US 2004O115258A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0115258A1 Stroppolo et al. (43) Pub. Date: Jun. 17, 2004

(54) ORAL PHARMACEUTICAL COMPOSITIONS (30) Foreign Application Priority Data CONTAINING CYCLODEXTRINS AS TASTE MASKINGAGENT Nov. 23, 2000 (GB)...... OO28575.9 (76) Inventors: Federico Stroppolo, Aldesago (CH); Publication Classification Franco Ciccarello, Mezzovico (CH); Rita Milani, Cannobio (CH); Lorenzo (51) Int. Cl." ...... A61K 31/724; A61 K 9/20 Bellorini, Monate (IT) (52) U.S. Cl...... 424/465; 514/58 Correspondence Address: (57) ABSTRACT Synnestvedt & Lechner 2600 Aramark Tower The application discloses oral pharmaceutical compositions 1101 Market Street which are tasted in the mouth during administration. Fast Philadelphia, PA 19107-2950 (US) dissolving tablets, chewable tablets and effervescent disper Sions are exemplified. To mask the taste of unpleasant (21) Appl. No.: 10/432,575 tasting active ingredients, it has been found that blending with cyclodextrin without the conventional complex forma (22) PCT Filed: Nov. 23, 2001 tion is effective. Consequently more economical modes of manufacture Such as Simple granulation and dry blending (86) PCT No.: PCT/GB01/05212 can be used. US 2004/0115258A1 Jun. 17, 2004

ORAL PHARMACEUTICAL COMPOSITIONS SUMMARY OF THE INVENTION CONTAINING CYCLODEXTRINS AS TASTE 0007. The present invention is based on the wholly MASKINGAGENT unexpected finding that cyclodextrin can be effective to FIELD OF THE INVENTION mask the taste of pharmaceutically active agents without the formulation of inclusion complexes between the cyclodex 0001. The present invention relates to the use of cyclo trin and the active agent, a Step conventionally thought to be dextrin for taste-masking in orally administered pharmaceu essential. This has important implications in terms of both tical compositions, to the pharmaceutical compositions products and production processes as regards simplicity and themselves and to processes for making them. economy. BACKGROUND 0008 Thus, in one aspect the present invention provides use of a cyclodextrin to mask the taste, and particularly the 0002 Cyclodextrins are cyclic oligosaccharides formed unpleasant taste, of an active ingredient in a pharmaceutical from O-(1,4)-linked D-glucopyranose units. C, Band Y-cy preparation adapted for oral administration, wherein the clodextrins consist of Six, Seven and eight units respectively. active ingredient in the preparation is Substantially uncom The molecules have a toroidal shape, with a hydrophobic plexed by the cyclodextrin. central cavity and a relatively hydrophilic outer Surface. This Structure enables cyclodextrins to bind appropriately sized 0009. A second aspect is a process of making a solid oral non-polar guest molecules, or moieties of guest molecules, pharmaceutical preparation which includes blending the within the hydrophobic central cavity, to form clathrate active ingredient-and particularly one that has an unpleas complexes. Because the exterior of the cyclodextrin is ant taste-with cyclodextrin under conditions which do not relatively hydrophilic, formation of Such complexes may promote complex formation between the cyclodextrin and therefore be used to increase the solubility of otherwise active ingredient. poorly Soluble molecules. 0010) A further aspect of the invention is the use, in the 0003. There has long been an interest in cyclodextrins in oral administration of a Solid pharmaceutical preparation of the pharmaceutical industry. They have been used to cyclodextrin blended but not complexed with active ingre increase the solubility, stability and bioavailability of a dient in the preparation to mask the taste of the uncomplexed variety of active drug molecules in drug formulations, and active ingredient. also to mask the taste of certain active ingredients, by 0011. A further aspect is the use, in the preparation of a exploiting this formation of complexes between the active Solid oral pharmaceutical preparation of the kind described, ingredient and the cyclodextrin. of cyclodextrin as a taste-masking agent for uncomplexed 0004. There is currently an increasing demand for orally active ingredient contained in the preparation. These and administrable formulations of pharmaceuticals, because of other aspects of the invention are set out in the claims. good associated patient compliance. However, conventional 0012 AS regards the nature of the active ingredient, the Solid tablet formulations which are Swallowed whole are invention may have use in any Situation in which it has a often not ideal for administration of active ingredients. taste which is Sought to be masked, and in particular when Many patients, especially the very young or old, find it this is an unpleasant or very unpleasant taste. difficult to Swallow tablets whole, and bioavailability of the active ingredient can be poor. More preferable therefore are 0013 We have noted that in the prior art EP0839 528 A effervescent or other soluble formulations which can be (Staroil Ltd.) dicloses use of B-cyclodextrin in mouth dissolved and drunk, chewable or fast melting tablets, and Soluble N-acetylcysteine compositions, in order to mask (by Slow release formulations Such as Sub-lingual tablets, which complexing) the taste of a Sulphated degradation product of are placed under the tongue and enable absorption of the N-acetylcysteine. Thus the cyclodextrin was disclosed for active ingredient into the bloodstream through the oral use to mask the taste not of the active ingredient, but of a mucosa. Such formulations may reduce the time taken for degradation product formed during Storage of the composi drugs to be taken up and begin to act, and increase the tion. Thus, the present proposals may not extend to prepa bioavailability of the drug. However patient compliance rations of kind described in which the active ingredient is may be low when the active ingredients have a markedly N-acetylcysteine. unpleasant taste. 0014. However, in general the invention may be used 0005 What is described here generally as “unpleasant with a wide variety of active ingredients. A non-exhaustive taste’ may be any of for example a bitter taste, burning taste, list of active ingredients whose taste could usefully by Salty taste or other generally revolting taste. It is well-known improved or masked include the following. in the pharmaceutical field that Some active ingredients taste 0015 Examples not limited of categories of actives that So Severely unpleasant that patient compliance in a tasted could be improved from taste point of view are: oral formulation is out of the question unless the taste can be masked. 0016. Abortifacients e.g. E2, Mife 0006 AS mentioned above, it is known that drug palat pristone ability can be improved by formation of cyclodextrin inclu 0017 ACE Inhibitors, e.g. Benazepril, Captopril, Sion complexes of the unpalatable active ingredient. See for Delapril, Enalapril, Imidapril, Ramipril: example U.S. Pat. No. 5,206,025 describing special freeze dried oral formulations of cyclodextrin complexes of active 0018 C-Adrenergic e.g. Adrenolone, ingredient, designed to disintegrate rapidly in the mouth and , , Epinephrine, , with masking of unpleasant-tasting active ingredient. Fenoxazoline, Ibopamine, , NafaZo US 2004/0115258A1 Jun. 17, 2004

