WO2004084864A1 - Formulations comprising tolterodine and cocoa powder and use thereof - Google Patents

Formulations comprising tolterodine and cocoa powder and use thereof Download PDF

Info

Publication number
WO2004084864A1
WO2004084864A1 PCT/IB2004/000859 IB2004000859W WO2004084864A1 WO 2004084864 A1 WO2004084864 A1 WO 2004084864A1 IB 2004000859 W IB2004000859 W IB 2004000859W WO 2004084864 A1 WO2004084864 A1 WO 2004084864A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation according
tolterodine
oil
administration
cocoa butter
Prior art date
Application number
PCT/IB2004/000859
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 AU2004224556A priority Critical patent/AU2004224556A1/en
Priority to JP2006506376A priority patent/JP2006521347A/en
Priority to CA002519119A priority patent/CA2519119A1/en
Priority to MXPA05010314A priority patent/MXPA05010314A/en
Priority to EP04720944A priority patent/EP1605920A1/en
Priority to BRPI0408743-7A priority patent/BRPI0408743A/en
Publication of WO2004084864A1 publication Critical patent/WO2004084864A1/en

Links

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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • 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)
    • A61K36/22—Anacardiaceae (Sumac family), e.g. smoketree, sumac or poison oak
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • 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)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • 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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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

