 um nozzle, 45 pressure 100 to 170 mbar, frequency about 1 kHz). 41 g of cetyl alcohol. 7 g of cetyl palmitate, 33 g of glyceryl tristearate and 17 g of paraffin are converted into a Example 22 clear melt at about 90° C. 2 g of (7R,8R,9R)-2,3-dimethyl 8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahy 59 g of glyceryl monostearate, 20g of cetyl palmitate and 50 droimidazo 1.2-h1.7naphthyridine are added, and the 20g of paraffin are converted into a clear melt at about 90° mixture is stirred until it is a clear solution. The clear melt C. 1 g of roflumilast is added, and the mixture is stirred until is prilled at about 70° C. in a suitable vibration prilling unit it is a dear solution. The clear melt is prilled at about 70° C. (conditions: 200 or 350 um nozzle, pressure 100 to 170 in a suitable vibration prilling unit (conditions: 200 or 350 55 mbar, frequency about 1 kHz). um nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). Example 29 Example 23 41 g of cetyl alcohol. 7 g of cetyl palmitate, 33 g of 60 glyceryl tristearate and 17 g of paraffin are converted into a 50 g of cetyl alcohol, 5 g of glyceryl monostearate, 10 g clear melt at about 90° C. 2 g of (7R,8R,9R)-2,3-dimethyl of cetyl paimitate, 10 g of glyceryl tristearate and 24.5 g of 8-hydroxy-7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahy paraffin are converted into a dear melt at about 90° C. 0.5 g. droimidazo 1.2-h1.7naphthyridine are added, and the of roflumilast is added, and the mixture is stirred until it is mixture is stirred until it is a clear solution. The clear melt a clear solution. The clear melt is prilled at about 70° C. in 65 is prilled at about 70° C. in a suitable vibration prilling unit a suitable vibration prilling unit (conditions: 200 or 350 um (conditions: 200 or 350 um nozzle, pressure 100 to 170 nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). mbar, frequency about 1 kHz). US 7,175,854 B2 41 42 Example 30 a temperature between 60–65° C. 10.0 g of pantoprazole Sodium sesquihydrate is added and Suspended homoge 38 g of glyceryl tripalmitate, 2 g of cholesterol and 59.5 neously. The suspension is prilled in the molten state at 60 g of paraffin are converted into a clear melt at about 100° C. to 65° C. and the drops thus produced are solidified in a Then 0.5g of ciclesonide is added, and the melt is prilled at 5 cooling Zone. about 75°C. in a suitable vibration prilling unit (conditions: 100 um nozzle, pressure 100 to 170 mbar, frequency about Example 38 1.3 kHz). 39.9 g of cetyl alcohol, 3 g of vinylpyrollidone/vinyl Example 31 10 acetate copolymer, 20g of cetyl palmitate, 2 g cholesterol, 17 g Solid paraffin and 0.1 g of sodium Stearate are converted 38 g of glyceryl tripalmitate, 10 g of cetyl alcohol. 2 g of into a clear melt. At a temperature between 56–60° C., 18.0 cholesterol and 49.5g of paraffin are converted into a clear g of pantoprazole Sodium sesquihydrate is added and Sus melt at about 100°C. Then 0.5g of ciclesonide is added, and pended homogeneously. The Suspension is prilled in the the melt is prilled at about 75° C. in a suitable vibration molten state at 60° C. and the drops thus produced are prilling unit (conditions: 100 um nozzle, pressure 100 to 170 15 Solidified in a cooling Zone. mbar, frequency about 1.3 kHz). Example 39 Example 32 47.9 g cetostearylic alcohol, 2 g of vinylpyrollidone/vinyl 36 g of cetyl alcohol, 60 g of glyceryl monostearate and 2 g of vinylpyrollidone/vinyl acetate copolymer and 2 g of acetate copolymer, 25g of cetyl palmitate, 1 g sitosterol, 15 pumafentrine are converted into a clear melt. The clear melt g solid paraffin and 0.1 g of sodium Stearate are converted is prilled at about 60° C. with a nozzle and the resulting into a clear melt. At a temperature between 56–60° C., 15.0 drops are solidified by cooling. g of pantoprazole Sodium sesquihydrate is added and Sus 25 pended homogeneously. The Suspension is prilled in the Example 33 molten state at 60° C. and the drops thus produced are Solidified in a cooling Zone. 30g glyceryl trimyristate, 45g glyceryl monostearate and The preparations obtained as in examples 1–39 have a 20 g cetyl alcohol are converted into a clear