line, , Tetrahydrozoline, TramaZO Clobenzorex, Clortermine, Fenfluramine, Norpseu line, Phenyilpropanolamine, , doephedrine, Pentorex, Phendimetrazine, Phenme Xylomethazoline trazine; 0019 B-Adrenergic AgonistS-.: Albuterol, bam 0033 Anthelmintics e.g. Arecoline, Aspidin, Aspi buterol, Clenbuterol, Clorprenaline, Dopexamine, dinol, Becanthone, Hycantone,. Ephedrine, Epinephrine, Ethylnorepinephrine, F enoterolo, F ormoterolo, Isoproterenolo, 0034 Antiallergics e.g. Amlexanox, Astemizole, Mabuterolo, Metaproterenolo, Methoxiphenamine, , Cromolyn, Fempiprane, Ibudilast, , , Oxatomide, Repirinast, Oxyfedrine, Reproterolo, Salmeterol, Soterenol, TaZanolast, HyStamine, B Beclomethasone, Dexam Terbutaline, Tulobuterol, Xanoterol ethasone, , , ; 0020 C. Adrenergic Blockers e.g. Dapiprazole, Fen Antialopecia agent. e.g. Cioteronel, Minoxidil Spiride, Nicergoline, , Yohimbine, 0035 Antiamebics e.g. Arsthinol, Carbasone, Chlor 0021 B-Adrenergic Blockers e.g.: Acebutolol, betamide, Chlorphenoxamide, Emetine, fumag A1prenolol, Atenolol, Befnolol, Betaxolol, Bpin gilline, Iodoquinol, Verapamil dolol, Bupranolol, Carazolol, Carteolol, Celiprolol, 0036 Antiarrhythmics e.g. Acebutol, Adenosine, Indenolol, Levobunolol, Mepindolol, Metipranolol, Ajmaline, Alprenolol, Amiodarone, Atenolol, Bupra Moprolol, Pindolol, Practolol, , Timolol; nolol, Carazolol, Carteolol, Cloranolol, Indenolol, 0022 Adrenocortical Steroids Ipratropium , Lidocaine, Pindolol, Pro pafenone, Propranoll, Quinidine, Timolol, Vera 0023 Adrenocorticotrop Hormones e.g. ACTH pamil, CoSintropin 0037 Antiarteriosclerotic e.g. Pyridinol ; 0024. deterrents e.g. Calcium lanamide Cit 0038 Antiarthritics/Antirheumatics e.g. Actarit, rate, Auranofin. Aurothioglucose, aurothioglicande, AZa 0025 Aldose reductase inhibitors e.g. Epalrestat, thioprine, Chloroquine, Gold Sodium thiosulfate, Tolrestat, Zopolrestati Hydroxchloroquine, Methotrexate: 0026 Aldosterone Antagonists e.g. Canrenone, 0039 Antiasthmatics e.g. Azelastine, Cromolyn, Spironolattone;. Ibudilast, Ketotifen, Montelukast, OXotomide, Pran lukast, , Zafirlukast, Zileuton, Beclom 0027 Anabolics e.g. Androisoxazole, Androstene ethasone, , , Flunisolide, diol, Methandriol, Methenolon, Methiltrienolone, Triamcinolon acetonide. Nandrolone; 0040 Antibacterials e.g. Amikacin, Gentamicin, 0028 , (Narcotic), e.g. , Kanamycin Neomicin, Tobramycin, Chlorampheni Buprenorphone, Codine and its derivatives, Fentanil, col, Thiamphenicol, Rifamide, Rifampin, Rifaximin, Meperidine, , and its dervia Cefaclor, Cefamandole Cefazolin, Cefime, Cefazo tives , Propiram, Propoxiphene, Sufen lin, Amoxicillin, Ampicillin, Oxacillin, Lindomycin, tanil: Erythromycin, Gramicidin, Teicoplanin, Vancomy cin, Chlortetracycline Doxycyline, Tetracycline, 0029 Analgesict (Non Narcotic) e.g. , Trimetoprim, Nifuradene, Nitrofurantoin, Ciprof Acetaminophen, AcetySalicyic acid, , loxacin, Ofloxacin, Lomefloxacin, Benzylsulamide, , Antypirine, , Benoxopro Chloraminet, Mafenide, Sulfabenzamide, Sulfaceta fen, , , , Carbi mide, Sulfadiazine, Sulfadoxine, Sulfaguanidine, phene, Chlortenoxazin, Cholin Salicyate, Clometa Sulfalene, Sulfanilamide, Sulfanylurea, Sulfafazolel cin, , Croropamide, Diflunisa1, , Sulfathiazole, AcedapSone, DapSone, Solasulfone, , , Flufenamiv acid, Flurbipro Ethinamide, Furonazide, Isoniazide, Streptomycin fen, Ibufenac, Salicylate, Indomethacin, , , , , 0041 Anticholinergics, e.g. Atropine, Fentomum , , , Propy bromide, Homatropine, Hyoscyamine, Ipratropium , Sutrofen, , Terofenamate, bromide, Isopropramide iodide, Scopolamine, Tropi , , Viminol; camide: 0030 Androgens e.g. Boldenone, Cloxotestoster 0042 Anticoagulants e.g. Acecumarol, Bromindi one, Mestanolone, Mesterolone, Methandros one, Clorindione, Columetarol, Dicumarol, tenolone, Norethandrolone, Normethandrone, Oxan Diphenadione, Fluindione, Heparin, Hirundin, Phen drolone, Oxymesterone, Oxymetholone, Prasterone, indione, Warfarin; Stanolone, Stanozolol, , 0043 e.g. Albutoin, Aloxidone, 0031 Angiotensin II antagonists e.g. Can Aminoglutethimide, Beclamide, Carbamazepine, desartan, EproSartan, IbeSartan, LOSartan, Va1Sartan: , Ethadine, Ethotoin, , Mephenytoin, , Nimethazepam, 0032) Anorexics, e.g. Aminorex, Amphecloral, , Paramethadione, Phenacemide, Phe Anphetamine, BenZphetamine, Chlorphentermine, nobarbital, Phenitoin, etc. US 2004/0115258A1 Jun. 17, 2004

