WO2002064124A2 - Medicament formulation containing a muscarinic agonist - Google Patents

Medicament formulation containing a muscarinic agonist Download PDF

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Publication number
WO2002064124A2
WO2002064124A2 PCT/EP2002/001374 EP0201374W WO02064124A2 WO 2002064124 A2 WO2002064124 A2 WO 2002064124A2 EP 0201374 W EP0201374 W EP 0201374W WO 02064124 A2 WO02064124 A2 WO 02064124A2
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WO
WIPO (PCT)
Prior art keywords
core
tablet according
weight
film
acid
Prior art date
Application number
PCT/EP2002/001374
Other languages
German (de)
French (fr)
Other versions
WO2002064124A3 (en
Inventor
Thomas Friedl
Karoline Bechtold-Peters
Michael Walz
Original Assignee
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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.)
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Application filed by Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim Pharma Gmbh & Co. Kg
Priority to CA002434976A priority Critical patent/CA2434976A1/en
Priority to JP2002563919A priority patent/JP2004518710A/en
Priority to MXPA03007272A priority patent/MXPA03007272A/en
Priority to AU2002247705A priority patent/AU2002247705A1/en
Priority to EP02716755A priority patent/EP1361871A2/en
Publication of WO2002064124A2 publication Critical patent/WO2002064124A2/en
Publication of WO2002064124A3 publication Critical patent/WO2002064124A3/en

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Classifications

    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the invention relates to a new pharmaceutical formulation containing the muscarinic agonist talsaclidine and processes for their preparation.
  • talsaclidine (Wal2014) is a compound with pharmacologically valuable properties.
  • muscarinic agonists can have great therapeutic benefits in the treatment of Alzheimer's disease.
  • Talsaclidin V has the following chemical structure:
  • the present invention relates to a tablet containing talsaclidine V, characterized in that it consists of a core containing the active ingredient talsaclidine and a film coating encasing this core.
  • the tablet according to the invention can also be referred to as a film tablet in the context of the present invention.
  • physiologically acceptable acid addition salts are understood to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. If necessary, can Production of the salts, mixtures of the abovementioned acids can also be used.
  • the salts of talsaclidine are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate and methanesulfonate.
  • the salts are particularly preferably selected from hydrochloride, hydrobromide and fumarate, the talsaclidin fumarate being of the greatest importance according to the invention.
  • the active ingredient may optionally be in the form of a hydrate.
  • the talsaclidine is preferably added in an anhydrous form.
  • the active ingredient is preferably used in crystalline, unground form or pin-ground form, but preferably in unground form.
  • Active ingredient is particularly preferably used in unmilled form, in which the particle size distribution lies within the following limits: D-io 20 20 ⁇ m, D 50 10-80 ⁇ m, D 90 ⁇ 300 ⁇ m.
  • the particle size distribution of the active ingredient used in the formulation according to the invention is particularly preferably in the following ranges: D-io ⁇ 5-15 ⁇ m, D 50 25-75 ⁇ m, D 90 ⁇ 275 ⁇ m.
  • D 5 and D o in 90 microns is the particle size ranges within which a passage amount of 10 volume%, 50 volume% and 90 volume% of the particles measured (cumulative volume distribution) is achieved.
  • talsaclidine V is present according to the invention at 0.5 to 25% by weight, preferably 0.7 to 20% by weight, particularly preferably about 0.9 to 15% by weight.
  • the proportion of V is particularly preferably between 9 and 14% by weight, based on the total mass of the core.
  • the proportion of 1, based on the total mass of the core of the film tablets according to the invention is between about 0.85 to 43% by weight, preferably between about 1.2 to 2% by weight 34% by weight, particularly preferably between about 1.5 to 26% by weight.
  • the proportion of 1 is particularly preferably in the case of Talsaclidin fumarate between about 15 and 24% by weight based on the total mass of the core.
  • the core of the pharmaceutical formulation according to the invention also contains at least one auxiliary as filler / dry binder.
  • modified lactose in particular spray-dried lactose
  • This auxiliary has proven to be particularly advantageous in the formulation according to the invention.
  • a preferred aspect of the present invention therefore relates to a film tablet containing talsaclidine, which contains, in addition to the active substance, modified lactose, in particular spray-dried lactose, particularly preferably spray-dried lactose monohydrate, as an adjuvant.
  • Spray-dried lactose is to be understood as lactose which is obtained by spray agglomeration when spray-drying a suspension of ⁇ -
  • Lactose monohydrate crystals are formed in an aqueous lactose solution.
  • the spray drying process results in a free-flowing powder with suitable granulometry for direct tableting (for example 80-100% ⁇ 250 ⁇ m) and an amorphous fraction of for example 5-25%, which is responsible for the high binding capacity of spray-dried lactose.
  • the weight ratio between the components of modified lactose, preferably spray-dried lactose, and active ingredient V contained in the core of the film-coated tablet is in a range from about 1: 1 to about 70: 1.
  • the ratio of modified, preferably spray-dried lactose to V is preferably in a range from about 1.5: 1 to. about 35: 1, particularly preferably in a range from about 2: 1 to about 8: 1.
  • the weight fraction of the modified, preferably spray-dried lactose, based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from approximately 20-70% by weight, preferably between approximately 30-60% by weight.
  • the core of the film-coated tablet according to the invention can also contain further auxiliaries or fillers.
  • preference can be given to those compounds which can act as dry binders.
  • Dry binders preferred according to the invention are selected from the group consisting of powder cellulose, microcrystalline cellulose, starch, povidone, cellulose derivatives and mixtures of these compounds. Powder cellulose and / or microcrystalline cellulose are preferred as binders, particularly preferably microcrystalline cellulose contain.
  • the weight ratio of modified, preferably spray-dried lactose to binder is preferably about 5: 1 to about 1: 4, preferably about 4: 1 to about 1: 3, particularly preferably about 3: 1 to 1: 2.
  • the weight ratio of spray-dried lactose to binder is particularly preferably in a range from about 2: 1 to about 1: 1.
  • the core of the film-coated tablet according to the invention may also contain disintegrants in addition to the above-mentioned components.
  • these disintegrants may also be referred to as disintegrants.
  • these are preferably selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethyl cellulose, dried corn starch and mixtures thereof.
  • sodium starch glycolate, crospovidone and croscarmellose, preferably sodium starch glycolate are particularly preferably used.
  • their proportion by weight based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from about 1-10% by weight, particularly preferably about 3-8% by weight.
  • the core of the film-coated tablet according to the invention may also contain flow regulators as further constituents.
  • Flow regulating agents in the context of the present invention are, for example, silicon dioxide, talc and magnesium stearate.
  • silicon dioxide is preferably used, particularly preferably in colloidal, highly disperse form. If the above-mentioned flow regulating agents are used, their proportion by weight, based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from approximately 0.1 to 5% by weight, preferably approximately 0.3 to 2% by weight, particularly preferably between 0.4 and 1.5 wt%.
  • the core of the film-coated tablet according to the invention can also contain flow agents, lubricants and release agents as further constituents.
  • stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate and mixtures thereof come into consideration within the scope of the present invention.
  • Stearic acid and magnesium stearate are preferably used according to the invention.
  • the proportion by weight, based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from approximately 0.1 to 5% by weight, preferably approximately 0.5 to 3% by weight, particularly preferably approximately 1-2% by weight.
  • a particularly good one Mold release in the production of the film-coated tablets according to the invention is achieved if magnesium stearate is used in an amount of at least 1.0% by weight, preferably about 1.5% by weight.
  • the film or film covering surrounding the core of the film-coated tablets according to the invention contains, as an essential component, a film-forming agent which is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and poly (ethyl acrylate) methyl methacrylate, the latter for example in the form of Eudragit NE 30 D. Alternatively Eudragit RL 30 D or Eudragit E 12.5 can also be used. The above-mentioned constituents can optionally also be used in the form of their mixtures.
  • Preferred film formers are hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose, with hydroxypropyl methyl cellulose and hydroxypropyl cellulose being particularly preferred according to the invention as film formers.
  • the above film formers can be used alone or in the form of their mixtures. If only one of the above-mentioned film formers is used, hydroxypropylmethyl cellulose is of particular importance in the context of the present invention.
  • the proportion by weight of film former, based on the total mass of the film coating of the film tablet according to the invention, is preferably in a range from about 20-95% by weight, preferably 30-90% by weight.
  • the film coating can contain, as further constituents, emulsifiers and plasticizers, such as, for example, polyethylene glycol, glycerol and propylene glycol, optionally in the form of their mixtures.
  • plasticizers such as, for example, polyethylene glycol, glycerol and propylene glycol, optionally in the form of their mixtures.
  • Polyethylene glycols are preferably used as plasticizers. Without restricting the subject matter of the invention, particularly preferred polyethylene glycols are, for example, polyethylene glycol 400 and polyethylene glycol 6000.
  • the weight fraction of plasticizer, based on the total mass of the film coating of the film-coated tablet according to the invention is preferably in a range from about 1-30% by weight, preferably 3- 25% by weight, particularly preferably 5-15% by weight.
  • the film coating of the film-coated tablet according to the invention can also contain color pigments and pigmentation aids.
  • color pigments and pigmentation aids examples include iron oxide, titanium dioxide, talc and their mixtures.
  • the film tablet according to the invention can be produced, for example, as described below.
  • the excipient spray-dried lactose is mixed together with the active ingredient 1 in a suitable free-fall mixer.
  • the premix of active ingredients obtained therefrom is then mixed in a suitable screening machine. This reduces the proportion of coarser active substance particles used in the manufacturing process. Depending on the particle size of the compound 1 used, it is also possible to dispense with the production of this premix with subsequent sieving.
  • further excipient is added to this active ingredient premix.
  • one or more further auxiliaries can also be added.
  • further formulation components such as disintegrants and flow regulators can be added during this process step.
  • the active ingredient / excipient mixture obtained in this way is then compressed on a suitable tablet press to give the film-coated tablet cores according to the invention.
  • the pressing force should be e.g. in the case of tablet cores containing 36 mg of talsaclidine V, they are kept in a range from 5 to 15 kN, preferably 8 to 12 kN. Higher compressive forces can lead to tablets with a slow release of the active ingredient. Lower compression forces can lead to mechanically unstable tablets.
  • the tablet cores can have different formats, preferably round biplane or biconvex and oval or oblong shapes.
  • the required and optional components of the film coating are taken up in a suitable solvent.
  • a suitable solvent According to the invention, water is preferably used as the solvent. When water is used as the solvent, some of the components of the film coating are in dispersed form.
  • the tablet cores previously obtained are coated with the desired film in a suitable coating device in analogy to the coating processes known in the prior art.
  • the following examples serve to illustrate formulations according to the invention. They are only to be understood as possible exemplary procedures, without restricting the invention to its content.
  • Lactose monohydrate 99.363 mg
  • Microcrystalline cellulose 90.450 mg
  • Titanium dioxide 1.750 mg
  • Lactose monohydrate (spray dried): 209.09 mg
  • Microcrystalline cellulose 102.00 mg
  • Titanium dioxide 1, 5696 mg
  • Kern talsaclidine fumarate 10.21 mg
  • Lactose monohydrate (spray dried): 203.99 mg
  • Microcrystalline cellulose 102.00 mg
  • Lactose monohydrate (spray dried): 193.77 mg
  • Microcrystalline cellulose 102.00 mg
  • Microcrystalline cellulose 102.00 mg
  • Kern talsaclidin fumarate 51.07 mg
  • Lactose monohydrate 163.13 mg
  • Microcrystalline cellulose 102.00 mg
  • Talsaclidine fumarate 61.29 mg lactose monohydrate (spray dried): 152.91 mg
  • Microcrystalline cellulose 102.00 mg
  • Kern talsaclidine fumarate 81, 72 mg
  • Lactose monohydrate (spray dried): 132.48 mg
  • Microcrystalline cellulose 102.00 mg
  • Talsaclidine fumarate 40.86 mg lactose monohydrate (spray dried): 66.24 mg
  • Microcrystalline cellulose 60.30 mg