Definitions

  • This invention relates to novel orally administered pharmaceutical formulations of tolterodine, optionally comprising salts, complexes, prodrugs and metabolites thereof, to the use of tolterodine, optionally comprising salts, prodrugs and metabolites thereof, for the manufacturing of a medicament to be administered orally for achieving an effect against overactive bladder, and to methods of treating overactive bladder by oral administration of tolterodine, optionally comprising salts, prodrugs and metabolites thereof.
  • Tolterodine is an effective and safe compound for treatment of overactive bladder.
  • the synthesis of tolterodine and its utility for the treatment of overactive bladder is disclosed in US 5,382,600 (Pharmacia & Upjohn AB).
  • An optimal efficacy/side effect profile is obtained at an oral dosage of 1 or 2 mg twice daily.
  • Tolterodine has a molecular weight of 325.0 and 475.6 as the tartrate salt.
  • the enantiomeric purity is > 99 %.
  • the pK a value is 9.87 and the solubility in water is about 11 mg/ml at room temperature.
  • the partition coefficient (Log P) between n-octanol and phosphate buffer at pH 7.32 is 1.83.
  • Tolterodine, PNU-200583 N,N-diiso-propyl-3-(2-hydroxy-5-methylphenyl)-3- phenylpropanamine.
  • the major metabolic pathway for the metabolism of tolterodine is mediated by cytochrome P4502D6 leading to the formation of a 5-HM metabolite, (R)-N,N- diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine.
  • This metabolite has a similar pharmacological profile as tolterodine - see Nilvebrant L, Gillberg P-G, Sparf B. "Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine.” Phannacol. Toxicol. (1997) 81 : 195-207.
  • N-dealkylated metabolite is mediated by CYP3 A and may be further metabolized to a N-dealkylated 5-hydroxymetabolite. See the below scheme.
  • One further metabolite is formed when a carboxylic acid group is formed at the CH2OH group of the 5-HM metabolite. Still one further metabolite is formed when a carboxylic acid group is fo ⁇ ned at the CH 2 OH group of the N-dealkylated 5-HM metabolite.
  • Tolterodine of the present invention encompasses the R-isomer, the S-isomer and the racemic mixture as well as salts, complexes, prodrugs and metabolites thereof.
  • Major effects are obtained from the R-isomer and the racemic mixture as well as from salts, complexes, prodrugs and metabolites thereof.
  • salts are tolterodine 1- tartrate and tolterodine mesylate.
  • Examples of complexes are complexes between tolterodine and beta-cyclodextrine and tolterodine and ion exchange compositions, such as ion exchange resinates.
  • Prior Art Above-mentioned US 5,382,600 does not disclose any formulation similar to the ones of the present invention.
  • WO 98/03067 discloses transdermal administration of the S-isomer of tolterodine.
  • WO 00/12070 discloses transdermal administration of the R-isomer and of the racemate of tolterodine. No prior art on tolterodine-containing formulations similar to the ones of the present invention has been found.
  • Chocolate which is different from cocoa powder as such, is very rarely used as an ingredient in pharmaceutical products, hitherto only in laxatives.
  • 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 is not known any compositions comprising tolterodine and chocolate.
  • die present invention as further described below, is both new and inventive.
  • the present invention provides an orally administered pharmaceutical formu- lation of tolterodine, optionally comprising salts, prodrugs and metabolites thereof for achieving an effect against overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence.
  • the administration can be to a human being or to an animal.
  • 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.
  • 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 tolterodine.
  • a “therapeutically effective amount” herein is an amount sufficient to achieve an effect against overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence.
  • urinary frequency is primarily meant a need to urinate more than 8 times over 24 hours or more than 2 times per night.
  • urinary urgency is primarily meant frequent, strong and sudden needs to urinate.
  • urge incontinence is primarily meant involuntary urination after a sudden need to urinate.
  • the amount of tolterodine be lower than an amount causing significant side effects.
  • 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.
  • An object of the invention is to provide novel orally administered pharmaceutical formulations of tolterodine 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 fo ⁇ nulations therapy for treating overactive bladder.
  • the formulation provides for discreet self-administration
  • the formulation does not give an immediate patient-perceived association with medicines, as do traditional tablets. 6) The formulation may provide for rapid transmucosal absorption, especially when buffering agents are added.
  • tolterodine- containing formulation for transmucousal delivery, that mainly 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 tissues in the oral cavity.
  • the formulation is such that it does not require addition of liquid at the time of administration.
  • the formulation does not increase the need for therapy, as there is no increase in the urinary burden - in comparison with conventional tablets being administered together with liquid. No additional urine is produced.
  • buffering agents provides for a transient change in local pH of the saliva. Thereby a higher fraction of tolterodine is transformed into its less ionized form. Thereupon the transmucousal permeation is facilitated, which enhances the absorption of the active agent.
  • the choice of the buffering system is dependent on the one or more pK a s of the active agent.
  • cocoa powder acts as taste masker and texturizer.
  • 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.
  • a preferred embodiment is a formulation, weighing around 400 mg, having the following preferred formulation (w/w):
  • a formulation weighing around 400 mg, is prepared with the following preferred 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 tolterodine 1-tartrate, cocoa powder, mannitol, maize starch, aspartame, acesulfame-K, titanium dioxide, monosodium glutamate 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.
  • 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 composition (w/w):
  • 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 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 (CBS), cocoa butter replacers (CBR) and cocoa butter improvers (CBI),
  • - 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
  • 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 buccal mucosa.
  • 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 dihydrochalcone), 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 dihydrochalcone), alitame, miraculin (miracle fruit), monellin (serendipity berry), stevside and/or salts thereof.
  • the emulsifier 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- 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.
  • Formulations according to the present inventions primarily constitute meltable and/or suckable oral tablets, but also include other suitable dosage forms for oral administration such as buccal patches, buccal paste and buccal sprays.
  • the present invention also encompasses tolterodine-containing formulations further comprising one or more other active agents having an effect against overactive bladder, such as oxobutynin, emepromium, trospium, propanetheline and darifenacin.
  • active agents having an effect against overactive bladder, such as oxobutynin, emepromium, trospium, propanetheline and darifenacin.
  • the present invention encompasses treating overactive bladder in a subject through administration to a subject of a tolterodine-containing orally administered pharmaceutical formulation as presented above, optionally together with one or more other agents having an effect against overactive bladder, and further optionally concomitantly with administration of agents for treating overactive bladder through one or more other routes of administration, such as through transdermal administration, peroral administration, administration by inhalation, administration by creams, salves and vagitories, and/or administration by injection.

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Biotechnology (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nutrition Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Physiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

A tolterodine-containing pharmaceutical formulation that comprises cocoa powder, process for manufacturing the formulation and use of the formulation for treating overactive bladder.

