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US007951398B2

(12) United States Patent (10) Patent No.: US 7,951,398 B2 Dietrich et al. (45) Date of Patent: *May 31, 2011 (54) PHARMACEUTICAL PREPARATION P '92. 6. 'i' COMPRISING AN ACTIVE DISPERSED ON A EP O 068378 B1 1, 1983 MATRIX EP O 120589 B1 10, 1984 EP O 125 756 A2 11, 1984 (75) Inventors: Rango Dietrich, Constance (DE); EP O 165545 A2 12, 1985 EP 0 204 285 A1 12, 1986 Rudolf Linder, Constance (DE); EP O 228 OO6 A1 T 1987 Hartmut Ney, Constance (DE) EP O 259 174 A1 3/1988 EP O 26.1912 A2 3, 1988 (73) Assignee: Nycomed GmbH, Constance (DE) EP O 264 883 A2 4, 1988 EP O 266 890 A1 5, 1988 (*) Notice: Subject to any disclaimer, the term of this EP O 268989 B1 6, 1988 EP O 307 078 B1 3, 1989 patent is extended or adjusted under 35 EP O3O8917 A2 3, 1989 U.S.C. 154(b) by 973 days. EP O 330 485 A1 8, 1989 This patent is Subject to a terminal dis- E. 93. s f 3.38 claimer. EP O 393 926 B1 10, 1990 EP O 399 267 A2 11/1990 (21) Appl. No.: 11/642,621 EP O 438 359 A1 T 1991 EP O 509 974 B1 10, 1992 1-1. EP O 535 529 B1 4f1993 (22) Filed: Dec. 21, 2006 EP O 537 532 B1 4f1993 O O EP O 563 O24 B1 9, 1993 (65) Prior Publication Data JP 2-270873 11, 1990 JP 3-31280 2, 1991 US 2007/O122474 A1 May 31, 2007 JP 3-284622 12/1991 JP 3-284686 12/1991 Related U.S. Application Data JP 5-27107O 10, 1993 (63) Continuation of application No. 10/433,398, filed as JP 9-5915.2 3, 1997 application No. PCT/EP01/14307 on Dec. 6, 2001, (Continued) now Pat. No. 7,175,854. OTHER PUBLICATIONS (30) Foreign Application Priority Data Hafner, et al., “Additive effects of phosphodiesterase-4 inhibition on effecs of rSP-C surfactant”, AM.JRespir Crit Care Med. vol. 161,No. Dec. 7, 2000 (EP) ...... OO 126847 5, pp. 1495-1500, (2000). Lewis, et al., “The physical and chemical stability of Suspensions of (51) Int. Cl. Sustained-released diclofenac microspheres'. J. Microencapsula A6 IK9/20 (2006.01) tion, vol. 15, No. 5, pp. 555-567, (1998). (52) U.S. Cl...... 424/464; 424/484; 424/489: 424/465; Safety Data Sheet, Crodesta SL40, HB03791, Aqua and Sucrose 424/469 Cocoate and , Croda Europe Ltd., 5 pages, (2004). (58) Field of Classification Search ...... 424/464 Safety Data Sheet, Crodesta F20, HB03668, Sucrose Distearate, See application file for complete search history. Croda Europe Ltd., 5 pages (2008). Safety Data Sheet, Crodesta F50, HB03669. Sucrose Distearate, (56) References Cited Croda Europe Ltd., 5 pages (2005). Safety Data Sheet, Crodesta F10, HB03671. Sucrose Distearate, U.S. PATENT DOCUMENTS Croda Europe Ltd., 5 pages, (2005). 3,065,142 A 11, 1962 Antonides Safety Data Sheet, Crodesta F110, HB03722. Sucrose Stearate and 4,006,227 A 2/1977 Gallegos et al. Sucrose Distearate, Croda Europe Ltd., 5 pages, (2005). 4,464,372 A 8, 1984 Bristol et al. Safety Data Sheet, Crodesta F160, HB03750, Sucrose Stearate, 4,833,149 A 5, 1989 PreSS Croda Europe Ltd., 4 pages, (2005). 5,041,442 A 8, 1991 Romero et al. 5,188,838 A 2f1993 Deleuil et al. 5,380,532 A 1/1995 Deleuil et al. Primary Examiner — Jake M. Vu 5,429,824 A 7, 1995 June (74) Attorney, Agent, or Firm — The Nath Law Group; 5,665,730 A 9/1997 Senn-Bilfinger et al. Joshua B. Goldberg; Sheldon M. McGee 5,677,302 A 10, 1997 Karimian et al. 5,719,161 A 2f1998 Rainer 5,762.953 A 6, 1998 Venkateshwaran (57) ABSTRACT 6,114,537 A 9/2000 Karimian et al. The present invention relates to the field of pharmaceutical 6,124.313 A 9, 2000 Grundler et al. 6,231,885 B1 5, 2001 Carrara technology and describes a novel advantageous preparation for an active ingredient. The novel preparation is suitable for 7,147,869 B2 * 12/2006 Dietrich et al...... 424/466 7, 175,854 B2* 2/2007 Dietrich et al. . ... 424/464 producing a large number of pharmaceutical dosage forms. In 7.357,943 B2 * 4/2008 Linder et al...... 424/442 the new preparation, an active ingredient is presentessentially FOREIGN PATENT DOCUMENTS uniformly dispersed in an excipient matrix composed of one DE 3O 11 490 A1 3, 1981 or more excipients selected from the group of fatty , DE 36 22036 A1 1, 1987 triglycerides, partial triglycerides and fatty acid esters. DE 39 17 232 A1 11, 1990 DE 691 01 493 T2 8, 1994 20 Claims, No Drawings US 7,951,398 B2 Page 2

FOREIGN PATENT DOCUMENTS WO 93.12090 6, 1993 JP 11 152224 6, 1999 W 2 : A1 E. JP 2000-865O2 3, 2000 JP 2000-516633 12/2000 WO 93.15056 8, 1993 WO 89.00570 1, 1989 WO 93.15071 8, 1993 WO 91.14677 10, 1991 WO 94f14.795 T 1994 WO 91f17164 11, 1991 WO 94.24130 10, 1994 WO 91, 18887 12/1991 WO 97.25O3O 7/1997 WO 92.06979 4f1992 WO 98.07400 2, 1998 WO 92,12969 8, 1992 WO 92/21328 12/1992 wo on 109 3, 2000 WO 93,08190 4f1993 * cited by examiner US 7,951,398 B2 1. 2 PHARMACEUTICAL PREPARATION Further subject matters are evident from the claims. COMPRISING AN ACTIVE DISPERSED ON A The preparations for the purpose of the invention prefer MATRIX ably comprise numerous individual units in which at least one active ingredient particle, preferably a large number of active This application is a continuation application of U.S. Ser. 5 ingredient particles, is present in an excipient matrix com No. 10/433,398, filed Sep. 11, 2003, now U.S. Pat. No. 7, 175, posed of the excipients of the invention (also referred to as 854, which was filed under 35 U.S.C. 371 from PCT Appli active ingredient units hereinafter). The active ingredient is cation No. PCT/EPO1/14307, filed Dec. 6, 2001. preferably essentially uniformly dispersed, in particular homogeneously dispersed or dissolved, in the excipient TECHNICAL FIELD 10 matrix. A preparation preferably comprises microspheres. The preparations of the invention are distinguished in par The present invention relates to the field of pharmaceutical ticular by high stability, a release of active ingredient which technology and describes a novel advantageous preparation can be controlled by the particle size and composition of the for an active ingredient. The novel preparation is suitable for 15 matrix, good flow characteristics, good compressibility and the production of a large number of pharmaceutical dosage by a uniform delivery of active ingredient. In the case of forms. acid-labile active ingredients it is moreover possible to achieve, through choice of the matrix excipients, an acid BACKGROUND ART resistance so that it is possible in the case of oral forms to dispense with an acid-resistant coating (enteric coating). In In order to achieve particular properties of a dosage form, the case of active ingredients which have an unpleasant taste Such as, for example, taste masking in the case of active or, for example, show a local effect in the mouth ingredients with an unpleasant taste, resistance to gastric after administration, it has been observed that an unpleasant juice in the case of acid-labile active ingredients or controlled taste of the active ingredient can be masked, and anesthetic release of an active ingredient, normally active ingredient 25 effects in the mouth can be avoided, by preparations of the pellets are provided with an appropriate functional coating. If invention. It is particularly worthy of mention that the prepa Such coated pellets are then further processed to dosage rations of the invention can be further processed to a large forms, for example shaped to tablets by compression with number of pharmaceutical dosage forms without thereby los excipients, there is a risk that the coating is damaged and thus ing a given functionality (Such as taste masking, resistance to the functionality is at least partly lost again. 30 gastric juice, slowing of release). Thus, for example, on com pression of the active ingredient units of the invention no or DESCRIPTION OF THE INVENTION negligible loss of functionality is observed even if deforma tion of the active ingredient units occurs. In contrast to this, It is an object of the present invention to provide a prepa with conventional pellets, which normally have a functional ration for active ingredients which is able to retain a desired 35 coating (Such as taste masking, resistance to gastric juice, functionality and can be further processed to a large number slowing of release), a certain degree of damage to the coating of pharmaceutical process forms with negligible impairment and thus to the functionality is observed on further processing of a given functionality. to dosage forms, for example on compression to tablets. This It has now been found, Surprisingly, that this object is may also lead in Some cases to active ingredient being achieved by a preparation in which an active ingredient is 40 released in an unwanted way. essentially uniformly dispersed in an excipient matrix com The particle size of the individual units is advantageously posed of one or more excipients selected from the group of less than or equal to 2 mm, preferably 50-800 um, particularly fatty alcohol, triglyceride, partial glyceride and fatty acid preferably 50-700 um and very particularly preferably ester. 50-600 um. Preference is given to microspheres of a particle The invention therefore relates to a preparation in which an 45 size of 50-500 um, particularly preferably of 50-400 um. active ingredient is essentially uniformly dispersed in an Particular preference is given to monomodal microspheres excipient matrix composed of one or more excipients selected with a particle size of 50-400 um, particularly of 50-200 um. from the group of fatty alcohol, triglyceride, partial glyceride Active ingredients of the invention are, in particular, active and fatty acid ester. pharmaceutical ingredients. Examples of active ingredients It has further been found that particularly advantageous 50 which may form part of the preparations of the invention are, preparations can be obtained by adding Solid paraffin to the in particular, the active pharmaceutical ingredients men excipient matrix. The invention therefore relates further to a tioned below: preparation in which an active ingredient is essentially uni Adrenergics: formly dispersed in an excipient matrix composed of at least ; ; ; deterenol; dipiv one solid paraffin together with one or more excipients 55 efrin, ; ; esproquin; ; selected from the group of fatty alcohol, triglyceride, partial hydroxyamphetamine; levonordefrin; ; norepi glyceride and fatty acid ester. nephrine; oxidopamine; ; ; The invention further relates to preparations in which an propylhexedrine; . active ingredient is essentially uniformly dispersed i) in an Adrenocorticosteroids: excipient matrix composed of a mixture comprising at least 60 ; desoxycorticosterone ; desoxycorti one fatty alcohol and at least one solid paraffin, ii) in an costerone pivalate; acetate; excipient matrix comprised of a mixture comprising at least acetate; ; hemisuccinate; meth one triglyceride and at least one solid paraffin, iii) in an ylprednisolone hemisuccinate; ; ; excipient matrix composed of a mixture comprising at least acetate; . one partial glyceride and at least one solid paraffin or iv) in an 65 Agents to Prevent Alcohol Abuse: excipient matrix composed of a mixture comprising at least disulfiram, acamprosate, milnacipran, fomepizole, lazabe one fatty acid ester and at least one solid paraffin. mide, nadide, nitrefazole; . US 7,951,398 B2 3 4 Antagonists: cypionate; enanthate; testosterone ketolaurate; canrenoate; ; ; mexrenoate; pro testosterone phenylacetate; testosterone propionate; tres renoate; , epostane, ; Oxprenoate, tolone. , , , . Anesthetic Additives: Amino Acids: Sodium oxibate. alanine; aspartic acid; cysteine; , isoleucine; leu (Non-Inhalation): cine; lysine; methionine; phenylalanine; proline; serine; ; amolanone; etoxadrol; . ; threonine; tryptophan; tyrosine; Valine. levoxadrol; methitural; ; ; minax Active ingredients for Ammonium Detoxification: olone; ; ; pramoxine; ; remifen arginine; arginine glutamate; arginine hydrochloride; 10 tanyl; Sufentanyl; ; . glutamic acid; Anesthetics (Local): Anabolics: ambucaine; amoxecaine; amylocaine, aptocaine; articaine; , bolandiol dipropionate; bolasterone; benoximate; benzyl alcohol; benzocaine; betoxycaine; biphe boldenone undecylenate; bolenol; bolnantalate; ethylestre namine; bucricaine; bumecaine; bupivacaine; butacaine; nol; metenolone acetate; metenolone enanthate; bolazine; 15 butamben; butanilicaine; carbizocaine; chloroprocaine mesteronole; metandienone; nandrolone; Oxandrolone; pras clibucaine; clodacaine; cocaine; dexivacaine; diamocaine; terone; stanozolone; tiomesterone; clostebol; mibolerone; dibucaine: dyclonine; elucaine; etidocaine; euprocin, fexic nandrolone cyclotate; norbolethone; quinbolone; Stenbolone aine; fomocaine; heptacaine; hexylcaine; hydroxyprocaine; acetate; ; Zeranol. hydroxytetracaine; isobutamben; ketocaine; leucinocaine; Analeptics: lidocaine; mepivacaine; meprylcaine; octocaine; orthocaine; modafinil; ; endomide; etamivan; fenoxypro oxethacaine; oxybuprocaine; parabutoxycaine; phenacaine; pazine; fenozolone; hexapradol; nialamide; nicethamide. pinoicaine; piperocaine; piridocaine; polidocanol: Analgesics: pramocaine; prilocaine; procaine; propanocaine; propipoc acetaminophen; ; aminobenzoate; aminoben aine; propoxycaine; proxymetacaine; pyrrocaine; Zoate; anidoxime; ; anilleridine; anilopam; aniro 25 quatacaine; quinisocaine; risocaine; rodocaine; ropivacaine; lac; antipyrine; aspirin; benoxaprofen; benzydamine; bicifa salicylalcohol; Suicaine; tetracaine; trapencaine; trimecaine. dine hydrochloride; brifentanil; bromadoline; bromfenac: Appetite Suppressants: buprenorphine; butacetin; butixirate; butorphanol; butorpha amfepramone; amfetamine; aminorex, amfecloral; anisac nol; ; carbaspirin calcium; carbiphene; carfen ril; benzfetamine; chlorphentermine; clobenzorex; cloforex: tanil; ciprefadol Succinate; ciramadol, ciramadol; clonixeril; 30 clominorex; clortermine; dexamfetamine; dexfenfluramine; clonixin; codeine; codeine phosphate; codeine Sulfate; conor difemetorex; etilamfetamine; etolorex; fenbutrazate; fencam phone; cyclazocine; dexoxadrol; dexpemedolac; dezocine: famin; fenfluramine; fenisorex; femproporex; fludorex; flumi diflunisal; dihydrocodeine; dimefadane; dipyrone; doXpi norex; formetorex; furfenorex; imanixil; indanorex.; levamfe comine; drinidene; enadoline; epirizole; tartrate; tamine; levofacetoperane; levofenfluramine; ethoxazene: etofenamate; eugenol; fenoprofen; fenoprofen 35 levopropylhexedrine; ; mefenorex: metamfepra calcium; fentanyl citrate; floctafenine; flufenisal; flunixin; mone; morforex, norpseudoephedrine; orlistat; ortetamine; flunixin meglumine; ; fluproduaZone; fluradoline; oxifentorex; pentorex, phendimetrazine; phenmetrazine; flurbiprofen; hydromorphone; ibufenac; indoprofen; ketazo phentermine;picilorex: Satietine, SetaZindol; sibutramine; tri cine, ketorfanol, ketorolac, letimide; levomethadyl acetate; florex; trifluorex. levomethadyl acetate hydrochloride; levonantradol; levor 40 Anthelmintics: phanol; lofemizole; lofentanil oxalate; lorcinadol, lomoxi abamectin; albendazole; albendazole oxide; amidantel; cam; magnesium salicylate; ; menabitan; amoScanate, antafenite; antazonite; anthelmycin; meperidine; meptazinol; methadone; methadyl acetate; antholimine; bephenium hydroxynaphthoate; bidimazium methopholine; methotrimeprazine; metkephamid acetate; iodide; bisbendazole; bithionoloxide; bitoscanate; bromox mimbane, mirfentanil; molinaZone; Sulfate; moX 45 anide; brotianide; bunamidine; butamisole; butonate; cam azocine; nabitan; nalbuphine; nalmexone; namoxyrate; nant bendazole; carbantel; ciclobendazole; clioxanide; closantel; radol; naproxen; naproxen; naproxol; nefopam; nexeridine; dexamisole; diamfenetide; dichlorvos; diethylcarbamazine: noracymethadol; ocfentanil; octaZamide, olvanil; ; dimantine; diphenan; doramectin; dribendazole; eprinomec ; oxycodone; oxycodone terephthalate; oxymor tin; epsiprantel; etibendazole; febantel; fenbendazole; phone; pemedolac, pentamorphone; pentazocine; pentazo 50 flubendazole; flurantel; ftalofyne; furodazole; haloxon; hexy cine; phenaZopyridine:phenyramidol; picenadol; pinadoline; lresorcinol; imcarbofos; ; kainic acid; mebenda pirfenidone; piroXicam olamine; pravadoline; prodilidine; Zole; metrifonate; metyridine; morantel; moxidectin; nafta profadol; propiram; propoxyphene; propoxyphene napsilate; lofoS; netobimin; niclofolan; niclosamide, nitramisole; proxazole; proXorphan; pyrroliphene; ; Salcolex; nitrodan; nitroscanate; nitroXinil; oltipraz; ontianil, oxantel Salethamide maleate; salicylamide; Salicylate meglumine; 55 oxfendazole; oxibendazole; oxyclozanide; parbendazole; Salsalate; salicylate; spiradoline; ; Sufentanil; tal pexantel; piperamide; adipate; piperazine calcium metacin; talniflumate; talosalate; tazadolene; tebufelone; edetate; piperamide praziquantel; proclonol; pyrantel pamo tetrydamine; tifurac; tilidine, tiopinac; tonazocine; tramadol; ate; pyrantel tartrate; pyrvinium pamoate, rafoxanide; resor trefentanil; trolamine; Veradoline; Verilopam; Volazocine; antel; salantel; spirazine; stilbanzium