WO2004084865A1 - Formulations comprising an active ingredient and cocoa powder and use thereof - Google Patents

Formulations comprising an active ingredient and cocoa powder and use thereof Download PDF

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Publication number
WO2004084865A1
WO2004084865A1 PCT/IB2004/000860 IB2004000860W WO2004084865A1 WO 2004084865 A1 WO2004084865 A1 WO 2004084865A1 IB 2004000860 W IB2004000860 W IB 2004000860W WO 2004084865 A1 WO2004084865 A1 WO 2004084865A1
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WIPO (PCT)
Prior art keywords
formulation according
oil
apis
chosen
administration
Prior art date
Application number
PCT/IB2004/000860
Other languages
French (fr)
Inventor
Nils-Olof Lindberg
Katarina Eva Anette Lindell
Alice C. Martino
Fredrik Per Nicklasson
Kristina Maarit Thyresson
Original Assignee
Pfizer Health Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Health Ab filed Critical Pfizer Health Ab
Priority to AU2004224557A priority Critical patent/AU2004224557B2/en
Priority to EP04720946A priority patent/EP1605921A1/en
Priority to CA002519155A priority patent/CA2519155A1/en
Priority to MXPA05010196A priority patent/MXPA05010196A/en
Priority to BRPI0408655-4A priority patent/BRPI0408655A/en
Priority to JP2006506377A priority patent/JP2006521348A/en
Publication of WO2004084865A1 publication Critical patent/WO2004084865A1/en

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    • 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.
  • 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.

Abstract

A pharmaceutical formulation comprising one or more active pharmaceutical ingredients (APIs) suitable for intraoral uptake, that comprises cocoa powder, a process for manufacturing the formulation and use of the formulation for medical treatment.

Description

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 pharma- 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 al 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. 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 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 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.
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 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. Also the administration is discreet being a big advantage e g at lectures and on the theatre. Further, 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.
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. 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 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. 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 claims.
The main advantages provided by a formulation according to the present invention are:
1) 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;
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; 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. 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. 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.
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 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 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 weight of around 200 - 1000 mg and has the following composition (w/w):
Figure imgf000005_0001
Figure imgf000006_0001
Examples
Below follows non-limiting examples on preparation of embodiments of the present invention. Example 1;
A formulation, weighing around 400 mg, is prepared having the following composition (w/w):
Figure imgf000006_0002
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. 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 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 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; 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):
Figure imgf000007_0001
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):
Figure imgf000007_0002
Orange flavor 1,0 Flavor
Soy lecithin 0,7 Emulsifϊer
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):
Figure imgf000008_0001
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):
Figure imgf000008_0002
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):
Figure imgf000009_0001
Example 7: 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):
Figure imgf000009_0002
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):
Figure imgf000010_0001
* 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 a weight of around 400 mg having the below ingredients (w/w):
Figure imgf000010_0002
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):
Figure imgf000010_0003
Figure imgf000011_0001
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):
Figure imgf000011_0002
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):
Figure imgf000011_0003
Figure imgf000012_0001
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):
Figure imgf000012_0002
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):
Figure imgf000012_0003
Figure imgf000013_0001
Example 15: 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):
Figure imgf000013_0002
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):
Figure imgf000013_0003
Figure imgf000014_0001
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:
Figure imgf000014_0002
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, 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; o the anxiolytics alprazolam, diazepam, lorazepam and oxazepam; o the hypnotics flunitrazepam, midazolam, nitrazepam, triazolam, zaleplone, zopiclone, zolpiderm, clometiazole and propiomazine; o the psychostimulant caffeine; o the drags against substance dependence bupropione, lobeline, naltrexone and methadone; 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; 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; 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; 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. 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. 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, 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.
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 (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBI),
- coconut, palmkernel oil and other similar oils characterized by being predominantly based on lauric and myristic acids, - 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 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 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.
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.
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, 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,
- 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- 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.
Further, 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.