Description

FORMULATIONS COMPRISING TOLTERODINE AND COCOA POWDER AND USE THEREOF
Field of the Invention
This invention relates to novel orally administered pharmaceutical formulations of tolterodine, optionally comprising salts, complexes, prodrugs and metabolites thereof, to the use of tolterodine, optionally comprising salts, prodrugs and metabolites thereof, for the manufacturing of a medicament to be administered orally for achieving an effect against overactive bladder, and to methods of treating overactive bladder by oral administration of tolterodine, optionally comprising salts, prodrugs and metabolites thereof.
Background
Tolterodine is an effective and safe compound for treatment of overactive bladder. The synthesis of tolterodine and its utility for the treatment of overactive bladder is disclosed in US 5,382,600 (Pharmacia & Upjohn AB). An optimal efficacy/side effect profile is obtained at an oral dosage of 1 or 2 mg twice daily.
Tolterodine has a molecular weight of 325.0 and 475.6 as the tartrate salt. The enantiomeric purity is > 99 %. The pKa value is 9.87 and the solubility in water is about 11 mg/ml at room temperature. The partition coefficient (Log P) between n-octanol and phosphate buffer at pH 7.32 is 1.83. Tolterodine, PNU-200583 N,N-diiso-propyl-3-(2-hydroxy-5-methylphenyl)-3- phenylpropanamine.
Figure imgf000002_0001
The major metabolic pathway for the metabolism of tolterodine is mediated by cytochrome P4502D6 leading to the formation of a 5-HM metabolite, (R)-N,N- diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine. This metabolite has a similar pharmacological profile as tolterodine - see Nilvebrant L, Gillberg P-G, Sparf B. "Antimuscarinic potency and bladder selectivity of PNU-200577, a major metabolite of tolterodine." Phannacol. Toxicol. (1997) 81 : 195-207. For the similarity to tolterodine in pharmacological profile, see Brynne N, Dalen P, Alvan G, Bertilssoα L and Gabrielsson J, Clin Pharmacol Ther 1998 (63): 529-39.
A N-dealkylated metabolite is mediated by CYP3 A and may be further metabolized to a N-dealkylated 5-hydroxymetabolite. See the below scheme.
Figure imgf000003_0001
Toitβrodins Atøtealkylated tαiterodine
CVF2D6
Figure imgf000003_0002
5-HM ^al yfate 5-H
One further metabolite is formed when a carboxylic acid group is formed at the CH2OH group of the 5-HM metabolite. Still one further metabolite is formed when a carboxylic acid group is foπned at the CH2OH group of the N-dealkylated 5-HM metabolite.
Tolterodine of the present invention encompasses the R-isomer, the S-isomer and the racemic mixture as well as salts, complexes, prodrugs and metabolites thereof. Major effects are obtained from the R-isomer and the racemic mixture as well as from salts, complexes, prodrugs and metabolites thereof. Examples of salts are tolterodine 1- tartrate and tolterodine mesylate. Examples of complexes are complexes between tolterodine and beta-cyclodextrine and tolterodine and ion exchange compositions, such as ion exchange resinates. Prior Art Above-mentioned US 5,382,600 does not disclose any formulation similar to the ones of the present invention.
WO 98/03067 discloses transdermal administration of the S-isomer of tolterodine.
WO 00/12070 discloses transdermal administration of the R-isomer and of the racemate of tolterodine. No prior art on tolterodine-containing formulations similar to the ones of the present invention has been found.
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 is not known any compositions comprising tolterodine and chocolate.
It has now surprisingly been found that an orally administered pharmaceutica] formulation of tolterodine, which may be administered without liquid, having sufficient taste masking of badly tasting ingredients, such as tolterodine and optional buffering agents, is obtained by tolterodine-containing formulations comprising cocoa powder as taste masker and texturizer. No similar formulations have been disclosed hitherto and the skilled person would not without inventive efforts have conceived the formulations of the present invention.
Hence die present invention, as further described below, is both new and inventive.
Summary of the invention
The present invention provides an orally administered pharmaceutical formu- lation of tolterodine, optionally comprising salts, prodrugs and metabolites thereof for achieving an effect against overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence. The administration can be to a human being or to an animal.
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 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 tolterodine. A "therapeutically effective amount" herein is an amount sufficient to achieve an effect against overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence. By "urinary frequency" is primarily meant a need to urinate more than 8 times over 24 hours or more than 2 times per night. By "urinary urgency" is primarily meant frequent, strong and sudden needs to urinate. By "urge incontinence" is primarily meant involuntary urination after a sudden need to urinate.
It is preferred that the amount of tolterodine be lower than an amount causing significant side effects.
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.
Also provided by the present invention are methods of use of formulations of the present invention for treatment of overactive bladder, and a method of use of a formulation of the invention for preparing a medicament. 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 tolterodine 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 foπnulations therapy for treating overactive bladder.
