AU2004224557A1

AU2004224557A1 - Formulations comprising an active ingredient and cocoa powder and use thereof

Info

Publication number: AU2004224557A1
Application number: AU2004224557A
Authority: AU
Inventors: Nils-Olof Lindberg; Katarina Eva Anette Lindell; Alice C. Martino; Fredrik Per Nicklasson; Kristina Maarit Thyresson
Original assignee: Pfizer Health AB
Current assignee: McNeil AB
Priority date: 2003-03-26
Filing date: 2004-03-16
Publication date: 2004-10-07
Anticipated expiration: 2024-03-16
Also published as: SE0300831D0; JP2011079841A; MXPA05010196A; BRPI0408655A; CL2004000564A1; TW200503782A; CN1764440A; EP1605921A1; AU2004224557B2; JP2006521348A; CA2519155A1; AR043772A1; ZA200507719B; WO2004084865A1

Description

WO 2004/084865 PCT/IB2004/000860 1 FORMULATIONS COMPRISING AN ACTIVE INGREDIENT AND COCOA POWDER AND USE THEREOF Field of the Invention This invention relates to novel orally administered pharmaceutical formulations of one or more active pharmaceutical ingredients (APIs), optionally comprising salts, 5 complexes, prodrugs and metabolites thereof, further comprising cocoa powder, to the use of one or more active pharmaceutical ingredients (APIs), optionally comprising salts, prodrugs and metabolites thereof, for the manufacturing of a medicament to be administered orally for achieving a pharmacological effect, and to methods of medical treatment of humans or animals by oral administration of one or more active pharmna 10 ceutical ingredients (APIs), optionally comprising salts, prodrugs and metabolites thereof. Background There is a need for orally administered pharmaceutical formulations of one or more active pharmaceutical ingredients (APIs) providing for a rapid, preferably intra 15 oral uptake, such as sublingual and/or buccal uptake, and having sufficient masking of badly tasting ingredients. Prior Art In "Development of oral acetaminophen chewable tablets with inhibited bitter taste", Suzuki et al, International Journal of Pharmaceutics 251 (2003) 123 - 132 is 20 disclosed combined use of sucrose, cocoa powder and the commercial bittermasking powder mixture Benecoat BMI-40 as corrigent against bitter taste of acetaminophen. In reality the main taste-masking effect of the Suzuki et al formulation is though achieved through the lipid matrix. But, the lipid matrix used, Witepsol H-15, is normally used for suppositories and is not suitable for oral or peroral formulations. Further, the amount of 25 acetaminophen in the formulations of Suzuki et al is well below the general therapeutic dose. In contrast to the present formulations the formulations of Suzuki et a are not intended for intraoral uptake, but for peroral administration and subsequent uptake in the gastro-intestinal tract. A therapeutically effective unit dose of acetaminophen is too high for being administered through uptake in the oral cavity. 30 Chocolate, which is different from cocoa powder as such, is very rarely used as an ingredient in pharmaceutical products, hitherto only in laxatives. One example is Ex Lax' being chocolated laxative pieces marketed by Novartis comprising sennosides.

WO 2004/084865 PCT/IB2004/000860 2 Purex, a laxative wherein phenolphthalein was formulated with chocolate, was marketed in the 1950s. It has now surprisingly been found that a rapid, preferably intraoral uptake of one or more APIs is achieved concomitantly with sufficient taste masking of badly 5 tasting ingredients through use of a formulation comprising said one or more APIs and further comprising cocoa powder as taste masker, filler and texturizer. Summary of the invention The present invention provides an orally administered pharmaceutical formula tion of one or more APIs, optionally comprising salts, complexes, prodrugs and metabo 10 lites thereof for achieving a pharmacological effect. The administration can be to a human being or to an animal. It is a primary objective to provide a formulation for a rapid onset through essentially intraoral uptake of one or more APIs. With "rapid onset" is herein meant that a therapeutic effect is achieved within a short period of time, preferably in less than 1 15 hour, more preferably in less than 30 minutes, following administration. The administration may be accomplished without the addition of liquid. Admini stration without added liquid is a big advantage in all those situations where e g clean water or other suitable liquid is not available, such as on travel. Also the administration is discreet being a big advantage e g at lectures and on the theatre. Further, use of the 20 present formulation, which should melt in the mouth rather than be swallowed, is of a great advantage to all those persons having difficulties in swallowing a traditional tablet. A particularly useful dosage form of the present invention is thus a formulation that disintegrates or melts in the mouth without need for drinking water or other fluid. The formulation is a dosage form comprising a therapeutically effective amount 25 of one or more APIs. It is preferred that the amount of the one or more APIs be lower than an amount causing significant side effects. Also provided by the present invention are methods of use of formulations of the present invention for medical treatment of a human or animal subject. Other features of this invention will be in part apparent and in part pointed out hereinafter. 30 An object of the invention is to provide novel orally administered pharmaceu tical formulations of one or more APIs comprising cocoa powder. A second object of the invention is to provide methods for preparing said formu lations.