Abstract

The invention relates to a novel medicament formulation containing the muscarinic agonist talsaclidine and to a method for the production thereof.

Description

Arzneimittelformulierung die einen muskarinischen Agonisten enthält Drug formulation containing a muscarinic agonist
Die Erfindung betrifft eine neue Arzneimittelformulierung enthaltend den muskarinischen Agonisten Talsaclidin und Verfahren zu deren Herstellung.The invention relates to a new pharmaceutical formulation containing the muscarinic agonist talsaclidine and processes for their preparation.
Hintergrund der Erfindung Talsaclidin (Wal2014) ist als muskarinischer Agonist eine Verbindung mit pharmakologisch wertvollen Eigenschaften. Muskarinische Agonisten können beispielsweise bei der Behandlung der Alzheimerschen Krankheit einen hohen therapeutischen Nutzen entfalten. Talsaclidin V weist die folgende chemische Struktur auf:Background of the Invention As a muscarinic agonist, talsaclidine (Wal2014) is a compound with pharmacologically valuable properties. For example, muscarinic agonists can have great therapeutic benefits in the treatment of Alzheimer's disease. Talsaclidin V has the following chemical structure:
Figure imgf000002_0001
Figure imgf000002_0001
Es ist Aufgabe der vorliegenden Erfindung, eine oral applizierbare pharmazeutische Formulierung bereitzustellen, die den Wirkstoff Talsaclidin relativ rasch und vollständig freisetzt. Es ist ferner Aufgabe der vorliegenden Erfindung, eine Formulierung bereitzustellen, die durch eine gute Handhabbarkeit während des Herstellprozesses gekennzeichnet ist und dadurch die technische Herstellung in reproduzierbarer Art und Weise bei gleichbleibend hoher Qualität erlaubt.It is an object of the present invention to provide an orally administrable pharmaceutical formulation which releases the active ingredient talsaclidine relatively quickly and completely. It is also an object of the present invention to provide a formulation which is characterized by easy handling during the manufacturing process and thereby allows the technical manufacture in a reproducible manner with a consistently high quality.
Detaillierte Beschreibung der ErfindungDetailed description of the invention
Vorstehend genannte Aufgaben werden durch die im Folgenden detailliert beschriebene Formulierung gelöst.The above-mentioned tasks are solved by the wording described in detail below.
Die vorliegende Erfindung betrifft eine Talsaclidin V enthaltende Tablette, dadurch gekennzeichnet, daß sie aus einem den Wirkstoff Talsaclidin enthaltenden Kern und einen diesen Kern ummantelnden Filmüberzug besteht. Die erfindungsgemäße Tablette kann im Rahmen der vorliegenden Erfindung auch als Filmtablette bezeichnet werden.The present invention relates to a tablet containing talsaclidine V, characterized in that it consists of a core containing the active ingredient talsaclidine and a film coating encasing this core. The tablet according to the invention can also be referred to as a film tablet in the context of the present invention.
Der Wirkstoff Talsaclidin liegt in der erfindungsgemäßen Formulierung vorzugsweise in Form eines physiologisch verträglichen Säureadditionssalzes vor. Als physiologisch verträgliche Säureadditionssalze werden erfindungsgemäß pharmazeutisch verträgliche Salze verstanden, die ausgewählt aus den Salzen der Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weinsäure und Maleinsäure sind. Gegebenenfalls können zur Herstellung der Salze auch Mischungen der vorgenannten Säuren eingesetzt werden. Erfindungsgemäß bevorzugt sind die Salze des Talsaclidins ausgewählt aus der Gruppe bestehend aus Hydrochlorid, Hydrobromid, Sulfat, Phosphat, Fumarat und Methansulfonat. Besonders bevorzugt sind die Salze ausgewählt aus Hydrochlorid, Hydrobromid und Fumarat, wobei dem Talsaclidinfumarat erfindungsgemäß die größte Bedeutung zukommt. Der Wirkstoff kann gegebenenfalls in Form eines Hydrats vorliegen. Erfindungsgemäß bevorzugt wird das Talsaclidin allerdings in einer wasserfreien Form zugesetzt. Vorzugsweise wird der Wirkstoff in kristalliner, unvermahlener Form oder stiftvermahlener Form, bevorzugt allerdings in unvermahlener Form eingesetzt. Besonders bevorzugt wird Wirkstoff in unvermahlener Form verwendet, bei dem die Teilchengrößenverteilung innerhalb folgender Grenzen liegt: D-io ≤ 20μm, D50 10-80μm, D90 < 300μm. Besonders bevorzugt liegt die Teilchengrößenverteilung des in die erfindungsgemäße Formulierung eingesetzten Wirkstoffs in folgenden Bereichen: D-io < 5 - 15μm, D50 25 - 75 μm, D90 < 275μm. Bei den vorstehend genannten Zahlenangaben für D10, D5o und D90 in μm (Mikrometer) handelt es sich um die Teilchengrößenbereiche innerhalb derer eine Durchgangssumme, von 10 Volumen- %, 50 Volumen-% bzw. 90 Volumen-% der gemessenen Partikel (kumulative Volumenverteilung) erreicht wird. Diese Werte wurden mit dem Verfahren der Laserdiffraktometrie bestimmt, im vorliegenden Fall speziell unter Anwendung einer sogenannten Trockendispergierung bei 2 bar Dispersionsdruck sowie einer Brennweite f = 500 mm, z.B. mit Hilfe eines Sympatec/RODOS Gerätes. Diese Methodik ist im Stand der Technik bekannt.The active ingredient talsaclidine is preferably present in the formulation according to the invention in the form of a physiologically tolerated acid addition salt. According to the invention, physiologically acceptable acid addition salts are understood to be pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. If necessary, can Production of the salts, mixtures of the abovementioned acids can also be used. According to the invention, the salts of talsaclidine are preferably selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate and methanesulfonate. The salts are particularly preferably selected from hydrochloride, hydrobromide and fumarate, the talsaclidin fumarate being of the greatest importance according to the invention. The active ingredient may optionally be in the form of a hydrate. According to the invention, the talsaclidine is preferably added in an anhydrous form. The active ingredient is preferably used in crystalline, unground form or pin-ground form, but preferably in unground form. Active ingredient is particularly preferably used in unmilled form, in which the particle size distribution lies within the following limits: D-io 20 20 μm, D 50 10-80 μm, D 90 <300 μm. The particle size distribution of the active ingredient used in the formulation according to the invention is particularly preferably in the following ranges: D-io <5-15 μm, D 50 25-75 μm, D 90 <275 μm. In the above figures for D 10, D 5 and D o in 90 microns (micrometers) is the particle size ranges within which a passage amount of 10 volume%, 50 volume% and 90 volume% of the particles measured (cumulative volume distribution) is achieved. These values were determined using the method of laser diffractometry, in the present case specifically using a so-called dry dispersion at a dispersion pressure of 2 bar and a focal length f = 500 mm, for example using a Sympatec / RODOS device. This methodology is known in the prior art.
