Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/185—Magnoliopsida (dicotyledons)
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/08—Bronchodilators
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/20—Hypnotics; Sedatives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/06—Antiarrhythmics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• 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 pharma- 10 ceutical ingredients (APIs), optionally comprising salts, prodrugs and metabolites thereof.
• APIs active pharmaceutical ingredients
• APIs active pharmaceutical ingredients
• APIs active pharmaceutical ingredients
• the present invention provides an orally administered pharmaceutical formulation of one or more APIs, optionally comprising salts, complexes, prodrugs and metabo- lites thereof for achieving a pharmacological effect.
• the administration can be to a human being or to an animal.
• Rapid onset is herein meant that a therapeutic effect is achieved within a short period of time, preferably in less than 1 hour, more preferably in less than 30 minutes, following administration.
• the administration may be accomplished without the addition of liquid.
• Administration 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.
• the administration is discreet being a big advantage e g at lectures and on the theatre.
• use of the 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 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.
• An object of the invention is to provide novel orally administered pharmaceutical formulations of one or more APIs comprising cocoa powder.
• a second object of the invention is to provide methods for preparing said formulations.
• a t hird 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.
• the invention is adapted for discreet self-administration.
• discreet self- administration herein is meant self-administration that does not draw attention to the existence of a need for therapy.
• the formulation provides for a rapid onset through essentially intraoral uptake of the one or more APIs; 2) The formulation does not require any added liquid at the time of administration;
• the formulation provides for discreet self-administration; 6) The formulation is easy to administer for persons having problems in swallowing;
• the formulation provides for increased bioavailability due to reduced first-pass metabolism
• the formulation may provide for an association of pleasure.
• 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, cocoa butter, amino acids, proteins, xanthines, amines, mono- and polysaccharides % phospholipids, flavonoids, pyrazines, etc.
• 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 or mechanical erosion, or a combination thereof after which the formulation may show adhesiveness towards the tissues in the oral cavity.
• the formulation is such that it does not require addition of liquid at the time of administration.
• buffering agents provides for a transient change in local pH of the saliva, which facilitates uptake in the oral cavity.
• cocoa powder acts as taste masker, filler and texturizer.
• a general embodiment of a formulation according to the present invention has a weight of around 200 - 1000 mg and has the following composition (w/w):
• a formulation weighing around 400 mg, is prepared having the following composition (w/w):
• Cocoa powder may be used in a non-alkalized form and in an alkalized form. 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 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.
• the mixture 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 rest of t he 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 hydrobromide 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 techniques, such as molding, extrusion or congealing, including pastiUation, when necessary after suitable preconditioning. Also other suitable manufacturing methods may be used.
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 6 Preparation of a further embodiment In essentially the same way as in Example 1 is manufactured a formulation ⁇ vith a weight of around 400 mg having the below ingredients (w/w):
• Example 2 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):
• Example 8 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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):
• Example 2 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:
• APIs active pharmaceutical ingredients
• the above one or more active pharmaceutical ingredients 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, 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 o the antimigraine preparations dihydroergotamine, ergotamine, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan; o the anti-Parkinson drags pramipexole, ropinirole and selegiline;
• 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, fructose, glucose, galactose, lactose, maltose, invert sugar, a pharmaceutically acceptable 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.
• a pharmaceutically acceptable 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: - cocoa butter and cocoa butter alternatives, including cocoa butter equivalents
• CBE cocoa butter substitutes
• CBR cocoa butter replacers
• CBI cocoa butter improvers
• the optional buffering agent s may be selected from one or more of carbonates, 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.
• 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 and/or salts thereof.
• 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 and/or salts thereof
• the emulsifier/solubiliser is preferably soy lecithin and/or egg lecithin, but may be exchanged for
• nonionic surfactant such as poloxamer, polyoxyethylene alkyl ether, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, monoglyce- ride, diglyceride and esther thereof, polyoxyethylene stearate, polyglycerolester of fatty acids, including polyglycerolpolyricinoleic acid (PGPR), sorbitan fatty acid ester,
• PGPR polyglycerolpolyricinoleic acid
• an anionic surfactant such as fatty acid, soap of fatty acid, lactylate, especially sodium and/or calcium stearoyllactylate, sodium lauryl sulfate and latanol,
• zwitterionic surfactant such as zwitterionic phospholipid, such as phosphati- 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 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.
• the present invention encompasses administration of the captioned 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.

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• Biomedical Technology (AREA)
• Natural Medicines & Medicinal Plants (AREA)
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• Diabetes (AREA)
• Heart & Thoracic Surgery (AREA)
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  • 2004-03-16 WO PCT/IB2004/000860 patent/WO2004084865A1/en active Application Filing
  • 2004-03-16 EP EP04720946A patent/EP1605921A1/en not_active Withdrawn
  • 2004-03-16 BR BRPI0408655-4A patent/BRPI0408655A/pt not_active IP Right Cessation
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