WO 2004/084865 PCT/IB2004/000860 3 A third object of the invention is methods for using said formulations in therapy for medical treatment of a human or animal subject. Formulations according to the present invention should preferably melt in the oral cavity, whereby intraoral uptake of the one or more APIs is favorized. 5 The invention is adapted for discreet self-administration. By "discreet self administration" herein is meant self-administration that does not draw attention to the existence of a need for therapy. Further objects of the invention will become apparent to one skilled in the art, and still other objects will become apparent hereinafter from the specification and 10 claims. The main advantages provided by a formulation according to the present inven tion are: 1) The formulation provides for a rapid onset through essentially intraoral uptake of the one or more APIs; 15 2) The formulation does not require any added liquid at the time of administration; 3) The formulation provides for good taste masking; 4) The formulation does not give an immediate patient-perceived association with medicines, as do traditional tablets; 5) The formulation provides for discreet self-administration; 20 6) The formulation is easy to administer for persons having problems in swallowing; 7) The formulation provides for increased bioavailability due to reduced first-pass metabolism; 8) The formulation may provide for an association of pleasure. The above advantages are the same for all APIs suited for the present invention. 25 This means that there is unity of invention as the gist of the invention, i e the addition of cocoa powder, is a common feature irrespective of the API being administered. Detailed Description of the Invention It is the primary object of the present invention to provide orally administered cocoa-powder-containing pharmaceutical formulations useful for medical treatment. 30 Cocoa powder is defined as cocoa nib with some fat removed and ground into a powder. Cocoa nib is defined as cocoa beans with the shell removed. Cocoa butter is defined as fat expelled from the center (kernels or nib) of cocoa beans. Cocoa powder is prepared from roasted cocoa beans. It is a complex compound, which consists of starch, WO 2004/084865 PCT/IB2004/000860 4 cocoa butter, amino acids, proteins, xanthines, amines, mono- and polysaccharides, phospholipids, flavonoids, pyrazines, etc. More specifically it is the object of the invention to provide such a formulation that disintegrates and/or melts in the oral cavity with or without the aid of salivary fluid 5 or mechanical erosion, or a combination thereof after which the formulation may show adhesiveness towards the tissues in the oral cavity. Preferably the formulation is such that it does not require addition of liquid at the time of administration. Optional addition of buffering agents provides for a transient change in local pH 10 of the saliva, which facilitates uptake in the oral cavity. It has surprisingly been found that a sufficient taste masking of badly tasting ingredients is achieved through the use of cocoa powder. The cocoa powder acts as taste masker, filler and texturizer. A general embodiment of a formulation according to the present invention has a 15 weight of around 200 - 1000 mg and has the following composition (w/w): Ingredient Amount Function (%) One or more APIs (base, prodrug, metabolite, salt or 0,03 - 12 API complex) One or more lipid ingredients 30 - 60 Lipid ingredient Cocoa powder 8 - 55 Taste masker, filler, texturizer Water-soluble or dispersible diluents, preferably as fine 0 - 40 Diluent particulate powder One or more sweetening agents 0,1 - 3 Sweetener One or more buffering agents 0-10 Buffer One or more flavoring agents 0 - 4 Flavorant One or more taste modifiers 0 - 3 Taste modifier One or more emulsifiers/solubilisers 0,3 - 6 Emulsifier/ solubiliser One or more coloring agents 0 - 3 Coloring WO 2004/084865 PCT/IB2004/000860 5 agents Examples Below follows non-limiting examples on preparation of embodiments of the present invention, 5 Example 1: A formulation, weighing around 400 mg, is prepared having the following composition (w/w): Ingredient Amount (%) Function Eletriptan hydrobromide 5,0 API Hydrogenated soybean oil 43,55 Lipid ingredient Cocoa powder 18,00 Taste masker, filler, texturizer Mannitol 12,00 Diluent Maize starch 14,90 Diluent Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Titanium dioxide 2,00 Coloring agent Sodium Chloride 0,60 Taste modifier Coffee and vanilla flavors 3,00 Flavoring agents Soy lecithin 0,70 Emulsifier Cocoa powder may be used in a non-alkalized form and in an alkalized form. 10 Both are useful in the present formulations. Alkalized cocoa powder is preferred when a somewhat milder taste is desirable. A part of the hydrogenated soybean oil is melted. The solid components, i e the API if solid (eletriptan hydrobromide is solid), cocoa powder, mannitol, maize starch, aspartame, acesulfame-K, titanium dioxide, sodium chloride and the flavoring agents if 15 solid, are added and mixed. A reduction of particle size of the solid components is performed by milling in a roll-refiner. If the solid components have already got the required particle size, e g by milling before the mixing with the fatty components, roll refining is dispensed with. After treatment in the roll-refiner the mixture is mixed with the rest of the melted fatty components or remelted, if solidified, and mixed with the WO 2004/084865 PCT/IB2004/000860 6 rest of the melted hydrogenated soybean oil. A mixing of the melt is performed in a suitable mixer. The liquid components, i e the API if liquid (eletriptan hydrobromicle is though solid and is handled as above), soy lecithin and the flavoring agents if liquid, are added. Tablets or other solid dosage forms are subsequently made using suitable 5 techniques, such as molding, extrusion or congealing, including pastillation, when necessary after suitable preconditioning. Also other suitable manufacturing methods may be used. Example 2: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with 10 a weight of around 500 mg having the below ingredients (w/w): Ingredient Amount (%) Function Terbutaline sulphate 0,50 Active Hydrogenated soybean oil 43,90 Lipid ingredient Cocoa powder 18,00 Taste masker, filler, texturizer Mannitol 18,00 Diluent Maize starch 13,35 Diluent Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Titanium dioxide 2,00 Coloring agent Mint and vanilla flavors 3,00 Flavoring agents Soy lecithin 1,00 Emulsifier Example 3: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 300 mg having the below ingredients (w/w): Ingredient Amount (%) Function Triazolam 0,05 Active Hydrogenated soybean oil 40,0 Lipid ingredient Cocoa powder 37,85 Taste masker, filler, texturizer Maize starch 20,0 Diluent Acesulfame-K 0,4 Sweetener WO 2004/084865 PCT/IB2004/000860 7 Orange flavor 1,0 Flavor Soy lecithin 0,7 Emulsifier Example 4: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 400 mg having the below ingredients (w/w): Ingredient Amount (%) Function Chlorpheniramine maleate 1,0 Active Cocoa powder 48,7 Taste masker, filler, texturizer Hydrogenated soybean oil 44,0 Lipid ingredient Titanium dioxide 2,5 Coloring agent Sodium Carbonate 1,0 Buffering agent Aspartame 0,2 Sweetener Acesulfame-K 0,1 Sweetener Vanilla flavor 1,5 Flavoring agent Soy lecithin 1,0 Emulsifier 5 Example 5: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 600 mg having the below ingredients (w/w): Ingredient Amount (%) Function Dextropropoxyphene hydrochloride 8,0 Active Hydrogenated soybean oil 45,0 Lipid ingredient Cocoa powder 20,0 Taste masker, filler, texturizer Mannitol 19,7 Diluent Aspartame 0,5 Sweetener Monosodium glutamate 0,5 Taste modifier Mint flavor 1,5 Flavoring agent Soy lecithin 0,7 Emulsifier 10 Example 6: Preparation of a further embodiment WO 2004/084865 PCT/IB2004/000860 8 In essentially the same way as in Example 1 is manufactured a formulation 'With a weight of around 400 mg having the below ingredients (w/w): Ingredient Amount (%) Function Famotidine 2,5 Active Hydrogenated soybean oil 42,3 Lipid ingredient Cocoa powder 18,0 Taste masker, filler, texturizer