Wird im Rahmen der vorliegenden Erfindung auf Salze des Talsaclidins Bezug genommen, wird dies durch die Bezeichnung kenntlich gemacht. Ein explizite Bezugnahme auf die Base Talsaclidin erfolgt dagegen durch Verwendung der Bezeichnung Y.If reference is made to salts of talsaclidine in the context of the present invention, this is indicated by the designation. However, an explicit reference to the base talsaclidine is made by using the designation Y.
Bezogen auf die Gesamtmasse des Kerns der erfindungsgemäßen Filmtabletten ist Talsaclidin V erfindungsgemäß zu 0,5 bis 25-Gew%, bevorzugt 0,7 bis 20-Gew%, besonders bevorzugt etwa 0,9 bis 15 Gew% enthalten. Besonders bevorzugt liegt der Anteil von V zwischen 9 und 14-Gew% bezogen auf die Gesamtmasse des Kerns. Wird Talsaclidin beispielsweise in Form des erfindungsgemäß bevorzugten Salzes 1 Talsaclidinfumarat in die erfindungsgemäße Formulierung eingesetzt, liegt der Anteil an 1 bezogen auf die Gesamtmasse des Kerns der erfindungsgemäßen Filmtabletten erfindungsgemäß zwischen etwa 0,85 bis 43-Gew%, bevorzugt zwischen etwa 1 ,2 bis 34-Gew%, besonders bevorzugt zwischen etwa 1 ,5 bis 26 Gew% enthalten. Besonders bevorzugt liegt der Anteil von 1 im Falle von Talsaclidinfumarat zwischen etwa 15 und 24-Gew% bezogen auf die Gesamtmasse des Kerns.Based on the total mass of the core of the film-coated tablets according to the invention, talsaclidine V is present according to the invention at 0.5 to 25% by weight, preferably 0.7 to 20% by weight, particularly preferably about 0.9 to 15% by weight. The proportion of V is particularly preferably between 9 and 14% by weight, based on the total mass of the core. If talsaclidine, for example in the form of the salt 1 talsaclidine fumarate preferred according to the invention, is used in the formulation according to the invention, the proportion of 1, based on the total mass of the core of the film tablets according to the invention, is between about 0.85 to 43% by weight, preferably between about 1.2 to 2% by weight 34% by weight, particularly preferably between about 1.5 to 26% by weight. The proportion of 1 is particularly preferably in the case of Talsaclidin fumarate between about 15 and 24% by weight based on the total mass of the core.
Der Kern der erfindungsgemäßen Arzneimittelformulierung enthält neben dem Wirkstoff ferner wenigstens einen Hilfsstoff als Füllstoff/Trockenbindemittel. Im Rahmen der vorliegenden Erfindung kommt dabei modifizierter Lactose, insbesondere sprühgetrockneter Lactose als Hilfsstoff eine besondere Bedeutung zu. Dieser Hilfsstoff hat sich bei der erfindungsgemäßen Formulierung als besonders vorteilhaft erwiesen. Ein bevorzugter Aspekt der vorliegenden Erfindung betrifft daher eine Talsaclidin enthaltende Filmtablette, die im Kern neben dem Wirkstoff modifizierte Lactose, insbesondere sprühgetrocknete Lactose, besonders bevorzugt sprühgetrocknetes Lactosemonohydrat als Hilfsstoff enthält.In addition to the active ingredient, the core of the pharmaceutical formulation according to the invention also contains at least one auxiliary as filler / dry binder. In the context of the present invention, modified lactose, in particular spray-dried lactose, is of particular importance as an auxiliary. This auxiliary has proven to be particularly advantageous in the formulation according to the invention. A preferred aspect of the present invention therefore relates to a film tablet containing talsaclidine, which contains, in addition to the active substance, modified lactose, in particular spray-dried lactose, particularly preferably spray-dried lactose monohydrate, as an adjuvant.
Unter spühgetrockneter Lactose ist solche Lactose zu verstehen, die durch Sprühagglomeration bei der Sprühtrocknung einer Suspension von α-Spray-dried lactose is to be understood as lactose which is obtained by spray agglomeration when spray-drying a suspension of α-
Lactosemonohydratkristallen in einer wässrigen Lactose-Lösung entsteht. Durch den Sprühtrocknungsprozeß resultiert ein frei fließendes Pulver mit zur Direkttablettierung geeigneter Granulometrie (beispielsweise 80-100% < 250μm) und einem amorphen Anteil von beispielsweise 5 - 25%, der für das hohe Bindevermögen von sprühgetrockneter Lactose verantwortlich ist.Lactose monohydrate crystals are formed in an aqueous lactose solution. The spray drying process results in a free-flowing powder with suitable granulometry for direct tableting (for example 80-100% <250 μm) and an amorphous fraction of for example 5-25%, which is responsible for the high binding capacity of spray-dried lactose.
Erfindungsgemäß liegt das Gewichtsverhältnis zwischen den im Kern der Filmtablette enthaltenen Komponenten modifizierte Lactose, bevorzugt sprühgetrocknete Lactose zu Wirkstoff V in einem Bereich von etwa 1 :1 bis etwa 70:1. Vorzugsweise liegt das Verhältnis von modifizierter, bevorzugt sprühgetrockneter Lactose zu V in einem Bereich von etwa 1 ,5:1 bis. etwa 35:1 , besonders bevorzugt in einem Bereich von etwa 2:1 bis etwa 8:1. Bevorzugt liegt der Gewichtsanteil der modifizierten, bevorzugt sprühgetrockneten Lactose bezogen auf die Gesamtmasse des Kerns der erfindungsgemäßen Filmtablette in einem Bereich von etwa 20 - 70 Gew%, bevorzugt zwischen etwa 30 - 60 Gew%.According to the invention, the weight ratio between the components of modified lactose, preferably spray-dried lactose, and active ingredient V contained in the core of the film-coated tablet is in a range from about 1: 1 to about 70: 1. The ratio of modified, preferably spray-dried lactose to V is preferably in a range from about 1.5: 1 to. about 35: 1, particularly preferably in a range from about 2: 1 to about 8: 1. The weight fraction of the modified, preferably spray-dried lactose, based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from approximately 20-70% by weight, preferably between approximately 30-60% by weight.
Der Kern der erfindungsgemäßen Filmtablette kann neben modifizierter, bevorzugt sprühgetrockneter Lactose und Wirkstoff ferner weitere Hilfsstoffe bzw. Füllstoffe enthalten. Erfindungsgemäß bevorzugt können solche Verbindungen eingesetzt werden, die als Trockenbindemittel fungieren können. Erfindungsgemäß bevorzugte Trockenbindemittel sind ausgewählt aus der Gruppe bestehend aus Pulvercellulose, mikrokristalline Cellulose, Stärke, Povidon, Cellulosederivaten und Gemische dieser Verbindungen. Bevorzugt sind als Bindemittel Pulvercellulose und /oder microkristalline Cellulose, besonders bevorzugt mikrokristalline Cellulose enthalten. Wird eines der vorstehend genannten Bindemittel der erfindungsgemäßen Formulierung zugesetzt, so beträgt das Gewichtsverhältnis von modifizierter, bevorzugt sprühgetrockneter Lactose zu Bindemittel bevorzugt etwa 5:1 bis etwa 1 :4, bevorzugt etwa 4:1 bis etwa 1 :3, besonders bevorzugt etwa 3:1 bis 1 :2. Erfindungsgemäß besonders bevorzugt liegt das Gewichtsverhältnis von sprühgetrockneter Lactose zu Bindemittel in einem Bereich von etwa 2:1 bis