iodide, Subendazole; Xorphanol; ; Zenazocinemesilate; Zomepirac. Sucap 60 tetramisole; thenium closilate; thiofuradene; tiabendazole; salcin. ticarbodine, tioxidazole; triclabendazole; triclofenol pipera Androgens: Zine; uredofos; Vincofos; Zilantel. androstanolone; ; mestanolone; mester Acne Therapeutics: olone; metandienone; methyltestosterone; nandrolone adapalene; adelmidrol; benzoyl peroxide; betacarotene; decanoate; nandrolone phenpropionate, nisterime; oxan 65 cioteronel; delanterone; ; doretinel; erythromy drolone; oxymesterone; oxymetholone; penmesterol; pras cin Salnacedin; etretinate; ; halofuginonen; terone; silandrone; stanozolol; testosterone; testosterone inocoterone acetate; isotretinoin, linolenic acid; manoalide; US 7,951,398 B2 5 6 masoprocol; ; motretinide; namirotene; rosterelone; ACE Inhibitors: Sumarotene; tazarotene; tematotene; tioXolone; topterone; alacepril; benazepril; benazeprilat; BMS-189921; BRL tradecamide; tretinoin, triadimenol; Zearalenone; Zeranol: 36378; captopril; ceronapril; CGS-13928C; cilazapril; Zimidoben. cilaZaprilat, dehydrocaptopril; delapril; enalapril; enalapri Bronchodilators: lat: EU-4867; EXP-7711; fasidotril; fosinopril; fosinoprilat; acefylline; azaspirium chloride; ; bamifylline; idrapril; imidapril; imidaprilat; indolapril; libenzapril: lisino bitoiterol; ; butaprost; ; cipamfylline; pril; mixanpril; moexipril; moexiprilat, moveltipril; omapat : doxaprost: doxofylline; dyphylline; enprofylline: rilat, orbutopril; pentopril; perindopril; perindoprilat, pivo ephedrine; eprozinol; etanterol; ; flutropium bro pril; quinapril; quinaprilat, ramipril; rentiapril; Sampatrilat; 10 SCH-54470; spirapril; spiraprilat; temocapril; temocaprilat; mide; : guaithylline; : Hoku-81: teprotide; trandolapril; trandolaprilat; utibapril; utibaprilat; hoquizil; imoxiterol, ipragratine; ipratropium ; iso Z-13752A; Zabicipril; zofenopril; Zofenoprilat. etharine; isoproterenol; ; ; meduita Renin Antagonists mium iodide; metaproterenol; mexafylline; nardeterol; nes CGP-38560; ciprokiren: CP-108671; enalkiren: ES-6864; tifylline; nisbuterol: picumeterol; piquizil; : 15 FK-906; remikiren; terlakiren, Zankiren. ; ; RO-24-4736: quaZodine; quinterenol; Antiallergics Such as PDE Inhibitors: racepinephrine; reproterol: ; ; ; arofylline; atizoram, AWD-12-281 (N-(3,5-dichloro-4-py salmeterol Xinafoate; sevitropium mesilate; Soterenol; Sul ridinyl)-2-1-(4-fluorobenzyl)-5-hydroxy-1H-indol-3-yl-2- fonterol; Suloxifen; TA-2005; theophylline; ; theo oxoacetamide); BAY-19-8004 (ethanesulfonic acid 2-(2,4- phylline ; tiaramide; tipetropium bromide; dichlorophenylcarbonyl)-3-ureidobenzofuran-6-yl ester); ; ; zindotrine; . benafentrine; CC-1088; CDC-801 (B-3-(cyclopentyloxy)-4- Beta-Blockers: methoxyphenyl-1,3-dihydro-1,3-dioxo-2H-isoindole-2- acebunolol; ; ; ; alprenoXime; propanamide); CDC-998; CI-1018; cilomilast (cis-4-cyano , , ; ; ; benzo 4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1- dioxine; ; ; ; bormetolol; 25 carboxylic acid); cilostazol; cipamfylline (8-amino-1,3-bis ; ; ; ; ; (cyclopropylmethyl)xanthine): D-4396: D-4418 N-(2,5- bufuralol; ; bunolol; ; ; dichloro-3-pyridinyl)-8-methoxy-5-quinoline ; burocrolol; , ; ; carboxamide; darbufelone; denbufylline; ER-21355; ; , , , , clo filaminast; ibudilast; IC-485; indolidan: laprafylline; lixazi ranolol; ; ; dexpropranolol, diac 30 none; MESOPRAM (-)-(R)-5-(4-methoxy-3-propoxyphe etolol; dichlorisoproterenol; dilevalol; ; dropra nyl)-5-methyloxazolidin-2-one: nitraquaZone; NM-702; nolol, ; ; ; esatenolol; esmolol; olprinone: ORG-20241 (4-(3,4-dimethoxyphenyl)-N2-hy ; fallintolol; ; flusoxolol; hydroxycarteolol; droxythiazole-2-carboxamidine); piclaimilast; pumafentrine hydroxytertatolol; ICI-118551; ; ; ((-)-cis-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a, 10b , ; isamoltan; ; ; levo 35 hexahydro-6-(4-diisopropylaminocarbonylphenyl)benzoc betaxolol; ; levocicloprolol; ; 1,6-naphthyridine); quazinone; RO-15-2041; roflumilast ; mephenoxalone; ; metalol; metipra (3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridyl)-4-(di nolol; ; mindodilon; ; ; nadox fluoromethoxy)-benzamide); rolipram; SCH-351591; olol, nafetolol, napitane; , neraminol; ; SH-636; tibenelast (5,6-diethoxybenzobthiophene-2-car nipradillol, oberadillol, Oxanamide; ; pacrinolol; 40 boxylic acid); tolafentrine; trequinsin; V-1 1294A (3-3-(cy ; , ; parodilol; ; clopentyloxy)-4-methoxyphenylmethyl-N-ethyl-8-(1-me penirolol; PHQA-33; ; pirepolol; ; prenal thylethyl)-3H-purin-6-amine); YM-58997 (4-(3- terol; , procinolol, pronetalol; propacetamol; pro bromophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)- pranolol, ; , ronactolol, ; one); YM-976 (4-(3-chlorophenyl)-1,7-diethylpyrido 2,3-d ; TA-2005; ; ; teoprolol; ; ter 45 pyrimidin-2(1H)-one); Zardaverine. thianolol; ; ; ; ; ; Other Antiallergics for Asthma Treatment: ; tribendilol; trigevolol: : ; ablukast, atreleuton; bunaprolast, cinalukast, crornitrile; Y-12541; ZAM1-1305. cromolyn; FPL-55712; iralukast; isamoxole: ; Adrenergic Agonists: L-648051; levcromakalim: lodoxamide ethyl: lodoxamide betanidine; bretylium tosilate; cromanidine; debrisoquine; 50 tromethamine; montelukast, oxarbazole; piriprost; ; ethomoxane:guabenXan; , guanacline:guanadrel; pobilukast, pranlukast, ritolukast, Sulukast; tiaramide; guanaZodine, guancidine, guanclofine; guanethidine; guan tibenelast; tomelukast: Verlukast; verofylline; Zafirlukast; facine; guanisoquine; guanoclor, guanoctine; . Zileuton. guanoxan; guanoxyfen; olmidine; ; pyroxamidine; Other Antiallergics (for Example Leukotriene Antago Solypertine; spirgetine. 55 nists): Alpha1 Antagonists: acitaZanolast; ; allinastine; altoqualine; amlex ; adoZelesin; ; ; benox anox; andolast; ; ataquimast; ; azelas athian; bunaZosin: CI-926; DL-017; dapiprazole; dihydroer tine; ; barmastine; batebulast; BAY-X-1005; BAY gotamine mesilate: ; euigenodilol; fenspiride; X-7195; bepiastine; ; BIIL-284; ; GI-231818: GYKI-12743: GYKI-16084; indoramine; meta 60 binizolast; ; bunaprolast; cabastine; carebastine; Zosin; MK-912; ; ; meldazosin; nesapidil; ; CI-959; ; ; CMI-977; cro ; ; peradoxime; peraquinsine; perati moglicic acid; cromolyn natrium; dametralast; ; Zole; perbufylline; phendioxan; ; phento ; ; doqualast; dorastine; lamine: podilfen; : ; RS-97078; prorox E-4704; efletirizine; ; enofelast; enoxamastebas ane; sertindole; SGB-1534; SL-89.0591; ; 65 tine; eclaZolast; ; ; flezelastine: HSR tedisamil: ; tibalosin, ; ; trima 609; KCA-757; ; ; linetastine; Zosin; upidosin: ; ; . ; LY-293111; mapinastine; meduitamium iodide: US 7,951,398 B2 7 8 meduitazin; minocromil, ; MK-886; ; bacitracin Zinc, bambermycins; benzoylpas calcium; beryth moXilubant; nedocromil, nedocromil calcium; nedocromil romycin; betamicin Sulfate; blapenem; biniramycin; biphe Sodium; nivimedone; noberastine; norastemizole; octastine; namine hydrochloride; bispyrithione magSulfeX; butikacin; ONO-4057; ontazolast; ; ; pentigetide: butirosin Sulfate; capreomycin Sulfate; carbadox; carbenicil perastine; piclopastine; picumast; pirquinoZol; poisonoak lin disodium; carbenicillinindanylsodium; carbenicillin phe extract; probicromil, proxicromil: quaZolast; ; nyl sodium; carbenicillin; carumonam sodium, cefaclor; quinotolast; raxofelast; repirinast; REV-5901-A, rocastine: cefadroxil, cefamandole; cefamandole nafate; cefamandole rupatadine: SKF-S-106203; sequifenadine; ; sudex Sodium, cefaparole; cefatrizine; cefazaflur Sodium, cefazolin; anox; tagorizine; ; taZanolast, tazifylline; temelas cefazolin Sodium, cefbuperaZone; cefdinir, cefepime; tine; , tetraZolast; texacromil; thiazinamium chlo 10 cefepime; cefetecol, cefixime; cefimenoxime; cefimetazole; ride; tiacrilast; tiprinast meglumine; tixanox; tranilast; cefnetazole Sodium, cefonicid monosodium, cefonicid WY-50295; ZD-3523: Zepastine. Sodium, cefoperaZone sodium, ceforanide; cefotaxime Amebicides: Sodium, cefotetan, cefotetan disodium, cefotiam, cefoxitin; 1B-bisamidine; berythromycin; bialamicol; carbarsone; cefoxitin Sodium; ce?pimizole; ce?pimizole sodium; ce?pira chloroquine; chloroquine; clamoxyquin; clioquinol; dehy 15 mide; ce?piramide Sodium; ce?pirome Sulfate; cefpodoxime droemetine; difetarSone; diloxanide; emetime; etofamide; proxetil, cefprozil, cefroxadine, cefsulodin Sodium, ceftazi lodoquinol; lachnumon: liroldine; paromomycin Sulfate; dime; ceftibuten, ceftizoxime Sodium, ceftriaxone sodium; pinafide; quinfamide; satranidazole; Stevaladil; Stirimazole; cefuroxime; cefuroxime axetil: cefuroxime pivoxetil: Symetine; teclozan, tetracycline; tilbroquinol; cefuroxime Sodium; cephacetrile sodium; cephalexin; ceph Antiandrogens: alexin; cephaloglycin; cephaloridine; cephalothin Sodium; abiraterone; benorterone; cioteronel; cyproterone; cephapirin Sodium; cephradine, cetocycline; cetophenicol; delanterone; delmadinone; ; epitioStanol; inoco chloramphenicol; chloramphenicol palmitate; chlorampheni terone; L-654066; minamestane; norgestimate; osaterone; col pantothenate complex; chloramphenicol sodium Succi Oxendolone; ; rosterelone; topterone; Zanoter nate; chlorhexidine phosphanilate; chloroxylenol; chlortetra OC. 25 cycline bisulfate; chlortetracycline; cinoxacin; ciprofloxacin; Antianemics: ciprofloxacin; cirolemycin, clarithromycin; clinafloxacin; ancestim; diciferron; epoetin alfa: epoetin beta; epoetin clindamycin; clindamycin; clindamycin palmitate; clinda epsilon; epoetin gamma; epoetin omega; ferrous Sulfate, mycin phosphate; clofazimine; cloxacillin benzathine; clox FK-352; folic acid; gleptoferron; glutathione monoisopropyl acillin Sodium; cloxyquin; colistimethate Sodium; colistin ester; leucovorin calcium; tucaresol; TYB-5220; Velaresol; 30 Sulfate; coumermycin; coumermycin Sodium: cyclacillin; Antianginals: cycloserine; dalfopristin; dapsone; daptomycin; demeclocy alinidine; amiodarone; besylate; amlodipine cline; demeclocycline; demecycline; denofungin; dlaveri maleate; azaclorzine: barnidipine; bertosamil: betaxolol; ber dine; dicloxacillin; dicloxacillin Sodium, dihydrostreptomy tosamil: bevantolol; bimakalim; butoprozine; carvedilol; cin Sulfate; dipyrithione; dirithromycin; doxycycline; CD-832; CERM-11956: cinepazet maleate; crobenetine: 35 doxycycline calcium: doxycycline fosfatex, doxycycline cyclovirubuxine-D; desocriptine; diproteverine; dopropidil; hyclate; droxacin Sodium; enoxacin; epicillin; epitetracy elgodipine; EMD-57283; eniporide; ethacizine; fantofarone: cline; erythromycin; erythromycin acistrate; erythromycin FK-409; flestolol; flosatidil; flosequinan; FR-46171; GP-1- estolate; erythromycin ethylsuccinate; erythromycin glu 468: GP-1-531; hyperin; ipramidil; isosorbide dinitrate; ceptate; erythromycin lactobionate; erythromycin propi ivabradine: KC-764; KRN-2391; KW-3635: ligustizine; lin 40 onate; erythromycin Stearate; ethambutol; ethionamide; sidomine; metoprolol Succinate; mibefradil; mildronate; fleroxacin; floxacillin; fludalanine; flumequine; fosfomycin; ; molsidomine; monatepil maleate; nafagrel; fosfomycin tromethamine; fumoxicillin; furazolium chlo NK-341; OP-2000; pirsidomine; pivazide; pranidipine; ride; furazolium tartrate; fusidate Sodium; fusidic acid; gen primidolol; ranolazine; SL-87.0495; ST-1324; tedisamil: tamicin Sulfate; gloXimonam; gramicidin; haloprogin; het tosifen; vatanidipine: Verapamil: Y-27152; Zatebradine. 45 acillin; hetacillin; hexedine; ibafloxacin; imipenem: Anxiolytics: isoconazole; isepamicin; isoniazid; josamycin; kanamycin adatanserin; ; binospirone mesilate; ; Sulfate; kitasamycin; levofluraltadone; levopropylcillin; glemanserin; ; mirisetron maleate; ; lexithromycin; lincomycin; lincomycin; lomefloxacin, lom ondansetron; ; pancopride; ; SeraZap efloxacin, lomefloxacin mesilate; loracarbef mafenide; ine; citrate; Zalospirone. 50 meclocycline; meclocycline Sulfosalicylate; megalomicin Antiarthritics: phosphate; medulidox; meropenem; methacycline; methacy AI-200; auranofin; aurothioglucose: cipemastat; etaner cline; methenamine; methenamine hippurate; methenamine cept; etebenecid; interleukin-6: leflunomide; lenercept; mandelate; methicillin Sodium; metioprim; metronidazole; lobenzarit; lodelaben: M-5010; parecoxib: rofecoxib; metronidazole phosphate; mezlocillin; mezlocillin Sodium; RS-130830; S-2474; TSA-234; Valdecoxib; 55 minocycline; minocycline; mirincamycin; monensin; mon Antiatherosclerotics: ensin Sodium; nafcillin sodium; nalidixate Sodium; nalidixic H-327/86; mifobate; lodazecar; riboflavin butyrate; time acid; natainycin; nebramycin; neomycin palmitate, neomy furone. cin Sulfate; neomycin undecylenate; netilmicin Sulfate; neu Bacteriostatics: tramycin; nifuiradene; nifuraldeZone; nifuratel; nifuratrone; acedapsone; acetosulfone sodium; alamecin, alexidine; 60 nifurdazil; nifurimide: nifiupirinol; nifurcquinazol; nifurthia amdinocillin; amdinocillin pivoxil, amicycline; amifloxacin; Zole; nitrocycline; nitrofurantoin: nitromide; norfloxacin; amifloxacin mesilate; amikacin; amikacin Sulfate; aminosali novobiocin Sodium; ofloxacin; onnetoprim; oxacillin cylic acid; aminosalicylate Sodium; amoxicillin; amphomy Sodium; oximonam; oximonam Sodium; oxolinic acid; cin; amplicillin; amplicillin Sodium; apalcillin sodium: apra oxytetracycline; oxytetracycline calcium; oxytetracycline; mycin; aspartocin, astromicin Sulfate; avilamycin; avoparcin; 65 paldimycin; parachlorophenol; paulomycin; pefloxacin; azithromycin; azlocillin; aziocillin Sodium; bacampicillin pefloxacin mesilate; penamecillin; penicillin G benzathine; hydrochloride; bacitracin; bacitracin methylene disalicylate: penicillin G. penicillin G procaine; penicillin G Sodium; peni US 7,951,398 B2 10 cillin V: penicillin V benzathine; penicillin V hydrabamine: tol; Sulthiame; thiopental sodium; tiletamine; ; penicillin V: pentizidone sodium; phenyl aminosalicylate; trimethadione; valproate sodium; Valproic acid; vigabatrin; piperacillin Sodium; pirbenicillin sodium; piridicillin ZonicleZole; Zonisamide. Sodium; pirimycin; pivampicillin; pivampicillin pamoate; : pivampicillin probenate; polymyxin B sulfate; porfiromycin; adatanserin; ; 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; bupropion; butacetin; ; mide; rifampin: rifapentine; rifaximin; rollitetracycline; roli caroxazone; ; , ; cilobamine 10 mesilate; clodaZon; ; cotinine fumarate; cyclin tetracycline nitrate; rosaramicin; rosaramicin butyrate; rosa dole; cypenamine; cyprolidol; cyproximide; daledalin tosy ramicin propionate; rosaramicin Sodium phosphate: late; dapoxetine; daZadrol maleate; dazepinil; ; rosaramicin Stearate; roSoxacin; roXarsone; roXithromycin; dexamisole; deximafen; ; dioxadrol; dothiepin; sancycline; Sanfetrinem sodium; Sarmoxicillin; Sarpicillin; ; dulloxetine; eclanamine maleate; encyprate; etoperi scopafungin; sisomicin; Sisomicin Sulfate; sparfloxacin; 15 done; fantridone; fehmetozole; femmetramide; fezolamine spectinomycin; spiramycin; stallimycin; Steffimycin; Strepto fumarate; ; ; fluoxetine; ; gam mycin Sulfate; streptonicoZid; Sulfabenz, Sulfabenzamide; fexine; guanoxyfen Sulfate; imafen; imiloxan; ; Sulfacetamide; Sulfacetamide Sodium; Sulfacytine; Sulfadiaz indeloxazine; ; ; isocarboxazid; ine; Sulfadiazine sodium; Sulfadoxine; Sulfalene; Sulfamera ketipramine fumarate; ; lortalamine; mapro Zine; sulfameter, Sulfamethazine; Sulfamethizole; Sul tiline; ; ; millacemide; minaprine; mir famethoxazole; Sulfamonomethoxine; SulfamoXole; tazapine; moclobemide; modaline Sulfate; napactadine; Sulfanilate Zinc, Sulfanitran; SulfaSalazine; Sulfasomizole; napamezole; ; nisoxetine; nitrafudam; Sulfathiazole; sulfazamet, Sulfisoxazole; sulfisoxazole acetyl: nomifensine maleate; ; phosphate: Sulfisboxazole diolamine; Sulfomyxin; Sulopenem; Sultamri , ; oxypertine; paroxetine; pheneizine cillin; Suncillin sodium; talampicillin, telcoplanin; tema 25 Sulfate; ; pizotyline; pridefine; prolintane; prot floxacing temocillin, tetracycline; tetracycline; tetracycline riptyline; quipazine maleate; rolicyprine; ; Sertra phosphate complex; tetroxoprim; thiamphenicol; thiphencil line; sibutramine; Sulpiride, SuritoZole; tametraline; tam lin; ticarcillin cresyl Sodium, ticarcillin disodium, ticarcillin pramine fumarate; ; thiazesim; thoZalinone; monosodium; ticlatone, tiodonium chloride; tobramycin; tomoxetine; ; trebenzomine; ; trimi tobramycin Sulfate; to Sufloxacin; trimethoprim; trimethop 30 pramine maleate; Venlafaxine; Viloxazine; Zimeldine; rim sulfate; trisulfapyrimidines; troleandomycin; trospecto Zometapine. mycin Sulfate; tyrothricin; Vancomycin; Vancomycin; Virgin Antidiabetics: iamycin; Zorbamycin. acetohexamide; bimoclomol; BM-17.0249; buformin; Anticholinergics: butoxamine; carbutamide; centpiperalone; chlorpropamide; 35 clomoxir; etoformin: etomoxir; fenbutamide: GI-262.570; alverine citrate; anisotropine methylbromide; atropine; gliamilide; glibenclamide; glibornuride; glibutimine; glic atropine oxide; atropine Sulfate; belladonna; benapry Zine; aramide; glicetanile sodium; gliciazide, glicondamide; benzetimide; benzilonium