Mannitol 17,5 Diluent Maize starch 12,85 Diluent Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Titanium dioxide 2,0 Coloring agent Monosodium glutamate 0,6 Taste modifier Lemon and vanilla flavors 3,0 Flavoring agents Soy lecithin 1,0 Emulsifier 5 Example 7: Preparation of a further embodiment In essentially the same way as in Example I is manufactured a formulation with a weight of around 400 mg having the below ingredients (w/w): Ingredient Amount (%) Function Metoclopramide HCI 2,63 Active Hydrogenated soybean oil 42,3 Lipid ingredient Cocoa powder 17,88 Taste masker, filler, texturizer Mannitol 17,5 Diluent Maize starch 12,85 Diluent Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Titanium dioxide 2,0 Coloring agent Monosodium glutamate 0,6 Taste modifier Vanilla flavours 3,0 Flavoring agents Soy lecithin 1,0 Emulsifier WO 2004/084865 PCT/IB2004/000860 9 Example 8: Preparation of a further embodiment 5 In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 400 mg having the below ingredients (w/w): Ingredient Amount (%) Function Glyceryl trinitrate* 0,13 Active Hydrogenated soybean oil 44,86 Lipid ingredient Cocoa powder 50,29 Taste masker, filler, texturizer Aspartame 0,62 Sweetener Mint and vanilla flavors 3,09 Flavoring agents Lecithin 1,03 Emulsifier * as an ethanolic solution Example 9: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with 10 a weight of around 400 mg having the below ingredients (w/w): Ingredient Amount (%) Function Hydralazine HCI 6,25 Active Hydrogenated soybean oil 40,65 Lipid ingredient Cocoa powder 44,75 Taste masker, filler, texturizer Aspartame 0,6 Sweetener Mint and vanilla flavors 1,0 Flavoring agents Lecithin 3,75 Emulsifier Sodium carbonate 3,0 Buffer Example 10: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 400 mg having the below ingredients (w/w): Ingredient Amount (%) Function Rosiglitazone maleate 1,25 Active WO 2004/084865 PCT/IB2004/000860 10 Hydrogenated soybean oil 43,5 Lipid ingredient Cocoa powder 47,25 Taste masker, filler, texturizer Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Vanilla flavors 3,0 Flavoring agents Lecithin 1,0 Emulsifier Sodium carbonate 3,75 Buffer Example 11: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 300 mg having the below ingredients (w/w): Ingredient Amount (%) Function Indometacin 8,30 API Hydrogenated soybean oil 43,55 Lipid ingredient Cocoa powder 18,00 Taste masker, filler, texturizer Mannitol 12,00 Diluent Maize starch 11,60 Diluent Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Titanium dioxide 2,00 Coloring agent Sodium Chloride 0,60 Taste modifier Citrus flavor 3,00 Flavoring agent Soy lecithin 0,70 Emulsifier 5 Example 12: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 300 mg having the below ingredients (w/w): Ingredient Amount (%) Function Baclofen 3,33 Active Hydrogenated soybean oil 44,17 Lipid ingredient WO 2004/084865 PCT/IB2004/000860 11 Cocoa powder 30,00 Taste masker, filler, texturizer Mannitol 18,00 Diluent Acesulfame-K 0,50 Sweetener Peppermint and vanilla flavors 3,00 Flavoring agents Soy lecithin 1,00 Emulsifier Example 13: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 800 mg having the below ingredients (w/w): Ingredient Amount (%) Function Caffeine 12,00 API Hydrogenated soybean oil 44,05 Lipid ingredient Cocoa powder 37,80 Taste masker, filler, texturizer Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Titanium dioxide 2,00 Coloring agent Sodium Chloride 0,60 Taste modifier Coffee and vanilla flavors 3,00 Flavoring agents Soy lecithin 0,30 Emulsifier 5 Example 14: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 500 mg having the below ingredients (w/w): Ingredient Amount (%) Function Timolol maleate 2,00 API Hydrogenated soybean oil 39,25 Lipid ingredient Cocoa powder 28,20 Taste masker, filler, texturizer Mannitol 15,00 Diluent Maize starch 11,90 Diluent WO 2004/084865 PCT/IB2004/000860 12 Aspartame 0,15 Sweetener Acesulfame-K 0,10 Sweetener Monosodium Glutamate 0,60 Taste modifier Blackcurrant flavor 2,00 Flavoring agent Soy lecithin 0,80 Emulsifier Example 15: Preparation of a further embodiment In essentially the same way as in Example I is manufactured a formulation with a weight of around 600 mg having the below ingredients (w/w): Ingredient Amount (%) Function Noscapine 8,33 API Hydrogenated soybean oil 41,70 Lipid ingredient Cocoa powder 28,00 Taste masker, filler, texturizer Mannitol 16,00 Diluent Aspartame 0,57 Sweetener Titanium dioxide 2,00 Coloring agent Banana flavor 2,60 Flavoring agent Soy lecithin 0,80 Emulsifier 5 Example 16: Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation with a weight of around 500 mg having the below ingredients (w/w): Ingredient Amount (%) Function Dextromethorphan HBr 1,50 API Hydrogenated soybean oil 42,50 Lipid ingredient Cocoa powder 32,10 Taste masker, filler, texturizer Mannitol 20,00 Diluent Aspartame 0,60 Sweetener Titanium dioxide 2,00 Coloring agent Cherry flavor 0,50 Flavoring agent WO 2004/084865 PCT/IB2004/000860 13 Soy lecithin 0,80 Emulsifier Example 17: Preparation of further embodiments In essentially the same way as in Example 1 are manufactured formulations with a weight from around 200 mg to around 1000 mg having the below ingredients: Ingredient Amount (%) Function One or more active pharmaceutical ingredients 0,03 -12 API (APIs) as base, prodrug, metabolite, salt or complex. One or more lipid ingredients 30- 60 Lipid ingredient Cocoa powder 8 -55 Taste masker, filler, texturizer Water-soluble or dispersible diluents, preferably as 0 -40 Diluent fine particulate powder One or more sweetening agents 0,1 -3 Sweetener One or more buffering agents 0 - 10 Buffer One or more flavoring agents 0 - 4 Flavor One or more taste modifiers 0- 3 Taste modifier One or more emulsifiers/solubilizers 0,3 -6 Emulsifier One or more coloring agents 0- 3 Coloring agents 5 The above one or more active pharmaceutical ingredients (APIs) is/are selected from APIs suitable for intraoral uptake, preferred, but non-limiting examples of which are o the antiinflammatory agents diclofenac, ketorolac, indometacin, tornoxicam, 10 piroxicam, tenoxicam, ketoprofen, celecoxib and roficoxib; o the muscle relaxants orphenadrine and baclofen; o the drugs affecting bone mineralization alendronic acid and risedronic acid; o the analgesics propoxyphene, buprenorfin, ketobenidon, hydromorphone, tramadol and morphine WO 2004/084865 PCT/IB2004/000860 14 o the antimigraine preparations dihydroergotamine, ergotamine, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan; o the anti-Parkinson drugs pramipexole, ropinirole and selegiline; o the anxiolytics alprazolam, diazepam, lorazepam and oxazepam; 5 o the hypnotics flunitrazepam, rmidazolam, nitrazepam, triazolam, zaleplone, zopiclone, zolpiderm, clometiazole and propiomazine; o the psychostimulant caffeine; o the drugs against substance dependence bupropione, lobeline, naltrexone and methadone; 10 a the gastric ulcer remedies famotidine and ranitidine; o the antispasmodic hyoscyamine; o the antiemetics metoclopramide, ondansetron, scopolamine, hyoscine, perfenazine, procloperazine, meclizine and haloperidol: o the antidiabetic agent rosiglitazone; 15 o the cardiovascular agents etilefrin, glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate; o the antihypertensive agent hydralazine; o the diuretics furosemide and amiloride; o the beta-receptor blocking agents propranolol and timolol; 20 o the calcium channel blocker amlodipine; o the ACE-inhibitors kaptopril, lisinopril and fosinopril; o the serum lipid reducing agent simvastatin; o the antipsoriatic acitretin; o the antiasthmatic terbutaline; 25 o the decongestants pseudoephedrine and phenylephrine; o the antidhiarroeal drug loperamide; o the antitussives dextromethorphane, codeine and noscapine, and o the antihistamines clemastine, chlorpheniramine, cyproheptadine, loratadine, acrivastine, diphenhydramine, cetirizine, doxylamine and dimenhydrinate. 30 Example 18: Preparation of alternative embodiments Useful embodiments are obtained by exchanging some of the excipients in the embodiments of the above examples 1 - 17 for equivalently functioning alternative compounds.