etwa 1 :1.In addition to modified, preferably spray-dried lactose and active ingredient, the core of the film-coated tablet according to the invention can also contain further auxiliaries or fillers. According to the invention, preference can be given to those compounds which can act as dry binders. Dry binders preferred according to the invention are selected from the group consisting of powder cellulose, microcrystalline cellulose, starch, povidone, cellulose derivatives and mixtures of these compounds. Powder cellulose and / or microcrystalline cellulose are preferred as binders, particularly preferably microcrystalline cellulose contain. If one of the abovementioned binders is added to the formulation according to the invention, the weight ratio of modified, preferably spray-dried lactose to binder is preferably about 5: 1 to about 1: 4, preferably about 4: 1 to about 1: 3, particularly preferably about 3: 1 to 1: 2. According to the invention, the weight ratio of spray-dried lactose to binder is particularly preferably in a range from about 2: 1 to about 1: 1.
Der Kern der erfindungsgemäßen Filmtablette kann neben vorstehend genannten Bestandteilen ferner Zerfallsmittel enthalten. Im Rahmen der vorliegenden Erfindung können diese Zerfallsmittel gegebenenfalls auch als Sprengmittel bezeichnet werden. Diese sind erfindungsgemäß bevorzugt ausgewählt aus der Gruppe bestehend aus Natriumstärkeglykolat, Crospovidon, Croscarmellose, Natrium- carboxymethylcellulose, getrocknete Maisstärke und Gemische davon. Besonders bevorzugt gelangen im Rahmen der vorliegenden Erfindung Natriumstärkeglykolat, Crospovidon und Croscarmellose, bevorzugt Natriumstärkeglykolat zur Anwendung. Werden vorstehend genannte Zerfallsmittel verwendet, liegt ihr Gewichtsanteil bezogen auf die Gesamtmasse des Kerns der erfindungsgemäßen Filmtablette bevorzugt in einem Bereich von etwa 1 - 10 Gew%, besonders bevorzugt bei etwa 3 - 8 Gew%.The core of the film-coated tablet according to the invention may also contain disintegrants in addition to the above-mentioned components. In the context of the present invention, these disintegrants may also be referred to as disintegrants. According to the invention, these are preferably selected from the group consisting of sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethyl cellulose, dried corn starch and mixtures thereof. In the context of the present invention, sodium starch glycolate, crospovidone and croscarmellose, preferably sodium starch glycolate, are particularly preferably used. If the above-mentioned disintegrants are used, their proportion by weight, based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from about 1-10% by weight, particularly preferably about 3-8% by weight.
Der Kern der erfindungsgemäßen Filmtablette kann als weitere Bestandteile ferner Fließregulierungsmittel enthalten. Als Fließregulierungsmittel kommen im Rahmen der vorliegenden Erfindung beispielsweise in Betracht Siliciumdioxid, Talkum und Magnesiumstearat. Erfindungsgemäß bevorzugt wird Siliciumdioxid verwendet, besonders bevorzugt in kolloidaler, hochdisperser Form. Werden vorstehend genannte Fließregulierungsmittel verwendet, liegt ihr Gewichtsanteil bezogen auf die Gesamtmasse des Kerns der erfindungsgemäßen Filmtablette bevorzugt in einem Bereich von etwa 0,1 - 5 Gew%, bevorzugt bei etwa 0,3 - 2 Gew%, besonders bevorzugt zwischen 0,4 und 1 ,5 Gew%.The core of the film-coated tablet according to the invention may also contain flow regulators as further constituents. Flow regulating agents in the context of the present invention are, for example, silicon dioxide, talc and magnesium stearate. According to the invention, silicon dioxide is preferably used, particularly preferably in colloidal, highly disperse form. If the above-mentioned flow regulating agents are used, their proportion by weight, based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from approximately 0.1 to 5% by weight, preferably approximately 0.3 to 2% by weight, particularly preferably between 0.4 and 1.5 wt%.
Der Kern der erfindungsgemäßen Filmtablette kann als weitere Bestandteile ferner Fließ-, Schmier- und Trennmittel enthalten. Hierzu kommen im Rahmen der vorliegenden Erfindung beispielsweise in Betracht Stearinsäure, Magnesiumstearat, Natrium-Stearylfumarat, Glyceroltribehenat und Gemische davon. Erfindungsgemäß bevorzugt werden Stearinsäure und Magnesiumstearat verwendet. Der Gewichtsanteil bezogen auf die Gesamtmasse des Kerns der erfindungsgemäßen Filmtablette liegt bevorzugt in einem Bereich von etwa 0,1 - 5 Gew%, bevorzugt bei etwa 0,5 - 3 Gew%, besonders bevorzugt bei etwa 1 - 2 Gew%. Eine besonders gute Formentrennwirkung bei der Herstellung der erfindungsgemäßen Filmtabletten wird erzielt, wenn Magnesiumstearat in einer Menge von wenigstens 1 ,0 Gew%, bevorzugt etwa 1 ,5 Gew% verwendet wird.The core of the film-coated tablet according to the invention can also contain flow agents, lubricants and release agents as further constituents. In this context, for example, stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate and mixtures thereof come into consideration within the scope of the present invention. Stearic acid and magnesium stearate are preferably used according to the invention. The proportion by weight, based on the total mass of the core of the film-coated tablet according to the invention, is preferably in a range from approximately 0.1 to 5% by weight, preferably approximately 0.5 to 3% by weight, particularly preferably approximately 1-2% by weight. A particularly good one Mold release in the production of the film-coated tablets according to the invention is achieved if magnesium stearate is used in an amount of at least 1.0% by weight, preferably about 1.5% by weight.
Der den Kern der erfindungsgemäßen Filmtabletten umschließende Film oder Filmüberzug enthält als einen wesentlichen Bestandteil einen Filmbildner, der ausgewählt ist aus Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Methylcellulose, Hydroxymethylcellulose, Hydroxyethylcellulose und Poly(ethylacrylat)methylmethacrylat, letzteres beispielsweise in Form von Eudragit NE 30 D. Alternativ dazu können ferner beispielsweise Eudragit RL 30 D oder auch Eudragit E 12.5 zum Einsatz gelangen. Vorstehend genannte Bestandteile können gegebenenfalls auch in Form ihrer Gemische zur Anwendung gelangen. Bevorzugte Filmbildner sind Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Hydroxymethylcellulose und Hydroxyethylcellulose, wobei Hydroxypropylmethylcellulose und Hydroxypropylcellulose erfindungsgemäß als Filmbildner besonders bevorzugt sind. Vorstehend aufgeführte Filmbildner können allein oder in Form ihrer Gemische zur Anwendung gelangen. Wird lediglich eine der vorstehend genannten Filmbildner verwendet, so kommt im Rahmen der vorliegenden Erfindung in diesem Zusammenhang der Hydroxypropylmethylcellulose ein besondere Bedeutung zu. Der Gewichtsanteil an Filmbildner bezogen auf die Gesamtmasse des Filmüberzugs der erfindungsgemäßen Filmtablette liegt bevorzugt