0044 , i.e.: , Fencaine, 0058 Anti-inflammatry nonsteroidal i.e.: Etofe , , , , namate , Mecofilenamic Acid, Tolfe Rolyciprine, , Metralindole, Amytrip namic Acid, Aceclofenac, Alclofenac, Bromfenac, tiline, Clomipramide, Desipramide, , Sodium, Etodolac, Ibufenac, Indometha Imipramide, Trimipramide, , etc. cin, Pirazolac, , Tolimetin, , Ketorolac, Alminoprofen, Fenoprofen, , 0045 Antidiabetic, i.e.: Buformin, Phenformin, , Ketoprofen, Naproxen, , Beno Insulin, Carbutamide, Chlorpopamide, Glipizide, rylate, , , , etc. Phenbutamide, Tolazamide, Tolbutamide, Tolcycla mide etc. 0059 Antimalarial i.e.; chloroquine, Chlorprodua nil, Cinchonide, Cycloguanil, Quinidine, etc. 0046) Antidiarreal, i.e.: Acetorphan, , DifenoXin, Diphenoxylate, Loperamide, Mebiquine, 0060 Antimigraine i.e.: Dolasetron, Ergocornine, etc Ergocriptyne, Ergot, Ergotamine, Lomerizine, Sumatriptan, etc. 0047 Antidiuretic, i.e.: Desmopressin, Felypressin, Ornipressin, Vasopressin, etc. 0061 Antiparkinsonian i.e.: Amantadine, Bro mocriptine, , Levodopa, etc. 0048 Antidote, i.e.: Acetylcysteine, Cysteamine, 0062 Antipsychotic i.e.: Alizapride, Amilsulpiride, Methionine, Folinic Acid, etc.. Sulpiride, , Haloperidol, Acetophena 0049 Antidyskinetic, i.e.: Amantidine, Clonidine, Zine, Chlorpromazine, Fluphenazine, Perazine, etc. Haloperidol, Pimozide, Tetrabenazine etc. 0063 i.e.: Acetaminophen, Alclofenac, 0050 Antiemetic, i.e.: Alizapride, AZasentron, Ben , Benorilate, Indomethacin, etc. Zquinamide, Bromopride, Buclizine, Chlorpromazine, Cyclizine, Domperidone, Granis 0064 Antispasmodic i.e.: Aminopromazine, Fento etron, Meclizine, Metoclopramide, Ondansentron, nium Bromide, Rociverine, Tiropramide, etc. Prochlorerazine, Scopolamine, Sulpiride, Tropist 0065 Antitussive ie.: Cloperastine, and rOn, etc. derivetives, Dextromethorphan. Morclofone, etc. 0051 Antifungal i.e.: Butenafine, Butoconazole, 0066 Antiulcerative i.e.: , , Econazole, Fenticonazole, Miconazole, Tolciclate, , , , , Tolindate, Fluconazole, Buclosamide, Triacetin, etc. , etc.. 0052 Antiglaucoma i.e.: Acetozolamide, Betaxolol, 0067. i.e.: , , Bupranolol, etc.. Broazepam, , , , , etc.. 0053 Antigout i.e.: Allopurinol, Colchicine, Probenecid, Sulfipyrazone, etc. 0068 Bronchodilator i.e.: Albuterol, Bambuterol, Calbiterol, Clenbuterol, Clorprenaline, Ephedrine, 0054 Anthistaminic i.e.: Acrivastine, Bromphe Ephineprine, Folmoterol, Metaproterenol, Salme niramine, Chlorpheniramine, Dimethindene, Phe terol, Terbutaline, Ipratroprium Bromide, Teophill niramine, Tolpropamine, Clemastine, ine and derivatives, etc.. Diphenidramine, Medrilamyne, Cetirizine, Chlorcy clizine, Cinnarizine, Hidroxy Zine, Fenethazine, 0069 Calcium i.e.: Diltiazem, Vera Promethazine, Loratadine, , Astemizole, pamil, Amlodipine, Lacidipine, Micardipine, Nife AZelastine, Ebastine, FeXofenadine, Terfenadine, dipine, Nomerizine, etc. etc.. 0070 Cardiotonic i.e.: Digitalin, Digitoxin, 0055 Anthyperlipoproteinemic i.e. Cholesti Digoxin, , Uabain, Scillaren, etc. ramine, Benzofibrate, , , Genfi 0071 Choleretic i.e.: Cholic Acid, Cynerin, Dehy brozil, , , Niceritrol, Thyrox drocholic Acid, Dehoxycolic Acid, Taurocolic Acid, ine, Carnitine, ChondroitinSulfate, Ornithine, etc.. , etc. 0072 Cholinergic i.e.: Acetylcholine, Ben 0056 Anthypertensive i.e.: Bufuralol, Acebutolol, Zepirinium Bromide, Carbachol, Neostigmine, Phy Atenolol, Carteolol, Metoprolol, Moprolol, Pindolol, SoStigmine, etc. Propranolol, Timolol, Chlorthiazide, Cyclopenthi azide, Hydroflumethazide, Benazepril, Captopril, 0073 CNS stimolant i.e.: Amphetamine, Caffeine, Lisinopril, Ramipril, Amlodipine, Felodipine, Laci Fenozolone, Phentermine, etc.. dipine, Nicardipine, Nitrendipine, Bethnide, 0074) Diuretic ie: Bendroflumethiazide, Benzyl Budralazine, ; , Phentola hytrochlorothiazide, Chlorothiazide, Indapamide, mine, BunaZosin, PraZosin, Reserpine, Furosemide, Mersalil, Candrenone, Oleandrin, Spironolattone, Ajmaline, Fenoldopam, , Methildopa, Acetazolamide, Butazolamide, Clopramide, Furo Minoxidil, etc. Semide, ISOSorbide, etc.. 0057 Antihypotensive i.e.: Dopamine, Etilefrin, 0075 Dopamine receptor i.e.: Bromocrip , Synephrine, etc. tine, Cabercoline, Dopexamine, Fenoldopam, etc.. US 2004/0115258A1 Jun. 17, 2004