WO 2004/084865 PCT/IB2004/000860 15 The cocoa powder may be used in its non-alkalized form, its alkalized form or in a mixture thereof. The diluents may be selected from one or more of the compounds sucrose, fruc tose, glucose, galactose, lactose, maltose, invert sugar, a pharmaceutically acceptable 5 polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt and glycerol, or polydex trose, or starch, or any mixture thereof, but only to such an extent that the taste-masking effect of the cocoa-powder remains sufficient. The lipid ingredient, being fatty components, may be chosen from one or more of the following compounds: 10 - cocoa butter and cocoa butter alternatives, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBI), - coconut, pahnlmkernel oil and other similar oils characterized by being predomi nantly based on lauric and myristic acids, 15 - palm oil, shea butter, karite butter, illipe butter, mango kernel oil, sal fat and other similar fats characterized by being predominantly based on palmitic, oleic and stearic acids, - corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils 20 characterized by being predominantly based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point, - fish oil, tallow, lard, butterfat and other animal derived fats, and - synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using no, acidic, alkaline or enzymatic catalysis, 25 whereby said compound/s is/are used as a single component or mixed with each other, being either crude or refined using physical or alkaline refining, or being sub jected to further processing including catalytic hydrogenation, interesterification, transesterification and fractionation. The optional buffering agent/s may be selected from one or more of carbonates, 30 bicarbonates, acetates, gluconates, glycerophosphates, phosphates or glycinates of sodium, potassium or ammonium, or mixtures thereof. Most phosphates are though less suitable because their taste usually is disagreeable and difficult to mask. Addition of buffering agents/s may increase the uptake through the mucosa in the oral cavity.

