US20060014832A1 - Highly pure bases of 3,3-dipheyl propylamine monoesters - Google Patents

Highly pure bases of 3,3-dipheyl propylamine monoesters Download PDF

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US20060014832A1
US20060014832A1 US10/532,836 US53283605A US2006014832A1 US 20060014832 A1 US20060014832 A1 US 20060014832A1 US 53283605 A US53283605 A US 53283605A US 2006014832 A1 US2006014832 A1 US 2006014832A1
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compound
formula
percent
weight
pharmaceutical formulation
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Armin Breitenbach
Claus Meese
Hans-Michael Wolff
Roland Drews
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UCB Pharma GmbH
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Schwarz Pharma AG
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Publication of US20060014832A1 publication Critical patent/US20060014832A1/en
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Priority to US12/141,489 priority Critical patent/US7989654B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • 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
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Definitions

  • This invention concerns high purity bases of 3,3-diphenylpropylamino monoesters, their manufacture and their use as drugs, in particular for transdermal and transmucosal administration.
  • the dysfunction lies in a malfunction of the bladder muscle. Frequently the cause is a stimulation or more precisely a hyperactivity of the muscarinic receptors. For this reason use of the antimuscarinic active ingredients Tolterodin and Oxybutynin is preferred for the treatment of the hyperactive bladder and the associated symptoms such as increased urinary urgency, abnormally frequent micturation or nocturia.
  • oxybutynin is an effective antimuscarinic agent that has serious side effects. Notably the pronounced dryness of the mouth is felt by many patients to be extremely unpleasant.
  • Tolterodin By comparison with Oxybutynin Tolterodin appears to exhibit lower muscarinic side effect rates.
  • Tolterodin In an organism Tolterodin is predominantly dealkylated into active main metabolites 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol by the cytochrome P450-isoenzyme 2D6 as well as—slowly—into inactive metabolites by the cytochrome P 450 isoenzyme 3A4.
  • Tolterodin is metabolized exclusively through the P450-isoenzyme, there is the potential danger of interactions with the breakdown of other agents, for example, with Warfarin (Colucci, Annals of Pharmacotherapy 33, 1999, 1173), antimycotics such as Ketoconazol (Brynne, Br J Clin Pharmacol 48, 1999, 564) macrolide antibiotics or protease inhibitors.
  • This danger is present particularly in the case of the so-called slow metabolizers, which have a lack of 2D6, metabolize Tolterodin exclusively through 3A4 and exhibit a distinctly increased Tolterodin concentration in plasma.
  • WO 99/58 478 describes new derivates of 3,3-diphenylpropylamines as active muscarinic ingredients.
  • the disclosed 3,3-diphenylpropylamine-derivates are prodrugs from 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy-methyl)phenol and are hydrolyzed by esterases upon entering through biological membranes as well as in plasma. For this reason the 2D6-dependent degradation device does not apply.
  • the bases of 3,3-diphenylpropylamines published in WO 99/58478 are manufactured by 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol being converted under alkaline conditions with an appropriate acid chloride, for example, isobutyric acid chloride (see Example Execution 3aa of WO 99/58478).
  • an appropriate acid chloride for example, isobutyric acid chloride
  • the product consistently contains 6-10% impurities of the starting substance (A), the used acylation agent as well as undesired reaction products in the form of the corresponding di-ester of the acylating reagent used (C) of the monoester (D) of the 4-hydroxy group (see FIG. 1 ) as well as by dimerization/polymerization.
  • WO 01/35957 teaches stable, crystalline salts of 3-3-diphenylpropylamine derivates, which, compared with the amorphic salts have the advantage of higher stability and higher purity.
  • Salts of this sort are basically suitable for therapeutic administration and may, for example, be used for oral or parenteral treatment.
  • the salt of the active ingredient is less suitable in many situations because its ionized form hinders passage of the skin or the mucous membrane in therapeutically effective amounts. If a transdermal or transmucosal application is desired, then the active ingredient that contains amines has to be frequently applied in the form of the base.
  • a free base of the general Formula I could be yielded in a purity of consistently above 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight and with a high yield above 80% (mol %) if the free base is manufactured by releasing it with an appropriate reagency from a high purity, crystalline salt.
  • A means hydrogen or deuterium
  • R stands for a group that is selected from C 1-6, -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it,
  • the free base is present in a degree of purity of above 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably, especially preferably above 99 percent by weight.
  • execution R is selected from the group methyl, ethyl, isopropyl, 1-propyl, 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl, hexyl C 4 -C 8 cycloalkyl or phenyl.
  • R is isopropyl (i-Pr) so that the compound is 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenyl isobutyrate (fesoterodine base).
  • the compounds of the general Formula 1 are present as a racemate, meaning as mixtures of the (R)- and (S) configured molecules.
  • the C-atom marked with a star “ ⁇ ” is present in (R)-format, whereby preferably over 98 percent by weight of the compound, especially preferably over 99 percent by weight of the compound and notably especially preferably over 99.5 percent by weight of the compound is present in the (R)-configuration.
  • the compound is the high purity free base from (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenyl isobutyrate (fesoterodine base) with a purity content of over 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight.
  • C 1-6 alkyl is understood to be a straight chain or branched chain hydrocarbon group with 1-6 C-atoms.
  • Preferred C 1-6 alkyls are non-substituted straight or branch chain groups, in particular selected from the group of methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, tertiary-butyl, pentyl and hexyl.
  • C 3-10 cycloalkyl is understood to mean a cyclical hydrocarbon group with 3-10 hydrocarbon atoms.
  • high purity is understood to mean a degree of purity of the monoester of the general Formula I of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight, meaning that an appropriately low proportion of diesters, dihydroxy compounds, 4-monoesters or polymers is present.
  • the degree of purity is determined as described in the techniques section.
  • free base is understood to mean that less than 10 percent by weight, preferably less than 5% or 3%, especially preferably less than 1% is of the compound of the general Formula I is present in the salt form.
  • the salt content is thereby determined as described in the techniques section.
  • the high purity bases of the general Formula I in compliance with the invention can be manufactured by their release from the high purity, crystalline salts of the general formula II: where A and R have the significance given above, X ⁇ is the acid residue of a physiological compatible acid and where the C-atom marked with “ ⁇ ” (a star) can be present in the (R)-configuration, in the (S)-configuration or as a mixture thereof.
  • Hydrochloric acid hydrobromic acid, phosphoric acid, sulphuric acid, nitric acid, acetic acid, propionic acid, palmitic acid, stearic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, DL-malic acid, L-( ⁇ )-malic acid, D-(+)-malic acid, DL-tartaric acid, L-(+)-tartaric acid, D-( ⁇ )-tartaric acid, citric acid, L-aspartic acid, L-(+)-ascorbic acid, D-(+)-glucuronic acid, 2-oxopropionic acid (pyruvic acid), furan-2-carboxylic acid (pyromucic acid), benzoic acid, 4-hydroxybenzoic acid, salicylic acid, vanillic acid, 4-hydroxycinnamic acid, gallic acid, hippuric acid (N-benzoyl-glycin), aceturic acid (N-ace
  • release reagents The corresponding high purity bases are released from this high purity compound of the general Formula II through the addition of the appropriate base reagents (“release reagents”).
  • the release reagents are, for example, alkaline compounds from the group of
  • Such reagents are preferred as release reagents that inhibit a precipitation of the bases of the 3,3-diphenylpropylamine monoesters in the particular solvent. In addition, a hydrolysis of the ester bond should be avoided.
  • An alkaline-, earth alkaline or ammonium hydrogen carbonate is especially preferred as the releasing reagent, whereby sodium hydrogen carbonate is notably especially preferred.
  • the salt of the Formula II is first absorbed in water and laced with a base releasing agent, for example, a hydrogen carbonate. This is then extracted by shaking using an appropriate solvent and the organic phase evaporated to a low small bulk until the high purity base of the Formula I remains behind as a viscous oil.
  • a base releasing agent for example, a hydrogen carbonate.
  • Solvents that are suitable for purification of the free base are in particular dichloromethane, tertiary-butyl-methyl ether, diethyl ether, ethyl methyl ketone as well as toluene, where dichloromethane is especially preferred.
  • the high purity salt of the Formula II is absorbed in an appropriate solvent and then conducted over a carrier, which contains immobilized ionic exchangers, for example.
  • the eluate then contains the high purity base of the general Formula I.
  • One object of the invention is therefore a procedure for the manufacture of a high purity free base of the general Formula I in which A means hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it in a purity of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight,
  • the inventive manufacturing process is preferably used to manufacture high purity bases of the general Formula I, in which the C-atom identified with “ ⁇ ” is present in the (R)-configuration and/or in which the substituent R is selected from the methyl, ethyl, iso-propyl, 1-propyl, 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group.
