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. Prostaglandin 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 Agonists e.g. Adrenolone, ingredient, designed to disintegrate rapidly in the mouth and Clonidine, Ephedrine, Epinephrine, Phenylephrine, with masking of unpleasant-tasting active ingredient. Fenoxazoline, Ibopamine, Methoxamine, NafaZo US 2004/0115258A1 Jun. 17, 2004 line, Pseudoephedrine, Tetrahydrozoline, TramaZO Clobenzorex, Clortermine, Fenfluramine, Norpseu line, Phenyilpropanolamine, Tuaminoheptane, doephedrine, Pentorex, Phendimetrazine, Phenme Tyramine 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, AZelastine, Cromolyn, Fempiprane, Ibudilast, Lodoxamide, Nedocromil, Oxatomide, Repirinast, Oxyfedrine, Reproterolo, Salmeterol, Soterenol, TaZanolast, HyStamine, B Beclomethasone, Dexam Terbutaline, Tulobuterol, Xanoterol ethasone, Flunisolide, Fluticasone, Triamcinolone; 0020 C. Adrenergic Blockers e.g. Dapiprazole, Fen Antialopecia agent. e.g. Cioteronel, Minoxidil Spiride, Nicergoline, PraZosin, 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, Propranolol, Timolol; nolol, Carazolol, Carteolol, Cloranolol, Indenolol, 0022 Adrenocortical Steroids Ipratropium bromide, Lidocaine, Pindolol, Pro pafenone, Propranoll, Quinidine, Timolol, Vera 0023 Adrenocorticotrop Hormones e.g. ACTH pamil, CoSintropin 0037 Antiarteriosclerotic e.g. Pyridinol Carbamate; 0024. Alcohol deterrents e.g. Calcium lanamide Cit 0038 Antiarthritics/Antirheumatics e.g. Actarit, rate, Disulfiram Auranofin. Aurothioglucose, aurothioglicande, AZa 0025 Aldose reductase inhibitors e.g. Epalrestat, thioprine, Chloroquine, Gold Sodium thiosulfate, Tolrestat, Zopolrestati Hydroxchloroquine,