in einem Bereich von etwa 20 - 95 Gew%, bevorzugt 30 - 90 Gew%.The film or film covering surrounding the core of the film-coated tablets according to the invention contains, as an essential component, a film-forming agent which is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and poly (ethyl acrylate) methyl methacrylate, the latter for example in the form of Eudragit NE 30 D. Alternatively Eudragit RL 30 D or Eudragit E 12.5 can also be used. The above-mentioned constituents can optionally also be used in the form of their mixtures. Preferred film formers are hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose, with hydroxypropyl methyl cellulose and hydroxypropyl cellulose being particularly preferred according to the invention as film formers. The above film formers can be used alone or in the form of their mixtures. If only one of the above-mentioned film formers is used, hydroxypropylmethyl cellulose is of particular importance in the context of the present invention. The proportion by weight of film former, based on the total mass of the film coating of the film tablet according to the invention, is preferably in a range from about 20-95% by weight, preferably 30-90% by weight.
Der Filmüberzug kann als weitere Bestandteile Emulgatoren und Weichmacher, wie beispielsweise Polyethylenglycol, Glycerin und Propylenglykol, gegebenenfalls in form ihrer Gemische enthalten. Bevorzugt gelangen Polyethylenglycole als Weichmacher zur Anwendung. Ohne den Gegenstand der Erfindung darauf zu beschränken seien als besonders bevorzugte Polyethylenglycole beispielsweise genannt Polyethylenglycol 400 und Polyethylenglycol 6000. Der Gewichtsanteil an Weichmacher bezogen auf die Gesamtmasse des Filmüberzugs der erfindungsgemäßen Filmtablette liegt bevorzugt in einem Bereich von etwa 1 - 30 Gew%, bevorzugt 3 - 25 Gew%, besonders bevorzugt bei 5 - 15 Gew%.The film coating can contain, as further constituents, emulsifiers and plasticizers, such as, for example, polyethylene glycol, glycerol and propylene glycol, optionally in the form of their mixtures. Polyethylene glycols are preferably used as plasticizers. Without restricting the subject matter of the invention, particularly preferred polyethylene glycols are, for example, polyethylene glycol 400 and polyethylene glycol 6000. The weight fraction of plasticizer, based on the total mass of the film coating of the film-coated tablet according to the invention, is preferably in a range from about 1-30% by weight, preferably 3- 25% by weight, particularly preferably 5-15% by weight.
Der Filmüberzug der erfindungsgemäßen Filmtablette kann ferner Farbpigmente und Pigmentierhilfsstoffe enthalten. Beispielsweise seien genannt Eisenoxid, Titandioxid, Talkum und deren Gemische.The film coating of the film-coated tablet according to the invention can also contain color pigments and pigmentation aids. Examples include iron oxide, titanium dioxide, talc and their mixtures.
Zur Herstellung der erfindungsgemäßen Filmtablette kann beispielsweise wie nachfolgend beschrieben vorgegangen werden. In einem geeigneten Freifallmischer wird der Hilfsstoff sprühgetrocknete Lactose gemeinsam mit dem Wirkstoff 1 vermischt. Die daraus erhaltene Wirkstoffvormischung wird anschließend in einer geeigneten Siebmaschine gemischt. Dadurch wird der Anteil eventuell in das Herstellverfahren eingesetzter gröberer Wirkstoffpartikel reduziert. Je nach Partikelgröße der eingesetzten Verbindung 1 kann auf die Herstellung dieser Vormischung mit anschließendem Siebvorgang auch verzichtet werden.The film tablet according to the invention can be produced, for example, as described below. The excipient spray-dried lactose is mixed together with the active ingredient 1 in a suitable free-fall mixer. The premix of active ingredients obtained therefrom is then mixed in a suitable screening machine. This reduces the proportion of coarser active substance particles used in the manufacturing process. Depending on the particle size of the compound 1 used, it is also possible to dispense with the production of this premix with subsequent sieving.
Zu dieser Wirkstoffvormischung wird in einem weiteren Verfahrensschritt weiterer Hilfsstoff zugesetzt. Dabei kann neben derm Zusatz der sprühgetrockneten Lactose auch die Zugabe eines oder mehrerer weiterer Hilfsstoff erfolgen. Ferner können während dieses Verfahrensschritts optionale weitere Formulierungsbestandteile wie Zerfallhilfsmittel und Fließregulierungsmittel zugesetzt werden. Nach beendetem Mischvorgang wird die erhaltene Mischung erneut gesiebt. Diese Zwischensiebung ist der essentielle Schritt zur Erzielung einer Arzneibuch konformen Gehaltseinheitlichkeit der Mischung. Zu dieser gesiebten Wirkstoffmischung erfolgt sodann die Zugabe des Fließ-, Scmier- und Trennmittels.In a further process step, further excipient is added to this active ingredient premix. In addition to the addition of the spray-dried lactose, one or more further auxiliaries can also be added. Furthermore, optional further formulation components such as disintegrants and flow regulators can be added during this process step. After the mixing process is complete, the mixture obtained is sieved again. This intermediate sieving is the essential step in achieving a uniformity of the mixture in accordance with the pharmacopoeia. The flow agent, lubricant and separating agent are then added to this sieved active ingredient mixture.
Das so erhaltene Wirkstoff-Hilfstoffgemisch wird anschließend auf einer geeigneten Tablettenpresse zu den erfindungsgemäßen Filmtablettenkernen verpreßt. Hierbei sollte die Preßkraft z.B. im Falle von Tablettenkernen, die 36 mg Talsaclidin V enthalten, in einem Bereich von 5 - 15 kN, bevorzugt 8 - 12 kN gehalten werden. Höhere Preßkräfte können zu Tabletten mit verlangsamter Wirkstoff-Freisetzung führen. Niedrigere Preßkräfte können zu mechanisch instabilen Tabletten führen. Die Tablettenkerne können unterschiedliche Formate aufweisen, bevorzugt sind runde biplane oder bikonvexe und ovale oder oblong Formen.The active ingredient / excipient mixture obtained in this way is then compressed on a suitable tablet press to give the film-coated tablet cores according to the invention. The pressing force should be e.g. in the case of tablet cores containing 36 mg of talsaclidine V, they are kept in a range from 5 to 15 kN, preferably 8 to 12 kN. Higher compressive forces can lead to tablets with a slow release of the active ingredient. Lower compression forces can lead to mechanically unstable tablets. The tablet cores can have different formats, preferably round biplane or biconvex and oval or oblong shapes.
Zur Herstellung der Filmüberzugssuspension werden die jeweils erforderlichen sowie die optionalen Bestandteile des Filmüberzugs in einem geeigneten Lösemittel aufgenommen. Erfindungsgemäß bevorzugt wird Wasser als Lösemittel verwendet. Bei Verwendung von Wasser als Lösemittel liegen die Bestandteile des Filmüberzugs zum Teil in dispergierter Form vor.To produce the film coating suspension, the required and optional components of the film coating are taken up in a suitable solvent. According to the invention, water is preferably used as the solvent. When water is used as the solvent, some of the components of the film coating are in dispersed form.