  • the inventive manufacturing process preferably serves for the manufacture of the high purity free base (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenyl isobutyrate, whereby (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenyl isobutyrate hydrogen fumarate is especially preferred for use as the initial compound of the Formula II.
  • the production of the high purity salts of the Formula II is known from WO 01/35957.
  • a solution of 2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenol is converted in a base solution with an acid chloride, for example, isobutyric acid chloride.
  • the resulting base with a low purity content is then laced with an acid, for example, fumaric acid, while being heated.
  • the resulting salt of the general Formula II can then be crystallized out in appropriate solvents. The crystals are then dissolved again and re-crystallized.
  • the yield of high purity free base of the Formula I in amounts to above 90% of the theory based on the amount of the 3,3-diphenylaminomonoester of the Formula II used.
  • inventive pure bases of the general Formula II are present in the form of an oil following manufacture and are stable at ⁇ 20° C.
  • inventive free bases are preferably stored in the presence of drying agents.
  • the inventive procedure allows for the first time the efficient isolation of the free base of the general Formula I in a high purity form.
  • the procedure is up-scalable and makes manufacture of the high purity compounds possible on an industrial scale and for the first time makes the high purity bases of the general Formula I containing pharmaceutical formulations available.
  • a further aspect of this invention is therefore a pharmaceutical formulation that comprises a compound of the general Formula I, which comprises as well as at least one pharmaceutically acceptable carrier, whereby A is either hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-6 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it in a purity of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight.
  • the inventive pharmaceutical formulation contains a compound of the general Formula 1 where R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferable that R be an isopropyl, and whereby it is especially preferable the C-atom identified with “ ⁇ ” is present in the (R)-configuration.
  • R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferable that R be an isopropyl, and whereby it is especially preferable the C-atom identified with “ ⁇ ” is present in the (R)-configuration.
  • the storage of the pharmaceutical formulations should preferably be done at ⁇ 25° C., especially preferably at ⁇ 8° C. and in the presence of drying agents.
  • inventive free bases are present in the pharmaceutical formulation in a slightly acidic environment, meaning at a pH of 3-7, preferably pH 3-6 or pH 3-5, since the stability of the free bases is highest under these conditions.
  • the pharmaceutical formulations be free from short chain C 1-8 alcohols and from C 1-4 alcohols in particular.
  • the arrangement of the pharmaceutical formulation primarily depends on the mode of administration as well as on the desired properties of the respective form of administration.
  • auxiliary agents known to the specialist in the area of pharmaceutical technology are qualified as pharmaceutically acceptable carriers, such as they are described in Sucker, Fuchs and Suiter, Pharmazeutician Technologie, Georg Thieme Verlag, Stuttgart, for example, and other reviews on appropriate forms of drugs.
  • Such a pharmaceutical formulation may be conventional but may also be arranged as a fast-releasing or retarding formulation dependent upon the special requirements of the patient.
  • inventive high purity bases of the general Formula I with controlled release of the active ingredient be used in pharmaceutical formulations for the transdermal or transmucosal application.
  • the pharmaceutical formulations which after an initial burst effect phase, are ensuring a constant flux rate through the skin or mucous membrane of a patient over a minimum of 24 hours, preferably over a minimum of 48 hours, are especially preferred.
  • the pharmaceutical formulation contains at least one polymer layer in which a high purity base of the general Formula I is dispersed or dissolved.
  • the release behavior of the active ingredient can be influenced through the composition of such a polymer layer. So, for example, the solubility behavior of active ingredients in the polymer matrix decisively determines the release of the active agent from transdermal/transmucosal therapeutic systems and by doing so determines the flux rates through the skin or the mucous membrane as well.
  • the polymer layer may contain pressure sensitive adhesive substances that make the attachment of the pharmaceutical composition to the skin or the mucous membrane of the patient possible.
  • a buccal formulation may be arranged as a mucoadhesive system from out of which there is retarded release of the active ingredient.
  • Adhesive polymers/copolymers such as PVP, pectin, carbopol, polyacrylates, cellulose derivates, chitosane or polyoxyethylene are used for the adhesion to the mucous membrane.
  • Appropriate examples and overviews are found, for example in U.S. Pat. No. 6,210,699; U.S. Pat. No. 4,855,142; U.S. Pat. No. 4,680,323; U.S. Pat. No. 5,700,478; U.S. Pat. No. 4,948,580; U.S.
  • the pharmaceutical formulation for the transdermal delivery of a high purity base of the Formula I is therefore arranged as a buccal formulation, in particular as a buccal patch, which incorporates at a minimum a polymer layer, in which the high purity base of the general Formula I is present either dissolved or dispersed.
  • This polymer layer that contains the high purity base preferably has mucoadhesive properties.
  • the pharmaceutical formulation for the transdermal delivery of a high purity base of the Formula I is arranged as a transdermal patch.
  • Transdermal patches also often identified as transdermal therapeutic systems TTS may be categorized in different ways whereby a distinction is often made between the following three main groups:
  • Especially preferred drugs in the sense of this invention are TTS of the matrix type, whereby monolithic TTS, in which the active ingredient is present in the adhesive matrix, are notably especially preferred.
  • polymer matrix or “matrix” in this patent application a layer or paste that contains polymers is comprehended whereby the term “polymer matrix” is incorporated by this.
  • total weight of the polymer matrix is understood to mean the weight of the polymer matrix including the active ingredient introduced into it and possible auxiliary agents.
  • Non-limiting examples for adhesive polymers/copolymers that are suitable for the manufacture of transdermal devices and which may contain the active ingredient of the general Formula I in dissolved, partially dissolved or dispersed form are silicone adhesives, ethyl vinyl acetate (EVA)-adhesives, styrene block copolymer (SXS)-adhesives, acrylate adhesives, polyurethane adhesives, vinyl acetate adhesives as well as the adhesive gums, for example, polyisobutylene, polybutadiene, neoprene or polyisoprene as well as suitable mixtures of these adhesives.
  • silicone adhesives ethyl vinyl acetate (EVA)-adhesives, styrene block copolymer (SXS)-adhesives, acrylate adhesives, polyurethane adhesives, vinyl acetate adhesives as well as the adhesive gums, for example, polyisobutylene, polybutadiene
  • the polymer adhesives known in patch technology of the silicone type, of the acrylate type, the SxS type, the ethyl vinyl acetate (EVA type) that are known from the state of the art are particularly suitable as contact adhesives.
  • the properties of these contact adhesives will be further explained more closely below.
  • the dosing of the compounds in compliance with invention is dependent on the age, weight a status of the patient, the type of application and the interval.
  • the effective daily dose lies in the 0.5-20 mg range.
  • at least 3 mg/day, for example 3-15 mg/day, preferably 4-12 mg/day is used.
  • a typical transdermal or transmucosal daily dose, for example, for fesoterodine, for an adult patient lies, for example, at a minimum of 3 mg, preferably in the 3-15 mg range and especially preferred between 4 and 12 mg.
  • a pharmaceutical composition which is suitable for once daily administration should therefore preferably contain 3-15 mg of a high purity base of the general Formula I.
  • the pharmaceutical composition is a transdermal formulation, it will generally be given around twice the amount of active ingredient to be administered.
  • a typical formulation for transdermal delivery of a high purity compound of the general Formula I in compliance with the invention consequently contains at least 6 mg active ingredient, but depending on the level of dosage and the application interval, it may also contain more than 10 mg, 20 mg, 30 mg, 40 mg or 50 mg of the high purity active ingredient of the general Formula I, for example, fesoterodine, per dosing unit. If a five or even seven day application interval is scheduled the active ingredient content of an individual dosing unit may also be above 70, 80, 90 or even over 100 mg.
  • the expression “dosing unit” is understood to mean a pharmaceutical formulation that contains a defined amount of active ingredient and that releases this following the one-time administration in patients over a predetermined period of time in a therapeutically effective amount.
  • the term “dosing unit” comprises both a tablet for application three times a day as well as a patch for weekly administration.
  • An object of this invention is therefore a dosing unit that comprises at least 3 mg of a compound of the general Formula I, as well as at least one pharmaceutically acceptable carrier, whereby A is either hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-6 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it and whereby the free base of the compound I is present in a purity of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight.
  • the dosing unit is given at least 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, 80 mg, 90 mg or even over 100 mg high purity active ingredient of the general Formula I.
  • the inventive dosing unit contains a compound of the general Formula 1 where R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferred that R is an isopropyl and whereby it is especially preferable that the C-atom identified with “ ⁇ ” be present in the (R)-configuration.