0.076 Dopaminep receptorp antagonist9. i.e.: Amisul Medrogestone, Medroxyprogesterone, Megestrol pride, Domperidone, Metoclopamide, Sulpiride, etc. acetato Norgesterone, Pentagestrone, , 0077 i.e.: Amylase, Lysozyme, Papain, etc.. etc.. 0097. Prolactin hinhibitor, i.e.: i.e: Bromocriptine, Cabergoline, LiSuride, Metergoline, Quinagoline, 0078 Expetorant i.e.: Ambroxol, Bromhexine, Car bocysteine, Guaiacol, Guaifenesin, etc.. etc.. 0098 Prostaglandin/Prostaglandin analog, i.e.: 0079 Gastric and Pancreatic secretion stimulant, i.e.: Carnitine Ceruletide etc. 0099 , , , , Limaprost, , , .E., 0080 Gastric proton pump inhibitor, i.e.: Lansopra Zole, Omeprazole, , etc. F etc.. 0100 Respiratory stimulant, i.e.: Almitrine, Beme 0081 Gastric secretion inhibitor, i.e.: Enterogas gride, Cropropamide, Dimorpholamine, Lobeline, trone, Octretide, , etc. Pyridopylline,etc. 0082 Gastroprokinetic, i.e.: Cinitapride, Cisapride, 0101 Retroviral transcriptase inhibitor, i.e.: Fenotozine, Loxiglumide, etc.. Delavirdine, Didanosine, Dideoxyadenosine, Lami 0083) Glucocorticoid, i.e.: Beclomethasone, Beth Vudine, Stavudine, Zidovudine ometasone, BudeSonide, Chloroprednisone, Clobeta 0102 /Hypnotic, i.e.: Accarbromal, Butoc Sone, Cortisone, Corticosterone, Deflazacort, Dex tamide, Di ethylbromoactamide, Niaprazine, Trime amethasone, Flumethasone, Fluocinolone toZine, , , , Amobar Acetonide, Fluazacort, Fuorometholone, bital, , Cyclopentobarbital, , Flunisolide, Fluprednisolone, Hydrocortisone, Mephobarbital, Narcobarbital, , Phe Methylprednisolone, , Prednisone, Tri nobarbital, , , , amcinolone etc. , , Lorttletazepam, 0084. Hemolytic, i.e.: Pheni1 hydrazine etc. Nitrazepam, , , Clomethia Zole Doxylamine, , , Meth 0085. H-receptor antagonist, i.e.: Cime aqualone, , etc. tidine, Ebrotidine, Famotidine, , Raniti dine, etc. 0103) Noradrenaline , i.e.: , Velanfaxine,etc. 0086 Laxative/Cathartic i.e.: Frangulin, phtaleine, PicoSulfate Sodium, etc. 0104 Serotonin reuptake agonist, i.e.: Buspirone, Eltoprazine, Ergotamine, Sumatriptan etc. 0087 antagonist, i.e.: Ibudilast, Mon telukast, Pranlukast, Zafirlukast etc. 0105 Serotonin receptor antagonist, i.e.: AZasen tron, Dolasentron, Granisentron, Ondasentron, 0088 Lipotropic, i.e.: Buserelin, Goserelin, Histre Ritanserin, Tropisentron, etc. lin, Leuprolide, Nafarelin, Triptorelin etc. 0106 Serotonin uptake inhibitor, i.e.: Fomexitine, 0089 Mineralcorticoid, i.e.: Aldosterone, Deoxy , etc.. corticosterone, Fludrocortisone etc.. 0107 Vasodilator, i.e.: Cinnarizine, Citicoline, 0090 inhibitor, i.e.: , Fenoxedil, Flunarizine, Lomerizine, Nicergoline, , , Selegeline, etc. Nimodipine, Papaverine, Amotriphene, Vincamine, Efloxate, Nitroglicerin, Pentrinitrol, Trapidil Brady 0091 Mucolitic, i.e.: Acetylcysteine, Bromexine, kinin, Inositol, Nicergoline, Pentifillyne, Tlazoline, Carbocysteine, LySOZime, Sobrerol, Tyloxapol, etc. etc. 0092 Muscle relaxant, i.e.: , Baclofen, 0.108 Vitamins, i.e.: Calcitriol, Ergosterol, Vitamin Curare, , Dandrolene bromide, Diaz D, D, D, AScorbic acid, B-Carotene, Vitamin B epam, Eperisone, Flumetramide, Mephenesin etc. Mephenaxolone, Methaxolone, Methocarbamol, Nimethazepam, Succyinylcholine Bromide Tet 0109 The solid pharmaceutical preparations of the razepam, Tubocurarine, etc. present inventions may take various forms. They may be buccal tablets adapted to dissolve in the mouth. Such tablets 0093 Narcotic Antagonist. i.e.: Amiphenazole, may be placed in the buccal cavity, on the tongue or between Naloxone, Naltaxone etc.. the cheek and gums, for dissolution over a period depending 0094) Nootropic, i.e.: , Besipiride, Pirac on the chosen excipients. One preferred embodiment is a etam, Vinconate, etc. fast-melting buccal tablets made from a fluidised-bed granu lated blend containing polyalcohol Such as is disclosed in 0095. Oxytocic, i.e.: Carboprost, Deaminooxytocic, our WO-A-99/04758. Ergonovine, Gemeprost, Methylergonovine, Oxyto cin, Prostaglandin E, Prostaglandin F" etc. 0110. Other suitable embodiments include Sublingual tablets, which are adapted to be placed under the tongue 0096 Progestogen, i.e.: Drospirenone, Dydrogester where the active ingredient can be absorbed directly into the one, Ethynodiol, Flurogestone acetato, Lynestrenol, blood Stream through the mucosa. US 2004/0115258A1 Jun. 17, 2004