Nach Fertigstellung der Überzugssuspension werden die zuvor erhaltenen Tablettenkerne in einem geeigneten Coatinggerät in Analogie zu im Stand der Technik bekannten Coatingverfahren mit dem gewünschten Film überzogen. Die nachfolgenden Beispiele dienen der Illustration erfindungsgemäßerer Formulierungen. Sie sind lediglich als mögliche, exemplarisch dargestellte Vorgehensweisen zu verstehen, ohne die Erfindung auf deren Inhalt zu beschränken.After completion of the coating suspension, the tablet cores previously obtained are coated with the desired film in a suitable coating device in analogy to the coating processes known in the prior art. The following examples serve to illustrate formulations according to the invention. They are only to be understood as possible exemplary procedures, without restricting the invention to its content.
Beispiel 1:Example 1:
Kerncore
Talsaclidinfumarat: 61 ,287 mgTalsaclidine fumarate: 61, 287 mg
Lactosemonohydrat (sprühgetrocknet): 99,363 mgLactose monohydrate (spray dried): 99.363 mg
Mikrokristalline Cellulose: 90,450 mgMicrocrystalline cellulose: 90.450 mg
Natriumstärkeglykolat: 13,500 mgSodium starch glycolate: 13,500 mg
Sliciumdioxid hochdispers: 1 ,350 mgHighly disperse silicon dioxide: 1,350 mg
Magnesiumstearat: 4.050 moMagnesium stearate: 4,050 mo
Total (Kern): 270,00 mgTotal (core): 270.00 mg
Filmüberzugfilm coating
Hydroxypropylmethylcellulose: 3,500 mgHydroxypropylmethyl cellulose: 3,500 mg
Polyethylenglycol 400 0,350 mgPolyethylene glycol 400 0.350 mg
Titandioxid: 1,750 mgTitanium dioxide: 1.750 mg
Talkum: 1 ,358 mgTalc: 1,358 mg
Eisenoxid (gelb): 0.042 mgIron oxide (yellow): 0.042 mg
Total (Überzug): 7,000 mgTotal (coating): 7,000 mg
Total (Filmtablette): 277,000 mgTotal (film-coated tablet): 277,000 mg
Beispiel 2:Example 2:
Kerncore
Talsaclidinfumarat: 5,11 mgTalsaclidine fumarate: 5.11 mg
Lactosemonohydrat (sprühgetrocknet): 209,09 mgLactose monohydrate (spray dried): 209.09 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mg Sliciumdioxid hochdispers: 3,40 mgSodium starch glycolate: 17.00 mg, highly dispersed slicium dioxide: 3.40 mg
Stearinsäure: 3,40 mgStearic acid: 3.40 mg
Total (Kern): 340,00 mg FilmüberzugTotal (core): 340.00 mg film coating
Hydroxypropylmethylcellulose: 1 ,1416 mgHydroxypropylmethyl cellulose: 1, 1416 mg
Polyethylenglycol 6000 1 ,4269 mgPolyethylene glycol 6000 1, 4269 mg
Titandioxid: 1 ,5696 mgTitanium dioxide: 1, 5696 mg
Talkum: 4,5662 mgTalc: 4.5662 mg
Methacrylsäurecopolymer Eudragit: 1 ,2843 mgEudragit methacrylic acid copolymer: 1, 2843 mg
Total (Überzug): 10,000 mgTotal (coating): 10,000 mg
Total (Filmtablette): 350,000 mgTotal (film-coated tablet): 350,000 mg
Beispiel 3:Example 3:
Kern Talsaclidinfumarat: 10,21 mgKern talsaclidine fumarate: 10.21 mg
Lactosemonohydrat (sprühgetrocknet): 203,99 mgLactose monohydrate (spray dried): 203.99 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mgSodium starch glycolate: 17.00 mg
Sliciumdioxid hochdispers: 3,40 mg Stearinsäure: 3,40 mgHighly disperse silicon dioxide: 3.40 mg stearic acid: 3.40 mg
Total (Kern): 340,00 mgTotal (core): 340.00 mg
Filmüberzug: analog Beispiel 2Film coating: analogous to example 2
Total (Filmtablette): 350,000 mgTotal (film-coated tablet): 350,000 mg
Beispiel 4:Example 4:
Kerncore
Talsaclidinfumarat: 20,43 mgTalsaclidine fumarate: 20.43 mg
Lactosemonohydrat (sprühgetrocknet): 193,77 mgLactose monohydrate (spray dried): 193.77 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mg Sliciumdioxid hochdispers: 3,40 mgSodium starch glycolate: 17.00 mg, highly dispersed slicium dioxide: 3.40 mg
Stearinsäure: 3,40 mgStearic acid: 3.40 mg
Total (Kern): 340,00 mg Filmüberzug: analog Beispiel 2Total (core): 340.00 mg Film coating: analogous to example 2
Total (Filmtablette): 350,000 mgTotal (film-coated tablet): 350,000 mg
Beispiel 5:Example 5:
Kerncore
Talsaclidinfumarat: 40,86 mg Lactosemonohydrat (sprühgetrocknet): 173,34 mgTalsaclidine fumarate: 40.86 mg lactose monohydrate (spray dried): 173.34 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mgSodium starch glycolate: 17.00 mg
Sliciumdioxid hochdispers: 3,40 mgHighly disperse silicon dioxide: 3.40 mg
Stearinsäure: 3,40 mg Total (Kern): 340,00 mgStearic acid: 3.40 mg total (core): 340.00 mg
Filmüberzug: analog Beispiel 2Film coating: analogous to example 2
Total (Filmtablette): 350,000 mgTotal (film-coated tablet): 350,000 mg
Beispiel 6:Example 6:
Kern Talsaclidinfumarat: 51 ,07 mgKern talsaclidin fumarate: 51.07 mg
Lactosemonohydrat (sprühgetrocknet): 163,13 mgLactose monohydrate (spray dried): 163.13 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mgSodium starch glycolate: 17.00 mg
Sliciumdioxid hochdispers: 3,40 mg Stearinsäure: 3,40 mgHighly disperse silicon dioxide: 3.40 mg stearic acid: 3.40 mg
Total (Kern): 340,00 mgTotal (core): 340.00 mg
Filmüberzug: analog Beispiel 2Film coating: analogous to example 2
Total (Filmtablette): 350,000 mg Beispiel 7:Total (film-coated tablet): 350,000 mg Example 7:
Kerncore
Talsaclidinfumarat: 61 ,29 mg Lactosemonohydrat (sprühgetrocknet): 152,91 mgTalsaclidine fumarate: 61.29 mg lactose monohydrate (spray dried): 152.91 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mgSodium starch glycolate: 17.00 mg
Sliciumdioxid hochdispers: 3,40 mgHighly disperse silicon dioxide: 3.40 mg
Stearinsäure: 3,40 mg Total (Kern): 340,00 mgStearic acid: 3.40 mg total (core): 340.00 mg
Filmüberzug: analog Beispiel 2Film coating: analogous to example 2
Total (Filmtablette): 350,000 mgTotal (film-coated tablet): 350,000 mg
Beispiel 8:Example 8:
Kern Talsaclidinfumarat: 81 ,72 mgKern talsaclidine fumarate: 81, 72 mg
Lactosemonohydrat (sprühgetrocknet): 132,48 mgLactose monohydrate (spray dried): 132.48 mg
Mikrokristalline Cellulose: 102,00 mgMicrocrystalline cellulose: 102.00 mg
Natriumstärkeglykolat: 17,00 mgSodium starch glycolate: 17.00 mg
Sliciumdioxid hochdispers: 3,40 mg Stearinsäure: 3,40 mgHighly disperse silicon dioxide: 3.40 mg stearic acid: 3.40 mg
Total (Kern): 340,00 mgTotal (core): 340.00 mg
Filmüberzug: analog Beispiel 2Film coating: analogous to example 2
Total (Filmtablette): 350,000 mg Beispiel 9:Total (film-coated tablet): 350,000 mg Example 9:
Kerncore
Talsaclidinfumarat: 40,86 mg Lactosemonohydrat (sprühgetrocknet): 66,24 mgTalsaclidine fumarate: 40.86 mg lactose monohydrate (spray dried): 66.24 mg
Mikrokristalline Cellulose: 60,30 mgMicrocrystalline cellulose: 60.30 mg
Natriumstärkeglykolat: 9,00 mgSodium starch glycolate: 9.00 mg
Sliciumdioxid hochdispers: 0,90 mgHighly disperse silicon dioxide: 0.90 mg
Stearinsäure: 2,70 mg Total (Kern): 180,00 mgStearic acid: 2.70 mg Total (core): 180.00 mg
Filmüberzug: analog Beispiel 1Film coating: analogous to example 1
Total (Filmtablette): 185,000 mg Total (film-coated tablet): 185,000 mg