WO 2004/084865 PCT/IB2004/000860 16 The sweetener may selected from one or more artificial sweeteners, such as sucrose, aspartame, acesulfame potassium, saccharine, sodium saccharine, cyclamate, glycyrrhizine, thaumatin (talin), sucralose, dihydrochalcone (neohesperidin dihydro chalcone), alitame, miraculin (miracle fruit), monellin (serendipity berry), stevside 5 and/or salts thereof. The emulsifier/solubiliser is preferably soy lecithin and/or egg lecithin, but may be exchanged for - a nonionic surfactant, such as poloxamer, polyoxyethylene alkyl ether, poly oxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce 10 ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids, including polyglycerolpolyricinoleic acid (PGPR), sorbitan fatty acid ester, - an anionic surfactant, such as fatty acid, soap of fatty acid, lactylate, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol, - a zwitterionic surfactant, such as zwitterionic phospholipid, such as phosphati 15 dylcholine and phosphatidylethanolamine, or mixtures, fractions or derivatives thereof or with lecithin. The taste modifier is preferably selected from sodium chloride, monosodium glutamate and ammonium glycyrrhizinate. The coloring agent is preferably selected from titanium dioxide, iron oxides and 20 aluminum lakes. Formulations according to the present inventions primarily constitute meltable and/or suckable oral tablets, but also include other suitable dosage forms for intraoral administration such as buccal patches, buccal pastes and buccal sprays. Further, the present invention encompasses administration of the captioned 25 formulations via the oral route concomitantly with administration APIs via one or more other routes, such as through transdermal administration, peroral administration, administration by inhalation, administration by creams, salves and vagitories, and/or administration by injection.