Claims

1. An orally administered pharmaceutical formulation comprising one or more active pharmaceutical ingredients (APIs), optionally comprising salts, complexes, prodrugs and metabolites thereof, c h a r a c t e ri 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 ^ c h a r a c t e r i z e d in that the one or more active pharmaceutical ingredients (APIs) is/are chosen from o the antϋnflammatory 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; o the anxiolytics alprazolam, diazepam, lorazepam and oxazepam; 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; 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 rosightazone; 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; 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; o the decongestants pseudoephedrine and phenylephrine; o the antidhiarroeal drug loperamide; o the antitussives dextrometho hane, codeine and noscapine, and o the antihistamines clemastine, chlorpheniramine, cyproheptadine, loratadine, 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 ri z e d in that the one or more lipid ingredients is/are chosen from - 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 predominantly based on lauric and myristic acids, - 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 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 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.
5. A formulation according to claim 4, characterized 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, characteri zed in that it further comprises one or more buffering agents.
7. A formulation according to claim 6, characterized 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.
8. A formulation according to any of the preceding claims, characterized in that it further comprises one or more sweeteners and optionally one or more flavoring agents.
9. A formulation according to claim 8, characterized in that the one or more sweeteners is/are sucrose, aspartame, acesulfame potassium, saccharine, sodium saccharine, cyclamate, glycyrrhizine, thaumatin (talin), sucralose, dihydrochalcone (neohesperidin dihydrochalcone), alitame, miraculin (miracle fruit), monellin (serendipity berry), stevside and/or salts thereof.
10. A formulation according to any preceding claim, characterized in that it further comprises one or more emulsifiers/solubilisers.
11. A formulation according to claim 10, characterized 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, 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,
- 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- dylcholine and phosphatidylethanolamine, or mixtures, fractions or derivatives thereof or with lecithin.
12. A formulation according to claim 11, characterized in that the one or more emulsifiers/solubilisers is/are chosen from lecithin, preferably soy lecithin and/or egg lecithin.
13. A formulation according to any preceding claim, characterized in that it further comprises a substance/substances chosen from one or more of the co impounds sucrose, fraαose, glucose, galactose, lactose, maltose, invert sugar, a pharmaceutically acceptable polyol such as xylitol, sorbitol, maltitol, mannitol, isomalt and glycerol, or polydextrose, or starch, or any mixture thereof.
14. A formulation according to any preceding claim, characterized 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, characterized in 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, characterized in that a unit dose thereof has a weight of around 200 - 1000 mg and comprises
Figure imgf000021_0001
wherein the one or more active pharmaceutical ingredients (APIs) is/are ch sen from APIs suitable for intraoral uptake, preferably one or more APIs chosen from o the anthnflammatory 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, hydromoφhone, tramadol and moφhine o the antimigraine preparations dihydroergotamine, ergotamine, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan; o the anti-Parkinson drags 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; o the psychostimulant caffeine; o the drags against substance dependence bupropione, lobeline, naltrexone and methadone; 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; 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; 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; o the decongestants pseudoephedrine and phenylephrine; o the antidhiarroeal drug loperamide; o the antitussives dextromethoφhane, codeine and noscapine, and o the antihistamines clemastine, chloφheniramine, cyproheptadine, loratadine, acrivastine, diphenhydramine, cetirizine, doxylamine and dimenhydrinate.
17. A formulation according to any preceding claim which is formulated as an oral dosage form and which provides for delivery of the one or more active pharmaceutical ingredients (APIs) mainly through intraoral delivery, preferably through sublingual 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.
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 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.
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JP2006521348A (en) 2006-09-21
TW200503782A (en) 2005-02-01
CL2004000564A1 (en) 2005-02-04
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AR043772A1 (en) 2005-08-10
EP1605921A1 (en) 2005-12-21
BRPI0408655A (en) 2006-03-28
AU2004224557A1 (en) 2004-10-07
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