melt. 5 g of particle size in the range 50–700 Lum. It is possible, for roflumilast is added, and homogeneously dispersed. The example by varying the processing conditions, to obtain melt is prilled at about 65° C. and the resulting drops are 30 larger particles. solidified in cooling Zone. Production of the Dosage Forms Example 34 Example A 80 g cetostearyl alcohol, 0.5 g Sodium Stearate, 5 g of 35 vinylpyrollidone/vinyl acetate copolymer and 12.5 g of 134.7 g of mannitol, 30 g of Kollidon R. 30 and 20 g of glycerol trimyristate are converted into a clear melt at about Xanthan are mixed dry. The mixture is granulated with water 70° C. 2 g of (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2- in a fluidized bed granulator. Granules with a particle size of methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2- 0.8-1.5 mm are obtained and are mixed with the preparation h1.7naphthyridine is added at 60° C. and dispersed homo 40 (125 g) obtained as in example 1. The mixture obtained in geneously. The mixture is prilled at 60° C. and the resulting this way is packed into bags (sachet) or if required drops solidified in a cooling Zone. together with further tablet exciplents—compressed to tab lets in a manner known to the skilled worker. Example 35 45 Example B 20 g glyceryl trimyristate, 14.5 g glyceryl monostearate, 60 g cetyl alcohol and 5 g vinylpyrollidone/vinyl acetate An amount which corresponds to 22.6 mg of pantoprazole copolymer are converted into a clear melt at 70° C. 0.5g of magnesium of the preparation obtained as in example 2 is ciclesonide is added and homogeneously dispersed. The mixed with 500 mg of lactose and 100 mg of xanthan. The dear melt is prilled and the resulting drops are solidified in 50 mixture is then mixed with flavoring Substances (Sweetener, cooling Zone. flavor) depending on the individual sense of taste, and thereafter packed in a bag (sachet). A Suspension for oral Example 36 intake is obtained by dissolving the contents of a bag in a 56.7 g of cetyl alcohol, 3 g of vinylpyrollidone/vinyl glass of water with stirring. acetate copolymer, 15 g of Solid paraffin, 15 g of cetyl Example C palmitate and 0.1 g of Sodium Stearate are converted into a clear melt. At a temperature between 56–60° C., 10.0 g of pantoprazole sodium sesquihydrate is added and Suspended An amount corresponding to 45.2 mg of pantoprazole homogeneously. The Suspension is prilled in the molten state Sodium sesquihydrate of the preparation from example 3 is at 60° C. and the drops thus produced are solidified in a 60 mixed with the appropriate amount of lactose. This mixture cooling Zone. is mixed with a mixture of citric acid and sodium carbonate. After addition of a suitable lubricant (for example sodium Example 37 stearyl fumarate) and addition of one or more suitable flavoring Substances, the resulting mixture is compressed 46.7 g of cetostearylic alcohol, 4 g of vinylpyrollidone/ 65 directly (without further granulation) to an effervescent vinyl acetate copolymer, 23 g solid paraffin, 0.3 g of sodium tablet. A suspension for oral intake is obtained by dissolving Stearate and 1 g sitosterol are converted into a clear melt. At a tablet in a glass of water. US 7,175,854 B2 43 44 Example D Example L An amount corresponding to 45.2 mg of pantoprazole 500 mg of a preparation from example 21 are granulated Sodium sesquihydrate of the preparation of example 4 is with water with 15 g of mannitol and 4 g of Kollidon. The mixed with lactose to improve the flow properties. The granules Sufficient for 100 single doses are packed into mixture is packed together with Suitable other active ingre capsules. dients (for example amoxicillin or NSAIDs in usual dosage forms) into hard gelatin capsules of a suitable size. Example M