bromide; biperiden; biperiden; glidaZamide; gilflumide; glimepiride; glipalamide; glipizide; biperiden lactate; clidinium bromide; cyclopentolate; dex gliquidone; glisamuride; glisentide; glisindamide; glisola etimide; dicyclomine; dihexyverine; domazoline fumarate; 40 mide; glisoxepide; glucagon; glyburide; glybuthiazol; glybu elantrine; elucaine; ethybenztropine; eucatropine; glycopyr Zole; glyclopyramide; glycyclamide; glyhexamide; glymi rolate; heteronium bromide; homatropine hydrobromide: dine sodium; glyoctamide; glyparamide; glypinamide; homatropine methylbromide; hyoscyamine; hyoscyamine glyprothiazol; glysobuzole; heptolamide: HMR-1964; insu hydrobromide; hyoscyamine Sulfate; isopropamide iodide; lin; insulin argine; insulin aspart; insulin dalanat; insulin mepenZolate bromide; methylatropine nitrate; metoquizine; 45 defalan; insulin detemir; insulin glargine; insulin human; oxybutynin chloride; parapenzolate bromide; pentapiperium insulin human, isophane; insulin human Zinc, insulin human methylsulfate; phencarbamide; poldine methylsulfate; pro Zinc, extended; insulin, isophane; insulin lispro; insulin, neu glumide; propantheline bromide; propenZolate: Scopolamine tral; insulin Zinc; insulin Zinc, extended; insulin Zinc; isagli hydrobromide; tematropium methylsulfate; tiquinamide; dole; JTT-501; JTT-608; mebenformin; metahexamide; met ; toguizine; triampyZine Sulfate; trihexyphenidyl; 50 formin; methyl palmoxirate; ; midaglizole; tropicamide. mitiglinide; nateglinide; NN-304; NVP-DPP-728; palmox Anticoagulants: irate sodium; PNU-106817; pramlintide; proinsulin human; ancrod; ardeparin sodium; bivalirudin; bromindione; seglitide acetate; tibeglisene; tiformin; tolaZamide; tolbuta dalteparin sodium; desirudin; dicumnarol; heparin calcium; mide; tolpyrramide; heparin sodium; lyapolate sodium; nafamo.stat mesilate; 55 Aldose Reductase Inhibitors: phenprocoumon; tinzaparin Sodium; warfarin sodium. AD-5467; alrestatin; ciglitaZone; darglitaZone; englita : Zone sodium, epairestat; fidarestat; imirestat; linogliride; albutoin: ameltolide; atolide; buramate; carbamazepine; linogliride; MCC-555; minalrestat; NZ-314; pioglitazone: cinromide; citenamide; , cyheptamide; deZina pirogliride; ponalrestat; Sorbinil; risarestat; rosiglitaZone; mide; dimethadione; divalproex sodium; ; ethosux 60 tendamistat; tolrestat; troglitaZone; Zenarestat; Zopolrestat. imide; ethotoin: , fluZinamide; fosphenytoin Alpha-Glucosidase Inhibitors: Sodium; gabapentin, ilepcimide; lamotrigine; magnesium acarbose; camiglibose; emiglitate; englitaZone; miglitol; Sulfate; mephenytoin: mephobarbital; methetoin: methSux moranoline; Voglibose. imide; millacemide: nabazenil; nafimidone; , Antidiarrheals: phenacemide; ; phenobarbital Sodium; phen 65 rolgamidine, diphenoxylate (Lomotil), metronidazole Suximide; : phenytoin Sodium; ; proga (Flagyl), (Medrol), sulfasalazine (AZul bide; ralitoline; remacemide; ropizine; sabeluzole; stiripen fidine). US 7,951,398 B2 11 12 Antidiuretics: gemfibrozil; lecimibide; lovastatin, ; pravastatin argipressin tannate; desmopressin acetate; lypressin. Sodium; probucol; simvastatin; tiqueside; Xenbucin; acifran; Antidotes: beloxamide; bezafibrate; boxidine; butoxamine; cetaben dimercaprol; edrophonium chloride; fomepizole; leucov Sodium; ciprofibrate; gemcadiol; halofenate; lifibrate; meglu orin calcium; levoleucoVorin calcium; ; prota tol; nafenopin; pimetine; theofibrate; tibric acid; treloxinate. mine Sulfate. Antihypertensives: Antiemetics: alfuzosin; alipamide; althiazide; amidulinsin; amiodipine alosetron; batanopride; bemesetron; benzquinamide; chlo besylate; amiodipine maleate; anaritide acetate; rpromazine; ; clebopride; ; dimen maleate; belfosdil; bemitradine; bendacalol mesilate; ben hydrinate; diphenidol; diphenidol; diphenidol pamoate; dola 10 droflumethiazide; benzthiazide; betaxolol; bethanidine sul setron mesilate; domperidone; dronabinol; fludorex; fate; bevantolol; biclodil; bisoprolol; bisoprolol fumarate; flumeridone; galdansetron; granisetron; granisetron; luro ; bupicomide; buthiazide: candoxatril; candoxatri setron mesilate; ; metoclopramide; metopimazine; lat, captopril; carvedilol; ceronapril; chlorothiazide Sodium; ondansetron; pancopride; ; prochlorpera cicletanine; cilaZapril; ; clonidine; clopamide; Zine edisylate; prochlorperazine maleate; ; thi 15 cyclopenthiazide; cyclothiazide, darodipine; debrisoquin ethylperazine; malate; thiethylperazine sulfate; delapril; diapamide; diazoxide; dilevalol; diltiazem maleate; trimethobenzamide; Zacopride. malate; ditekiren, doxazosin mesilate, ecadotril; enalapril Antiepileptics: maleate; enalaprilat, enalkiren; endralazine mesilate; epithi ; ; tolgabide. azide, eprosartan; eprosartan mesilate; fenoldopam mesilate; Antiestrogens (Non-Steroidal): flavodilol maleate; flordipine; flosequinan; fosinopril clometherone; , nafoxidine; Sodium; fosinoprilat, guanabenz, guanabenZ acetate; guana nitromifene citrate; raloxifene; tamoxifen citrate; toremifene cline Sulfate; guanadrel Sulfate; guancydine; guanethidine citrate; trioxifene mesilate. monosulfate; guanethidine Sulfate; ; guanisoquin Antifibrinolytics: Sulfate; guanoclor Sulfate; guanoctine; guanoxabenz, guan camo.stat; nafamoStat mesilate. 25 oxan Sulfate; guanoxyfen Sulfate; hydralazine; hydralazine Fungistatics: polistirex, hydroflumethiazide; indacrinone; indapamide; acrisorcin; ambruticin; amphotericin B; azaconazole; aza indolaprif ; indoramin; indorenate; lacidipine; serine; basifungin: bifonazole; biphenamine; bispyrithione leniquinsin; levcromakalim, lisinopril; ; losartan; magSulfex, butoconazole nitrate; calcium undecylenate; can losulazine; ; mecamylamine; medroxalol; dicidin; carbol-fuchsin, chlordantoin: ciclopiroX, ciclopiroX 30 medroxalol; methalthiazide; methyclothiazide; ; olamine; cillofungin; cisconazole; clotrimazole; cuprimyxin; methyldopate; , metolaZone; metoprolol fuma denofungin; dipyrithione; doconazole; econazole; econazole rate; metoprolol succinate; metyrosine; minoxidil; monatepil nitrate; enilconazole; ethonam nitrate; fenticonazole nitrate; maleate; muZolimine; nebivolol; ; of ornine; par filipin; fluconazole; flucytosine; fungimycin; griseofulvin; gyline; paZoxide; pelanserin; perindopril erbumine; phe hamycin; isoconazole; itraconazole; kalafungin; ketocona 35 noxybenzamine; pinacidil; pivopril; polythiazide, prazosin; Zole; lomofimgin; lydimycin; mepartricin; ; primidolol; prizidilol, quinapril; quinaprilat, quinazosin; miconazole nitrate; monensin; monensin Sodium; naftifine; quinelorane; quinpirole; quinuclium bromide: ramipril; rau neomycin undecylenate; nifuratel; nifurmerone; nitralamine; wolfia serpentina; reserpine; Saprisartan; Saralasin acetate; nystatin; octanoic acid; orconazole nitrate; oxiconazole Sodium nitroprusside; ; tasosartan; teludipine; nitrate; oxifungin; parconazole; partricin; iodide; proclonol; 40 temocapril; teraZosin; terlakiren; ; tiamenidine; pyrithione Zinc, pyrrolnitrin; rutamycin; sangulnarium chlo ticrynafen; tinabinol; tiodaZosin; tipentosin; trichlormethiaz ride, Saperconazole; scopafungin; selenium sulfide; sinefun ide; ; trimethaphan camsylate; trimoxamine; tripa gin, Sulconazole nitrate; terbinafine; terconazole; thiram; mide; Xipamide; Zankiren, Zofenoprilat arginine. ticlatone; tioconazole; tolciclate; tolindate; tolnaftate; triace Antihypotensives: tin, triafungin; undecylenic acid; viridofulvin, Zinc unde 45 ciclafrine; . cylenate; Zinoconazole. Antiinflammatory Agents: Glaucoma Drugs: alclofenac; dipropionate; algestone alprenoXime; colforsin; dapiprazole; diplivefrin, naboctate; acetonide; alpha amylase; , ; amfenac pilocarpine; pimabine. Sodium; amiprilose; anakinra; anirolac, anitraZafen; apaZone; : 50 balsalazide disodium; bendazac, benoxaprofen; benzy acrivastine; phosphate; astemizole; aZatadine damine; bromelains; broperamole; ; carprofen; maleate; barmastine; bromodiphenhydramine; bromphe cicloprofen; cintaZone; cliprofen; proplonate; clo niramnine maleate; maleate; cetirizine; chlo betaSone butyrate; clopirac, proplonate; rpheniramine maleate; chlorpheniramine polistirex: cinnariz cormethasone acetate; cortodoxone; ; ; ine; clemastine; clemastine fumarate; closiramine aceturate; 55 ; dexamethasone dipropionate; diclofenac; cycliramine maleate; cyclizine; ; dexbro diclofenac sodium; diacetate; diflumidone mpheniramnine maleate; maleate; sodium; diflunisal; ; diftalone; dimethylsulfox dimethindene maleate; diphenhydramine citrate; diphenhy ide; ; endrysone; enlimomab; enolicam Sodium; dramnine; dorastine, Succinate; ; levo epirizole; etodolac, etofenamate; felbinac; fenamole; fen cabastine; loratadine; ; noberastine; 60 bufen, fenclofenac; fenclorac, fendosal; fenpipalone; fen citrate; pyrabrom, pyrilamine maleate; pyroxamnine male tiazac, flazalone; ; ; flumizole; ate; rocastine; rotoxamine; tazifylline; temelastine; terfena acetate; flunixin; flunixin meglumine; dine; citrate; tripelennamine; ; butyl; acetate; fluguaZone; flurbiprofen; Zolamine. fluretofen; propionate; furaprofen; furobufen; Lipid-Lowering Agents: 65 ; halobetasol propionate; acetate; cholestyramine resin; clofibrate; colestipol; crilvastatin: ibufenac; ibuprofen; ibuprofen aluminum: ibuprofen piconol: dalvastatin; dextrothyroxine sodium; fluvastatin Sodium; ilonidap; indomethacin; indomethacin Sodium; indoprofen; US 7,951,398 B2 13 14 indoxole; intrazole; acetate; isoxepac; isoxi irinotecan; lanreotide acetate; letrozole; leuprolide acetate; cam, ketoprofen; lofemizole; lornoxicam, lonazolac, lotepre liarozole; lometrexol Sodium; lomustine; losoxantrone; dinoletabonate; meclofenamate sodium; ; masoprocol; maytansine; mechlorethamine; megestrol dibutyrate, mefenamic acid; mesalamine; mese acetate; melengestrol acetate; melphalan; menogaril; mer claZone; methylprednisolone Suleptanate; momiflumate; captopurine; methotrexate; methotrexate sodium; metoprine; nabumetone; naproxen; naproxen Sodium; naproxol; nima meturedepa; mitindomide; mitocarcin; mitocromin: mitogil Zone; olSalazine Sodium; orgotein; orpanoxin: Oxaprozin, lin; mitomalcin, mitomycin; mitosper, mitotane; mitox oxyphenbutaZone; paranyline; pentosan polysulfate Sodium; antrone, mycophenolic acid; nocodazole; nogalamycin; phenbutaZone sodium glycerate; pirfenidone; piroxicam, ormaplatin: oxisuran, paclitaxel, pegaspargase; peliomycin; piroXicam cinnamate; piroxicam olamine; pirprofen; pred 10 pentamustine; peplomycin Sulfate; perfosfamide; pipobro nazate; prifelone; prodolic acid; produaZone; proxazole; man; piposulfan; piroXantrone; plicamycin; plomestane; por proxazole citrate; ; romazarit; Salcolex; salnace fimer sodium; porfiromycin; ; procarbazine; din; Salsalate; sanguinarium chloride; seclaZone; sermetacin; puromycin; puromycin; pyrazofurin: riboprine; rogletimide; Sudoxicam, Sulindac; Suprofen; talmetacin; talniflumate; safmgol, Safingol: Semustine; simtraZene; sparfosate Sodium; talosalate; tebufelone; tenidap; tenidap Sodium; tenoxicam, 15 sparsomycin; spirogermanium; spiromustine; spiroplatin: tesicam, tesimide, tetrydamine, tiopinac; pivalate; streptonigrin: streptozocin; strontium chloride Sr 89: tolimetin; tolmetin sodium; ; triflumidate; zidometa Sulofenur; talisomycin; taxane; taxoid; tecogalan Sodium; cin; Zomepirac sodium. tegafur, teloxantrone; temoporfin, teniposide; teroxirone; tes Antimalarials: tolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tira acedapsone; amodiaquine; amduinate; arteflene; chloro paZamine; topotecan; toremifene citrate; trestolone acetate; quine; chloroquine; chloroquine phosphate; cycloguanil triciribine phosphate; trimetrexate; trimetrexate glucuronate; pamoate; enpiroline phosphate; halofantrine; hydroxychloro triptorelin; tubulozole; uracil mustard; uredepa; vapreotide; quine Sulfate; mefloquine; menoctone; mirincamycin; pri verteporfin; vinblastine sulfate; Vincristine sulfate; Vindesine; maquine phosphate; pyrimethamine; quinine Sulfate; tebu vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; quine. 25 Vinleurosine sulfate; Vinorelbine tartrate; Vinrosidine sulfate; Microbicides: Vinzolidine Sulfate; Vorozole; Zeniplatin: Zinostatin: Zorubi aztreonam; chlorhexidine gluconate; imidurea: lyc cin. etamine; nibroxane: piraZmonam sodium; propionic acid; Active Ingredient for Combination Therapy with Cytostat pyrithione sodium; Sanguinarium chloride; tigemonam ics: dicholine. 30 imipramine and desipramine. Antimigraine Agents: Antiparkinson Agents: almotriptan; alniditan; avitriptan; azasetron; azatadine: benztropine mesilate; biperiden; biperiden; biperiden lac bemesetron; BIBN-4096BS: BMS-181885; bromocriptine: tate; carmantadine; ciladopa; dopamantine; ethopropazine; dolasetron; donitriptan; ebalZotan; eletriptan; ergotamine; lazabemide; levodopa; lometraline; mofegiline; naxagolide; froVatriptan; lprazochrome; IS-159; ; lomerizine: 35 pareptide Sulfate; procyclidine; quinetorane; ropinirole; sel LY-334370; LY-53857; metergoline; metergotamine; methy egiline; tolcapone; trihexyphenidyl, antiperistaltic: difenox sergide; naratriptan: ORG-GC-94, oxetorone; pipethiadene: imide; difenoxin; diphenoxylate; fluperamide; lidamidine; ; propisergide; rizatriptan; Sergolexole; Sumatriptan; loperamide; malethamer; nufenoXole; paregoric. tropanserin; tropoxin; UK-1 16044; ; Zatosetron; Antiproliferative Active Ingredients: Zolmitriptan. 40 piritreximisethionate. Active Ingredients for Sea Sickness and Vomiting: Antiprotozoal Active Ingredients: buclizine; cyclizine lactate; naboctate. amodiaquine; azanidazole; bamnidazole; carnidazole; Cytostatics: chlortetracycline bisulfate; chlortetracycline; flubendazole; acivicin; aclarubicin; acodazole; acronine; adoZelesin; flunidazole; halofuginone hydrobromide; imidocarb: aldesleukin; altretamine; ambomycin; ametantrone acetate; 45 ipronidazole; metronidazole; misonidazole; moXnidazole; ; amsacrine; anastrozole; anthramycin; nitarSone; partricin; puromycin; puromycin; ronidazole; asparaginase; asperlin; azacitidine; azetepa; azotomycin; Sulnidazole; tinidazole. batimastat; benzodepa; bicalutamide; bisantrene; bisnafide Active Ingredients for Treating Pruritus: dimesilate; bizelesin; bleomycin Sulfate; brequinar Sodium; cyproheptadine; ; methdilazine; trimeprazine bropirimine; buSulfan, cactinomycin; calusterone; carace 50 tartrate. mide; carbetimer, carboplatin: carmustine; carubicin; carZe Psoriasis Active Ingredients: lesin, cedefingol; chlorambucil; cirolemycin; cisplatin: acitretin; anthralin; azaribine; calcipotriene; cyclohexim cladribine; crisinatol mesilate; cyclophosphamide; cytara ide; enazadrem phosphate; etretinate; liaroZole fumarate; bine; dacarbazine; dactinomycin; daunorubicin; decitabine; lonapalene; tepoxalin. dexormaplatin; deZaguanine; deZaguanine mesilate; diazi 55 Neuroleptics: quone; docetaxel, doxorubicin, doxorubicin; droloxifene; maleate; alentemol hydrobromide; alper droloxifene citrate; dromostanolone propionate; duaZomy tine; ; maleate; benperidol; benzindopy cin; ediatrexate; eflomithine; elsamitrucin; enloplatin; enpro rine; brofbxine; bromperidol; bromperidol decanoate: mate; epipropidine; epirubicin; erbulozole; esorubicin; estra ; ; butaperazine maleate; carphena mustine; estramustine phosphate sodium; etanidazole; 60 Zine maleate; carvotroline; chlorpromazine; chlorpromazine; ethiodized oil I 131; etoposide: etoposide phosphate: eto ; cinperene, cintriamide; clomacran phos prine; fadrozole; fazarabine; fenretinide; floxuridine; fludara phate; ; ; clopipazan mesilate; clo bine phosphate; fluorouracil; flurocitabine; fosquidone; fos roperone; clothiapine; clothixamide maleate; ; triecin Sodium; gemcitabine; gemcitabine; gold Au 198; cyclophenazine; ; ; fenimide; ; hydroxyurea; idarubicin; ifosfamide: ilmofosine; interferon 65 ; fluiphenazine decanoate; fluiphenazine enan alfa-2a: interferon alfa-2b; interferon alfa-n1; interferon alfa thate; ; fluspiperone; ; flutroline; n3; interferon beta-I a; interferon gamma-Ib, iproplatin: ; halopemide; ; ; US 7,951,398 B2 15 16 ; imidoline; ; maZapertine Succinate; nocloprost; ornoprostil; oxoprostol; remiprostol; rioprostil; ; mesoridazine besylate; ; milenper rosaprostol; SC-30249; spiriprostil; TEI-1226; tiprostanide; one; millipertine; molindone; ; neflumozide: Ocaperi trimoprostil; done: ; oxiperomide; ; pentiapine Other Antiulcer Agents maleate; ; pimozide; ; pipamperone; 5 aluminium; AD-1308; benexate; benzotript: ; palniitate; ; prochlor beperidium iodide: bifemelane; BTM-1086; cadexomer edisylate; prochlorperazine maleate; ; iodine; ; CF-19415: CHINOIN-127; darenzepine: remoxipride; remoxipride; rimcazole; Seperidol; sertindole; deboxamet; detralfate; DH-6615; dosmalfate; ecabapide: setoperone; ; ; thioridazine; thiothix ecabet; esaprazole; espatropate, ; irsogladine; ene; thiothixene; tioperidone; tioSpirone; ; tri 10 KW-5805; lactalfate; lozilurea: MAR-99; MCI-727; MDL 201034; mezolidon; molfarnate; nolinium bromide; nuven fluperidol; ; triflupromazine; . Zepine; octreotide; P-1 