0111. A further embodiment is a chewable tablet. Tech active blends prepared by Simple granulations using minimal niques and materials for making chewable tablets are well Solvent. These analyses showed both components retaining known. their original melting points, with no appearance of different 0112 A further embodiment is a preparation adapted to melting-point Solids which would indicate complex forma be dissolved or dispersed in a carrier Such as water for tion. Thus, particular embodiments of the present invention ingestion. Again, Suitable excipients for these purposes are are those in which the active ingredient is at least mostly, or well known and it may be necessary only to include the essentially, or Substantially entirely uncomplexed by the necessary cyclodextrin in the preparation. For example, cyclodextrin. Any Suitable method may be used for deter effervescent agents Such as bicarbonates may be included in mining this situation, although as explained above it is not the formulation. The preparation may be in the form of critical to the technical effectiveness of the cyclodextrin in tablets, granules or powder. The cyclodextrin for use accord taste masking. ing to the present invention may be an O, B, or Y-cyclodex trin. Besides the commonly available C, B, and Y-cyclodex 0117 Other pharmaceutical excipients may also be trins, cyclodextrin derivatives Such as hydroxypropyl-B- blended or granulated into the active-cyclodextrin mixture. cyclodextrin, and acylated and modified cyclodextrins, for The nature of these excipients will depend upon the required example those described in U.S. Pat. Nos. 5,654,422 and final form of the pharmaceutical. For example, for prepara 5,633,368 (both to Hirsenkorn) and WO91/13100 (Austra tion of fast-melting formulations according to WO -A-99/ lian Commercial Research and Development Ltd.), are also 04758, polyalcohol such as any one or more of xylitol, available for use in the invention. In a preferred embodiment Sorbitol, mannitol, maltitol, erythritol and lactitol may be the cyclodextrin is a 3-cyclodextrin or derivative thereof. included. 0113 Pharmaceutical formulations according to the 0118. The preparation may contain an ingestible acid present invention may be prepared by any Suitable method component, e.g. citric acid, typically up to 30 wt % of the which creates a homogeneous mixture of active ingredient total. and cyclodextrin without requiring any particular processes conditions to generate complexes between active and cyclo 0119) The preparations may contain effervescence agent dextrin. Mixtures may be prepared by Simple dry blending, Selected from various acid and/or base components. Suitable or by blending with a Small quantity of water or other acids include citric, tartaric, malic, fumaric, adipic, Succinic Solvent to facilitate homogenisation. Actives may be granu and alginic acids. Acid Salts and anhydrides may also be lated with cyclodextrin using a fluid bed granulator (pre used. ferred) or a granulating blender, using Sufficient water or other Suitable Solvent to achieve a Satisfactory granulation, 0120 Suitable bases include Solid carbonates and bicar but generally without Such quantities of water as might give bonates. rise to Significant complex formulation, e.g. by converting 0121 Preferably the preparation contains not more than the mix to a paste or Slurry. about 10 wt % of effervescent agent, but this may be varied 0114 Whatever the mode of preparation, in the light of in accordance with known practice. our new discovery it is not necessary to take any measures to achieve complexation of the active ingredient by the 0.122 The pharmaceutical compositions of the present cyclodextrin. Since complex formation is typically time invention may contain a single active ingredient or a plu consuming and expensive this represents a simplification rality of active ingredients. Where more than one active and corresponding possible economic advantage in the ingredient has a taste which is required to be masked, the present procedures and products. quantity of cyclodextrin can be adjusted appropriately. 0115 By way of explanation, there are a number of well 0123 Satisfactory taste masking can typically be recognised methods for forming cyclodextrin inclusion achieved using a molar ratio of active or actives to cyclo complexes: the Solution method, the co-precipitation dextrin of between 0.9:1 and 1:25, preferably between 1:1 method, the neutralisation method, the Slurry method, the and 1:15. kneading method and the grinding method, e.g. as Sum 0.124 Specific embodiments of the present invention are marised in T. LoftSSon, Pharmaceutical Technology Europe, illustrated by the following examples. October 99 Vol.11(10). These generally involve prolonged and intensive mixing of the active with the cyclodextrin, often under carefully controlled conditions, and Sometimes EXAMPLE 1. with application of heat, followed by isolation or purifica 0.125 Fast melting tablets each containing 10 mg Dex tion of the complexes. tromethorphan HBr and 2 mg Chlorpheniramine maleate 0116. The skilled reader would appreciate that the pres were prepared as follows. ence of Some complexed active ingredient is not generally actually detrimental in the eventual preparation. Rather, it is positively advantageous for processing reasons to Simplify Dextromethorphan HBr 10 g the process in Such a way that complex formation is rela Chlorpheniramine maleate 2 g tively unlikely to take place, or takes place to only a very Xylitol 106 g Sorbitol 325 g limited extent or not at all. Thus, the presence of a minor f-cyclodextrin 300 g amount of complex active ingredient does not take a com Citric acid 8 g position outside the Scope of the present invention. Never theless we have carried out thermal analysis of cyclodextrin/ US 2004/0115258A1 Jun. 17, 2004