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 adequate taste masking;
2) The formulation does not require any added liquid at the time of administration;
3) By not adding liquid at administration use of the formulation does not increase the need for therapy, as mere is no increase in the urinary burden - in comparison with conventional tablets being administered together with liquid.
4) The formulation provides for discreet self-administration;
5) The formulation does not give an immediate patient-perceived association with medicines, as do traditional tablets. 6) The formulation may provide for rapid transmucosal absorption, especially when buffering agents are added.
Detailed Description of the Invention
It is the primary object of the present invention to provide pharmaceutical tolterodine-containing formulations useful for treatment of overactive bladder, comprising detrusor instability, detrusor hyperreflexia, urinary frequency, urinary urgency and urge incontinence.
More specifically it is the object of the invention to provide such a tolterodine- containing formulation, for transmucousal delivery, that mainly 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 tissues in the oral cavity.
Preferably the formulation is such that it does not require addition of liquid at the time of administration. By not adding liquid at administration use of the formulation does not increase the need for therapy, as there is no increase in the urinary burden - in comparison with conventional tablets being administered together with liquid. No additional urine is produced.
Optional addition of buffering agents provides for a transient change in local pH of the saliva. Thereby a higher fraction of tolterodine is transformed into its less ionized form. Thereupon the transmucousal permeation is facilitated, which enhances the absorption of the active agent. For those skilled in the art it is evident that the choice of the buffering system is dependent on the one or more pKas of the active agent.
It has surprisingly been found that a sufficient taste masking of badly tasting ingredients, such as tolterodine itself and/or buffering agents, is achieved through the use of cocoa powder. The cocoa powder acts as taste masker and texturizer.
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.
A preferred embodiment is a formulation, weighing around 400 mg, having the following preferred formulation (w/w):
Figure imgf000007_0001
Examples
Below follows non- limiting examples on preparation of embodiments of the present invention. Example 1; Preparation of a preferred embodiment
A formulation, weighing around 400 mg, is prepared with the following preferred composition (w/w):
Figure imgf000007_0002
Figure imgf000008_0001
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 tolterodine 1-tartrate, cocoa powder, mannitol, maize starch, aspartame, acesulfame-K, titanium dioxide, monosodium glutamate 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 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 pastillation, when necessary after suitable preconditioning. Also other suitable manufacturing methods may be used. Example 2: Preparation of another embodiment In essentially the same way as in Example 1 is manufactured a formulation, weighing around 500 mg, having the following preferred composition (w/w):
Figure imgf000009_0001
Example 3: 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 composition (w/w):
Figure imgf000009_0002
Figure imgf000010_0001
Example 4: Preparation of alternative embodiments
Useful embodiments are obtained by exchanging some of the excipients in the embodiments of the above examples 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, fruc- tose, 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 predomi- nantly 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 subject- ted to further processing including catalytic hydrogenation, interesterification, tran- sesterification 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 buccal mucosa.
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 dihydrochalcone), alitame, miraculin (miracle fruit), monellin (serendipity berry), stevside and/or salts thereof.
The emulsifier 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- 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.
Formulations according to the present inventions primarily constitute meltable and/or suckable oral tablets, but also include other suitable dosage forms for oral administration such as buccal patches, buccal paste and buccal sprays.
The present invention also encompasses tolterodine-containing formulations further comprising one or more other active agents having an effect against overactive bladder, such as oxobutynin, emepromium, trospium, propanetheline and darifenacin. Further, the present invention encompasses treating overactive bladder in a subject through administration to a subject of a tolterodine-containing orally administered pharmaceutical formulation as presented above, optionally together with one or more other agents having an effect against overactive bladder, and further optionally concomitantly with administration of agents for treating overactive bladder through one or more other routes of administration, 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 tolterodine, optionally comprising salts, complexes, prodrugs and metabolites thereof, charac- terizedin that it comprises cocoa powder.