100; pifarnine;; plaunotol; Antirheumatics: polaprezinc.; ; RGH-2961; rispenzepine; rotrax auranofin; aurothioglucose: bindarit; lobenzarit Sodium; ate; ; siltenZepine; ; ; Sucroso phenylbutaZone; piraZolac, prinomide tromethamine; 15 fate; ; ; teniloxazine; ; tio seprilose. propamine; ; triletide; tritlozine; ; Antischistosomal Agents: UH-AH-37; Zolenzepine; . becanthone; hycanthone; lucanthone; niridazole; oxam Agents for Treating Urolithiasis: niquine; pararosaniline pamoate; teroxalene. benzoic acid; cysteamine; cysteamine; tricitrates. Active Ingredients for Treating Seborrhea: Virustatic Agents: chloroxine; piroctone; piroctone olamine; resorcinol abacavir, acemannan; aciclovir, adefovir, alovudine; alvir monoacetate. cept Sudotox; atevirdine; amantadine, aranotin; arildone; Antispasmolytics: atevirdine; avridine: BW-935-U83; calanolide B: cidofovir; stilonium iodide; . cipamfylline; cytarabine; DAPD; delavirdine; desciclovir; Antithrombotics: 25 didanosine; disoxaril; DPC-083; edoxudine; ; argatroban; anagrelide; bivalirudin; dalteparin Sodium; emivirine; enviradene; enviroxime; famciclovir; famotine; domitroban; daltroban; danaparoid sodium; daZOXiben: fiacitabine; fialuridine; fosarilate; foscarnet sodium; fosfonet E-3040; efegatran sulfate; enoxaparin sodium; ifetroban: sodium; ganciclovir; GW-420867X; idoxuridine; kethoxal; ifetroban sodium; KW-3635; LCB-2853; linotroban; mipi L-697661; lamivudine; lobucavir; memotine; methisaZone; troban; NM-702; picotamide: ramatroban; ridogrel; S-1452: 30 nevirapine; NSC-678323; penciclovir; pirodavir, ribavirin; samixogrel; seratrodast; Sulotroban; terbogrel; tinzaparin rimantadine, S-1153; Saquinavir, Somantadine; Sorivudine; sodium; trifenagrel. statolon; stavudine; talviraline; thioctic acid; tillorone; triflu Antitussives: ridine; trovirdine; U-93923; Valaciclovir; Vidarabine; Vidara benproperine; benzonatate; bibenzonium bromide: brom bine; Vidarabine; viroxime; Zalcitabine; zidovudine; Zin hexine; butamirate citrate; butetamate; clobutinol; chlo 35 ViroXime. fedanol; codeine; codeine polistirex; codoxime; dex Active Ingredients for Treating Benign Prostate Hyperpla tromethorphan; dextromethorphan polistirex; S1a. dihydrocodeine; dimethoxanate; dropropizine; drotebanol: alfuzosin; CEP-701; doxazosin; dutasteride; FK-143; eprazinone; ethyl dibunate; fedrilate; guaiapate; hydroc GI-231818: GYKI-16084; levormeloxifene: pirfenidone: odone; hydrocodone polistirex, iquindamine; isoaminile; lev 40 RS-97078; tamsulosin; sitoglusid. dropropizine; levopropoxyphene napsylate; medazomide; Active Ingredients for Treating Osteoporosis: meprotixol; moguisteine; morclofone; nepinalone; noscap alendronic acid; butedronic acid; clodronic acid; EB-1053; ine; pemerid nitrate; pentoxyverine; pholcodine; picoperine; etidronic acid; ibandronic acid; incadronic acid; medronic ; prenoXdiazine; promolate; saredutant; sodium acid; minodronic acid; neridronic acid; olpadronic acid; dibunate; Suxemerid Sulfate; thebacon; tipepidine; 45 oxidronic acid; pamidronic acid; piridironic acid; ranelic acid; Vadocaine; Zipeprol. risedronic acid; tiludronic acid; YM-529; Zoledronic acid. Antiulcer Agents: Carbonic Anhydrase Inhibitors: H2 antagonists acetazolamide; AL-4414A, diclofenamide; dorzolamide; BL-6271; BL-6341A: BMY-25368; BRL-28390; cimeti methazolamide; seZolamide: Sulocarbilate. dine; dalcotidine; donetidine; ; etintidine; famoti 50 Antiarrhythmics: dine: ICI-162846; icotidine; IGN-2098; isotiquimide; lafuti abanoquil: ACC-9164, acecainide; actisomide; adenosine; dine; lamtidine; ; : mifentidine: ajmaline; alinidine; almokalant; alprafenone; amafolone; ; ; oSutidine; , pibutidine; ambasilide; ameltolide; amiodarone; aprindine, aprindine; pifatidine; ramixotidine; ; ranitidine bismuth cit artilide; asocainol; AWD-G-256; azimilide; benderizine; rate; ranitidine nitrate; roxatidine; ; TAS, tiotidine; 55 benrixate; benzodioxine; berlafenone; bertosamil: bidiso venritidine; WHR-2348;YM-14471; Zaltidine; . mide; bisaramil: BRL-32642; bucainide; bucromarone; Proton Pump Inhibitors bunaftine; buquineran; butobendine, butoprozine; capobenic disuprazole; : FPL-65372-XX: H-335/25; acid; carbizocaine; carcainium chloride; cariporide; H-405/02; HN-11203: IY-81149; ; leminopra carocainide; cercainide; cibenzoline; cifenline; ciprafamide; Zole; lucartamide: N-2220; NC-1300; nepaprazole; omepra 60 CL-284027; clamikalant; clofilium phosphate: CV-6402; Zole; ; pantoprazole sodium; picartamide; pico CVT-510; cyclovirobuxine-D, D-230; detajmium bitartrate; prazole; pumaprazole; ; saviprazole; SCH disobutamide; dexsotalol; dioxadilol; ; disobuta 28080; SKF-95-601, SKF-96067; SKF-97574; T-330; T-776: mide; disopyramide; dofetilide; drobuline; dronedarone: ; ufiprazole: YH-1885;YM-19020. droxicainide; E04771; E-0747; E-4031; edifolone; emilium 65 tosilate; emopamil: encainide, eproxindine; erocainide; arbaprostil; butaprost, deprostil; dimethyldinoprostone; ; fepromide; flecainide; fluzoperide; gallanilide; dimoxaprost, enisoprost; ; mexiprostil; ; glemanserin; guafecainol: GYKI-23107: GYKI-38233; hep US 7,951,398 B2 17 18 tacaine; hydroxyfenone; ibutilide; indecainide; ipazilide; Diuretics: itrocainide; ketocainol; L-702958; L-706000; levosemo acetazolamide; acetothiazide, alipamide, altizide; tiadil; lorajmine; lorcainide; meobentine; mexiletine; amanozine; ambuphylline; ambuside; amiloride; aminome milacainide; modecainide; moracizine; moxaprindine; tradine; amisometradine; ampyrimine; apaxifylline; murocainide; nibentan; nicainoprol; nipekalant; nofecainide; azolimine; azosemide; bemetizide; bemitradine; bendroflu oxiramide; palatrigine; penticainide; pentisomide; pilsicain methiazide; benzamil; benzolamide; benzthiazide; benzylhy ide; pirmenol; pirolaZamide; prajmalium bitartrate; prano drochlorothiazide; besulpamide; besunide, brocrinat; bumet lium chloride; prifuroline; procainamide; ; anide; butizide; ; carmetizide; chlorazanil; pyrinoline; quinacainol; quindonium bromide; ; chlorothiazide; chlorthalidone, cicletanine; clazolimine; clo 10 pamide; clorexolone; CVT-124; dicirenone; disulfamide: recainam, riloZarone; risotilide; ronipamil; ropitoin, sematil etamiphylline; ethacrynate Sodium; ethacrynic acid; etofyl ide; sinomenine; Solpecainol; Sparteine; stirocainide; Stoba line: etozolin; fenguizone: FK-352: FR-113453; furosemide: dine: SR-47063; Sulamserod; Suricainide; tedisamil: terikal hydrochlorothiazide; hydroflumethiazide; indacrinone; inda ant; tiracizine; tocainide; tosifen; transcainide; trecetilide; Zocainone. pamide: isosorbide; KW-3902; lemidosul; mannitol; mebu 15 tizide; mefruside; methalthiazide; methazolamide; methy Cardiotonics: clothiazide; meticrane; metolaZone; muZolimine; niravoline; acadesine; acetyldigitoxin; acetyldigoxin; acrihellin; acto OPC-31260; oxprenoate; ozolinone; paraflutizide; penflutiz digin; adibendan; amrinone; amselamine; ; arpro ide; piretanide; polythiazide; canrenoate; propazolamide; midine: AWD-122-239; bemoradan; bucladesine; butopam prorenoate; prorenone; pytamine; quincarbate; quineth ine; carbazeran; cariporide; carperitide; carsatirin; CGS azone; RPH-2823: S-8666; sitalidone; spironolactone: 13928C; cilobradine; CK-2 130; CK-2289; collforsin; spirorenone; spiroxasone; SR-48692; sulciamide: Sullicrinat: CV-6402; ; deslanoside; dexraZOxane; digitalis; Sulocarbilate; Sulosemide, Sumetizide, teclothiazide, tiamiz digitoxin; digoxin; , dobutamine; docarpamine; ide; tienilic acid; torsemide; triamterene; trichlormethiazide; domipizone: ; doridosine: doxaminol; DPI-201 triflocin; tripamide: TRK-820; ularitide; urea; xipamide. 106; draflazine; eniporide; enoximone; ER-21355; evodi 25 Ectoparasiticides: carbaril; clidafidine, cypermethrin; amine; falipamil: FK-664; fosfructose; FR-113453; eprinomectin; fenclofos; fenvalerate; ivermectin; lindane; FR-46171; gapromidine; gitaloxin; gitoformate; JP-1-468; moxidectin: nifluridide; permethrin; temefos. GP-1-531; GP-668; heptaminol; ; ibopamine: Emetics: imaZodan; indolidan; isamoltan; isomazole; levacecamine; apomorphine. 30 Enzyme Inhibitors: levdobutamine; levosimendan; limaprost; linsidomine; lix acetohydroxamic acid; alrestatin Sodium; aprotinin; azinone; MCI-154; medorinone; meproscillarin; meriben benazepril; benazeprilat; benurestat; bromocriptine; bro dan; metildigoxin; mildronate; milrinone; mioflazine; mixi mocriptine mesilate; cilastatin Sodium; flurofamide; lergot dine; MS-857; nanterinone; neraminol; NKH-477; rile; lergotrile mesilate; levcycloserine; libenZapril; pento olprinone; OPC-18750; otenzepad; oxfenicine; pelrinone; 35 pril; pepstatin; perindopril; polignate Sodium; sodium pengitoxin; pentrinitrol; peruvosid; pimobendan; piroxi amylosulfate; Sorbinil; spirapril; spiraprilat; taleranol; tepro mone, pirsidomine; prinoXodan; prisotinol; propionylcar tide; tolfamide; Zofenopril calcium. nitine; proscillaridin; quaZinone; quaZodine; quindonium Estrogens: bromide; ramnodigin; revizinone; saterinone; siguaZodan; chlorotrianisene; dienestrol; diethylstilbestrol; diethylstil simendan; Sulmazole; thevetosid; toborinone; ubide 40 bestrol diphosphate; equilin; epimestrol; estradiol; estradiol carenone; Vesnarinone; VPA-985. cypionate; estradiolenanthate; estradiol undecylate; estradiol Choleretic Agents: Valerate; estraZinol hydrobromide; estriol; estrofurate; estro alibendol; azintamide: boldine; cicloxilic acid, cinametic gens, conjugated; estrogens, esterified; estrone; estropipate; acid; clanobutin; dehydrocholic acid; dibuprol; epomediol; ethinyl estradiol; fenestrel; mestranol; nylestriol: quinestrol exiproben; febuprol; fencibutirol; fenipentol; hexacyprone: 45 Fibrinolytics: hymecromone; menbutone; moduizone; piproZolin; proZap acexamic acid; amediplase; anistreplase: aprotinin; biso ine; sincalide; tenylidone; terbuprol; tocamphyl; trepibutone. brin lactate; brinase; brinolase; camo.stat; fibrinolysin; inica Cholinergic Agents: rone; iduindamine; nattokinase; pamiteplase; picotamide; aceclidine; bethanechol chloride; carbachol; demecarium Staplabin; Streptokinase; taurine; tiZabrin; tranexamic acid; bromide; dexpanthenol; echothiophate iodide; isoflurophate: 50 Free-Radical Scavenger: methacholine chloride; neostigmine bromide; neostigmine pegorgotein. methylsulfate; physostigmine; physostigmine salicylate; Motility-Increasing Active Ingredients: physostigmine Sulfate; pilocarpine; pilocarpine; pilocarpine cisapride (Propulsid); metoclopramide (Reglan), hyos nitrate; pyridostigmine bromide. cyamine (Levsin). Cholinergic Agonists: 55 Glucocorticosteroids: Xanomeline; Xanomeline tartrate. ; alclometaSone; algestone acetonide; Cholinesterase Inhibitors: amcinafal; amcinafide; ; ; amelometa acetohydroxamic acid; DMPS; amiphenazole; obidoxime Sone; beclomethasone dipropionate; bendazacort; chloride; pralidoxime chloride; pralidoxime iodide; prali ; ; betamethasone ben doXime mesilate. 60 Zoate; betamethasone dipropionate; betamethasone sodium Coccidiostats: phosphate; ; budesonide; ; aklomide; amidapsone; amprolium; arprinocid; bitipa butixocort propionate; CGP-13774; ; ciclometa Zone; buquinolate; ciadox; claZuril; clopidol; decoquinate; Sone; ciprocinonide; clobetasol; clobetasol 17-propionate; diclaZuril; dinitolamide; dinsed; halofuginone; letraZuril; ; acetate; ; clo narasin; nequinate; nicarbazine; nifursemizone; ponaZuril; 65 prednol; cloticaSone; cloticasone propionate; CMJ, cormeta produinolate; robenidine; semduramicin; SulaZuril; Sulfanit Sone; corticotropin; corticotropin; corticotropin Zinc hydrox ran; tiaZuril; to Sulur. ide; acetate; ; ; deflazacort; US 7,951,398 B2 19 20 ; deprodone propionate; acetonide; Immunoregulators: desonide; desoximetasone; desoxycortone; dexamethasone; aZarole; mesilate; frentizole; oxamisole; ris ; dexamethasone sodium phos tianol phosphate; thymopentin; tilomisole. phate; ; ; diflorasone; diflucor Immunostimulants: tolone; pivalate; difluprednate; ; loxoribine; teceleukin. : ; drocinonide; FSDCICM; fluaza Immunosuppressants: cort; acetonide; flucloronide; fludrocortisone; azathioprine; azathioprine sodium; cyclosporine; dal ; ; ; flumox troban; gusperimus trihydrochloride; Sirolimus; tacrolimus. onide; flunisolide; acetonide; ; Active Ingredients for Treating Impotence: fluocortin; ; ; fluocortolone 10 abanoquil; alprostadil; amlodipine; BMS-193884; caproate; fluorometholone; flupamesone; deleduanine: doxazosin, E-4010; glycerol trinitrate; IC-351; acetate; ; ; fluprednisolone val melanotan II; minoxidil; nitraquaZone; papaverine; phenoxy erate; flurandrenolide; fluticaSone; ; benzamine; praZosin; quinelorane; Sildenafil; UK-1 14542: : gestonorone caproate; GW-215864X; 15 urapidil; Vardenafil; VIP; yohimbin; GW-250945; halcinonide; halocortolone; ; LHRH Antagonists: halopredone acetate; ; hydrocortisone; deslorelin; goserelin; histrelin; lutrelin acetate; nafarelin ; ; hydrocor acetate. tisone buteprate; ; hydrocortisone Hepatoprotectant: enbutate; hydrocortisone sodium phosphate, hydrocortisone malotilate. Sodium Succinate; ; enb Luteolytics: utate; isoflupredone; , ; locicor fenprostalene. tolone; locicortolone dicibate; etabonate; Cerebrotonics: ; meclorisone; medry Sone; ; aloracetam; alvameline; aniracetam; apaxifylline; apti methylprednisolone; methylprednisolone acetate; methyl 25 ganel; azetirelin; brovincamine; cebaracetam; cevimeline; prednisoloxime Sodium phosphate; methylprednisolone CI-844; CI-933; demiracetam; dimoxamine; donepezil; Sodium Succinate; furoate; naflocort; ; dupracetam; edaravone; ensaculin; fasoracetam; FK-960; nivaZol; acetate; ; ; gavestinel; igmesine; muracetam; IOS-11212; JTP-4819; ; ; ; prednisolone KST-5410; leteprinim; ligustizine; linopirdine; MCI-225; acetate; prednisolone farnesylate; prednisolone hemisucci 30 milameline; MKC-231; NDD-094; nebracetam; nicorac etam; nizofenone; ONO-1603; OP-2507; OPC-141 17: nate; prednisolone sodium phosphate; prednisolone sodium oxiracetam; pikamilone; piracetam; piraxelate; pirglutargine; Succinate; ; ; ; pramiracetam; pyritinol; quilostigmine; ribaminol; rivastig ; prednival; procinonide; ; rimex mine; rolziracetam; sabcomeline; sapropterin; SIB-1553A: olone; rofileponide; TBI-PAB; propionate: 35 sibopirdine: sipatrigine:SM-10888; SNK-882: SR-46559-A: timobesone; tipredane; tiXocortol; ; tral staco?ylline: T-588; T-82; TAK-147; talsaclidine; taltirelin; onide; ; ; triamcino tamitinol; tenilsetam; Vinconate; Vinpocetine; Xaliproden; lone acetonide Sodium; triamcinolone benetonide; triamcino Xanomeline; YM-796; YM-900: Z-321; Zifrosilone. lone diacetate; ; triamcinolone Mucolytics: hexacetonide; triclonide; . 