  • R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferred that R is an isopropyl and whereby it is especially preferable that the C-atom identified with “ ⁇ ” be present in the (R)-configuration.
  • the dosing unit contains the free base from (R)-2-[3-(1,1-diisopropylamino)-1-phenylpropyl]-4-(hydroxy methyl)phenyl isobutyrate (fesoterodine free base) with a degree of purity of 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight.
  • the flux rate through the skin of the patient should be as constant as possible in order to avoid fluctuations of the concentration in the plasma.
  • the daily dose should therefore be administered in the case of an application area of 50 cm 2 , preferably a maximum of 40 cm 2 , in a steady state flux through the human skin of more than 6 ⁇ g/cm 2 /hour, preferably of more than 8 ⁇ g/cm 2 /hour, especially preferably of more than 10 ⁇ g/cm 2 /hour and notably especially preferably of more than 12 ⁇ g/cm 2 /hour, whereby the flux rates are determined according to Tanojo in a model of human skin in-vitro as described in Example Execution 3.2.
  • the invention also concerns the manufacture of drugs.
  • the high purity bases in compliance with the invention are for use during manufacture of a medicine, particularly for the treatment of incontinence, notably especially for the treatment of urge incontinence, as well as for the treatment of hyperactivity of the detrusor, pollakisuria, nocturia or imperative urinary urgency.
  • A means hydrogen or deuterium
  • R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it and whereby the free base is present in a purity of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight for the manufacture of a medicine, preferably a medicine for transdermal or transmucosal delivery.
  • the compound of the general Formula I where R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferred that R is an isopropyl and whereby it is especially preferred that the C-atom identified with “ ⁇ ” be present in the (R)-configuration, is used for the manufacture of the above names drugs.
  • the high purity bases of the Formula I may, for example, be used for manufacture of the more available buccal drugs, e.g. sprays, mucoadhesive pellets or fast dissolving wafers, as described in WO 02/02085 for example.
  • transdermal formulations for example, ointments, creams, lotions, sprays, pastes, foils or patches containing an active ingredient.
  • the high purity base of the general Formula I is preferably used for the manufacture of a medicine for retarded transdermal or transmucosal delivery and for this purpose is preferably introduced into an adhesive or a non-adhesive polymer matrix.
  • One object of the invention is therefore the use of a free base of the general Formula I, in which A is hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it and whereby the free base is present in a purity of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight,
  • a medicine for the manufacture of a medicine, preferably a medicine for transdermal or transmucosal delivery characterized by the fact that the compound of the Formula I is present either dissolved or dispersed in a polymer layer, preferably in a self-adhesive polymer layer.
  • the compound of the general Formula I is used for the manufacture of the above named transdermal medicine, whereby R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferred that R be an isopropyl and whereby it is especially preferred the C-atom identified with “ ⁇ ” be present in the (R)-configuration.
  • R is selected out of the methyl, ethyl, 1-propyl, isopropyl (i-Pr), 1-butyl, 2-butyl, tertiary-butyl, iso-butyl, pentyl and hexyl group, whereby it is especially preferred that R be an isopropyl and whereby it is especially preferred the C-atom identified with “ ⁇ ” be present in the (R)-configuration.
  • the high purity compound of the general Formula libe present in the form of the free base with a combined salt part of less than 10 percent by weight, especially preferable less than 5% or 3%, notably especially preferable less than 1%.
  • the compound of the general Formula I should therefore be added to the polymer matrix paste, preferably already in the form of the high purity free base at the time of the manufacture of the inventive devices.
  • TABLE 2 Loading of the active Flux ⁇ g/cm 2 /Day ingredient (in steady state; (Percent by Matrix after 24 hours) Contact weight weight Mouse Human Lot-No adhesive Procedure fesoterodine) (g/m 2 ) Skin skin 20111080 1 Acrylate Solvent 15 100 705 n.d. 20302060 1 Acrylate Solvent 15 87 n.d. 332.64 20111085 1 EVA Hot melt 15 84 510 323.7 20111086 1 Silicone Hotmelt 15 63 495 n.d.
  • FIG. 2 shows that in those cases which the high purity base of (R)-fesoterodine in an amount of 15 percent by weight was introduced into appropriate adhesive matrices of the SXS or EVA type, TTS leads to flux rates that make therapeutically desired daily doses with the corresponding application surface of 5-50 cm 2 possible in the case of the trials using in-vitro human skin as follows (Table 3): TABLE 3 Flux rate fesoterodine through human skin (mg/day) based on the TTS size Contact TTS size adhesive 5 cm 2 10 cm 2 20 cm 2 30 cm 2 40 cm 2 50 cm 2 EVA 1.6 3.2 6.5 9.7 13 16 SXS 1.9 3.8 7.6 11.4 15.2 19 Silicone/ 2.5 5 10 15 20 25 Cer + PVAc Acrylate 1.7 3.3 6.6 10 13.3 16.7 (Durotak 87-4287)
  • the in-vitro model used according to Tanojo (J. Control Rel. 45 (1997) 41-47) has proven to be an excellent model in which the in-vitro flux rates measured correlated outstandingly with the in-vivo flux rates, which were measured in several clinical studies.
  • the result of this is that the therapeutically desired daily flux rates of active ingredient of a minimum 3 mg, for example, 3-15 mg, preferably of 4-12 mg or 6-12 mg can be achieved through use of the inventive TTS.
  • Flux rates of fesoterodine (high purity free base) through mammalian skin comparable to in-vitro could be achieved from acrylate and silicone based matrices as well ( FIG. 3 , Table 2).
  • the invention concerns the use of a free base of the general Formula I, in which A is hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-6 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it and whereby the free base is present in a purity of above 97 percent by weight minimum, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight,
  • a medicine for transdermal delivery characterized by the fact that the compound of the general Formula I is introduced into a polymer layer, preferably into a self-adhesive polymer layer and that the medicine a compound of the general Formula I is released in a daily dose of 0.5 mg-20 mg/day, preferably of at least 3 mg/day, for example, 3-15 mg/day, preferably 4-12 mg/day and notably especially preferably 6-12 mg/day through the skin of a mammal, in particular through human skin.
  • the medicine contains the high purity base of fesoterodine as the active ingredient.
  • the invention therefore concerns the use of a high purity compound of the general Formula I used for the manufacture of a medicine, whereby the medicine
  • FIG. 2 shows, the delivery of the active ingredient from such drugs is largely constant over a minimum 24 hours following an initial burst effect phase.
  • the invention concerns the use of a high purity combination of the general Formula I, for example, fesoterodine for the manufacture of a medicine, whereby the medicine after an initial burst effect phase releases the solution of the general Formula I over a minimum of 24 hours, preferably over a minimum of 36 hours at a constant flux rate.
  • steady-state is understood to mean a dynamic equilibrium that adjusts itself after an initial lag phase following application of the inventive device for the first time.
  • Step-state flux rate is understood to mean a flux-rate that adjusts after the initial lag phase.
  • lag phase initial burst effect phase
  • flux rate through human skin is understood to mean a flux rate that was measured according to Tanojo in an in-vitro human skin model as described in Example Execution 3.2.
  • the preferred polymer matrices are self-adhesive polymer matrices of the EVA-, SXS, silicone or acrylate type, the properties and manufacture of which are described in more detail in the following:
  • the preferred silicone adhesives are amine resistant, pressure sensitive, polymeric organosiloxane adhesives.
  • silicone contact adhesives represent polymeric dimethylsiloxanes; however in principle other organic residues, such as ethyl or phenyl groups, for example, may also be available instead of the methyl groups.
  • Amine resistant silicone contact adhesives are generally characterized in that they contain not any or only a few free silanol functions because the Si—OH-groups were alkylated. Such adhesives are described in EP 180 377. Condensates or mixtures of silicone resins and polymeric organosiloxane adhesives such as described in US RE 35 474 are especially preferred adhesives.
  • Suitable adhesives are sold, for example, by Dow Corning as the so-called Bio-PSA adhesives.
  • Bio-PSA adhesives are sold, for example, by Dow Corning as the so-called Bio-PSA adhesives.
  • Bio-PSA adhesives are particularly suitable, especially in a 40:60 to 60:40 ratio.
  • Patch matrices based on silicone adhesives are processed predominantly in solvent based procedures.
  • a solution of contact adhesives and active ingredient are manufactured in a first step in an organic solvent or a mixture of solvents.
  • the solution is spread out and laminated, and the solvent is then removed.
  • Such a procedure is described as an example in WO 99/49852.
  • An alternative procedure that dispenses with the use of organic solvents is the hot melt procedure.
  • the polymer or the contact adhesive are melted at temperatures between 70 and 200° C., preferably between 90 and 160° C. and especially preferably between 100 and 150° C. and the active ingredient introduced into the homogenized matrix melt.