Claims

1. An orally administered pharmaceutical formulation comprising one or more active pharmaceutical ingredients (APIs), optionally comprising salts, complexes, 5 prodrugs and metabolites thereof, c h a r a c t e r i z e d in that it comprises cocoa powder and in that the one or more APIs is/are chosen among APIs suitable for intraoral uptake.

2. A formulation according to claim 1, c h a r a c t e r i z ed in that the one or more active pharmaceutical ingredients (APIs) is/are chosen from 10 o the antiinflammatory agents diclofenac, ketorolac, indometacin, tornoxicam, piroxicam, tenoxicam, ketoprofen, celecoxib and roficoxib; o the muscle relaxants orphenadrine and baclofen; o the drugs affecting bone mineralization alendronic acid and risedronic acid; o the analgesics propoxyphene, buprenorfin, ketobenidon, hydromorphone, 15 tramadol and morphine o the antimigraine preparations dihydroergotamine, ergotamine, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan; o the anti-Parkinson drugs pramipexole, ropinirole and selegiline; o the anxiolytics alprazolam, diazepam, lorazepam and oxazepam; 20 o the hypnotics flunitrazepam, midazolam, nitrazepam, triazolam, zaleplone, zopiclone, zolpiderm, clometiazole and propiomazine; o the psychostimulant caffeine; o the drugs against substance dependence bupropione, lobeline, naltrexone and methadone; 25 o the gastric ulcer remedies famotidine and ranitidine; o the antispasmodic hyoscyamine; o the antiemetics metoclopramide, ondansetron, scopolamine, hyoscine, perfenazine, procloperazine, meclizine and haloperidol: o the antidiabetic agent rosiglitazone; 30 o the cardiovascular agents etilefrin, glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate; o the antihypertensive agent hydralazine; o the diuretics furosemide and amiloride; o the beta-receptor blocking agents propranolol and timolol; WO 2004/084865 PCT/IB2004/000860 18 o the calcium channel blocker amlodipine; o the ACE-inhibitors kaptopril, lisinopril and fosinopril; o the serum lipid reducing agent simvastatin; o the antipsoriatic acitretin; 5 o the antiasthmatic terbutaline; o the decongestants pseudoephedrine and phenylephrine; o the antidhiarroeal drug loperamide; o the antitussives dextromethorphane, codeine and noscapine, and o the antihistamines clemastine, chlorpheniramine, cyproheptadine, loratadine, 10 acrivastine, diphenhydramine, cetirizine, doxylamine and dimenhydrinate.