2. A formulation according to claim 1, characterized in that tolterodine essentially is in its R-isomeric form.
3. A formulation according to claim 1, characterized in that tolterodine essentially is in its S-isomeric form.
4. A formulation according to claim 1, characterized in that tolterodine essentially is in racemic form.
5. A formulation according to claim l.characterizedin that it administers the tolterodine metabolite (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethyl- phenyl)-3-phenylpropanamine, optionally together with tolterodine.
6. A formulation according to any of the preceding claims, characterize d in that it further comprises one or more lipid ingredients.
7. A formulation according to claim 6, characterized 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, alkahne 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.
8. A formulation according to claim 7, 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).
9. A formulation according to any of the preceding claims, characterize d in that it further comprises one or more buffering agents.
10. A formulation according to claim 9, 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.
11. A formulation according to any of the preceding claims, characterize d in that it further comprises one or more sweeteners and optionally one or more fla vo ring agents .
12. A formulation according to claim 11, 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 (seren- dipity berry), stevside and/or salts thereof.
13. A formulation according to any preceding claim, characterized in that it further comprises one or more emulsifiers/solubilisers.
14. A formulation according to claim 13, 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.
15. A formulation according to claim 14, characterized in that the one or more emulsifiers/solubilisers is/are chosen from lecithin, preferably soy lecithin and/or egg lecithin.
16. A formulation according to any preceding claim, characterized in that it further comprises a substance/substances chosen 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 polydextrose, or starch, or any mixture thereof.
17. An orally administered pharmaceutical formulation, characterized in that a unit dose thereof has a weight of around 400 mg and comprises
Figure imgf000015_0001
18. An orally administered pharmaceutical formulation, characterized in that a unit dose thereof has a weight of around 500 mg and comprises
Figure imgf000016_0001
19. An orally administered pharmaceutical formulation comprising tolterodine, optionally comprising salts, complexes, prodrugs and metabolites thereof, charac- t e r i z e d in that a unit dose thereof has a weight of around 200 - 1000 mg and comprises
Figure imgf000016_0002
Figure imgf000017_0001
20. 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 other agents having an effect against overactive bladder.
21. A formulation according to claim 20, c h a r ac t e r i z e d in that the one or more other agents is/are chosen from oxobutynin, emepromium, trospium, propan- etheline and darifenacin.
22. A formulation according to any preceding claim which is formulated as an oral dosage form and which provides for delivery of tolterodine mainly through the buccal mucosa and/or other mucosa of the oral cavity.
23. Use of a formulation according to any preceding claim for the manufacture of a medicament useful for treatment of overactive bladder.
24. Method for treating overactive bladder in a subject comprising administration of a tolterodine-containing orally administered pharmaceutical formulation according to anyone of claims 1 - 22 to the subject.
25. Method for treating overactive bladder in a subject comprising administration of a tolterodine-containing orally administered pharmaceutical formulation according to anyone of claims 1 - 22 to the subject concomitantly with administration of tolterodine and/or one or more other agents having an effect against overactive bladder through one or more other routes of administration.
26. Method for treating overactive bladder in a subject according to claim 25 wherein the one or more other routes are chosen from transdermal and peroral administration, and administration by inhalation and injection.
PCT/IB2004/000859 2003-03-26 2004-03-16 Formulations comprising tolterodine and cocoa powder and use thereof WO2004084864A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AU2004224556A AU2004224556A1 (en) 2003-03-26 2004-03-16 Formulations comprising tolterodine and cocoa powder and use thereof
JP2006506376A JP2006521347A (en) 2003-03-26 2004-03-16 Formulation containing tolterodine and cocoa powder and use thereof
CA002519119A CA2519119A1 (en) 2003-03-26 2004-03-16 Formulations comprising tolterodine and cocoa powder and use thereof
MXPA05010314A MXPA05010314A (en) 2003-03-26 2004-03-16 Formulations comprising tolterodine and cocoa powder and use thereof.
EP04720944A EP1605920A1 (en) 2003-03-26 2004-03-16 Formulations comprising tolterodine and cocoa powder and use thereof
BRPI0408743-7A BRPI0408743A (en) 2003-03-26 2004-03-16 formulations comprising tolterodine and cocoa powder and their use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0300830-7 2003-03-26
SE0300830A SE0300830D0 (en) 2003-03-26 2003-03-26 New formulations and use thereof