  • the adhesive matrix that contains the active ingredient is cooled again so that the active ingredient is exposed to a thermal load in general for less than 5 minutes, if desired even for 4, 3, and 2 or even for less than 1 minute.
  • the active ingredient is present in the solidified polymer melt.
  • the active ingredient is broadly shielded from critical environmental influences (light, oxygen).
  • This procedure has the advantage over the solvent based procedure that the high purity bases of the general Formula I are not exposed to any solvent influences but instead are able to be added immediately into the hot melt, where after a short homogenization they are stabilized in the cooling polymer matrix.
  • the hot melt procedure is preferably carried out in an extruder, for example, in a twin screw extruder, as described in WO 99/48493.
  • the silicone adhesives are generally too viscous, meaning they have a dynamic viscosity of above 150 Pa's.
  • suitable additives softeners
  • softeners for silicone are glycerol monolaurate or lauryl acetate as described in EP 835 136, waxes of the formula R—C(O)—OR′ as described in EP 360 467, alkylmethyl siloxane waxes as described in EP 524 775, siloxanated polyether waxes as described in EP 663. 431 or organic waxes as described in US RE 36 754.
  • the softeners are added to the silicone adhesive in a quantity of 1-30 percent by weight based on the total mixture of the hot-meltable adhesive mixture.
  • the preferred softeners are organic waxes as described in US RE 36 754, for example, ozokerite wax, ceresine wax, paraffin wax, candelilla wax, carnauba wax, beeswax or mixtures of these waxes, where ozokerite and ceresine are absolutely, especially preferred.
  • Ready-made hot-meltable silicone contact adhesives in particular mixtures of silicone contact adhesives with ceresine or ozokerite may be obtained at Dow Corning, Mich.
  • a silicone contact adhesive For example, through the addition of 10 percent by weight ceresine wax to a silicone contact adhesive, it was possible to lower the dynamic viscosity of the resulting contact adhesive mixture from above 150 Pa's to below 50 Pa's at a processing temperature of 150° C.
  • Such a silicone based contact adhesive mixture can be processed very well in a temperature range of from 70° C. to 200° C., and in particular in the range between 100° C. and 150° C. in a hot melt procedure.
  • hot-meltable silicone contact adhesives are excellently suited for the transdermal delivery of the compounds of the general Formula I.
  • One object of the invention is therefore a device for the transdermal delivery of a compound of the Formula I in which A means hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it,
  • the compound of the general Formula I was introduced into a polymer layer (adhesive matrix) in the form of a free base, with a degree of purity of above 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and absolutely especially preferably above 99 percent by weight, whereby the adhesive matrix incorporates an amino-resistant silicone.
  • the adhesive matrix is based on a hot-meltable mixture of a silicone based contact adhesive and at least one softener, in particular an organic wax, for example, ozokerite.
  • a silicone based contact adhesive and at least one softener, in particular an organic wax, for example, ozokerite.
  • the inventive silicone-based matrix was into the high purity base of fesoterodine as the active ingredient.
  • hot-meltable is understood to mean that the adhesive exhibits a dynamic viscosity of at the highest 150, preferably 120 Pa's at the highest, at an accepted working temperature during a hot melt procedure of, for example, 160° C.
  • a further aspect of the invention is a medicine for the transdermal delivery of a compound of the general Formula I comprising an adhesive matrix that comprises:
  • Silicone adhesives can be bought commercially and are sold, for example, by Dow Corning as Bio-PSA Q7-4300 or Bio-PSA Q7-4200. Hot-meltable silicone adhesives incorporating mixtures of PSA 7-4300 with organic waxes like ozokerite or ceresine are also obtainable from Dow Corning.
  • FIG. 3 / 4 shows the in-vitro flux through mouse skin that was achieved using a silicone based patch manufactured in a hot melt procedure that contains ozokerite as a softener for the adhesive matrix and that contains the high purity free base of fesoterodine in the adhesive matrix.
  • EVA adhesives are hot-meltable contact adhesives, which are based on ethylene vinyl acetate-copolymers (“EVA-contact adhesive”). EVA-adhesives such as these are described in U.S. Pat. No. 4,144,317 for example. EVA-adhesives feature good adhesive properties, simple manufacture and processing as well as good skin compatibility. EVA-adhesives can be obtained, for example, at Beardow Adams (1 3/BA).
  • One object of the invention is therefore a device for the transdermal delivery of a compound of the Formula I in which A means hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it,
  • the compound of the general Formula I was introduced into a-self adhesive polymer layer (adhesive matrix) in the form of a free base, with a degree of purity of over 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight, whereby the adhesive matrix comprises an adhesive of the EVA type.
  • the EVA-based adhesive matrix has been manufactured in a hot, melt procedure.
  • the inventive EVA-based matrix was introduced into the high purity base of fesoterodine as the active ingredient.
  • FIGS. 2 and 3 illustrate the in-vitro flux rates through human skin and mouse skin respectively, that were achieved using an EVA-based patch manufactured in a hot melt procedure that contains the high purity base of fesoterodine in the adhesive matrix.
  • SxS contact adhesives may be processed in both solvent based manufacturing procedures and hot melt procedures.
  • SxS contact adhesives is understood to mean styrene block copolymer based adhesives that carry non-elastomeric styrene blocks at the ends and elastomeric blocks in the middle.
  • the elastomeric blocks may, for example, consist of polyethylene butylene, polyethylene propylene, polybutadiene, polyisobutylene or polyisopropene.
  • Suitable SxS adhesives are described in U.S. Pat. No. 5,559,165 or U.S. Pat. No. 5,527,536 for example and feature good adhesive properties, simple manufacture and processing as well as good skin compatibility.
  • SxS contact adhesives may be obtained both commercially (e.g. as Duro Tak 378-3500 at National Starch & Chemical) and manufactured for oneself using hot melt extrusion equipment during the production of patches containing an active ingredient.
  • a styrene block copolymer e.g. Shell Kraton GX1657 or Kraton D-1107CU
  • an aliphatic and/or aromatic resin e.g. Keyser Mackay Regalite R1090 or Regalite R1010 or Regalite R1100
  • an oil e.g. Shell Ondina 933 or Ondina 941
  • the active ingredient is dosed into the contact adhesive manufactured in this way in the extruder and the paste laminated on foil sheets.
  • Typical exemplary parts by weight: polymer:resin: oil are e.g. 100:120:20 or 100:200:50.
  • the properties of the SxS contact adhesives can be adapted to the desired properties of the TTS (adhesive strength, minimum cold flow, duration of adherence, releasing profile of the active ingredient, etc.) by varying these proportions of amounts.
  • One object of the invention is therefore a device for the transdermal delivery of a compound of the Formula I in which A means hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it,
  • the compound of the general Formula I was introduced into a self-adhesive polymer layer (adhesive matrix) in the form of a free base, with a degree of purity of over 98 percent by weight, preferably above 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and absolutely especially preferably above 99 percent by weight, whereby the adhesive matrix incorporates a contact adhesive on an SXS-basis.
  • the SXS-based adhesive matrix has been manufactured in a hot melt procedure.
  • the inventive SXS-based matrix was introduced into the high purity base of fesoterodine as the active ingredient.
  • FIGS. 2 and 3 illustrate the in-vitro flux rates through human skin and mouse skin respectively, that were achieved using an SXS-based patch manufactured in a hot melt procedure into which the high purity free base of fesoterodine was introduced.
  • antioxidants are preferably added to SXS-based adhesive matrices.
  • An example for a commercially obtainable, suitable antioxidant is Irganox® (CIBA).
  • Polyacrylates are produced through the radical polymerization of (meth)acrylic acid derivates, whereby other suitable compounds, such as vinyl acetate, for example, may be used as other monomers.
  • suitable compounds such as vinyl acetate, for example.
  • the expression “polyacrylate” in this patent application includes polymers that comprises units that are based on acrylic acids and/or meth-acrylic acids as well as copolymers and mixtures of them.
  • the resulting contact adhesives can be constituted in such a way that they exhibit specific properties, meaning a favorable solvent capacity for the active ingredient, a desired movability of the active ingredient in the matrix as well as a desired transfer-rate through the skin.
  • the transfer rate is significantly limited by the distribution coefficients and the resorption of the active ingredient through the skin.
  • the pressure sensitive contact adhesive of the polyacrylate type may be a homopolymer and/or copolymer of at least one acrylic acid and/or meth-acrylic acid derivative in the form of a solution in an organic solvent.
  • the polyacrylate type contact adhesive may be cross-linkable or non-cross-linkable.