40 acetylcysteine; adamexine; ambroXol; bencisteine; brom Hemostatics: hexine; brovanexine; carbocysteine; cartasteine; cistinexine; aminocaproic acid; oXamarin; Sulmarin; thrombin; tranex dacisteine; danosteine; dembrexine; domiodol; erdosteine; amic acid. erythromycin Salnacedin, erythromycin Stinopate; guaime Hormones: sal; IDB-1031; isalsteine; letosteine; mecysteine; mesna; diethylstilbestrol; progesterone; 17-hydroxy progesterone; 45 midesteine; moguisteine; neltenexine; nesosteine; omonas medroxyprogesterone; norgestrel; norethynodrel; estradiol; teine; OXabrexine; prenisteine; Salmisteine; Stepronin; tasul megestrol (Megace); norethindrone; levonorgestrel; ethyn dine; taurosteine; telmesteine; tiopronin. diol; ethinyl estradiol; mestranol; estrone; equilin; 17-alpha Mydriatics: dihydroequilin; equilenin; 17 alpha dihydroequilenin; 17-al berefrine. pha-estradiol; 17-beta-estradiol; leuprolide (lupron); 50 Neuroprotective Agents: glucagon; testolactone; clomiphene; han memopausal gona maleate. dotropins; human chorionic gonadotropin; urofollitropin; NMDA Antagonists: bromocriptine; gonadorelin; luteinizing hormone releasing ACPC; aptiganel: BMY-14802: CGP-37849; CP-101606: hormone and analogs; gonadotropins; ; testosterone; dizocilpine; EAA-090; eliprodil; felbamate: FPL-12495; dehydroepiandrosterone; androstenedione; dihydroestoster 55 gavestinel; harkoseride; HU-211; ipenoxazone: L-695902; one; relaxin; oxytocin, vasopressin; folliculostatin; follicle lanicemine; licostinel; ligustizine; midafotel; milnacipran; regulatory protein; gonadoctrinins; oocyte maturation inhibi nebostinel; remacemide; selfotel; seratrodast; spermidine; tor; insulin growth factor, follicle stimulating hormone; spermine: UK-240255; ZD-9379. luteinizing hormone; tamoxifen, corticorelin ovine triftutate; Nonhormonal Derivatives: cosyntropin; metogest: pituitary, posterior, seractide acetate; 60 . Somalapor, Somatrem; somatropin; somenopor; somidobove. Oxytocics: HMG-CoA Reductase Inhibitors: carboprost; carboprost methyl; carboprost tromethamine; lovastatin (Mevacor); simvastatin (Zocor); pravastatin dinoprost, dinoprost tromethamine; dinoprostone; ergono (Pravachol); fluvasatin (Lescol). vine maleate; meteneprost; methylergonovine maleate; oxy Immunomodulators: 65 tocin, Sparteine Sulfate. dimepranol acedoben; imiquimod; interferon beta-Ib; Plasminogen Activators: lisofylline; mycophenolate mofetil: prezatide copper acetate. alteplase; urokinase. US 7,951,398 B2 21 22 PAF Antagonists: Serotonin Inhibitors: lexipafant. cinanserin; fenclonine; fonazine mesilate; Xylamidine Aggregation Inhibitors: tosylate. acadesine; beraprost; beraprost sodium; ciprostene cal Stimulants: cium; itaZigrel; lifarizine; OXagrelate. amfonelic acid; amphetamine Sulfate; ampyZine Sulfate; Progestins: arbutamine; azabon: caffeine; ceruletide; ceruletide diethy algestone acetophenide; amadinone acetate; anagestone lamine; cisapride; dazopride fumarate; dextroamphetamine; acetate; ; clingestol; clogestone dextroamphetamine Sulfate; difluanine; dimefline, dox acetate; clomegestone acetate; ; ; apram; etryptamine acetate; ethamivan; fenethylline; fluba ; ethynerone; ethynodiol diacetate; 10 nilate; flurothyl; histamine phosphate; indriline; mefexam ; flurogestone acetate; gestaclone; ; ide; methamphetamine hydrochloride; methylphenidate; gestonorone caproate; gestrinone; haloprogesterone; hydrox pemoline, pyrovalerone; Xamoterol: Xamoterol fumarate. yprogesterone caproate; levonorgestrel; lynestrenol; Suppressants: ; medroxyprogesterone acetate; methynodiol amflutizole; coxchicine; taZofelone. diacetate; norethindrone; norethindrone acetate; norethyno 15 Active Ingredients for Treating Symptomatic Multiple drel; norgestimate; ; norgestrel; oXogestone Sclerosis: phenpropionate; progesterone; quingestanol acetate; fampiridine. ; tigestol. Synergistic Agents: Prostate Growth Inhibitors: proadifen. pentomone. Thyroid Hormones: Prothyrotropin: levothyroxine sodium; liothyronine sodium; liotrix. protirelin. Thyroid Inhibitors: Psychotropic Agents: methimazole; propyithiouracil. minaprine. Thyromimetics: Calcium Regulators: 25 thyromedan. alfacalcidol; calcifediol; calcipotriol, calcitonin; calcitriol: Tranquilizers: dihydrotachysterol: doxercalciferol: falecalcitriol; lexacalci , ; ; ; clo tol; maxacalcitol; secalciferol; seocalcitol; tacalcitol; bazam, dipotassium; clorazepate monopotas Relaxants: sium; ; ; enciprazine; adiphenine; alcuronium chloride; aminophylline; 30 ; ; ; hydroxy Zine aZumolene Sodium; baclofen; ; ; pamoate; , , lorZafone, ; loxap chlorphenesin ; chlorZoxazone: cinflumide: cin ine succinate; : nabilone; ; ; namedrine; clodanolene; ; dantrolene; dant ; piremperone; , roliprarn, , rolene sodium; femalamide; fenyripol; fetoxylate; flavoxate: taciamine; , ; ; Valnoctamide. , flumetramide; flurazepam, hexafluorenium bro 35 Agent for Treating Cerebral Ischemia: mide; isomylamine; ; mebeverine; meSuprine; dextrorphan. metaxalone; methocarbamol; methixene; nafomine malate; Agent for Treating Paget’s Disease: neleZaprine maleate; papaverine; pipoxolan, quinctolate; tiludronate disodium. ; ritodrine; rolodine; theophylline Sodium glycinate; UricoSuric Agents: thiphenamil: xilobam. 40 benzbromarone; irtemazole; probenecid; Sulfinpyrazone. Scabicides: Vasoconstrictors: : crotamiton. adrenalone; amidefrine mesilate; angiotensin amide; caf Sclerosing Agents: aminol; cilutazolin; clonazoline; ; domaZoline; clobenoside; ethanolamine oleate; morrhuate sodium: ola epinephrine; epinephrylborate; ; indanazoline; mine; tribenoside. 45 mephentermine; methysergide; metizoline; metrafazoline; : ; nemazoline; oxedrine; ; phe . namaZoline; ; phenylpropanolamine polis Hypnotics/Sedatives: tirex, tefazoline, tetry Zoline; tinazoline; tramaZoline; Xylom ; alonimid; ; sodium; etazoline. ; ; ; butabarbital sodium; 50 Vasodilators: ; capuride; carbocloral; betaine; chloral alprostadil; azaclorzine; bamethan sulfate; bepridil; buter hydrate; chlordiazepoxide; cloperidone; clorethate: izine; cetiedil citrate; chromonar; clonitrate; diltiazem; dipy , dexclamol; , ; ridamole; droprenilamine; erythrity1 tetranitrate; ; ; : ; fenobam; fluni ; fostedil; hexobendine; inositol niacinate, iproX trazepam, , ; , 55 amine; isosorbide dinitrate; isosorbide mononitrate; isoxSu ; ; ; ; prine; lidoflazine; mefenidil; mefenidil fumarate; mibefradil midaflur; ; ; pentobarbital sodium; dihydrochloride; mioflazine; mixidine; nafronyl oxalate: ; ; , , roletamide; nicardipine; nicergoline; nicorandil; nicotinyl alcohol; nife ; secobarbital sodium; ; thalidomide: dipine; ; nisoldipine; Oxfenicine; oXprenolol; pen ; trepipam maleate; , tricetamide; triclo 60 taerythritol tetranitrate; pentoxifylline; pentrinitrol; perhex fos sodium; trimetozine; , ; , iline maleate; pindolol, pirsidomine; prenylamine; propatyl tartrate. nitrate; Suloctidil; terodiline; tipropidil; tolazoline: xanthinol Selective Adenosine Al Antagonists: niacinate. apaxifylline Active Ingredients for Wound Healing: Serotonin Antagonists: 65 erSofermin. altanserin tartrate; , ; , tro Xanthine Oxidase Inhibitors: panserin allopurinol, oxypurinol US 7,951,398 B2 23 24 In a preferred embodiment of the invention, the active 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-meth ingredient is a PDE (phosphodiesterase) inhibitor, particu ylbenzylamino)-2-methylimidazol-2-a-pyridine, larly preferably PDE 4 inhibitor, especially N-(3,5-dichloro 3-hydroxymethyl-8-(2-methoxycarbonylamino-6-meth pyrid-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxyben ylbenzyloxy)-2-methylimidazol-2-a-pyridine, Zamide (INN: roflumilast) its N-oxide or a pharmacologically 5 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2,3- suitable salt of roflumilast or of its N-oxide. The preparation dimethylimidazol-2-alpyridine, of N-(3,5-dichloropyrid-4-yl)-3-cyclopropylmethoxy-4-dif 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)-2, luoromethoxybenzamide, its pharmacologically Suitable 3-dimethylimidazol-2-alpyridine, salts and its N-oxide, and the use of these compounds as 8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-2,3- phosphodiesterase (PDE) 4 inhibitors is described in the 10 dimethylimidazol-2-alpyridine, international application WO95/01338. In a particularly pre 8-(2-ethoxycarbonylamino-6-methylbenzylamino)-2,3- ferred embodiment of the invention, the active ingredient is a phosphodiesterase (PDE) 3/4 inhibitor, in particular (-)-cis dimethylimidazol-2-alpyridine, 9-ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphe 8-(2-isobutoxycarbonylamino-6-methylbenzylamino)-2, nyl)-2-methyl-1,2,3,4,4a, 10b-hexahydrobenzoc1.6naph 15 3-dimethylimidazol-2-alpyridine, thyridine (INN: pumafentrine). The preparation of (-)-cis-9- 8-(2-isopropoxycarbonylamino-6-methylbenzylamino)-2, ethoxy-8-methoxy-6-(4-diisopropylaminocarbonylphenyl)- 3-dimethylimidazol-2-alpyridine, 2-methyl-1,2,3,4,4a, 10b-hexahydrobenzoc 1.6 8-(2-tert-butoxycarbonylamino-6-methylbenzylamino)- naphthyridine and its pharmacologically Suitable salts, and 3-hydroxymethyl-2-methylimidazol-2-a-pyridine, the use of this compound as phosphodiesterase (PDE) 3/4 8-(2-tert-butoxycarbonylamino-6-methylbenzyloxy)-3- inhibitor is described in the international application WO98/ hydroxymethyl-2-methylimidazol-2-a-pyridine, 21208. 8-2-(2-methoxyethoxy)carbonylaminol-6-methylben The matrix of the invention is outstandingly suitable as Zyloxy-2-methylimidazo[1,2-alpyridine-3-, dosage form for active ingredients from the class of Sub 8-2-(2-methoxyethoxy)carbonylaminol-6-methylben stances known as reversible H, K"-ATPase inhibitors, which 25 Zylamino-2-methylimidazo[1,2-a-pyridine-3-methanol, are also referred to as reversible proton pump inhibitors or 8-2-(2-methoxyethoxy)carbonylaminol-6-methylben APAS (acid pump antagonists). Reversible proton pump Zylamino)-2,3-dimethylimidazo[1,2-a-pyridine, inhibitors or APAS are disclosed, for example, in the patent 8-2-(2-methoxyethoxy)carbonylaminol-6-methylben document DE-A3917232, EP-A-0399267, EP-A-0387821, Zyloxy-2-methylimidazo[1,2-alpyridine-3-methanol, JP-A-3031280, JP-A-2270873, EP-A-0308917, EP-A- 30 8-2-(2-methoxyethoxy)carbonylaminol-6-methylben 0268989, EP-A-0228006, EP-A-0204285, EP-A-0165545, Zyloxy-2,3-dimethylimidazo[1,2-alpyridine, EP-A-0125756, EP-A-0120589, EP-A-0509974, DE-A 3-hydroxymethyl-2-methyl-8-benzyloxyimidazol-2-a 3622036, EP-A-0537532, EP-A-0535529, JP-A-3284686, pyridine, JP-A-3284622, U.S. Pat. No. 4,833,149, EP-A-0261912, 3-hydroxymethyl-2-trifluoromethyl-8-benzyloxyimidazo WO-A-9114677, WO-A-9315055, WO-A-9315071, WO-A- 35 1.2-alpyridine, 93.15056, WO-A-93.12090, WO-A-9212969, WO-A- 1,2-dimethyl-3-cyanomethyl-8-benzyloxyimidazo[1,2-a 9118887, EP-A-0393926, EP-A-0307078, U.S. Pat. No. pyridine, 5,041,442, EP-A-0266890, WO-A-94.14795, EP-A- 2-methyl-3-cyanomethyl-8-benzyloxyimidazol-2-apy 0264883, EP-A-0033094, EP-A-0259174, EP-A-0330485, ridine, WO-A-8900570, EP-A-0368158, WO-A-91 17164, WO-A- 40 3-butyryl-8-methoxy-4-(2-methylphenylamino)quino 9206979, WO-A-9312090, WO-A-9308.190, U.S. Pat. No. line, 5,665,730, DE-A 3011490, U.S. Pat. No. 4,464,372, EP-A- 3-butyryl-8-hydroxyethoxy-4-(2-methylphenylamino) 0068378, WO-A-9424130, U.S. Pat. No. 5,719,161, U.S. Pat. quinoline, No. 6,124.313, WO-A-9527714, WO-A-96.17830, WO-A- 3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydropy 9837080, WO-A-99.55705, WO-A-9955706, WO-A- 45 rano 2.3-climidazol-2-alpyridine, 0010999, WO-A-001 1000, especially in the documents WO 3-hydroxymethyl-2-methyl-9-(4-fluorophenyl)-7H-8.9- A-9842707, WO-A-9854 188, WO-A-0017200, WO-A- dihydropyrano 2.3-climidazol-2-alpyridine, 0026217 and WO-A-0063211, and in other patent documents (+)-3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihy which relate to compounds which inhibit gastric acid secre dropyrano 2.3-climidazol-2-alpyridine, tion and have a quinoline, imidazol-2-alpyridine, 7,8,9,10 50 (-)-3-hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihy tetrahydroimidazo 1.2-h1.7naphthyridine or 7H-8,9-dihy dropyrano 2.3-climidazol-2-alpyridine, dropyrano 2.3-climidazol-2-alpyridine basic structure. 8-(2-ethyl-6-methylbenzylamino)-3-(hydroxymethyl)-2- Examples of reversible proton pump inhibitors or APAS methylimidazol-2-alpyridine-6-carboxamide, which should be mentioned as preferred are, interalia: N-(2-hydroxyethyl)-8-(2,6-dimethylbenzylamino)-2,3- AU-461 2-1-(2-methyl-4-methoxyphenyl)-6-(2.2.2-trif 55 dimethylimidazol-2-alpyridine-6-carboxamide, luoroethoxy)-2,3-dihydro-1H-pyrrolo3.2-cquinolin-4- 8-(2-ethyl-6-methylbenzylamino)-2,3-dimethylimidazo ylamino-1-ethanol, 1.2-alpyridine-6-carboxamide, DBM-819 3-1-(4-methoxy-2-methylphenyl)-6-methyl 8-(2-ethyl-6-methylbenzylamino)-N,2,3-trimethylimi 2,3-dihydro-1H-pyrrolo-3.2-cquinolin-4-ylaminol-pro dazol-2-alpyridine-6-carboxamide, panol, 60 8-(2,6-dimethylbenzylamino)-2,3-dimethylimidazo 1,2- KR-60436 2-1-(4-methoxy-2-methylphenyl)-6-(trifluo apyridine-6-carboxamide, romethoxy)-2,3-dihydro-1H-pyrrolo3.2-cquinolin-4- 8-(2-ethyl-4-fluoro-6-methylbenzylamino)-2,3-dimeth ylaminoethanol. ylimidazol-2-alpyridine-6-carboxamide, R-105266; YJA-20379-8 (+)-1-8-ethoxy-4-(1(R)-phe 8-(4-fluoro-2,6-dimethylbenzylamino)-2,3-dimethylimi nylethyl)amino-1.7-naphthyridin-3-yl)-1-butanone. 65 dazol-2-alpyridine-6-carboxamide, 8-(2-methoxycarbonylamino-6-methylbenzylamino)-2,3- 8-(2,6-diethylbenzylamino)-2,3-dimethylimidazo 1,2-a dimethylimidazol-2-alpyridine, pyridine-6-carboxamide,

US 7,951,398 B2 27 28 proton pump inhibitors, for example Substituted phenylmeth and in the form of Solvates and, in particular, also hydrates of ylsulfinyl-1H-, cycloheptapyridin-9-ylsulfi the salts of the active ingredients. nyl-1H-benzimidazoles or pyridin-2-ylmethylsulfinylth The active ingredients may also be chiral compounds. It is ienoimidazoles, are disclosed in DE-A-35 31 487, EP-A-0 therefore also possible for the pure enantiomers of the active 434999 and EP-A-0 234 485 respectively. Examples which ingredients and mixtures thereof in any mixing ratio to be may be mentioned are 2-2-(N-isobutyl-N-methylamino) present in the preparations of the invention. benzylsulfinylbenzimidazole (INN: leminoprazole) and The fatty alcohol is preferably a linear, saturated or unsat 2-(4-methoxy-6,7,8,9-tetrahydro-5H-cycloheptabpyridin urated primary alcohol with 10-30 carbon atoms. It is prefer 9-ylsulfinyl)-1H- (INN: nepaprazole). The ably a primary alcohol with 10 to 18 carbon atoms in linear 10 chains. Examples of fatty alcohols which may be mentioned acid-labile proton pump inhibitors are chiral compounds. The are cetyl alcohol, myristyl alcohol, lauryl alcohol or Stearyl term acid-labile proton pump inhibitor also encompasses the alcohol, with preference forcetyl alcohol. It is also possible if pure enantiomers of the acid-labile proton pump inhibitors desired for mixtures of fatty alcohols to be present. and their mixtures in any mixing ratio. Pure enantiomers The triglyceride is glycerol with its three hydroxyl groups which may be mentioned by way of example are 5-methoxy 15 esterified by carboxylic acids. The carboxylic acids are pref 2-(S)-(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfi erably monobasic carboxylic acids with 8 to 22 carbonatoms, nyl)-1H-benzimidazole (INN: esomeprazole) and (-)-panto preferably naturally occurring carboxylic acids. It is possible prazole. The acid-labile proton pump inhibitors are moreover in this case for the carboxylic acids to be different or, prefer present as such or, preferably, in the form of their salts with ably, identical. Examples which may be mentioned are bases. Examples of salts with bases which may be mentioned tristearate, tripalmitate and, particularly preferably, are sodium, potassium, magnesium or calcium salts. If the trimyristate (these triglycerides are commercially available acid-labile proton pump inhibitors are isolated in crystalline under the name Dynasan 118, 116 and 114 respectively). It is form, they may contain variable amounts of solvent. The term also possible if desired for mixtures of triglycerides to be acid-labile proton pump inhibitor therefore also represents present. according to the invention all solvates, in particular all 25 The fatty acid ester is the ester of an alcohol with a fatty hydrates, of the acid-labile proton pump inhibitors and their acid. The alcohol in this case is preferably a linear, saturated salts. Such a hydrate of the salt of an acid-labile proton pump or unsaturated primary alcohol with 10-30, preferably with 12 inhibitor with a base is disclosed, for example, in WO91/ to 18, carbon atoms. The fatty acid is preferably a monobasic 19710. Acid-labile proton pump inhibitors which may be carboxylic acid with 8 to 22, in particular 12 to 18, carbon mentioned as particularly preferred are pantoprazole sodium 30 atoms, preferably a naturally occurring carboxylic acid. Fatty sesquihydrate (pantoprazole Sodiumx1.5 H2O), (-)-panto acid esters preferred according to the invention have a melting prazole Sodium sesquihydrate, pantoprazole magnesium point above 30° C. Examples of fatty acid esters which may dihydrate, magnesium, omeprazole and esome be mentioned are cetyl palmitate, which is commercially prazole. available for example under the name Cutina R CP. It is also In another preferred embodiment of the invention, the 35 possible if desired for mixtures of fatty acid esters to be active ingredient is a glucocorticosteroid, in particular present. ciclesonide. The solid paraffin is preferably paraffinum solidum (cer The active ingredients may, depending on the nature of the esin). It is also possible alternatively to use ozokerite, for active ingredient, also be present in the preparations of the example. It is also possible if desired to use mixtures. invention in the form of a salt of the active ingredient. Par 40 The partial glyceride is according to the invention glycerol ticular mention may be made of the pharmacologically Suit in which one or two hydroxyl groups are esterified by car able salts of the inorganic and organic acids normally used in boxylic acids. The carboxylic acids are preferably monobasic pharmaceutical technology. Suitable as Such are, on the one carboxylic acids with 8 to 22 carbon atoms, preferably natu hand, water-soluble and water-insoluble acid addition salts rally occurring carboxylic acids, in particular Stearic acid, with acids such as, for example, hydrochloric acid, hydrobro 45 palmitic acid and myristic acid. It is possible in this case for mic acid, phosphoric acid, nitric acid, Sulfuric acid, acetic the carboxylic acids to be different or, preferably, the same. acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hy Examples which may be mentioned are glycerol monostear droxybenzoyl)-benzoic acid, butyric acid, Sulfosalicylic acid, ate, glycerol distearate and glycerol monopalmitate, glycerol maleic acid, lauric acid, malic acid, fumaric acid, Succinic dipalmitate. It is also possible if desired for mixtures of partial acid, oxalic acid, tartaric acid, embonic acid, Stearic acid, 50 glycerides to be present. Sulfonic acid, methanesulfonic acid or 3-hydroxy-2- If desired, the mixtures in the individual active ingredient naphthoic acid, the acids being employed for preparing the units may include one or more other pharmaceutically Suit salts in the equimolar ratio of amounts, or a ratio differing able excipients. Other suitable excipients which may be men therefrom, depending on whether the acid is monobasic or tioned by way of example are polymers, Sterols and in the polybasic and depending on which salt is required. 