Claims

Patentansprücheclaims
1 ) Talsaclidin V enthaltende Tablette, dadurch gekennzeichnet, daß sie aus einem den Wirkstoff Talsaclidin enthaltenden Kern und einen diesen Kern ummantelnden Filmüberzug besteht.1) Tablet containing talsaclidine V, characterized in that it consists of a core containing the active ingredient talsaclidine and a film coating encasing this core.
2) Tablette nach Anspruch 1 , dadurch gekennzeichnet, daß der Kern ferner den Hilfsstoff modifizierte Lactose, bevorzugt sprühgetrocknete Lactose enthält.2) Tablet according to claim 1, characterized in that the core further contains the auxiliary modified lactose, preferably spray-dried lactose.
3) Tablette nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß Talsaclidin in Form eines Säureadditionssalzes 1 vorliegt, welches ausgewählt ist aus den Salzen der Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Phosphorsäure, Methansulfonsäure, Essigsäure, Fumarsäure, Bernsteinsäure, Milchsäure, Zitronensäure, Weinsäure und Maleinsäure.3) Tablet according to claim 1 or 2, characterized in that talsaclidine is in the form of an acid addition salt 1, which is selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
4) Tablette nach einem der Ansprüche 1 , 2 oder 3, dadurch gekennzeichnet, daß der Kern Talsaclidin V zu 0,5 bis 25-Gew%, bevorzugt 0,7 bis 20-Gew% enthält.4) Tablet according to one of claims 1, 2 or 3, characterized in that the core contains talsaclidine V to 0.5 to 25% by weight, preferably 0.7 to 20% by weight.
5) Tablette nach einem der Ansprüche 2 bis 4, dadurch gekennzeichnet, daß das Gewichtsverhältnis zwischen den im Kern der Filmtablette enthaltenen Komponenten modifizierte Lactose zu Wirkstoff V in einem Bereich von etwa 1 :1 bis etwa 70:1 , vorzugsweise zwischen etwa 1 ,5:1 bis etwa 35:1.5) Tablet according to one of claims 2 to 4, characterized in that the weight ratio between the components contained in the core of the film tablet modified lactose to active ingredient V in a range from about 1: 1 to about 70: 1, preferably between about 1.5 : 1 to about 35: 1.
6) Tablette nach einem der Ansprüche 2 bis 5, dadurch gekennzeichnet, daß der Kern ferner ein Trockenbindemittel enthält.6) Tablet according to one of claims 2 to 5, characterized in that the core further contains a dry binder.
7) Tablette nach Anspruch 6, dadurch gekennzeichnet, daß im Kern das Gewichtsverhältnis von modifizierter Lactose zu Trockenbindemittel im Bereich von etwa 5:1 bis etwa 1 :4, bevorzugt etwa 4:1 bis etwa 1 :3 liegt.7) Tablet according to claim 6, characterized in that in the core the weight ratio of modified lactose to dry binder is in the range of about 5: 1 to about 1: 4, preferably about 4: 1 to about 1: 3.
8) Tablette nach einem der Ansprüche 2 bis 7, dadurch gekennzeichnet, daß der Kern ferner ein Zerfallsmittel enthält.8) Tablet according to one of claims 2 to 7, characterized in that the core further contains a disintegrant.
9) Tablette nach Anspruch 8, dadurch gekennzeichnet, das der Gewichtsanteil des Zerfallsmittels bezogen auf die Gesamtmasse des Kerns in einem Bereich von etwa 1 - 10 Gew% liegt. 10) Tablette nach einem der Ansprüche 2 bis 9, dadurch gekennzeichnet, daß der Kern ferner ein Fließregulierungsmittel enthält.9) Tablet according to claim 8, characterized in that the weight fraction of the disintegrant based on the total mass of the core is in a range of about 1-10% by weight. 10) Tablet according to one of claims 2 to 9, characterized in that the core further contains a flow regulating agent.
11 ) Tablette nach Anspruch 10, dadurch gekennzeichnet, das der Gewichtsanteil 5 des Fließregulierungsmittels bezogen auf die Gesamtmasse des Kerns in einem Bereich von etwa 0,1 - 5 Gew% liegt.11) Tablet according to claim 10, characterized in that the weight fraction 5 of the flow control agent based on the total mass of the core is in a range of about 0.1-5% by weight.
12) Tablette nach einem der Ansprüche 2 bis 11 , dadurch gekennzeichnet, daß der Kern ferner Fließ-, Schmier- und Trennmittel enthält.12) Tablet according to one of claims 2 to 11, characterized in that the core further contains flow, lubricant and release agents.
1010
13) Tablette nach Anspruch 12, dadurch gekennzeichnet, das der Gewichtsanteil der Fließ-, Schmier- und Trennmittels bezogen auf die Gesamtmasse des Kerns in einem Bereich von etwa 0,1 - 5 Gew% liegt.13) Tablet according to claim 12, characterized in that the weight fraction of the flow, lubricant and release agent based on the total mass of the core is in a range of about 0.1 - 5% by weight.
15 14) Tablette nach einem der Ansprüche 1 bis 13, dadurch gekennzeichnet, daß der den Kern der erfindungsgemäßen Filmtabletten umschließende Film als einen wesentlichen Bestandteil einen Filmbildner, der ausgewählt ist aus Hydroxypropylmethylcellulose, Hydroxypropylcellulose, Methylcellulose, Hydroxymethylcellulose, Hydroxyethylcellulose,15 14) Tablet according to one of claims 1 to 13, characterized in that the film surrounding the core of the film tablets according to the invention as an essential component a film former which is selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose,
20 Poly(ethylacrylat)methylmethacrylat, beispielsweise in Form von Eudragit NE20 poly (ethyl acrylate) methyl methacrylate, for example in the form of Eudragit NE
30 D, Eudragit RL 30 D, Eudragit E 12.5 und Gemische dieser Filmbildner enthält.30 D, Eudragit RL 30 D, Eudragit E 12.5 and mixtures of these film formers.
15) Tablette nach Anspruch 14, dadurch gekennzeichnet daß der Gewichtsanteil 5 an Filmbildner bezogen auf die Gesamtmasse des Filmüberzugs der erfindungsgemäßen Filmtablette in einem Bereich von etwa 20 - 95 Gew% liegt.15) Tablet according to claim 14, characterized in that the weight fraction 5 of film former based on the total mass of the film coating of the film-coated tablet according to the invention is in a range of about 20-95% by weight.
16) Tablette nach einem der Ansprüche 14 oder 15, dadurch gekennzeichnet, daß 0 der Filmüberzug als weiteren Bestandteil Emulgatoren und Weichmacher enthält.16) Tablet according to one of claims 14 or 15, characterized in that 0 contains the film coating as a further component emulsifiers and plasticizers.
17) Tablette nach Anspruch 16, dadurch gekennzeichnet, daß der Gewichtsanteil an Weichmacher bezogen auf die Gesamtmasse des Filmüberzugs in einem 5 Bereich von etwa 1 - 30 Gew% liegt. 17) Tablet according to claim 16, characterized in that the proportion by weight of plasticizer, based on the total mass of the film coating, is in a range from about 1 to 30% by weight.
PCT/EP2002/001374 2001-02-15 2002-02-09 Medicament formulation containing a muscarinic agonist WO2002064124A2 (en)