  • the cross-linking reagent links the polymer chains using reactive groups. This may result in an increased cohesion of the contact adhesive.
  • the polymer contact adhesive of the polyacrylate type consists of the following monomers at a minimum:
  • Acrylic acid acrylamide, hexyl-acrylate, 2-ethyl-hexyl-acrylate, hydroxy-ethyl-acrylate, octyl-acrylate, butyl-acrylate, methyl-acrylate, glycidyl-acrylate, methyl-acrylate, meth acrylic acid, methacrylamide, hexyl-methacrylate, 2-ethyl-hexyl amide-acrylate, octyl-methacrylate, methyl-methacrylate, glycidyl-methacrylate, vinyl acetate, vinyl pyrrolidon, allyl-acrylate.
  • polymer contact adhesives of the acrylate type, cross-linkable contact adhesives that are polymerized from a combination of the following monomers are preferred:
  • the following compounds can be named as preferred cross-linking preparations: Diphenyl-methane-4-diisocyanate, hexamethylene-diisocyanate, titanium-acetyl acetonate, aluminum-acetyl acetonate, ferrous-acetyl acetonate, zinc-acetyl acetonate, magnesium-acetyl acetonate, zirconium-acetyl acetonate, 2-ethyl-1,3-hexanediol-titanate, tetra-isooctyl-titanate, tetra-nonyl-titanate, polyfunctional propylene-imine-derivate, ether-derivate from melamine-formaldehyde-resin, high methylated urethane-resin, imine-melamine-resin.
  • the non-cross linkable contact adhesives may be polymerized, preferably from a combination of the following monomers:
  • a few contact adhesives may be used in the form of an aqueous dispersion (the dispersive type).
  • the usage of these dispersive type contact adhesives may bring the advantage that no inflammable or toxic solvents become vaporized during the coating and drying.
  • Dispersive type contact adhesives may be polymerized preferably from a combination of the following monomers:
  • Suitable polyacrylates for use in this invention are cross-linked by multivalent metal ions in order to improve the physical properties of the contact adhesive or in order to adapt it to the specific requirements.
  • the metal ions are normally applied in the form of metal chelate compounds, which are soluble in organic solvents.
  • suitable cross-linking agents are aluminum acetyl acetonate and titanium acetyl acetonate.
  • the solubility capacity generally depends on the type and the quantity of the free functional groups in the contact adhesive.
  • the most preferred contact adhesives for use in the device of this invention are the polyacrylates with polar groups, in particular with the free hydroxy groups.
  • Examples of such contact adhesives are the polyacrylates for the manufacture of which polar monomers, such as e.g. hydroxy-ethyl-acrylate, hydroxy-ethyl-methacrylate, acrylic acid or methacrylic acid are used in an amount of approximately 1-10% (w/w), especially preferably in a quantity of 3-8% (w/w), absolutely especially preferably in an amount of 4-6% (w/w).
  • Such contact adhesives are obtainable commercially under the brand name Duro-Tak® (National Starch & Chemicals; Hamburg).
  • especially preferred for use in the device of this invention are the contact adhesives of the polyacrylate type, where hydroxy-ethyl-acrylate and/or hydroxyl-ethyl-methacrylate monomers are admixed during polymerization in a quantity of 3-8% (w/w), notably especially preferably in a quantity of 4-6% (w/w).
  • Such a contact adhesive may be obtained according to the general procedure that is described in US patent 5,498,418 as follows:
  • the contact adhesive can be obtained through radical polymerization.
  • a mixture consisting of 21 to 40 percent by weight vinyl acetate, 55-70 percent by weight of an acrylic acid C 2 4-alkyl ester and 3 to 10 percent by weight of an acrylic acid C 2-4 hydroxyl acrylic ester is manufactured in an organic solvent with 100 percent by weight monomers in the mixture.
  • a conventional cross-linked agent in an organic solvent and—optionally—the active ingredient of the quality required in the transdermal device (patch) for the intended usage is admixed, if necessary in an organic solvent.
  • the mixture of the particular acrylate vinyl acetate copolymer obtained is cross-linked in an additional step, conducted through heating and through the removal of the organic solvent or the mixture of solvents used.
  • the active ingredient obtained is “built into” the contact adhesive substance in a special way through the successive and additional cross-linking of the special acrylate vinyl acetate copolymer.
  • the acrylate vinyl acetate copolymer can be polymerized and cross-linked in the absence of the active ingredient. The active ingredient is then added during the application of the acrylate vinyl acetate copolymer when the patch is manufactured.
  • the acrylate vinyl acetate copolymer has a relative viscosity of 3.0 to 4.2 at 20° C.
  • the mixture contains 2-ethyl hexane acrylate and hydroxyl ethyl acrylate monomers in addition to vinyl acetate.
  • the subsequent cross-linking of the special acrylate vinyl acetate copolymers is performed with a titanium acid ester consisting of polybutyl-titanate and/or titanium acetyl acetonate, preferably in a quantity of 0.3 to 3 percent by weight proportional to the weight of the copolymer.
  • the following steps can cover a process for the manufacture of a TTS in compliance with this invention:
  • a first step the manufacture of a solution of a copolymer, in which the active ingredient, in the amount required for the intended use of the TTS as well as a conventional cross-linker or a mixture of it, is optionally contained, and whereby the copolymer is obtained through the radical polymerization of a mixture of monomers consisting of 21 to 40 percent by weight vinyl acetate, 55 to 70% by weight of an acrylic acid-C 2-8 alkyl ester and 1 to 10 percent by weight of an acrylic acid-C 2-4 hydroxy.
  • One form of execution of such a process is characterized by the fact that the acrylate vinyl acetate copolymer—optionally—the active ingredient and the cross-linkable agent are dissolved at the start in a solvent, which contains 20 to 40 percent by weight ethanol or an ethanol methanol mixture, with a ratio of solid components consisting of 40 to 60 percent by weight of the mixture of the special acrylate vinyl acetate copolymer of the cross-linkable agent and the active ingredient.
  • the active ingredient is only added to the dispersion after cross-linking of the acrylate, which is then spread on the protective film following homogenization.
  • a particularly preferred contact adhesive for use in this invention are the commercially available contact adhesives Duro-Tak® 387-2287 and Duro-Tak® (3)87 (National Starch & Chemicals; Hamburg).
  • the Duro-Tak contact adhesive is mixed in an appropriate solvent with the desired amount of the active ingredient and the resulting homogenous dispersion spread out in the thickness desired. Finally the solvent or the mixture of solvents is removed at raised temperatures (50-70° C.).
  • One object of the invention is therefore a device for the transdermal delivery of a compound of the Formula I in which A means hydrogen or deuterium, R stands for a group that is selected from C 1-6 -alkyl, C 3-10 -cycloalkyl or phenyl, which may each be substituted with C 1-3 -alkoxy, fluorine, chlorine, bromine, iodine, nitro, amino, hydroxyl, oxo, mercapto or deuterium and where the C-atom marked with a star “ ⁇ ” may be present in the (R)-configuration, the (S)-configuration or as a mixture of it,
  • the compound of the general Formula I was introduced into a polymer layer, preferably a self-adhesive polymer layer (adhesive matrix) in the form of a free base, with a degree of purity of above 97 percent by weight, preferably above 98 percent by weight, especially preferably above 98.5 percent by weight and notably especially preferably above 99 percent by weight, whereby the polymer layer incorporates at least one polymer of the acrylate and/or methacrylate type.
  • FIG. 3 shows the in-vitro flux rates through mouse skin that were achieved with an acrylate based patch manufactured in a hot melt procedure in which the high purity free base of fesoterodine was introduced into the adhesive matrix.
  • the above described polymer matrices of the transdermal devices containing an active ingredient in compliance with the invention may contain other auxiliary agents and additives.
  • auxiliary agents and additives examples are buffers, solutizing agents, chemical stabilizers, antioxidants, other auxiliary agents for retarding as well as skin penetration enhancers.
  • Skin penetration enhancers may be added, for example, to enlarge the amount of active ingredient that permeates through the skin or to shrink the application area of the device.
  • Non-limiting examples of common penetration enhancers are alcohols, in particular short chained alcohols such as ethanol, fatty alcohols, e.g. lauryl alcohol, polyalcohols such as glycerin, amides, e.g.
  • aromatic amides like N,N-diethyl-m-toluamide, amino acids, azones, oils like menthol or peppermint oil; fatty acids and their esters like oleic acids, lauryl acids, isopropyl myristate or glycerol monolaurate; macrocycles such as for example, cyclopentadecanon; phospholipides such as lecithin for example; 2-pyrrolidones, sulfoxides such as dimethyl sulfoxide for example.
  • a hydrophilic component such as a hydrophilic polymer for example, may be added to the adhesive matrix as another component.