55 case of acid-labile active ingredients—basic compounds. On the other hand, salts with bases are also suitable. Examples of polymers which may be mentioned are povi Examples of salts with bases which may be mentioned are done (e.g. Kollidon(R) 17, 30 and 90 from BASF), vinylpyr alkali metal (lithium, Sodium, potassium) or calcium, alumi rolidone/vinyl acetate copolymer and polyvinyl acetate. Oth num, magnesium, titanium, ammonium, meglumine or ers which may be mentioned are cellulose ethers such as, for guanidinium salts, the bases being employed for preparing 60 example, methylcellulose, ethylcellulose (Ethocel(R) and the salts also in the equimolar ratio of amounts or in a ratio hydroxypropylmethylcellulose, cellulose esters such as cel differing therefrom. lulose acetate phthalate (CAP), cellulose acetate trimellitate The skilled worker is aware that active ingredients and their (CAT), hydroxypropylmethylcellulose phthalate (HP50 and salts may, if they are isolated, for example, in crystalline HP55) or hydroxypropylmethylcellulose acetate succinate form, contain various amounts of Solvents. The active ingre 65 (HPMCAS), methacrylic acid/methyl methacrylate copoly dients will therefore also be present in the preparations of the mer or methacrylic acid/ethyl methacrylate copolymer invention in the form of Solvates and, in particular, hydrates, (Eudragit(R) L). The polymer is preferably povidone or ethyl US 7,951,398 B2 29 30 cellulose. It is also possible if desired for mixtures of poly ent, 15 to 60% solid paraffin, 5 to 50% fatty alcohol, 5 to 10% mers to be present. It is possible by adding Suitable polymers, fatty acid ester and 10 to 50% triglyceride or partial glyceride. for example, to influence the pharmaceutical properties of the In another embodiment, the invention relates to a prepara individual active ingredient units (e.g. delivery of the active tion in which an active ingredient is essentially uniformly ingredient). Particularly preferred polymers according to the dispersed in an excipient matrix composed of at least one fatty invention are povidone or ethylcellulose. alcohol together with at least one excipient selected from the The sterol is preferably a phytosterol or a Zoosterol. group of solid paraffin or polymer. The polymer is preferably Examples of phytosterols which may be mentioned are ergos ethylcellulose or povidones. Such preparations preferably terol, Stigmasterol, sitosterol, brassicasterol and campesterol. consist of 0.05 to 25% active ingredient, 20 to 90% fatty Examples of Zoosterols which may be mentioned are choles 10 terol and lanosterol. It is also possible if desired for mixtures alcohol, 10 to 80% solid paraffin and/or 0.05 to 2% ethylcel of sterols to be present. lulose. Such preparations consist in particular of 0.1 to 20% Examples of suitable basic compounds are inorganic basic active ingredient, 25 to 80% fatty alcohol, 10 to 70% solid salts such as ammonium carbonate and sodium carbonate, paraffin and/or 0.1 to 1.5% ethylcellulose. Such preparations salts of fatty acids such as sodium Stearate, amines such as 15 particularly preferably consist of 0.5 to 15% active ingredi meglumine, di-, triethylamine and TRIS(2-amino-2-hy ent, 25 to 70% fatty alcohol, 10 to 60% solid paraffin and/or droxymethyl-1,3-propanediol) or fatty amines such as Steary 0.2 to 1% ethylcellulose. lamine. Stearylamine and Sodium Stearate may be mentioned In the case of acid-labile active ingredients, in particular as preferred. The addition of basic compounds to the mixtures the acid-labile proton pump inhibitors, preferred individual in the individual units results, in the case of acid-labile active active ingredient units of the invention consist of 2-70% ingredients, in particularly stable preparations and prevents active ingredient, 10-60% fatty alcohol, 10-60% solid paraf possible discolorations. fin, 1-15% polymer and 0.1-2% of a basic compound. Further The proportion (in percent by weight) of active ingredient preferred individual active ingredient units of the invention in the individual active ingredient unit depends on the type of consist of 2-70% active ingredient, 10-60% triglyceride, active ingredient and is advantageously 0.01-90%. The pro 25 10-60% solid paraffin, 1-15% polymer and 0.1-2% of a basic portion of active ingredient is preferably 0.1-70%, particu compound. Other preferred individual active ingredient units larly preferably 5-40%, in particular 10-20%. The proportion of the invention consist of 2-70% active ingredient, 10-60% of fatty alcohol in the individual active ingredient unit is fatty acid ester, 10-60% solid paraffin, 1-15% polymer and advantageously 10-70%, preferably 20-70%, particularly 0.1-2% of a basic compound. Particularly preferred indi preferably 20-60% and in particular 30-60%. The proportion 30 of triglyceride in the individual active ingredient unit is vidual active ingredient units of the invention consist of advantageously 10-70%, preferably 20-70%, particularly 5-40% active ingredient, 20-60% fatty alcohol, 10-60% solid preferably 20-60% and in particular 30-60%. The proportion paraffin, 1-15% polymer and 0.1-1% of a basic compound. of partial glyceride in the individual active ingredient unit is Further particularly preferred individual active ingredient advantageously 10-70%, preferably 20-70%, particularly 35 units of the invention consist of 5-40% active ingredient, preferably 20-60% and in particular 30-60%. The proportion 20-60% triglyceride, 10-60% solid paraffin, 1-15% polymer of fatty acid ester in the individual active ingredient unit is and 0.1-1% of a basic compound. Other particularly preferred advantageously 10-70%, preferably 20-70%, particularly individual active ingredient units of the invention consist of preferably 20-60% and in particular 30-60%. The proportion 5-40% active ingredient, 20-60% fatty acid ester, 10-60% of solid paraffin is advantageously 10-70%, preferably 40 solid paraffin, 1-15% polymer and 0.1-1% of a basic com 20-60% and in particular 30-60%. If present, the proportion pound. of polymer in the individual active ingredient unit is expedi Examples of active ingredient units of the invention con ently 1-25%, preferably 1-10%, particularly preferably tain 5-40% pantoprazole sodium sesqulhydrate, 10-40% 5-10%. If present, the proportion of sterol is expediently cetyl alcohol, 5-60% solid paraffin, 1-5% polymer and 0.1- 1-10%, preferably 1-5%. If present, the proportion of basic 45 0.2% of a basic compound. Further examples of active ingre compound is 0.05-5%, preferably 0.1-1%. dient units of the invention contain 5-40% pantoprazole Preferred individual active ingredient units of the invention sodium sesquihydrate, 10-40% glyceryl tripalmitate, 5-60% consist of 2-70% active ingredient, 10-60% fatty alcohol, solid paraffin, 1-5% polymer and 0.1-0.2% of a basic com 10-60% solid paraffin and 1-15% polymer. Further preferred pound. Other examples of active ingredient units of the inven individual active ingredient units of the invention consist of 50 tion contain 5-40% pantoprazole Sodium sesquihydrate, 2-70% active ingredient, 10-60% triglyceride, 10-60% solid 10-40% glyceryl tripalmitate, 5-60% solid paraffin, 1-5% paraffin, 1-15% polymer. Other preferred individual active polymer and 0.1-0.2% of a basic compound. Still other ingredient units of the invention consist of 2-70% active examples of active ingredient units of the invention contain ingredient, 10-60% fatty acid ester, 10-60% solid paraffin and 10-20% pantoprazole sodium sesquihydrate, 20-40% triglyc 1-15% polymer. 55 eride, 40-70% solid paraffin, 1-5% sterol and 0.05-0.1% of a In one embodiment, the invention relates to a preparation in basic compound. which an active ingredient is essentially uniformly distributed The individual active ingredient units can be produced for in an exciplent matrix composed of a mixture of at least one example by spray drying or, preferably, by spray solidifica Solid paraffin, a fatty alcohol, a fatty acid ester and a partial tion, in particular also by spray prilling. Production is par glyceride or triglyceride. Such preparations preferably con 60 ticularly preferably by prilling, in particular by vibration sist of 0.05 to 25% active ingredient, 10 to 70% solid paraffin, prilling. 5 to 80% fatty alcohol, 2 to 20% fatty acid ester and 5 to 80% For the spray solidification or prilling expediently the triglyceride or partial glyceride. Such preparations consist, in matrix excipients are liquefied to give a melt. The active particular, of 0.1 to 20% active ingredient, 15 to 65% solid ingredient is dissolved or dispersed in this solution, and the paraffin, 5 to 70% fatty alcohol. 2 to 15% fatty acid ester and 65 resulting solution or dispersion is sprayed or, preferably, 5 to 70% triglyceride or partial glyceride. Such preparations prilled in a Suitable apparatus. A dispersion of the active particularly preferably consist of 0.5 to 15% active ingredi ingredient in a melt of the excipients is preferably used. US 7,951,398 B2 31 32 Spray solidification takes place in a manner known perse. his expert knowledge. In the case of oral dosage forms it is A detailed description of this technique is to be found in P. B. Surprisingly possible to dispense with the enteric coating. Deasy, Microencapsulation and Related Drug Processes In the case of rapidly disintegrating tablets, suitable excipi (1984). ents are, in particular, those excipients which on oral intake of The individual active ingredient units are particularly pref the tablet bring about rapid disintegration of the tablets. Exci erably produced by Solidification from liquid phase by gen pents which on oral intake of the tablet bring about rapid erating drops by means of vibrating nozzles and by Solidify disintegration of the tablet preferably comprise one or more ing the drops which are formed, after they have stabilized, by substances selected from the group of fillers and disinte drying or cooling in a suitable medium (preferably gaseous or grants. One or more other excipients from the group of lubri liquid). The Suitable medium may be, for example, cooled gas 10 cants, flavors, flavoring Substances and Surface-active Sub Such as air or . Processes of this type and correspond stances are preferably present in the rapidly disintegrating ing apparatuses are disclosed in DE 2725924, EPO 467 221, dosage form of the invention. Binders can also be present if WO99/33555 and WOOOf 24382. desired. The rapidly disintegrating dosage form particularly It is particularly preferred according to the invention in the preferably comprises a mixture of at least one filler, one prilling process for the liquid phase flowing to the nozzle to be 15 disintegrant and one lubricant. Fillers suitable according to kept at a constant temperature. The solidification preferably the invention are, in particular, basic fillers such as calcium takes place by instantaneous cooling in a suitable cooling carbonate (e.g. MagGran R. CC or Destab(R95) and sodium medium. In prilling, moreover, it is preferred for the liquid carbonate, Sugar alcohols such as mannitol (e.g. Pearlitol(R) or phase flowing to the nozzle, the vibrating nozzle and the drops Parteck R. M.), sorbitol (e.g. Karion(R), xylitol or maltitol, formed by prilling to be kept at a constant temperature until starches such as corn starch, potato starch and wheat starch, their spherical shape has stabilized, and for the solidification microcrystalline cellulose, Saccharides such as glucose, lac of the drops after their stabilization to be carried out instan tose, levulose. Sucrose and dextrose. In a preferred develop taneously by cooling with a gaseous or liquid cooling ment of the invention, the rapidly disintegrating dosage form medium. Systems Suitable for prilling by means of vibrating of the invention comprises as filler a mixture of a basic filler nozzles are marketed, for example, by Brace GmbH, Aizenau, 25 (in particular calcium carbonate) and a Sugar alcohol (in Germany. It is possible by means of prilling using vibrating particular Sorbitol or mannitol). Disintegrants Suitable nozzles to obtain the individual active ingredient units in the according to the invention are, in particular, insoluble poly form of microspheres with a narrow monomodal particle size vinylpyrrolidone (insoluble PVP crospovidone), sodium car spectrum in the particle size range from 50 Lum to 2 mm. The boxymethylstarch, Sodium carboxymethylcellulose, alginic narrow monomodal particle size spectrum and the uniform 30 acid and starches able to carry out the function of a disinte spherical shape of the microspheres obtained in this way are grant (e.g. Starch 1500). Suitable lubricants which may be expected to result in a uniformly smooth surface, a uniform, mentioned are sodium stearyl fumarate, magnesium stearate, defined delivery of active ingredient and, in relation to pas calcium Stearate, Stearic acid, talc and highly disperse silica sage through the stomach in the case of oral dosage forms (Aerosil). Suitable surface-active substances which may be (owing to the Small particles), a behavior like that of a solu 35 mentioned are sodium lauryl sulfate or Tween(R) 20, 60 or 80. tion. The microspheres of the invention are distinguished in Binders suitable according to the invention are polyvinylpyr particular by high stability, a release of active ingredient rolidone (PVP Polyvidon R, K25,90) or mixtures of PVP with which can be controlled via the particle size and composition polyvinyl acetate (e.g. Kollidon R. 64), gelatin, corn starch of the matrix, good flow characteristics, good compressibility mucilage, preswollen starches (Starch 1500), hydroxypropy and a uniform delivery of active ingredient. It is particularly 40 lmethylcellulose (HPMC) or hydroxypropylcellulose worthy of mention that the microspheres can be further pro (L-HPC). cessed to a large number of pharmaceutical dosage forms The proportion (in percent by weight based on the finished without thereby losing a given functionality (Such as taste tablet) of filler in the rapidly disintegrating tablet is advanta masking, resistance to gastric juice, slowing of release). geously from 1 to 99% by weight. The proportion of filler is The microspheres are preferably monomodal micro 45 preferably from 30 to 95% by weight, and the proportion is spheres with a particle size range of 50-800 um, preferably very particularly preferably from 60 to 85% by weight. 