Publications (1)

Publication Number Publication Date
WO2004084864A1 true WO2004084864A1 (en) 2004-10-07

Family

ID=20290785

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2004/000859 WO2004084864A1 (en) 2003-03-26 2004-03-16 Formulations comprising tolterodine and cocoa powder and use thereof

Country Status (12)

Country Link
EP (1) EP1605920A1 (en)
JP (1) JP2006521347A (en)
CN (1) CN1764441A (en)
AR (1) AR043773A1 (en)
AU (1) AU2004224556A1 (en)
BR (1) BRPI0408743A (en)
CA (1) CA2519119A1 (en)
CL (1) CL2004000625A1 (en)
MX (1) MXPA05010314A (en)
SE (1) SE0300830D0 (en)
WO (1) WO2004084864A1 (en)
ZA (1) ZA200506710B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8802239B2 (en) 2009-10-16 2014-08-12 Dow Corning Toray Co., Ltd. Treatment composition for wipe paper
US8900645B2 (en) 2007-06-13 2014-12-02 Otsuka Pharmaceuticals Co., Ltd. Equol-containing extract, method for production thereof, method for extraction of equol, and equol-containing food

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1907136B (en) * 2006-07-28 2010-08-25 张新生 Vegetation health care milk-like liquid and preparation method thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB918955A (en) * 1960-05-19 1963-02-20 Thomae Gmbh Dr K Pharmaceutical laxative compositions comprising 4,4-dihydroxy-2-amino triphenylmethane
WO2000030641A1 (en) * 1998-11-23 2000-06-02 Pharmacia & Upjohn Ab Nicotine-containing pharmaceutical compositions giving a rapid transmucosal absorption
JP2001114668A (en) * 1999-10-13 2001-04-24 Meiji Seika Kaisha Ltd Chocolate preparation
WO2001034139A1 (en) * 1999-11-11 2001-05-17 Pharmacia Ab Pharmaceutical formulation containing tolterodine and its use

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB918955A (en) * 1960-05-19 1963-02-20 Thomae Gmbh Dr K Pharmaceutical laxative compositions comprising 4,4-dihydroxy-2-amino triphenylmethane
WO2000030641A1 (en) * 1998-11-23 2000-06-02 Pharmacia & Upjohn Ab Nicotine-containing pharmaceutical compositions giving a rapid transmucosal absorption
JP2001114668A (en) * 1999-10-13 2001-04-24 Meiji Seika Kaisha Ltd Chocolate preparation
WO2001034139A1 (en) * 1999-11-11 2001-05-17 Pharmacia Ab Pharmaceutical formulation containing tolterodine and its use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 25 April 2001 (2001-04-25), ISHIKURA, TOYOAKI ET AL: "Pharmaceutical chocolate preparations using cocoa butter substitutes", XP002289558, retrieved from STN Database accession no. 2001:290825 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8900645B2 (en) 2007-06-13 2014-12-02 Otsuka Pharmaceuticals Co., Ltd. Equol-containing extract, method for production thereof, method for extraction of equol, and equol-containing food
US8993014B2 (en) 2007-06-13 2015-03-31 Otsuka Pharmaceutical Co., Ltd. Equol-containing extract, method for production thereof, method for extraction of equol, and equol-containing food
US9192185B2 (en) 2007-06-13 2015-11-24 Otsuka Pharmaceutical Co., Ltd. Equol-containing extract, method for production thereof, method for extraction of equol, and equol-containing food
US10681930B2 (en) 2007-06-13 2020-06-16 Otsuka Pharmaceutical Co., Ltd. Equol-containing extract, method for production thereof, method for extraction of equol, and equol-containing food
US8802239B2 (en) 2009-10-16 2014-08-12 Dow Corning Toray Co., Ltd. Treatment composition for wipe paper

Also Published As

Publication number Publication date
AU2004224556A1 (en) 2004-10-07
JP2006521347A (en) 2006-09-21
CL2004000625A1 (en) 2005-01-07
BRPI0408743A (en) 2006-03-28
AR043773A1 (en) 2005-08-10
CA2519119A1 (en) 2004-10-07
CN1764441A (en) 2006-04-26
SE0300830D0 (en) 2003-03-26
MXPA05010314A (en) 2006-05-19
EP1605920A1 (en) 2005-12-21
ZA200506710B (en) 2006-11-29

Similar Documents

Publication Publication Date Title
AU2004224557B2 (en) Formulations comprising an active ingredient and cocoa powder and use thereof
DE69916486T2 (en) PHARMACEUTICAL COMPOSITIONS CONTAINING NICOTINE WITH FAST TRANSMUCOSAL ABSORPTION
RU2286153C2 (en) New preparations and uses thereof
US20070122456A1 (en) Nicotine and Cocoa Powder Compositions
US20100069397A1 (en) Sexual dysfunction compounds
AU2002334522A1 (en) New formulations and use thereof
US20100197742A1 (en) New formulations and use thereof
ZA200506710B (en) Formulations comprising tolterodine and cocoa powder and use thereof
US20040191345A1 (en) New formulations and use thereof
CA2495527C (en) New sexual-dysfunction-compound-containing rapid-onset pharmaceutical formulations comprising cocoa powder and use thereof
TW200423959A (en) New formulations and use thereof

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 200506710

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 2004224556

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2004720944

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 3881/DELNP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2519119

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2004224556

Country of ref document: AU

Date of ref document: 20040316

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2004224556

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2006506376

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 20048080871

Country of ref document: CN

Ref document number: PA/a/2005/010314

Country of ref document: MX

WWP Wipo information: published in national office

Ref document number: 2004720944

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0408743

Country of ref document: BR