  • hydrophilic polymers may serve as solubility facilitators or crystallization inhibitors for the compounds of the general Formula I and contribute to a uniform distribution of the active ingredient in the adhesive matrix.
  • Appropriate hydrophilic polymers for use in the TTS in compliance with the invention may, for example, be chosen from the group of the polysaccharides, substituted polysaccharides, polyethylene oxides, polyvinyl acetates, polyvinyl pyrrolidones (PVP), PVP with appropriate softeners, polyethylene glycols, polypropylene glycols, polyacrylates, copolymers from polyvinyl pyrrolidone and (poly)vinyl acetate, copolymers from ethylene and vinyl acetate as well as polyvinyl alcohols with a suitable softener, for example, glycerin.
  • PVP polyvinyl pyrrolidones
  • Preferred hydrophilic polymers are PVP, polyethylene oxide (PEO), polyvinyl acetate (PVAc) as well as copolymers from PVP and vinyl acetate.
  • the hydrophilic polymers may be added to the adhesive layer, for example, in a portion of 0.5-40 percent by weight based on the total weight of the adhesive layer. Preferably 2-25 percent by weight, especially preferably 2-15 percent by weight of 2-10 percent by weight hydrophilic polymers are added.
  • hydrophilic polymers that exhibit a dynamic melting viscosity of a maximum 150 Pa's, preferably less than 120 Pa's and especially preferred below 80 Pa's, at temperatures below 170° C. are especially suitable for use in a hot melt procedure.
  • a suitable softener for example, glycerin, is eventually to be added beforehand if the dynamic viscosity of the hydrophilic polymer is too low at the desired processing temperature.
  • hydrophilic polymers may be advantageous, particularly in the case of very hydrophobic adhesive matrices, for example, silicone, polyisobutylene or SXS matrices.
  • the free bases of the 3,3-diphenylpropylamine-monoester tend towards a drop in concentration, for example, as a result of hydrolysis and interchange esterification. It was then surprisingly determined that the 3,3-diphenylpropylamine-monoesters can be stabilized significantly in matrices with hydrophilic constituent parts.
  • fesoterodine While, for example, the free base of fesoterodine is decomposed as an oil after storage for 6 months at 5° C. to around 3-4%, a drop in concentration cannot be established or only established essentially to a lesser extent when fesoterodine is incorporated in matrices, which contain polar components.
  • matrices for example, that contain polyacrylates, in particular polyacrylates with polar groups, EVA or mixtures of silicone adhesives with hydrophilic polymers, for example, PVP or PEO, (Table 4). TABLE 4 Stabilization of fesoterodine in various matrices during storage 5° C.
  • fesoterodine in matrices consisting of EVA adhesives, polyacrylate adhesives or mixtures of silicone adhesives with hydrophilic polymers such as PEO or PVP leads to a distinct stabilization of the fesoterodine and is independent of the manufacturing process (the hot melt or the solvent procedure).
  • One form of execution of the invention therefore concerns matrices or pharmaceutical formulations or devices in which the compounds of the general Formula I as a free base are subject to a slower drop in concentration than is the case if the free base is stored under identical conditions, not embedded in a polymer as an oil.
  • Preferred forms of execution are those which at 5° C. and/or at 25° C. lead to a 2-, 3-, 7- or 10-fold stabilization of the 3,3-diphenylpropylamine monoester by comparison with storage as a free base.
  • Especially preferred pharmaceutical formulations or devices in compliance with the invention are those in which the free base is present in a polymer layer, in which a drop in concentration of a compound of the general Formula I of less than 3%, preferably of less than 2% or 1% in the case of 6-month storage at 4° C. and of less than 10%, preferably less than 5% and especially preferably less than 3% or 1.5% in the case of 3-month storage at 25° C. and 60% atmospheric moisture occurs.
  • Preferred matrices are those which contain 50-95 percent by weight of an contact adhesive that is chosen from the group of the
  • matrices in compliance with the invention are polyacrylates, in particular those with polar groups. These matrices exhibit both an excellent releasing profile for fesoterodine and outstanding stabilization properties for 3,3-diphenyl propylamine monoesters.
  • TTS sizes of approximately 50 cm 2 are accepted by patients.
  • the size of the TUS is typically up to 40 cm 2 , preferably sizes are between 5 and 35 cm 2 and especially preferably between 10 and 30 cm 2 .
  • the matrix weight of the TTS typically varies between 30 and 300 g/m 2 , whereby the matrices with a weight of 40-200 g/m 2 and especially 40-150 g/m 2 , are preferred.
  • the loading of the active ingredient depends on the absorption/liberation capacity of the respective matrix for the active ingredient as well as on the manufacturing procedure.
  • the loading rate of the active ingredient makes sense between 5 and approximately 40 percent by weight based on the total weight of the matrix containing the active ingredient whereby the lower maximum loading rates between 7 and 30 percent by weight are preferred, and in particular between 8 and 20 percent by weight for the manufacture of a 1-3 day TTS. If a medicine is to be manufactured for a 7-day administration of a compound of the general Formula I, then comparatively higher active ingredient concentrations above, for example, 15-40 percent by weight are used.
  • the loading lies preferably at a minimum of 2 mg/m 2 .
  • Another object of the invention is a method as a prevention and/or treatment of is incontinence, hyperactivity of the detrusor, hyperactivity of the bladder, pollakisuria, nocturia or imperative urinary urgency through the administration of a compound of the general Formula I as a free base, and with the degree of purity in compliance with the invention as described in the above, on a mammal, in particular on a person, who requires the prevention against or the treatment of the above named diseases.
  • the batch was washed once with each of 250 ml water, 250 ml. approximate 5% aqueous NaHCO 3 solution and 250 ml water.
  • the dichloromethane extract dried over Na 2 SO 4 was evaporated to a low small bulk on a rotary evaporator to constant weight, whereby a pale yellow, high viscosity oil was left.
  • Fesoterodine (107.7 mg (R)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl isobutyric acid ester, B) is covered with a layer distilled water and stirred at room temperature. After two days of stirring, the reaction batch remains unchanged two-phase. No organic material (B or E) could be detected by thin layer chromatography in the aqueous phase at the top (silica gel, solvent system petroleum ether/acetone/triethylamine, 70/20/10 percent by volume).
  • 8.5 g of a silicone-based contact adhesive mixture from the silicone adhesive Bio-PSA 7-4300 (Dow Corning, Mich.) was heated to 150° C. with 5 percent by weight ozokerite or ceresine (obtainable from Dow Corning) for around 20 minutes until a homogenous melt came into being.
  • 1.5 g fesoterodine (high purity free base) was added and the mixture kept for a further 5 minutes at 150° C.
  • the mixture was then homogenized by hand and laminated onto a pre-warmed foil (120° C., gap width 250 ⁇ m). 5 cm 2 pieces were cut out for the releasing tests.
  • Belly and back skin in a thickness of approximately 120 to 150 ⁇ m was used for the flux measurements through mouse skin in a horizontal diffusion cell.
  • the measurement of the active ingredient flux through the skin preparation is made per HPLC (tower spherisorb 5CN 25 cm) under the following conditions: 4 parts by volume acetonitrile/6 parts by volume H 2 O/0.1% parts by volume TFA, 35° C., 225 nm, 1 ml flux
  • a HPLC method was used to determine the chemical purity of fesoterodine that is based on the separation at a stationary reversed phase and used for the gradient elution of a solvent.

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090005309A1 (en) * 2007-05-18 2009-01-01 Auspex Pharmaceuticals, Inc. Substituted piperidines
US20090005431A1 (en) * 2007-06-30 2009-01-01 Auspex Pharmaceuticals, Inc. Substituted pyrrolidines
US20090086651A1 (en) * 2007-10-02 2009-04-02 Luft Siegfried J Intelligent collection and management of flow statistics
US20090270515A1 (en) * 2006-09-25 2009-10-29 Peter Gruber Active ingredient containing stabilised solid medicinal forms and method for the production thereof
US20100152483A1 (en) * 2008-12-10 2010-06-17 Chemi S.P.A. Solid forms of fesoterodine fumarate
US20100256231A1 (en) * 1998-05-12 2010-10-07 Ucb Pharma Gmbh Novel derivatives of 3,3-diphenylpropylamines
WO2011029005A1 (en) 2009-09-03 2011-03-10 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Crystalline forms of fesoterodine fumarate and fesoterodine base
EP2316432A1 (de) * 2009-10-30 2011-05-04 ratiopharm GmbH Zusammensetzung enthaltend Fesoterodin und Ballaststoffe
US20120035363A1 (en) * 2008-05-13 2012-02-09 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-...