50-500 um, particularly preferably 50-400 um, in particular The proportion (in percent by weight based on the finished 50-200 um. tablet) of disintegrant in the rapidly disintegrating tablet is The particle size of the active ingredient employed in the usually from 1 to 30% by weight. The proportion of disinte spray drying or spray Solidification, prilling or vibration pril 50 grant is preferably from 2 to 15% by weight. The proportion ing is advantageously less than or equal to 100 um, in par of disintegrant is particularly preferably from 5 to 10% by ticular less than 40 um. The particle size is preferably in the weight. range 1-20 um, particularly preferably in the range 3-15um. The proportion (in percent by weight based on the finished Such a particle size can beachieved, for example, by grinding tablet) of lubricant in the rapidly disintegrating tablet is usu the active ingredient in a suitable mill. 55 ally from 0.1 to 5% by weight. The proportion of lubricant is The individual active ingredient units (preparations) of the preferably from 0.3 to 3% by weight. The proportion of invention can then be used as basis for producing the dosage lubricant is particularly preferably from 0.5 to 2% by weight. forms of the invention. Examples which may be mentioned The proportion (in percent by weight based on the finished are dosage forms of the invention, to which the preparations tablet) of individual active ingredient units in the rapidly can be processed, as Suspensions, gels, tablets, coated tablets, 60 disintegrating tablet is usually from 1 to 90% by weight. The multicomponent tablets, effervescent tablets, rapidly disinte proportion of individual active ingredient units is preferably grating tablets, powders in Sachets, coated tablets, capsules, up to 70% by weight, in particular from 10 to 50% by weight. Solutions or else Suppositories. Preferred dosage forms in this The proportion is very particularly preferably from 15 to 25% connection are oral dosage forms, in particular tablets. Par by weight. ticular preference is given to rapidly disintegrating tablets and 65 The proportion (in percent by weight based on the finished effervescent tablets. The excipients suitable for the desired tablet) of binder can be up to 10% by weight, and it can dosage forms are familiar to the skilled worker on the basis of preferably be up to 5% by weight. US 7,951,398 B2 33 34 If desired, one or more flavoring Substances (e.g. flavors or 1 to 20% by weight based on the solution or suspension ready Sweeteners) can additionally be present in the rapidly disin for use, preferably 1 to 15% by weight and very preferably 5 tegrating tablet. This makes it possible, for example, to to 10%. Water is preferably used as solvent or dispersant for achieve an improvement of the taste of the rapidly disinte the solution or Suspension. grating tablet. These substances are added in conventional Other suitable excipients which may be present in the amountS. Solution or Suspension of the invention are, for example, The rapidly disintegrating tablet is produced by processes flavoring Substances (such as flavors and Sweeteners), buffer known to the skilled worker. The rapidly disintegrating tablet Substances, preservatives or else emulsifiers. Flavors are usu is preferably produced by ally added in a proportion of from 0.05 to 1% by weight. i) dry mixing of filler and/or disintegrant; 10 Other flavoring Substances by way of example are acids Such ii) production of granules of filler and binder and mixing of as citric acid, Sweeteners such as Saccharin, aspartame, cycla the granules with a disintegrant or mate Sodium or maltol, which are added according to the iii) dry granulation (briqueting or compacting) of one or desired result. Examples of emulsifiers are lecithins, sodium more excipient components. lauryl sulfate. Tweens(R or Spans, which are normally added The individual active ingredient units are Subsequently 15 in a proportion of from 0.01 to 1% by weight. Preservatives admixed to the mixtures obtained in i), ii) or iii) and then, if Such as benzoic acid, salts of benzoic acid, methyl 4-hydroxy desired, flavors/flavoring Substances and finally also one or benzoate, propyl 4-hydroxybenzoate, Sorbic acid or salts more lubricants are admixed. The mixture obtained in this thereofare preferably also added. The proportion depends on way can be compressed in a tablet press under conventional the preservative used and is normally from 0.1 to 4% by conditions. weight based on the Solution or Suspension ready for use. Rapid disintegration of the tablet means according to the The solution or suspension of the invention is produced by invention disintegration of the tablet in about 60 seconds or techniques known to the skilled worker. If a powder for recon less when the tablet is subjected to a disintegration test as stitution is to be produced, preferably a mixture of the indi described in the European Pharmacopoeia (3rd edition, 1997) vidual active ingredient units with the thickener and, where 2.9.1 disintegration time of tablets and capsules. 25 appropriate, further excipients is produced. This powdered In the case of Solutions and Suspensions, Suitable excipi mixture for reconstitution is then mixed with a suitable ents are, in particular, those excipients which are normally amount of water immediately before administration. Solution used to produce Solutions or Suspensions. Particularly Suit or Suspension ready for use is normally produced by intro able according to the invention are excipients with which it is ducing the individual active ingredient units into a dispersion possible to produce a thickened base. Such as thickeners. 30 of the thickener and, where appropriate, of additives in water Examples of thickeners of the invention are Xanthan, Substi or, alternatively, by introducing the thickener into a disper tuted celluloses, polyvinylpyrrolidone (polyvidone types), sion of the individual active ingredient units in water. sheet silicates, alginates or alginic acids. Also possible if In a preferred embodiment, the invention relates to rapidly desired is a mixture of two or more different thickeners. The disintegrating tablets or solutions or Suspension which com proportion of thickener depends on the desired viscosity or 35 prise preparations of the invention with PDE inhibitors as consistency intended for the solution or Suspension ready for active ingredients. Preferred PDE inhibitors in this case are use. A solution or suspension with a viscosity of less than 500 roflumilast and pumafentrine. mPas (determined with a rotational viscometer) is particu The dosage forms of the invention can be employed for the larly preferred. The proportion of xanthan, based on the solu treatment and prevention of all diseases which are regarded as tion or suspension ready for use, is usually from 0.1 to 1% by 40 treatable or preventable by use of the particular active ingre weight. The proportion of substituted celluloses depends on dient. The dosage forms contain the particular active ingre the viscosity levels of the celluloses and is usually from 0.1 to dient in the dose usual for treating the particular disease. 10% by weight based on the solution or suspension ready for The production of dosage forms and preparations of the use. Examples of substituted celluloses of the invention invention is described by way of example below. The follow which may be mentioned are carboxymethylcellulose, ethyl 45 ing examples illustrate the invention in detail without restrict cellulose or methylcellulose or hydroxypropylcellulose. The ing it. proportion of polyvinylpyrrolidone (poly Vidone types) is normally from 0.1 to 10% by weight based on the solution or EXAMPLES Suspension ready for use. Sheet silicates such as the Veegum or bentonites can be employed alone or in combination with 50 Production of the Preparations (Active Ingredient Units) water-soluble thickeners. The total proportion of thickener is then advantageously from 0.1 to 7% by weight based on the Example 1 Solution or Suspension ready for use. Alginates and are usually added in a proportion of from 0.1 to 10% by 50 g of solid paraffin, 34.9 g of cetyl alcohol and 0.1 g of weight based on the solution or Suspension ready for use. 55 Stearylamine are converted into a clear melt. 5.0 g of povidone Further pharmaceutical excipients preferably employed are is dissolved in the clear melt. At a temperature between insoluble, crosslinked polyvinylpyrrolidone (crospovidones) 56-60° C. 10.0 g of pantoprazole sodium sesquihydrate is and microcrystalline cellulose. It is observed in this case that added and Suspended homogeneously. The Suspension is a loose sediment forms and prevents agglomeration of the prilled in the molten state, and the drops thus produced are individual active ingredient units. The ratio of crospovidones 60 Solidified in a cooling Zone. to the individual active ingredient units is advantageously from 1:1 to 0.5:1 (based on weight). Microcrystalline cellu Example 2 lose, which is normally employed in a proportion of from 0.5 to 5% 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, is likewise suitable for this purpose. The proportion of 65 Stearylamine are converted into a clear melt. 4.0 g of povidone individual active ingredient units in the Solution or Suspen is dissolved in the clear melt. At a temperature between sion ready for use is usually according to the invention from 56-60° C. 10.0 g of pantoprazole magnesium is added and US 7,951,398 B2 35 36 Suspended homogeneously. The Suspension is prilled in the nozzle head during this. The resulting drops are solidified molten state, and the drops thus produced are solidified in a with air at a temperature of -30°C. in a cooling Zone. cooling Zone. Example 9 Example 3 18 g of tristearin, 60 g of solid paraffin and 5 g of choles terol are converted into a clear melt. The clear melt is cooled 45.0 g of solid paraffin, 33.8 g of cetyl alcohol, 1.0 g of to 56-60° C. 10 g of pantoprazole sodium sesquihydrate are B-sitosterol and 0.2 g of stearylamine are converted into a introduced and homogeneously dispersed. The Suspension is clear melt. 1.0 g of povidone and 4.0 g of ethylcellulose are prilled in the molten state in a prilling unit (from Brace) with dissolved in the clear melt. At a temperature between 56-60 10 vibrating nozzles, and the resulting drops are solidified in a C. 15.0 g of pantoprazole Sodium sesquihydrate is added and cooling Zone. Suspended homogeneously. The Suspension is prilled in the molten state, and the drops thus produced are solidified in a Example 10 cooling Zone. 15 18 g of cetyl palmitate, 40 g of Solid paraffin and 2 g of Example 4 are converted into a clear melt. The clear melt is cooled to 56-60° C. 10 g of pantoprazole sodium sesquihy 52.0 g of solid paraffin, 30.3 g of cetyl alcohol and 0.2 g of drate are introduced and homogenized until a uniform Sus Stearylamine are converted into a clear melt. 5.0 g of povidone pension results. The Suspension is prilled in the molten state is dissolved in the clear melt. At a temperature between in a prilling unit (from Brace) with vibrating nozzles, and the 56-60° C. 12.5g of pantoprazole sodium sesquihydrate is resulting drops are solidified in a cooling Zone. added and Suspended homogeneously. The Suspension is Example 11 prilled in the molten state, and the drops thus produced are Solidified in a cooling Zone. 50 g of solid paraffin and 40g of cetyl palmitate (Cutina(R) 25 CP) are converted into a clear melt at 100°C. The clear melt Example 5 is cooled to 50-60° C. 10 g of pantoprazole sodium sesquihy drate are introduced and Suspended homogeneously. The Sus 77.2 g of cetyl alcohol and 0.3 g of stearylamine are con pension is prilled in the molten state in a prilling unit (from verted into a clear melt. 10.0 g of povidone is dissolved in the Brace) with vibrating nozzles (200um nozzle), and the result clear melt. At a temperature between 56-60° C. 12.5 g of 30 ing drops are solidified in a cooling Zone. pantoprazole sodium sesquihydrate is added and Suspended homogeneously. The Suspension is prilled in the molten state, Example 12 and the drops thus produced are solidified in a cooling Zone. 50 g of solid paraffin and 40g of cetyl alcohol are converted Example 6 35 into a clear melt at 100° C. The clear melt is cooled to 50-60° C. 10g of pantoprazole sodium sesquihydrate are introduced 47 g of Solid paraffin, 40 g of glyceryltripalmitate (Dyna and Suspended homogeneously. The Suspension is prilled in san 116, from Hils) and 3 g of sitosterol are converted into a the molten state in a prilling unit (from Brace) with vibrating clear melt at 100° C. and cooled to 55-60° C. 10 g of lanso nozzles (200um nozzle), and the resulting drops are solidified prazole are added and Suspended homogeneously. The Sus 40 in a cooling Zone. pension is put in the feed container of a prilling unit (from Example 13 Brace) and prilled from a 200 um nozzle at about 0.1 bar. A periodic vibration with a frequency of about 390 HZ is trans 50 g of solid paraffin and 40g of glyceryl trimyristate are mitted to the nozzle head during this. The resulting drops are converted into a clear melt at 100°C. The clear melt is cooled solidified in a cooling Zone with air at a temperature of -30° 45 to 50-60° C. 10 g of pantoprazole sodium sesquihydrate are C. introduced and Suspended homogeneously. The Suspension is prilled in the molten state in a prilling unit (from Brace) with Example 7 vibrating nozzles (200um nozzle), and the resulting drops are Solidified in a cooling Zone. 15 g of glyceryl trimyristate (Dynasan 114), 15 grams of 50 glyceryl tripalmitate (Dynasan 116), 50 grams of Solid par Example 14 affin and 5 g of cholesterol are converted into a clear melt at about 100° C. The clear melt is cooled to about 55-65° C. 15 47 g of Solid paraffin, 40 g of glyceryl tripalmitate (Dyna g of rabeprazole are added, the active ingredient is uniformly san 116, from Hills) and 3 g of sitosterol are converted into a dispersed, and the homogeneous Suspension is prilled as in 55 clear melt at 100° C. and cooled to 55-60° C. 10 g of lanso example 6. prazole are added and Suspended homogeneously. The Sus pension is put into the feed container of a prilling unit (from Example 8 Brace) and prilled from a 200 um nozzle at about 0.1 bar. A periodic vibration with a frequency of about 390 HZ is trans 10 g of glyceryl tripalmitate (Dynasan 116), 20g of glyc 60 mitted to the nozzle head during this. The resulting drops are eryl trimyristate (Dynasan 114), 52 g of solid paraffin and 3 g solidified in a cooling Zone with air at a temperature of -30° of sitosterol are converted into a clear melt at about 100° C. C. The clear melt is cooled to 55-65°C. 15 g of omeprazole Mg are added and Suspended homogeneously. The Suspension is Example 15 put in the feed container of a prilling unit (from Brace) and 65 prilled through a 200 um nozzle at 90 mbar. A periodic vibra 30g of tristearin, 60 g of solid paraffin and 4 g of sitosterol tion with a frequency of about 400 Hz is transmitted to the and 0.07 g stearylamine are converted into a clear melt. The US 7,951,398 B2 37 38 clear melt is cooled to 56-60° C. 15 g of pantoprazole sodium suitable vibration prilling unit (conditions: 200 or 350 um sesquihydrate are introduced and homogeneously dispersed. nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). The Suspension is prilled in the molten state in prilling unit (from Brace) with vibrating nozzles, and the resulting drops Example 23 5 are solidified in a cooling Zone. 50 g of cetyl alcohol, 5g of glyceryl monostearate, 10g of cetyl palmitate, 10 g of glyceryl tristearate and 24.5 g of Example 16 paraffin are converted into a clear melt at about 90° C. 0.5g of roflumilast is added, and the mixture is stirred until it is a clear 17.5 g of glyceryl trimyristate (Dynasan 114), 67.5 g of solution. The clear melt is prilled at about 70° C. in a suitable solid paraffin and 5 g of cholesterol are converted into a clear 10 vibration prilling unit (conditions: 200 or 350 um nozzle, melt at about 100° C. The clear melt is cooled to about 55-65° pressure 100 to 170 mbar, frequency about 1 kHz). C. 10g of pantoprazole are added, and the active ingredient is uniformly dispersed, and the homogeneous Suspension is Example 24 prilled as in example 6. 15 70 g of cetyl alcohol and 29.5g of paraffin are converted Example 17 into a clear melt at about 90° C. 0.5g of roflumilast is added, and the mixture is stirred until it is a clear solution. The clear melt is prilled at about 75 to 80°C. in a suitable vibration 98 g of cetyl alcohol and 1 g of solid paraffin are converted prilling unit (conditions: 200 or 350 um nozzle, pressure 100 into a clear melt at about 90° C. 1 g of roflumilast is added, and to 170 mbar, frequency about 1 kHz). the mixture is stirred until it is a clear solution. The clear melt is prilled at about 70° C. in a suitable vibration prilling unit Example 25 (conditions: 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). 97.7 g of cetyl alcohol and 0.3 g of ethylcellulose are converted into a clear melt at about 90° C.2 g of pumafentrine Example 18 25 is added, and the mixture is stirred until it is a clear Solution. The clear melt is prilled at about 75 to 80° C. in a suitable 90 g of glyceryl monostearate are converted into a clear vibration prilling unit (conditions: 200 or 350 um nozzle, melt at about 90° C. 10 g of roflumilast is added, and the pressure 100 to 170 mbar, frequency about 1 kHz). mixture is stirred until it is a clear solution. The clear melt is 30 Example 26 prilled at about 70° C. in a suitable vibration prilling unit (conditions: 200 or 350 um nozzle, pressure 100 to 170 mbar, 69 g of cetyl alcohol, 5g of cetyl palmitate, 10g of glyceryl frequency about 1 kHz). tristearate and 15 g of paraffin are converted into a clear melt at about 90° C. 1 g of pumafentrine is added, and the mixture Example 19 35 is stirred until it is a clear solution. The clear melt is prilled at about 70° C. in a suitable vibration prilling unit (conditions: 88 g of glyceryl myristate and 11.2 g of paraffin are con 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency verted into a clear melt at about 90° C. 0.8g of roflumilast is about 1 kHz). added, and the mixture is stirred until it is a clear solution. The clear melt is prilled at about 70° C. in a suitable vibration 40 Example 27 prilling unit (conditions: 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). 40 g of cetyl alcohol. 7 g of cetyl palmitate, 33 g of glyceryl tristearate and 15 g of paraffin are converted into a clear melt Example 20 at about 90° C. 5g of (7R,8R,9R)-2,3-dimethyl-8-hydroxy 45 7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo 96 g of cetyl alcohol and 2 g of ethylcellulose are converted 1.2-h1.7naphthyridine are added, and the mixture is into a clear melt at about 90° C.2 g of roflumilast is added, and stirred until it is a clear solution. The clear melt is prilled at the mixture is stirred until it is a clear solution. The clear melt about 70° C. in a suitable vibration prilling unit (conditions: is prilled at about 70° C. in a suitable vibration prilling unit 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency (conditions: 200 or 350 um nozzle, pressure 100 to 170 mbar, 50 about 1 kHz). frequency about 1 kHz). Example 28 Example 21 41 g of cetyl alcohol. 