0.126 were granulated together with just sufficient water active dose. Although good in mechanical and dissolution for granulation, containing 10 g of PEG. To the dried properties, the tablets had a very unpleasant bitter taste I the granulate was added: mouth.

EXAMPLE 3 Aspartame 10 g Magnesium stearate 5 g 0.135 Chewable tablets each containing 10 mg Dex Vanilla flavour 24g tromethorphan HBr, 2 mg Chlorpheniramine maleate and 6.67 mg Lysozyme HCl were prepared as follows. 0127. This mixture was blended for 15 minutes to reach homogeneity, and the resulting mixture compressed on a rotating tabletting machine, with a toroidal punch of 13 mm Dextromethorphan HBr 10 g Chlorpheniramine maleate 2 g diameter, to give tablets weighing 800 mg each. Fructose 70 g Maize starch 70 g 0128. The resulting tablets showed good mechanical Sorbitol 528.33 g characteristics and had a pleasant taste when dissolved in the Lysozyme HCI 6.67 g buccal cavity. f-cyclodextrin 350 g Citric acid 10 g Comparison 1 0129. Example 1 was repeated omitting the cyclodextrin 0.136 were granulated together with just sufficient water, and adjusting the total weight to 500 mg to achieve the same for granulation, containing 10 g PVP K 25. To the dried active dose. The tablets had good mechanical and dissolu granulate was added tion characteristics but a very unpleasant Strong bitter taste in the mouth.

EXAMPLE 2 Aspartame 14g Acesulfame K 1 g 0130 Fast melting tablets each containing 10 mg Dex Magnesium stearate 6 g tromethorphan HBr, 2 mg Chlorpheniramine maleate and Orange flavour 22 g 6.67 mg Lysozyme HCl were prepared as follows. 0.137 The mixture was blended for 15 minutes to reach homogeneity, and the resulting mixture compressed on a Dextromethorphan HBr 10 g Chlorpheniramine maleate 2 g rotating tabletting machine with a toroidal punch of 16 mm Xylitol 106 g diameter, to give tablets weighing 1100 mg each. Sorbitol 318.3 g Lysozyme HCI 6.67 g 0.138. The resulting tablets showed good mechanical f-cyclodextrin 300 g Citric acid 8 g characteristics and had a pleasant taste when chewed. Comparison 3 0131 were granulated together with just sufficient water 0.139 Example 3 was repeated omitting the cyclodextrin for granulation, containing 10 g of PEG. To the dried and adjusting the tablet weight to 750 mg to maintain the granulate was added: dose of active ingredients. The tablet had a very unpleasant Strong bitter taste when chewed.