US20120115840A1 (en) * 2008-12-18 2012-05-10 Lech Ciszewski Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10315917A1 (de) * 2003-04-08 2004-11-18 Schwarz Pharma Ag Hochreine Basen von 3,3-Diphenylpropylaminmonoestern
DE10315878B4 (de) 2003-04-08 2009-06-04 Schwarz Pharma Ag Vorrichtung zur transdermalen Verabreichung von Fesoterodin und Verwendung
JP5254799B2 (ja) * 2006-09-26 2013-08-07 株式会社カネカ 遊離アミンの製造方法
TWI520732B (zh) * 2011-01-18 2016-02-11 輝瑞有限公司 固體分子分散液
CN105074114B (zh) 2013-03-15 2018-10-26 亨特道格拉斯公司 用于辊支撑的建筑覆盖件的位置锁定
EP3074700A4 (en) 2013-11-29 2018-05-16 Kim, No Eul Plastic hot water boiler

Citations (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2556636A (en) * 1948-06-23 1951-06-12 Schering Corp gamma-substituted propylamine type antihistamines
US2567245A (en) * 1948-05-10 1951-09-11 Schering Corp Aryl-(2-pyridyl)-amino alkanes and their production
US2676964A (en) * 1950-06-07 1954-04-27 Schering Corp 3-pyridyl propylamine antihistamine substances
US3261841A (en) * 1961-05-03 1966-07-19 Sterling Drug Inc N-substituted 1,5-iminocycloalkanes and -alkenes
US3446901A (en) * 1966-08-25 1969-05-27 Geistlich Soehne Ag Antidepressant compositions containing diphenylpropylamine derivatives
US4988730A (en) * 1986-07-11 1991-01-29 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyar Rt Diphenkylpropylamines for the therapy of heart disease
US5382600A (en) * 1988-01-22 1995-01-17 Pharmacia Aktiebolag 3,3-diphenylpropylamines and pharmaceutical compositions thereof
US5559269A (en) * 1992-11-06 1996-09-24 Pharmacia Ab 3,3-diphenylpropylamines, their use and preparation
US5922914A (en) * 1996-12-31 1999-07-13 Pharmacia & Upjohn Company Process to prepare tolterodine
US6310248B2 (en) * 1999-12-30 2001-10-30 Pharmacia Ab Process and intermediates
US6517864B1 (en) * 1998-08-27 2003-02-11 Pharmacia Ab Transdermally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder
US6566537B2 (en) * 1999-12-30 2003-05-20 Pharmacia Ab Process and intermediates
US20030152624A1 (en) * 2001-12-20 2003-08-14 Aldrich Dale S. Controlled release dosage form having improved drug release properties
US20030158176A1 (en) * 2001-10-26 2003-08-21 Ivan Richards Quaternary ammonium compounds
US6630162B1 (en) * 1999-11-11 2003-10-07 Pharmacia Ab Pharmaceutical formulation and its use
US6713464B1 (en) * 1998-05-12 2004-03-30 Schwarz Pharma Ag Derivatives of 3,3-diphenylpropylamines
US20040064821A1 (en) * 2002-09-30 2004-04-01 Philip Rousselle Implementing request/reply programming semantics using publish/subscribe middleware
US6770295B1 (en) * 1998-08-27 2004-08-03 Pharmacia Ab Therapeutic formulation for administering tolterodine with controlled release
US6783769B1 (en) * 1999-05-18 2004-08-31 Schwarz Pharma Ag Transdermal therapeutic system TTS containing tolterodine
US6809225B2 (en) * 2000-07-07 2004-10-26 Schwarz Pharma Ag Method for producing 3,3-diarylpropylamines
US6809214B2 (en) * 2000-06-14 2004-10-26 Schwartz Pharma Ag Shortened synthesis of 3,3-diarylpropylamine derivatives
US20050004223A1 (en) * 2003-04-25 2005-01-06 Slatter John Gregory Novel 3,3-diphenylpropylamines useful in therapy
US6858650B1 (en) * 1999-11-16 2005-02-22 Schwarz Pharma Ag Stable salts of novel derivatives of 3,3-diphenylpropylamines
US6911217B1 (en) * 1998-11-11 2005-06-28 Pharmacia Ab Controlled release bead, a method of producing the same and multiple unit formulation comprising it
US6936718B2 (en) * 2001-11-29 2005-08-30 Schering Corporation Preparation of rotamer mixtures of pharmaceutical salts

Family Cites Families (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE766207C (de) 1940-07-08 1952-12-22 Ig Farbenindustrie Ag Verfahren zur Herstellung von basischen Verbindungen der Diarylmethanreihe
DE925468C (de) * 1941-08-13 1955-03-21 Hoechst Ag Verfahren zur Herstellung von ª†, ª†-Diaryl-propyl-aminen
GB624117A (en) * 1946-12-07 1949-05-27 Wellcome Found Improvements in and relating to the preparation of substituted allylamines and propylamines
GB627139A (en) * 1947-05-28 1949-07-29 Wellcome Found Improvements in and relating to the preparation of quaternary ammonium salts of substituted propanolamines, allylamines and propylamines
BE497819A (zh) 1947-10-28
CH285388A (de) 1948-11-09 1952-08-31 Michael Dr Erlenbach Verfahren zur Herstellung einer basischen Verbindung.
DE830193C (de) 1948-11-09 1952-02-04 Farbwerke Hoechst Vormals Meis Verfahren zur Herstellung von basischen Verbindungen
GB685696A (en) 1948-11-23 1953-01-07 Schering Corp Process for the manufacture of anti-histaminic compounds
NL74271C (zh) 1949-09-05
DK111894A (zh) * 1962-11-15
GB1025041A (en) * 1964-02-21 1966-04-06 Hoechst Ag Process for the manufacture of diphenylalkylamines
GB1169944A (en) * 1966-08-25 1969-11-05 Geistlich Soehne Ag Novel 3,3-Diphenylpropylamines and processes for the preparation thereof
US4675009A (en) * 1977-11-07 1987-06-23 Lec Tec Corporation Drug dispensing device for transdermal delivery of medicaments
SE8800207D0 (sv) * 1988-01-22 1988-01-22 Kabivitrum Ab Nya aminer, deras anvendning och framstellning
US5271940A (en) * 1989-09-14 1993-12-21 Cygnus Therapeutic Systems Transdermal delivery device having delayed onset
CA2132865C (en) * 1992-05-13 2003-12-02 Eun S. Lee Transdermal administration of oxybutynin
US6071970A (en) 1993-02-08 2000-06-06 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
WO1996012477A1 (en) * 1994-10-21 1996-05-02 Leiras Oy Controlled release oral delivery system containing oxybutynin
EP0924983A4 (en) * 1996-07-19 1999-08-25 Gunnar Aberg S (-) - TOLTERODINE FOR THE TREATMENT OF URINARY AND GASTROINTESTINAL DISORDERS
AU732112B2 (en) 1996-12-12 2001-04-12 Dds Drug Delivery Service Gesellschaft Zur Forderung Der Forschung In Pharmazeutischer Technologie Und Biopharmazie Mbh Formulation in the form of a matrix material-excipient compound, matrix material-active substance compound and/or matrix material-excipient-active substance compound, and processes for the preparation thereof and the use thereof for the preparation of tablets and/or other larger matrix units
SE9701144D0 (sv) 1997-03-27 1997-03-27 Pharmacia & Upjohn Ab Novel compounds, their use and preparation
EP0872233A1 (en) 1997-04-14 1998-10-21 Janssen Pharmaceutica N.V. Antiretroviral compositions with improved bioavailability
AU8532798A (en) * 1997-06-13 1998-12-30 Roland Bodmeier Compounds which delay the release of active substances
US20030086972A1 (en) * 2000-08-09 2003-05-08 Appel Leah E. Hydrogel-driven drug dosage form
AR033711A1 (es) * 2001-05-09 2004-01-07 Novartis Ag Composiciones farmaceuticas
US20030027856A1 (en) * 2001-06-29 2003-02-06 Aberg A.K. Gunnar Tolterodine metabolites
GB0117619D0 (en) * 2001-07-19 2001-09-12 Phoqus Ltd Pharmaceutical dosage form
EP1423700A2 (en) * 2001-09-04 2004-06-02 Pfizer Limited Affinity-assay for the human erg potassium channel
EP1423092A2 (en) * 2001-09-05 2004-06-02 Vectura Limited Functional powders for oral delivery
KR20040039436A (ko) * 2001-09-27 2004-05-10 파마시아 에이비 약학 조성물
US20030144352A1 (en) * 2001-11-05 2003-07-31 Cammarata Sue K. Antimuscarinic aerosol