7 g of cetyl palmitate, 33 g of glyceryl 84 g of glyceryl monostearate and 8 g of paraffin are 55 tristearate and 17 g of paraffin are converted into a clear melt converted into a clear melt at about 90° C. 8 g of roflumilast at about 90° C. 2 g of (7R,8R,9R)-2,3-dimethyl-8-hydroxy is added, and the mixture is stirred until it is a clear Solution. 7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo The clear melt is prilled at about 70° C. in a suitable vibration 1.2-h1.7naphthyridine are added, and the mixture is prilling unit (conditions: 200 or 350 um nozzle, pressure 100 stirred until it is a clear solution. The clear melt is prilled at to 170 mbar, frequency about 1 kHz). 60 about 70° C. in a suitable vibration prilling unit (conditions: 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency Example 22 about 1 kHz). 59 g of glyceryl monostearate, 20g of cetyl palmitate and Example 29 20g of paraffin are converted into a clear melt at about 90° C. 65 1 g of roflumilast is added, and the mixture is stirred until it is 41 g of cetyl alcohol. 7 g of cetyl palmitate, 33 g of glyceryl a clear solution. The clear melt is prilled at about 70° C. in a tristearate and 17 g of paraffin are converted into a clear melt US 7,951,398 B2 39 40 at about 90° C. 2 g of (7R,8R,9R)-2,3-dimethyl-8-hydroxy melt. At a temperature between 56-60° C. 10.0 g of pantopra 7-(2-methoxyethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo Zole sodium sesquihydrate is added and Suspended homoge 1.2-h1.7naphthyridine are added, and the mixture is neously. The suspension is prilled in the molten state at 60°C. stirred until it is a clear solution. The clear melt is prilled at and the drops thus produced are solidified in a cooling Zone. about 70° C. in a suitable vibration prilling unit (conditions: Example 37 200 or 350 um nozzle, pressure 100 to 170 mbar, frequency about 1 kHz). 46.7 g of cetostearylic alcohol, 4 g of vinylpyrollidone/ vinyl acetate copolymer, 23 g solid paraffin, 0.3 g of sodium Example 30 Stearate and 1 g sitosterol are converted into a clear melt. At a 10 temperature between 60-65° C. 10.0 g of pantoprazole 38g of glyceryl tripalmitate, 2 g of cholesterol and 59.5g Sodium sesquihydrate is added and Suspended homoge of paraffin are converted into a clear melt at about 100° C. neously. The suspension is prilled in the molten state at 60 to Then 0.5g of ciclesonide is added, and the melt is prilled at 65° C. and the drops thus produced are solidified in a cooling ZO. about 75°C. in a suitable vibration prilling unit (conditions: 15 100 um nozzle, pressure 100 to 1.70 mbar, frequency about Example 38 1.3 kHz). 39.9 g of cetyl alcohol, 3 g of vinylpyrollidone/vinyl Example 31 acetate copolymer, 20g of cetyl palmitate, 2 g cholesterol, 17 g Solid paraffin and 0.1 g of sodium Stearate are converted into 38 g of glyceryl tripalmitate, 10 g of cetyl alcohol. 2 g of a clear melt. At a temperature between 56-60° C. 18.0 g of cholesterol and 49.5g of paraffin are converted into a clear pantoprazole sodium sesquihydrate is added and Suspended melt at about 100°C. Then 0.5g of ciclesonide is added, and homogeneously. The Suspension is prilled in the molten state the melt is prilled at about 75° C. in a suitable vibration at 60° C. and the drops thus produced are solidified in a prilling unit (conditions: 100 um nozzle, pressure 100 to 170 cooling Zone. mbar, frequency about 1.3 kHz). 25 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 acetate copolymer, 25g of cetyl palmitate, 1 g sitosterol, 15 g. g of vinylpyrollidone/vinyl acetate copolymer and 2 g of 30 Solid paraffin and 0.1 g of sodium Stearate are converted into pumafentrine are converted into a clear melt. The clear melt is a clear melt. At a temperature between 56-60° C. 15.0 g of prilled at about 60°C. with a nozzle and the resulting drops pantoprazole sodium sesquihydrate is added and Suspended are solidified by cooling. homogeneously. The Suspension is prilled in the molten state at 60° C. and the drops thus produced are solidified in a Example 33 35 cooling Zone. The preparations obtained as in examples 1-39 have a 30g glyceryl trimyristate, 45g glyceryl monostearate and particle size in the range 50-700 um. It is possible, for 20 g cetyl alcohol are converted into a clear melt. 5 g of example by varying the processing conditions, to obtain roflumilast is added, and homogeneously dispersed. The melt larger particles. is prilled at about 65° C. and the resulting drops are solidified 40 Production of the Dosage Forms in cooling Zone. Example A Example 34 134.7 g of mannitol, 30 g of Kollidon R. 30 and 20 g of 80 g cetostearyl alcohol, 0.5 g Sodium Stearate, 5 g of 45 Xanthan are mixed dry. The mixture is granulated with water vinylpyrollidone/vinyl acetate copolymer and 12.5g of glyc in a fluidized bed granulator. Granules with a particle size of erol trimyristate are converted into a clear melt at about 70° C. 0.8-1.5 mm are obtained and are mixed with the preparation 2 g of (7R,8R,9R)-2,3-dimethyl-8-hydroxy-7-(2-methoxy (125 g) obtained as in example 1. The mixture obtained in this ethoxy)-9-phenyl-7,8,9,10-tetrahydroimidazo 1.2-h1.7 way is packed into bags (sachet) or—ifrequired together with naphthyridine is added at 60° C. and dispersed homoge 50 further tablet excipients—compressed to tablets in a manner neously. The mixture is prilled at 60° C. and the resulting known to the skilled worker. drops solidified in a cooling Zone. Example B Example 35 55 An amount which corresponds to 22.6 mg of pantoprazole 20g glyceryl trimyristate, 14.5g glyceryl monostearate, 60 magnesium of the preparation obtained as in example 2 is g cetyl alcohol and 5 g vinylpyrollidone/vinyl acetate copoly mixed with 500 mg of lactose and 100 mg of xanthan. The mer are converted into a clear melt at 70° C. 0.5 g of mixture is then mixed with flavoring Substances (Sweetener, ciclesonide is added and homogeneously dispersed. The clear flavor) depending on the individual sense of taste, and there melt is prilled and the resulting drops are solidified in cooling 60 after packed in a bag (sachet). A Suspension for oral intake is ZO. obtained by dissolving the contents of a bag in a glass of water with stirring. Example 36 Example C 56.7 g of cetyl alcohol, 3 g of vinylpyrollidone/vinyl 65 acetate copolymer, 15 g of solid paraffin, 15 g of cetyl palmi An amount corresponding to 45.2 mg of pantoprazole tate and 0.1 g of sodium Stearate are converted into a clear Sodium sesquihydrate of the preparation from example 3 is US 7,951,398 B2 41 42 mixed with the appropriate amount of lactose. This mixture is and addition of flavoring Substances and Sweeteners, the mix mixed with a mixture of citric acid and sodium carbonate. ture obtained in this way is directly compressed to an effer After addition of a suitable lubricant (for example sodium vescent tablet. Placing the tablet in a glass of water results, stearyl fumarate) and addition of one or more suitable flavor after dissolution thereof, in a Suspension ready for drinking. ing substances, the resulting mixture is compressed directly 5 (without further granulation) to an effervescent tablet. A sus Example K pension for oral intake is obtained by dissolving a tablet in a glass of water. 100 mg of a preparation from example 20 are mixed with 1.9 g of lactose and packed into 10 hard gelatin capsules. Example D 10 Example L An amount corresponding to 45.2 mg of pantoprazole Sodium sesquihydrate of the preparation of example 4 is 500 mg of a preparation from example 21 are granulated mixed with lactose to improve the flow properties. The mix with water with 15 g of mannitol and 4 g of Kollidon. The ture is packed together with Suitable other active ingredients 15 granules Sufficient for 100 single doses are packed into cap (for example amoxicillin or NSAIDs in usual dosage forms) Sules. into hard gelatin capsules of a suitable size. Example M Example E 2O 1 g of a preparation from example 26 are mixed with 0.2g 300 mg of lactose are added to an amount corresponding to of Xanthan, 0.1 g of saccharin Sodium, 1.5g of mannitol and 30 mg of lansoprazole of the preparation of example 6. The 0.3 g of dry orange flavor and packed into a Sachet. The two components are mixed with citric acid and sodium car suspension after stirring into about 100 ml of water is ready bonate and, after addition of a suitable lubricant (for example for use. Sodium Stearyl fumarate) and addition of Suitable flavoring 25 Substances, compressed to a tablet. Example N Example F 200 mg of a preparation from example 27 are mixed with 670 mg of Destab95SE, 2270 mg of Pearlitol 300 DC and 50 450 mg of sucrose and 300 mg of xanthan are added to an 30 mg of crospovidone in a free-fall mixer. 10 mg of magnesium amount corresponding to 30 mg of rabeprazole of the prepa Stearate are then added through a screen. This mixture is ration of example 7. The components are mixed, and masking pressed in a tablet press. flavors are added. The granules are packed into Sachets. The contents of a Sachet can be put into a glass of water and is Example O ready for use after stirring. 35 40 mg of a preparation from example 30 are mixed with Example G 500 mg of MagGran CC, 200 mg of Karion and 70 mg of crospovidone in a free-fall mixer. 12 mg of magnesium Stear 60 grams of the preparation of example 8 are mixed dry ate are then added through a screen, followed by brief mixing with 140 grams of mannitol, 30 grams of Kollidon 30 and 20 40 again. The mixture obtained in this way is compressed in a grams of Xanthan. The mixture is granulated with water in a tablet press. fluidized bed granulator. Granules with a particle size of 0.8-1.5 mm are obtained. The mixture obtained in this way is packed into bags (sachets). 1. Preparation from example 22 12.500 mg 45 2. Lactose-1-hydrate 172.125 mg Example H 3. Corn starch 45.000 mg 4. Polyvidon (R) 25 12.500 mg 5. Polyvidone insoluble 12.500 mg 140 g of mannitol, 30 g of Kollidon 30 and 20 g of xanthan 6. Flavors 2.500 mg are mixed dry and then granulated with water in a fluidized 7. Aspartame 0.375 mg bed granulator. The resulting granules are screened. The 50 8. Citric acid 2.500 mg screen fraction from 0.8 to 1.5 mm is mixed with 6.98 g of 9. Magnesium Stearate 2.500 mg preparation from example 18 and packed into bags (sachets). Total 262.500 mg Example I 55 Production: 2. and 3. are granulated with a solution of 4. 5g of a preparation of example 17 are mixed with 50 g of The granules are dried and screened. 5. is admixed using a lactose and 8 g of Xanthan. Sweeteners and flavors are added free-fall mixer, and then 6. 7. and 8. are incorporated. 1. is to the mixture, and it is packed into bags (Sachets). A suspen admixed and finally 9. is briefly admixed using a free-fall sion ready for drinking is obtained by stirring a bag into a mixer. The mixture obtained in this way is compressed in a glass of water. 60 tablet press. Example J 1. Preparation from example 23 25.000 mg 12.5 mg of a preparation from example 19 are mixed with 2. Cellactose (R) 229.625 mg the appropriate amount of lactose. This mixture is mixed with 65 3. Sodium carboxymethylstarch 12.500 mg a mixture of sodium carbonate and citric acid. After addition 4. Flavors 2.500 mg of a suitable lubricant (for example sodium stearyl fumarate) US 7,951,398 B2 44 -continued 5. The preparation according to claim 1, wherein the excipient matrix is composed of at least one solid paraffin 5. Aspartame 0.375 mg 6. Citric acid 2.500 mg together with one or more excipients selected from the group 7. Magnesium Stearate 2.500 mg consisting of a fatty alcohol, a triglyceride, a partial glyceride and a fatty acid ester. Total 275.000 mg 6. The preparation according to claim 5 in which the active ingredient is i) present in a matrix composed of a mixture Production: 2. and 3. are mixed. 4.5. and 6. are incorpo comprising at least one fatty alcohol and at least one solid rated. 1. is admixed and finally 9. is briefly admixed using a paraffin, ii) present in a matrix composed of a mixture com free-fall mixer. The mixture obtained in this way is com 10 prising at least one triglyceride and at least one solid paraffin, pressed in a tablet press. iii) present in a matrix composed of a mixture comprising at least one partial glyceride and at least one solid paraffin or iv) present in a matrix composed of a mixture comprising at least 1. Preparation from example 22 12.500 mg 15 one fatty acid ester and at least one solid paraffin. 2. Lactose-1-hydrate 49.660 mg 7. The preparation according to claim 1, wherein the micro 3. Corn starch 13.390 mg 4. Polyvidon (R) K90 1.300 mg spheres have a particle size in the range of 50-500 um. 5. Mannit 32.240 mg 8. The preparation according to claim 1, wherein the micro 6. PVP insoluble 12.890 mg spheres have a particle size in the range of 50-400 um. 7. Flavors 0.330 mg 9. The preparation according to claim 1, wherein the partial 8. Magnesium Stearate 1.650 mg glyceride is selected from the group consisting of glycerol Total 123.960 mg monostearate, glycerol distearate, glycerol monopalmitate, glycerol dipalmitate and mixtures thereof. Production: 2. and 3. are granulated with a solution of 4. 10. The preparation according to claim 9, wherein the The granules are dried and screened. 1.5. 6. and 7... is admixed 25 partial glyceride is glycerol monostearate. using a free-fall mixer, and then 8. is briefly admixed using a 11. The preparation according to claim 1, wherein the fatty free-fall mixer. The mixture obtained in this way is com alcohol is selected from the group consisting of cetyl alcohol, pressed in a tablet press. myristyl alcohol, lauryl alcohol, Stearyl alcohol and mixtures thereof. 30 12. The preparation according to claim 11, wherein the fatty alcohol is cetyl alcohol. 1. Preparation from example 22 12.500 mg 2. Lactose-1-hydrate 70.300 mg 13. The preparation according to claim 1, obtainable by 3. Potatoe starch 19.480 mg prilling a solution or dispersion of the active ingredient in the 4. Corn starch 2.370 mg melt of the excipients using a vibrating nozzle. 5. sodium carboxymethylstarch 1.900 mg 35 6. Flavors 0.330 mg 14. A method of manufacturing a preparation according to 7. Magnesium Stearate 0.950 mg claim 1, comprising the step of prilling a solution or disper sion of the active ingredient in the melt of the excipients using Total 105.930 mg a vibrating nozzle. 40 15. A pharmaceutical dosage form comprising a prepara Production: 2. and 3. are granulated with a solution of 4. tion as claimed in claim 1 and further comprising one or more The granules are dried and screened. 1. 5. and 6. is admixed pharmaceutical excipients. using a free-fall mixer, and then 7. is briefly admixed using a 16. The pharmaceutical dosage form according to claim free-fall mixer. The mixture obtained in this way is com 15, which is selected from the group consisting of Suspen pressed in a tablet press. 45 sions, gels, tablets, coated tablets, multi-component tablets, The invention claimed is: effervescent tablets, rapidly disintegrating tablets, powders in 1. A preparation in which an active ingredient selected Sachets, coated tablets, capsules, solutions and Suppositories. from the group of PDE4 inhibitors is essentially uniformly 17. The pharmaceutical dosage form as claimed in claim 16 dispersed or dissolved in an excipient matrix comprising one in the form of a rapidly disintegrating tablet, wherein the or more excipients selected from the group consisting of a 50 excipients are excipients which bring about rapid disintegra fatty alcohol, a triglyceride, a partial glyceride and a fatty acid tion of said tablet. ester, wherein the preparation is in the form of microspheres. 18. The tablet as claimed in claim 17, further comprising 2. The preparation according to claim 1, further comprising one or more excipients selected from the group consisting of one or more additional other pharmaceutically Suitable lubricants, flavors, flavoring Substances and Surface-active excipients in the excipient matrix. 55 Substances. 3. The preparation according to claim 2, further comprising 19. The pharmaceutical dosage form according to claim one or more other excipients selected from the group consist 16, which is a suspension or solution. ing of polymers and sterols in the excipient matrix. 20. A suspension or solution according to claim 19, com 4. The preparation according to claim 1, wherein the prising one thickener or a mixture of two or more thickeners. excipient matrix comprises one or more excipients selected 60 from the group consisting of a fatty alcohol, a triglyceride and a partial glyceride.