Priority Applications (5)

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CA002434976A CA2434976A1 (en) 2001-02-15 2002-02-09 Medicament formulation containing a muscarinic agonist
JP2002563919A JP2004518710A (en) 2001-02-15 2002-02-09 Pharmaceutical formulations containing muscarinic agonists
MXPA03007272A MXPA03007272A (en) 2001-02-15 2002-02-09 Medicament formulation containing a muscarinic agonist.
AU2002247705A AU2002247705A1 (en) 2001-02-15 2002-02-09 Medicament formulation containing a muscarinic agonist
EP02716755A EP1361871A2 (en) 2001-02-15 2002-02-09 Medicament formulation containing a muscarinic agonist

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DE10106971A DE10106971A1 (en) 2001-02-15 2001-02-15 Drug formulation containing a muscarinic agonist
DE10106971.5 2001-02-15

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DE (1) DE10106971A1 (en)
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2140867A1 (en) * 2007-03-29 2010-01-06 Daiichi Sankyo Company, Limited Pharmaceutical composition
WO2010033045A1 (en) * 2008-09-16 2010-03-25 Igor Anatolievich Pomytkin Compositions and methods for prevention or treatment of beta amyloid deposition
US9402907B2 (en) 2011-08-10 2016-08-02 Daiichi Sankyo Company, Limited Pharmaceutical composition containing diamine derivative
US9918975B2 (en) 2010-03-19 2018-03-20 Daiichi Sankyo Company, Limited Method for improving dissolution of anticoagulant agent

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0370415A1 (en) * 1988-11-22 1990-05-30 Boehringer Ingelheim Kg Quinuclidines, their pharmaceutical use and process for their preparation
WO1998030243A1 (en) * 1997-01-08 1998-07-16 Warner-Lambert Company Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease
WO1998046225A1 (en) * 1997-04-11 1998-10-22 Eli Lilly And Company Method for treating schizophrenia
WO1998046601A1 (en) * 1997-04-11 1998-10-22 Eli Lilly And Company Composition for treating pain
DE19851126A1 (en) * 1998-11-06 2000-05-11 Boehringer Ingelheim Pharma Use of talsaclidine for treating schizophrenia

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0370415A1 (en) * 1988-11-22 1990-05-30 Boehringer Ingelheim Kg Quinuclidines, their pharmaceutical use and process for their preparation
WO1998030243A1 (en) * 1997-01-08 1998-07-16 Warner-Lambert Company Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease
WO1998046225A1 (en) * 1997-04-11 1998-10-22 Eli Lilly And Company Method for treating schizophrenia
WO1998046601A1 (en) * 1997-04-11 1998-10-22 Eli Lilly And Company Composition for treating pain
DE19851126A1 (en) * 1998-11-06 2000-05-11 Boehringer Ingelheim Pharma Use of talsaclidine for treating schizophrenia

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2140867A1 (en) * 2007-03-29 2010-01-06 Daiichi Sankyo Company, Limited Pharmaceutical composition
EP2140867A4 (en) * 2007-03-29 2013-07-03 Daiichi Sankyo Co Ltd Pharmaceutical composition
US9149532B2 (en) 2007-03-29 2015-10-06 Daiichi Sanykyo Company, Limited Pharmaceutical composition
US9707296B2 (en) 2007-03-29 2017-07-18 Daiichi Sankyo Company, Limited Pharmaceutical composition
EP2140867B1 (en) 2007-03-29 2017-08-30 Daiichi Sankyo Company, Limited Pharmaceutical composition
WO2010033045A1 (en) * 2008-09-16 2010-03-25 Igor Anatolievich Pomytkin Compositions and methods for prevention or treatment of beta amyloid deposition
US9918975B2 (en) 2010-03-19 2018-03-20 Daiichi Sankyo Company, Limited Method for improving dissolution of anticoagulant agent
US9402907B2 (en) 2011-08-10 2016-08-02 Daiichi Sankyo Company, Limited Pharmaceutical composition containing diamine derivative

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WO2002064124A3 (en) 2002-12-05
UY27170A1 (en) 2002-09-30
MXPA03007272A (en) 2003-12-04
EP1361871A2 (en) 2003-11-19
JP2004518710A (en) 2004-06-24
AR033862A1 (en) 2004-01-07
DE10106971A1 (en) 2002-08-29
CA2434976A1 (en) 2002-08-22

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