3. A formulation according to any of the preceding claims, c h a r a c t e r i z e d in that it further comprises one or more lipid ingredients.

4. A formulation according to claims 3, c h a r a c t e r i z ed in that the one or more lipid ingredients is/are chosen from 15 - cocoa butter and cocoa butter alternatives, including cocoa butter equivalents (CBE), cocoa butter substitutes (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBI), - coconut, palmkernel oil and other similar oils characterized by being predomi nantly based on lauric and myristic acids, 20 - palm oil, shea butter, karite butter, illipe butter, mango kernel oil, sal fat and other similar fats characterized by being predominantly based on palmnitic, oleic and stearic acids, - corn oil, sunflower oil, hybrid sunflower oil, soybean oil, rapeseed oil, canola oil, olive oil, ricebran oil, cottonseed oil, arachis (peanut, groundnut) oil and other oils 25 characterized by being predominantly based on oleic, linoleic and linolenic acids and hydrogenated to a suitable melting point, - fish oil, tallow, lard, butterfat and other animal derived fats, and - synthetic fats, reesterified fats, hard fats obtained by a chemical reaction of fatty acids with glycerol using no, acidic, alkaline or enzymatic catalysis, whereby said 30 compound(s) is/are used as a single component or mixed with each other, being either crude or refined using physical or alkaline refining, or being subjected to further processing including catalytic hydrogenation, interesterification, transesterification and fractionation. WO 2004/084865 PCT/IB2004/000860 19

5. A formulation according to-claim 4, c h a r a c t e r i z ed in that the one or more lipid ingredients is/are chosen from cocoa butter equivalents (CBE), cocoa butter substitutes (CBS) and cocoa butter replacers (CBR).

6. A formulation according to any of the preceding claims, c h a r a c t e r i z e d 5 in that it further comprises one or more buffering agents.

7. A fomulation according to claim 6, c h a r a c t e r i z ed in that the one or more buffering agents is/are chosen from carbonates, bicarbonates, acetates, gluconates, glycerophosphates, phosphates or glycinates of sodium, potassium or ammonium, or mixtures thereof. 10

8. A formulation according to any of the preceding claims, c h a r a c t e r i z e d in that it further comprises one or more sweeteners and optionally one or more flavoring agents.

9. A formulation according to claim 8, c h a r a c t e r i z ed in that the one or more sweeteners is/are sucrose, aspartame, acesulfame potassium, saccharine, sodium 15 saccharine, cyclamate, glycyrrhizine, thaumatin (talin), sucralose, dihydrochalcone (neohesperidin dihydrochalcone), alitame, miraculin (miracle fruit), monellin (seren dipity berry), stevside and/or salts thereof.

10. A formulation according to any preceding claim, c h a r a c t e r i z e d in that it further comprises one or more emulsifiers/solubilisers. 20

11. A formulation according to claim 10, c h a r a c t e r i z ed in that the one or more emulsifiers/solubilisers is/are chosen from - lecithin, preferably soy lecithin and/or egg lecithin, - a nonionic surfactant, such as poloxamer, polyoxyethylene alkyl ether, poly oxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce 25 ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids (including polyglycerolpolyricinoleic acid (PGPR)), sorbitan fatty acid ester, - an anionic surfactant, such as fatty acid, soap of fatty acid, lactylate, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol, - a zwitterionic surfactant, such as zwitterionic phospholipid, such as phosphati 30 dylcholine and phosphatidylethanolamine, or mixtures, fractions or derivatives thereof or with lecithin.

12. A formulation according to claim 11, c h a r a c t e r i z ed in that the one or more emulsifiers/solubilisers is/are chosen from lecithin, preferably soy lecithin and/or egg lecithin. WO 2004/084865 PCT/IB2004/000860 20

13. A formulation according to any preceding claim, c h a r a c t e r i z e d in that it further comprises a substance/substances chosen from one or more of the coln pounds sucrose, fructose, glucose, galactose, lactose, maltose, invert sugar, a pharma ceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt and 5 glycerol, or polydextrose, or starch, or any mixture thereof.