Aspartame 10 g EXAMPLE 4 Magnesium stearate 5 g Tangerine flavour 24g 0140. Effervescent tablets each containing 10 mg Dex tromethorphan HBr, 2 mg Chlorpheniramine maleate and 6.67 mg lysozyme HCl were prepared as follows: 0132) The mixture was blended for 15 minutes to reach homogeneity, and the resulting mixture compressed on a rotating tabletting machine with a toroidal punch of 13 mm diameter, to give tablets weighing 800 mg each. Dextromethorphan HBr 10 g Chlorpheniramine maleate 2 g 0133. The resulting tablets showed good mechanical Lysozyme HCI 6.67 g characteristics and pleasant taste when dissolved in the f-cyclodextrin 350 g buccal cavity. Citric acid Comparison 2 0141 were granulated with just sufficient water for 0134 Example 2 was repeated omitting the cyclodextrin, granulation, containing 18 g of B-carotene. To the resultant adjusting the tablet weight to 500 g to achieve the same dry granulate was added US 2004/0115258A1 Jun. 17, 2004

EXAMPLE 6 0151 Water soluble granulate was prepared as follows. Sodium bicarbonate 694 g Sorbitol 911.3 g Aspartame 20 g Acesulfame K 8 g Orange flavour 80 g Ibuprofen 200 g Sorbitol 2706 g 0142. The mixture was dried for 20 minutes, and com f-cyclodextrin 1000 g pressed on a rotating tabletting machine with a toroidal Citric acid 14 g punch of 22 mm diameter, to give tablets weighing 3500 mg each. 0143. The resulting tablets showed good mechanical 0152 were granulated with just sufficient water. To the characteristics and pleasant taste when dissolved in water resultant dried granulate was added and drunk. Comparison 4 0144. Example 4 was repeated omitting the cyclodextrin Aspartame 20 g and adjusting the tablet Size to achieve the same dose. The Orange flavour 60 g tablets dissolved well but the solution had an unpleasant bitter taste. 0153. The mixture was blended for 15 minutes to reach EXAMPLE 5 homogeneity, and divided into 4000 mg doses packaged into aluminium paper Sachets containing 200 mg ibuprofen each. 0145 Fast melting tablets each containing 2 mg bro mpheniramine maleate and 5 mg phenylephrine HCl were 0154) The resultant granulates had a pleasant taste when prepared as follows: dissolved in water and drunk. 0146 Brompheniramine maleate 2g Comparison 6 O155 Example 6 was repeated omitting the cyclodextrin Phenylephrine HCI 5 g and reducing Sachet contents to 3000 mg to maintain dose Mannitol 500 g Sorbitol 349 g size. The dissolved granules had an unpleasant burning and f-cyclodextrin 199 g irritating taste. Citric acid 22 g Crospovidine 60 g EXAMPLE 7 0156 Water soluble granulates containing 50 mg keto 0147 were granulated together in just sufficient water for granulation, containing 15 g of PEG. To the resultant dry profen per dose were prepared as follows. granulate was added Ketoprofen 60 g Saccharose 787 g Aspartame 10 g f-cyclodextrin 1116 g Magnesium stearate 8g Citric acid 7 g Orange flavour 30 g Saccharine 10 g Orange flavour 30 g 0.148. The mixture was blended for 15 minutes to reach homogeneity, and compressed on a rotating tabletting O157 were dry-blended at room temperature for 15 min machine with a toroidal punch of 13 mm diameter, to give utes to reach homogeneity. The resultant mixture was tablets weighing 1200 mg each. divided into 2000 mg doses packaged into aluminium paper 014.9 The resulting tablets showed good mechanical Sachets. characteristics and pleasant taste when dissolved in the buccal cavity. 0158. The resultant granulates had a pleasant taste when dispersed in water and drunk. Comparison 5 Comparison 7 0150. Example 5 was repeated omitting the cyclodextrin and adjusting tablet Size to 1001 mg to maintain the dose. 0159. When the cyclodextrin was omitted from the The resulting tablets had good mechanical properties but an Example 7 preparation the dispersed granulates had an unpleasant bitter taste when dissolved in the mouth. unpleasant irritating and burning taste. US 2004/0115258A1 Jun. 17, 2004

EXAMPLE 8 EXAMPLE 10 0160 Water soluble granulates containing 70 mg 0169 Fast melting tablets each containing 2 mg bro Sumatriptan per dose were prepared as follows. mpheniramine maleate, 5 mg phenylephrine HCl, and 10 mg dextromethorphan were prepared as follows.

Sumatriptan 70 g Saccharose 1037 g Brompheniramine maleate 2 g f-cyclodextrin 1345 g Phenylephrine HCI 5 g Citric acid 8 g Dextromethorphan HCl 10 g Saccharine 10 g Mannitol 450 g Orange flavour 30 g Sorbitol 176 g f-cyclodextrin 375 g Citric acid 12 g 0.161 were simply blended for 15 minutes at room tem perature to reach homogeneity. The resultant mixture was divided into 2500 mg doses packaged into aluminium paper 0170 were granulated together with just sufficient water. Sachets. To the resultant granulate was added 0162 The resultant granulates exhibited a pleasant taste when dispersed in water and drunk. Aspartame 10 g Magnesium stearate 10 g Comparison 8 Apple flavour 30 g 01.63 Example 8 was repeated omitting the cyclodextrin, Crospovidine 120 g reducing the dose to 1155 g to maintain the active dose. Dispersed in water, the granulate had an unpleasant bitter 0171 The mixture was blended for 15 minutes to reach taSte. homogeneity, and compressed on a rotating tabletting machine with a toroidal punch of 8 mm diameter, to give EXAMPLE 9 tablets weighing 1200 mg each. 0164. Fast melting tablets each containing 0.66 mg 0172 The resulting tablets showed good mechanical B-methasone disodium phosphate were prepared as follows. characteristics, and a pleasant taste when dissolved in the buccal cavity. Comparison 10 f-methasone disodium phosphate 0.66 g Mannitol 42.5 g. 0173 Example 10 was repeated omitting the cyclodextrin Sorbitol 20 g and with the tablets at 825 mg to give the same active dose. Xylitol 25.1 g f-cyclodextrin 21 g The resulting tablets had good mechanical properties but an Citric acid 4 g unpleasant and persistent bitter taste when dissolved in the mouth. Comparison 11 0.165 were granulated together in just sufficient water for granulation containing 15 g of PEG. To the resultant granu 0.174 Fast-melting tablets, each containing 100 mg of late was added aceclofenac, were prepared as follows.