Example E 10 1 g of a preparation from example 26 are mixed with 0.2 g of Xanthan, 0.1 g of saccharin sodium, 1.5 g of mannitol 300 mg of lactose are added to an amount corresponding and 0.3 g of dry orange flavor and packed into a sachet. The to 30 mg of lansoprazole of the preparation of example 6. suspension after stirring into about 100 ml of water is ready The two components are mixed with citric acid and sodium for use. carbonate and, after addition of a suitable lubricant (for example sodium Stearyl fumarate) and addition of Suitable 15 Example N flavoring Substances, compressed to a tablet. 200 mg of a preparation from example 27 are mixed with Example F 670 mg of Destab95SE, 2270 mg of Pearlitol 300 DC and 50 mg of crospovidone in a free-fall mixer. 10 mg of 450 mg of sucrose and 300 mg of xanthan are added to an magnesium Stearate are then added through a screen. This amount corresponding to 30 mg of rabeprazole of the mixture is pressed in a tablet press. preparation of example 7. The components are mixed, and masking flavors are added. The granules are packed into Example O Sachets. The contents of a sachet can be put into a glass of water and is ready for use after stirring. 25 40 mg of a preparation from example 30 are mixed with 500 mg of MagGran CC, 200 mg of Karion and 70 mg of Example G crospovidone in a free-fall mixer. 12 mg of magnesium stearate are then added through a screen, followed by brief 60 grams of the preparation of example 8 are mixed dry mixing again. The mixture obtained in this way is com with 140 grams of mannitol, 30 grams of Kollidon 30 and 20 30 pressed in a tablet press. grams of Xanthan. The mixture is granulated with water in a fluidized bed granulator. Granules with a particle size of Example P 0.8-1.5 mm are obtained. The mixture obtained in this way is packed into bags (sachets). 35 Example H 1. Preparation from example 22 12.500 mg 2. Lactose-1-hydrate 172.125 mg 140 g of mannitol, 30 g of Kollidon 30 and 20 g of 3. Corn starch 45.000 mg Xanthan are mixed dry and then granulated with water in a 4. Polyvidon (R) 25 12.500 mg fluidized bed granulator. The resulting granules are 40 5. Polyvidone insoluble 12.500 mg screened. The screen fraction from 0.8 to 1.5 mm is mixed 6. Flavors 2.500 mg with 6.98g of preparation from example 18 and packed into 7. Aspartame 0.375 mg 8. Citric acid 2.500 mg bags (sachets). 9. Magnesium Stearate 2.500 mg Example I 45 Total 262.500 mg 5 g of a preparation of example 17 are mixed with 50 g of lactose and 8 g of xanthan. Sweeteners and flavors are Production: 2. and 3. are granulated with a solution of 4. added to the mixture, and it is packed into bags (sachets). A The granules are dried and Screened. 5. is admixed using a Suspension ready for drinking is obtained by stirring a bag free-fall mixer, and then 6., 7. and 8. are incorporated. 1. is into a glass of water. 50 admixed and finally 9. is briefly admixed using a free-fall mixer. The mixture obtained in this way is compressed in a Example J tablet press. 12.5 mg of a preparation from example 19 are mixed with Example Q the appropriate amount of lactose. This mixture is mixed 55 with a mixture of sodium carbonate and citric acid. After addition of a suitable lubricant (for example sodium stearyl fumarate) and addition of flavoring Substances and Sweet 1. Preparation from example 23 25.000 mg eners, the mixture obtained in this way is directly com 2. Cellactose (R) 229.625 mg pressed to an effervescent tablet. Placing the tablet in a glass 60 3. Sodium carboxymethylstarch 12.500 mg of water results, after dissolution thereof, in a suspension 4. Flavors 2.500 mg ready for drinking. 5. Aspartame 0.375 mg 6. Citric acid 2.500 mg Example K 7. Magnesium Stearate 2.500 mg 65 Total 275.000 mg 100 mg of a preparation from example 20 are mixed with 1.9 g of lactose and packed into 10 hard gelatin capsules. US 7,175,854 B2 45 46 Production: 2. and 3. are mixed. 4., 5. and 6. are incor alcohol, a triglyceride, a partial glyceride and a fatty acid porated. 1. is admixed and finally 9. is briefly admixed using ester, wherein the preparation is in the form of microspheres. a free-fall mixer. The mixture obtained in this way is 2. The preparation according to claim 1, further compris compressed in a tablet press. ing one or more additional other pharmaceutically Suitable excipients are present in the excipient matrix. Example R 3. The preparation according to claim 2, further compris ing one or more other excipients selected from the group consisting of polymers and sterols are present in the excipi ent matrix. 