KR100540035B1 (ko) * 2002-02-01 2005-12-29 주식회사 태평양 다단계 경구 약물 방출 제어 시스템
DE10224107A1 (de) * 2002-05-29 2003-12-11 Gruenenthal Gmbh Kombination ausgewählter Opioide mit anderen Wirkstoffen zur Therapie der Harninkontinenz
AU2003236947A1 (en) * 2002-06-07 2003-12-22 Ranbaxy Laboratories Limited Modified release, multiple unit drug delivery systems
ITMI20021329A1 (it) * 2002-06-14 2003-12-15 Recordati Chem Pharm Nuove ossialchilammine sostituite
AU2003268361A1 (en) * 2002-08-30 2004-03-19 Watson Pharmaceuticals, Inc. Drug delivery system for treating urinary incontinence
DE10315878B4 (de) * 2003-04-08 2009-06-04 Schwarz Pharma Ag Vorrichtung zur transdermalen Verabreichung von Fesoterodin und Verwendung
DE10315917A1 (de) * 2003-04-08 2004-11-18 Schwarz Pharma Ag Hochreine Basen von 3,3-Diphenylpropylaminmonoestern

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2567245A (en) * 1948-05-10 1951-09-11 Schering Corp Aryl-(2-pyridyl)-amino alkanes and their production
US2556636A (en) * 1948-06-23 1951-06-12 Schering Corp gamma-substituted propylamine type antihistamines
US2676964A (en) * 1950-06-07 1954-04-27 Schering Corp 3-pyridyl propylamine antihistamine substances
US3261841A (en) * 1961-05-03 1966-07-19 Sterling Drug Inc N-substituted 1,5-iminocycloalkanes and -alkenes
US3446901A (en) * 1966-08-25 1969-05-27 Geistlich Soehne Ag Antidepressant compositions containing diphenylpropylamine derivatives
US4988730A (en) * 1986-07-11 1991-01-29 Chinoin Gyogyszer Es Vegyeszeti Termekek Gyar Rt Diphenkylpropylamines for the therapy of heart disease
US5382600A (en) * 1988-01-22 1995-01-17 Pharmacia Aktiebolag 3,3-diphenylpropylamines and pharmaceutical compositions thereof
US5559269A (en) * 1992-11-06 1996-09-24 Pharmacia Ab 3,3-diphenylpropylamines, their use and preparation
US5922914A (en) * 1996-12-31 1999-07-13 Pharmacia & Upjohn Company Process to prepare tolterodine
US20040186061A1 (en) * 1998-05-12 2004-09-23 Schwarz Pharma Ag Novel derivatives of 3,3-diphenylpropylamines
US6713464B1 (en) * 1998-05-12 2004-03-30 Schwarz Pharma Ag Derivatives of 3,3-diphenylpropylamines
US6517864B1 (en) * 1998-08-27 2003-02-11 Pharmacia Ab Transdermally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder
US6770295B1 (en) * 1998-08-27 2004-08-03 Pharmacia Ab Therapeutic formulation for administering tolterodine with controlled release
US20030124179A1 (en) * 1998-08-27 2003-07-03 Pharmacia Ab Transdermally administered tolterodine as anti-muscarinic agent for the treatment of overactive bladder
US6911217B1 (en) * 1998-11-11 2005-06-28 Pharmacia Ab Controlled release bead, a method of producing the same and multiple unit formulation comprising it
US6783769B1 (en) * 1999-05-18 2004-08-31 Schwarz Pharma Ag Transdermal therapeutic system TTS containing tolterodine
US6630162B1 (en) * 1999-11-11 2003-10-07 Pharmacia Ab Pharmaceutical formulation and its use
US6858650B1 (en) * 1999-11-16 2005-02-22 Schwarz Pharma Ag Stable salts of novel derivatives of 3,3-diphenylpropylamines
US6689916B2 (en) * 1999-12-30 2004-02-10 Pharmacia Ab Phenyl propenone compounds
US6566537B2 (en) * 1999-12-30 2003-05-20 Pharmacia Ab Process and intermediates
US6310248B2 (en) * 1999-12-30 2001-10-30 Pharmacia Ab Process and intermediates
US6809214B2 (en) * 2000-06-14 2004-10-26 Schwartz Pharma Ag Shortened synthesis of 3,3-diarylpropylamine derivatives
US6809225B2 (en) * 2000-07-07 2004-10-26 Schwarz Pharma Ag Method for producing 3,3-diarylpropylamines
US20030158176A1 (en) * 2001-10-26 2003-08-21 Ivan Richards Quaternary ammonium compounds
US6890920B2 (en) * 2001-10-26 2005-05-10 Pharmacia & Upjohn Company Quaternary ammonium compounds
US6936718B2 (en) * 2001-11-29 2005-08-30 Schering Corporation Preparation of rotamer mixtures of pharmaceutical salts
US20030152624A1 (en) * 2001-12-20 2003-08-14 Aldrich Dale S. Controlled release dosage form having improved drug release properties
US20040064821A1 (en) * 2002-09-30 2004-04-01 Philip Rousselle Implementing request/reply programming semantics using publish/subscribe middleware
US20050004223A1 (en) * 2003-04-25 2005-01-06 Slatter John Gregory Novel 3,3-diphenylpropylamines useful in therapy

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100256231A1 (en) * 1998-05-12 2010-10-07 Ucb Pharma Gmbh Novel derivatives of 3,3-diphenylpropylamines
US7985772B2 (en) * 1998-05-12 2011-07-26 Ucb Pharma Gmbh Derivatives of 3,3-diphenylpropylamines
US20090270515A1 (en) * 2006-09-25 2009-10-29 Peter Gruber Active ingredient containing stabilised solid medicinal forms and method for the production thereof
US10603280B2 (en) 2006-09-25 2020-03-31 Losan Pharma Gmbh Active ingredient containing stabilised solid medicinal forms and methods for the production thereof
US10206879B2 (en) 2006-09-25 2019-02-19 Losan Pharma Gmbh Active ingredient containing stabilised solid forms and method for the production thereof
US9775807B2 (en) * 2006-09-25 2017-10-03 Losan Pharma Gmbh Stabilized solid medicinal forms containing active ingredient and method for the production thereof
US20090005309A1 (en) * 2007-05-18 2009-01-01 Auspex Pharmaceuticals, Inc. Substituted piperidines
US20090005431A1 (en) * 2007-06-30 2009-01-01 Auspex Pharmaceuticals, Inc. Substituted pyrrolidines
US20090086651A1 (en) * 2007-10-02 2009-04-02 Luft Siegfried J Intelligent collection and management of flow statistics
US8404839B2 (en) * 2008-05-13 2013-03-26 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy} quinazoline difumarate Form A
US20120035363A1 (en) * 2008-05-13 2012-02-09 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-...
US20100152483A1 (en) * 2008-12-10 2010-06-17 Chemi S.P.A. Solid forms of fesoterodine fumarate
US8049031B2 (en) 2008-12-10 2011-11-01 Chemi S.P.A. Solid forms of fesoterodine fumarate
US20120115840A1 (en) * 2008-12-18 2012-05-10 Lech Ciszewski Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid
WO2011029005A1 (en) 2009-09-03 2011-03-10 Teva Gyogyszergyar Zartkoruen Mukodo Reszvenytarsasag Crystalline forms of fesoterodine fumarate and fesoterodine base
WO2011050961A1 (de) * 2009-10-30 2011-05-05 Ratiopharm Gmbh Zusammensetzung enthaltend fesoterodin und ballaststoffe
EP2316432A1 (de) * 2009-10-30 2011-05-04 ratiopharm GmbH Zusammensetzung enthaltend Fesoterodin und Ballaststoffe

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JP2006522758A (ja) 2006-10-05
KR100912451B1 (ko) 2009-08-14
DE502004005560D1 (de) 2008-01-03
AU2004228163B2 (en) 2007-06-07
NO20055078L (no) 2005-10-31
EP1613584B1 (de) 2007-11-21
ZA200502679B (en) 2006-04-26
HK1087399A1 (en) 2006-10-13
DE10315917A1 (de) 2004-11-18
RU2005134170A (ru) 2006-07-27
US20090012159A1 (en) 2009-01-08
JP2010215643A (ja) 2010-09-30
MXPA05003562A (es) 2005-06-03
UA81803C2 (en) 2008-02-11
AU2004228163A1 (en) 2004-10-21
CN1802345A (zh) 2006-07-12
WO2004089872A1 (de) 2004-10-21
RU2394019C2 (ru) 2010-07-10
EP1613584A1 (de) 2006-01-11
BRPI0406221A (pt) 2005-08-09
KR20060006012A (ko) 2006-01-18
ES2297409T3 (es) 2008-05-01

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