Aceclofenac 100 g Aspartame 1.25 g Mannitol 320 g Magnesium stearate 0.625 g Sorbitol 154 g Apple flavour 3.6 g. Xylitol 195 g f-cyclodextrin 481 g Citric acid 18 g 0166 The mixture was blended for 15 minutes to reach homogeneity, and compressed on a rotating tabletting machine with a toroidal punch of 8 mm diameter, to give 0.175 were granulated together with just sufficient water tablets weighing 120 mg each. for granulation, containing 15 g of PEG. To the resultant dried granulate was added 0167 The resulting tablets showed good mechanical characteristics and pleasant taste when dissolved in the buccal cavity. Aspartame 41 g Comparison 9 Magnesium stearate 6 g Glycirrhiza and Alpine flavouring 55 g 0168 When Example 9 was repeated without the cyclo dextrin, reducing the tablet weight to 99 mg to maintain the active content, the resulting tablet had good mechanical 0176) The mixture was blended for 15 minutes to homo properties but an unpleasant and very bitter taste when geneity and compressed to 1385 mg tablets on a rotating dissolved in the mouth. tableting machine using a 16 mm-diameter toroidal punch. US 2004/0115258A1 Jun. 17, 2004

0177. The tablets had good mechanical properties, and a 10. A Solid oral pharmaceutical preparation according to pleasant taste when dissolved in the buccal cavity. any one of the preceding claims in which the cyclodextrin is B-cyclodextrin or derivative thereof. Comparison 11 11. A process of preparing a Solid oral pharmaceutical 0.178 Example 11 was repeated omitting the cyclodex preparation, adapted for oral administration by dispersion of trin, and producing 842 mg tablets (with a 13 mm punch) to pharmaceutically-active ingredient from the Solid prepara achieve the same 100 mg dose of aceclofenac. tion in the mouth, or by drinking an aqueous dispersion of 0179 The resulting tablets had good mechanical proper the Solid preparation; ties but an unpleasant and persistent bitter taste when the process comprising blending the pharmaceutically dissolved in the buccal cavity. active ingredient with cyclodextrin to produce Said 1. A Solid oral pharmaceutical preparation, adapted for preparation as a mixture containing the active ingredi oral administration by dispersion of pharmaceutically active ent Substantially uncomplexed by the cyclodextrin. ingredient from the Solid preparation in the mouth, or by 12. A process according to claim 11 in which the mixture drinking an aqueous dispersion of the Solid preparation; of cyclodextrin and active ingredient is granulated with the preparation comprising a blend of Said active ingre Sufficient liquid for granulation but insufficient liquid to dient with cyclodextrin as taste-masking agent for the convert the mixture to a paste. active ingredient which is not complexed thereby. 13. A process according to claim 11 comprising com 2. A Solid oral pharmaceutical preparation according to pressing the granulate to form tablets. claim 1 in the form of a tablet. 14. A proceSS according to any one of claims 11 to 13 3. A Solid oral pharmaceutical preparation according to including dry-mixing the cyclodextrin and active ingredient claim 2 in which the tablet is formulated as a Solid buccal at ambient temperature or without heating. tablet, as a Soluble Sub-lingual tablet or as a chewable tablet. 15. A process according to any one of claims 11 to 14 in 4. A Solid oral pharmaceutical preparation according to which the resulting preparation is in accordance with any claim 1 in the form of a granulate or dry blend. 5. A Solid oral pharmaceutical preparation according to one of claims 2 to 10. any one of the preceding claims which contains polyalcohol 16. The use, in the oral administration of a Solid pharma blended with the cyclodextrin and active ingredient. ceutical preparation by dispersion of pharmaceutically-ac 6. A Solid oral pharmaceutical preparation according to tive ingredient from the Solid preparation in the mouth, or by any one of the preceding claims which contains ingestible drinking an aqueous dispersion of the Solid preparation, of organic acid or acid Salt blended with the cyclodextrin and cyclodextrin blended but not complexed with the active active ingredient. ingredient in the preparation to mask the taste of the uncom 7. A Solid oral pharmaceutical preparation according to plexed active ingredient. any one of the preceding claims which contains flavour 17. The use, in the preparation of a Solid pharmaceutical and/or Sweetener. preparation adapted for oral administration by dispersion of 8. A Solid oral pharmaceutical preparation according to pharmaceutically-active ingredient from the Solid prepara any one of the preceding claims which contains an effer tion in the mouth, or by drinking an aqueous dispersion of VeScence agent. the Solid preparation, of cyclodextrin mixed with the active 9. A Solid oral pharmaceutical preparation according to ingredient to mask the taste of the active ingredient which is any one of the preceding claims in which the molar ratio of not complexed with the cyclodextrin. the active ingredient to cyclodextrin is between 0.9:1 and 1:25.