10 1. Preparation from example 22 12.500 mg 4. The preparation according to claim 1, wherein the 2. Lactose-1-hydrate 49.660 mg excipient matrix comprises one or more excipients selected 3. Corn starch 13.390 mg from the group consisting of a fatty alcohol, a triglyceride 4. Polyvidon (R) K 90 1.300 mg and a partial glyceride. 5. Mannit 32.240 mg 6. PVP insoluble 12.890 mg 5. The preparation according to claim 1, wherein the 7. Flavors 0.330 mg 15 excipient matrix is composed of at least one solid paraffin 8. Magnesium Stearate 1.650 mg together with one or more excipients selected from the group consisting of a fatty alcohol, a triglyceride, a partial glyc Total 123.960 mg eride and a fatty acid ester. 6. The preparation according to claim 5 in which the Production: 2. and 3. are granulated with a solution of 4. active ingredient is i) present in a matrix composed of a The granules are dried and screened. 1., 5., 6. and 7... is mixture comprising at least one fatty alcohol and at least one admixed using a free-fall mixer, and then 8. is briefly Solid paraffin, ii) present in a matrix composed of a mixture admixed using a free-fall mixer. The mixture obtained in this comprising at least one triglyceride and at least one solid way is compressed in a tablet press. paraffin, iii) present in a matrix composed of a mixture 25 comprising at least one partial glyceride and at least one Example S Solid paraffin or iv) present in a matrix composed of a mixture comprising at least one fatty acid ester and at least one solid paraffin. 7. The preparation according to claim 1, wherein the 30 microspheres have a particle size in the range of 50–500 um. 1. Preparation from example 22 12.500 mg 2. Lactose-1-hydrate 70.300 mg 8. The preparation according to claim 1, wherein the 3. Potatoe starch 19.480 mg microspheres have a particle size in the range of 50–400 um. 4. Corn starch 2.370 mg 9. The preparation according to claim 1, wherein the 5. Sodium carboxymethylstarch 1.900 mg partial glyceride is selected from the group consisting of 6. Flavors 0.330 mg 35 glycerol monostearate, glycerol distearate, glycerol mono 7. Magnesium Stearate 0.950 mg palmitate, glycerol dipalmitate and mixtures thereof. Total 105.930 mg 10. The preparation according to claim 9, wherein the partial glyceride is glycerol monostearate. 11. The preparation according to claim 1, wherein the Production: 2. and 3. are granulated with a solution of 4. 40 fatty alcohol is selected from the group consisting of cetyl The granules are dried and screened. 1. 5. and 6. is admixed alcohol, myristyl alcohol, lauryl alcohol, Stearyl alcohol and using a free-fall mixer, and then 7. is briefly admixed using mixtures thereof. a free-fall mixer. The mixture obtained in this way is 12. The preparation according to claim 11, wherein the compressed in a tablet press. fatty alcohol is cetyl alcohol. The invention claimed is: 45 13. The preparation according to claim 1, obtainable by 1. A preparation in which an active ingredient which is prilling a solution or dispersion of the active ingredient in N-(3.5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-dif the melt of the excipients using a vibrating nozzle. luoromethoxybenzamide (INN: roflumilast), the N-oxide of 14. A pharmaceutical dosage form comprising a prepara roflumilast or a pharmacologically Suitable Salt of roflumi tion as claimed in claim 1 further comprising one or more last or of its N-oxide is essentially uniformly dispersed or 50 additional pharmaceutical excipients. dissolved in an excipient matrix comprising one or more excipients selected from the group consisting of a fatty UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7,175,854 B2 Page 1 of 1 APPLICATIONNO. : 10/433398 DATED : February 13, 2007 INVENTOR(S) : Dietrich et al. It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Claim 1, Column 45, Lines 47-48, Please delete “N- (3.5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4- difluoromethoxybenzamide and replace with --N- (3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4- difluoromethoxybenzamide --

Signed and Sealed this Tenth Day of April, 2007 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office