14. A formulation according to any preceding claim, c h a r a c t e r i z ed in that it further comprises one or more taste modifiers, preferably chosen from sodium chloride, monosodium glutamate and ammonium glycyrrhizinate.

15. A formulation according to any preceding claim, c h a r a c t er i z e d in 10 that it further comprises one or more coloring agents, preferably chosen from titanium dioxide, iron oxides and aluminum lakes.

16. A formulation according to any preceding claim, c h a r a c t e r i z e d in that a unit dose thereof has a weight of around 200 - 1000 mg and comprises Ingredient Amount Function (% w/w) One or more active pharmaceutical ingredients (APIs) as 0,03 -12 API base, prodrug, metabolite, salt or complex One or more lipid ingredients 30 - 60 Lipid ingredient Cocoa powder 8 - 55 Taste masker, filler, texturizer Water-soluble or dispersible diluents 0- 40 Diluent One or more sweetening agents 0,1 -3 Sweetener One or more buffering agents 0 - 10 Buffer One or more flavoring agents 0 - 4 Flavor One or more taste modifiers 0- 3 Taste modifier One or more emulsifiers/solubilizers 0,3 -6 Emulsifier/ solubiliser One or more coloring agents 0 - 3 Coloring agents WO 2004/084865 PCT/IB2004/000860 21 wherein the one or more active pharmaceutical ingredients (APIs) is/are chosen from APIs suitable for intraoral uptake, preferably one or more APIs chosen from a the antiinflammatory agents diclofenac, ketorolac, indometacin, tornoxicarn, piroxicam, tenoxicam, ketoprofen, celecoxib and roficoxib; 5 a the muscle relaxants orphenadrine and baclofen; o the drugs affecting bone mineralization alendronic acid and risedronic acid; o the analgesics propoxyphene, buprenorfin, ketobenidon, hydromorphone, tramadol and morphine o the antimigraine preparations dihydroergotamine, ergotamine, eletriptan, 10 naratriptan, rizatriptan, sumatriptan and zolmitriptan; o the anti-Parkinson drugs pramipexole, ropinirole and selegiline; o the anxiolytics alprazolam, diazepam, lorazepam and oxazepam; o the hypnotics flunitrazepam, midazolam, nitrazepam, triazolam, zaleplone, zopiclone, zolpiderm, clometiazole and propiomazine; 15 o the psychostimulant caffeine; o the drugs against substance dependence bupropione, lobeline, naltrexone and methadone; o the gastric ulcer remedies famotidine and ranitidine; o the antispasmodic hyoscyamine; 20 o the antiemetics metoclopramide, ondansetron, scopolamine, hyoscine, perfenazine, procloperazine, meclizine and haloperidol: o the antidiabetic agent rosiglitazone; o the cardiovascular agents etilefrin, glyceryl trinitrate, isosorbide dinitrate and isosorbide mononitrate; 25 o the antihypertensive agent hydralazine; o the diuretics furosemide and amiloride; o the beta-receptor blocking agents propranolol and timolol; o the calcium channel blocker amlodipine; o the ACE-inhibitors kaptopril, lisinopril and fosinopril; 30 o the serum lipid reducing agent simvastatin; o the antipsoriatic acitretin; o the antiasthmatic terbutaline; o the decongestants pseudoephedrine and phenylephrine; o the antidhiarroeal drug loperamide; WO 2004/084865 PCT/IB2004/000860 22 o the antitussives dextromethorphane, codeine and noscapine, and o the antihistamines clemastine, chlorpheniramine, cyproheptadine, loratadine, acrivastine, diphenhydramine, cetirizine, doxylamine and dimenhydrinate.

17. A formulation according to any preceding claim which is formulated as an 5 oral dosage form and which provides for delivery of the one or more active pharma ceutical ingredients (APIs) mainly through intraoral delivery, preferably through sub lingual and/or buccal delivery.

18. Use of a formulation according to any preceding claim for the manufacture of a medicament useful for medical treatment of a human being or of an animal. 10

19. Method for medical treatment of a human or animal subject comprising administration of an orally administered pharmaceutical formulation according to anyone of claims 1 - 17 to the subject.

20. Method for medical treatment of a human or animal subject comprising administration of an orally administered pharmaceutical formulation according to 15 anyone of claims 1 - 17 to the subject concomitantly with administration of one or more active pharmaceutical ingredients (APIs) via one or more other routes of administration.

21. Method for medical treatment of a subject according to claim 20 wherein the one or more other routes are chosen from transdermal and peroral administration, and administration by inhalation and injection. 20