WO2000035459A1 - New solid metriphonate formulations - Google Patents

New solid metriphonate formulations Download PDF

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Publication number
WO2000035459A1
WO2000035459A1 PCT/EP1999/009769 EP9909769W WO0035459A1 WO 2000035459 A1 WO2000035459 A1 WO 2000035459A1 EP 9909769 W EP9909769 W EP 9909769W WO 0035459 A1 WO0035459 A1 WO 0035459A1
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Prior art keywords
pharmaceutical formulation
metrifonate
solid pharmaceutical
microcrystalline cellulose
formulation according
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PCT/EP1999/009769
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German (de)
French (fr)
Inventor
Fritz Schückler
Karl Geisen
Johanna Berberich
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Bayer Aktiengesellschaft
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Priority to AU30369/00A priority Critical patent/AU3036900A/en
Publication of WO2000035459A1 publication Critical patent/WO2000035459A1/en

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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to new solid preparations of metrifonate which have high stability and at the same time have improved tableting or tablet properties, and to processes for their preparation and use.
  • Metrifonate also known as Dipterex
  • Metrifonate is suitable, among other things. for the treatment of diseases of the central nervous system such as Alzheimer's disease, schizophrenia, depression, dyskinesia tarditiva, amnesia after electroconvulsive therapy, snoring or sleep apnea.
  • the substance has long been used in the treatment of schistosomiasis.
  • WO 96/38155 also mentions metrifonate as a precursor in the therapy of diseases of the central nervous system.
  • US 3,111,457 discloses oral administration of metrifonate to internal parasitic animals, particularly horses. It has been found that the addition of approximately up to 30% by weight of aluminum hydroxide to the orally administered active ingredient produces a retarding effect and the active ingredient thereby exhibits less toxicity.
  • German Offenlegungsschrift 25 43 975 describes solid metrifonate preparations with a cellulose content of 22 to 25% by weight. These solid preparations are only stable against rearrangement or other types of decomposition if buffer substances such as calcium hydrogen phosphate or disodium hydrogen phosphate which increase the pH are added, so that an aqueous dispersion generated from this preparation has a pH of 6.5-7.5 Has. The water content of this solid
  • the preparation must not exceed 2.5% by weight.
  • a composition of the acetylcholinesterase inhibitor galantamine which is structurally unrelated to metrifonate and contains microcrystalline cellulose and acts against rheumatic diseases is disclosed in WO 97/29750.
  • microcrystalline cellulose contains up to 6% by weight of water and has a pH of at least pH 5 (information and method according to 'European Pharmacopoeia, Official German Edition; 3rd Edition, Deutscher maschiner Verlag, Stuttgart, 1997; p.665 -666.)
  • Cellulose is increased to over 50 wt .-% based on the total weight of the preparation. This increases the water content in the solid pharmaceutical preparation to values greater than 2.5% by weight and the pH can drop below the limit of pH 6.5 described in the prior art.
  • Material properties of solid pharmaceutical preparations containing metrifonate according to the invention are, for example, tablet properties such as breaking strength, hardness and mechanical strength of tablets, such as e.g. Abrasion.
  • Formulation properties according to the invention are, for example, the flowability of powders, from which e.g. Tablets can be pressed.
  • the stability of the active ingredient means the stability of metrifonate in the solid pharmaceutical preparation, in particular against rearrangement to DDVP.
  • a pharmaceutical preparation according to the invention should, for example, be regarded as stable if the metrifonate content of this pharmaceutical preparation does not fall below 92.5% by weight of the starting content under standard storage conditions (e.g. 25 ° C., 60% relative atmospheric humidity, 3 years, packed in glass bottles) and the DDVP content not higher than 0.3% by weight based on the declared
  • Metrifonate content in the pharmaceutical preparation increases.
  • Solid pharmaceutical formulations in the sense of the invention are tablets, capsules, dragees, powders and granules, preferably tablets.
  • solid drug formulations can be prepared in a known manner using other inert, non-toxic, pharmaceutically acceptable additives such as e.g. Cellulose derivatives (e.g. methyl cellulose), starch, polyvinylpyrrolidone, synthetic rock flour (e.g. highly disperse silica, silicates); Sugar (e.g. cane, milk and dextrose), sugar alcohols (e.g.
  • Mannitol, sorbitol, xylitol e.g. sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone
  • lubricants eg magnesium stearate, talc, stearic acid
  • flavors e.g. magnesium stearate, talc, stearic acid
  • Preferred pharmaceutical formulations according to the invention are those whose microcrystalline cellulose content is between 60 and 90% by weight.
  • the proportion by weight of metrifonate in the total weight of the pharmaceutical formulation is less than 50% by weight, preferably 7-38.5% by weight.
  • the proportion by weight of the additives in the total weight of the pharmaceutical formulation is 0 to 5%, preferably 1.5 to 3%.
  • Solid pharmaceutical formulations which do not contain buffer salts are particularly preferred.
  • Buffer salts in the sense of the invention are, for example, calcium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate or dipotassium hydrogen phosphate, alkali and alkaline earth metal citrates and acetates, alkali metal, alkaline earth metal and ammonium carbonates, or sodium and ammonium chloride.
  • the solid drug formulations are suitable for the manufacture of drugs that can be used to treat diseases of the central nervous system, such as Alzheimer's disease, schizophrenia, depression, dyskinesia tarditiva, amnesia after electroconvulsive therapy, snoring or sleep apnea.
  • diseases of the central nervous system such as Alzheimer's disease, schizophrenia, depression, dyskinesia tarditiva, amnesia after electroconvulsive therapy, snoring or sleep apnea.
  • These drugs are preferably used to treat Alzheimer's disease.
  • the solid preparations according to the invention have excellent long-term chemical stability. After 2 years of storage of a solid preparation of the composition according to Example 1 under standardized climatic conditions (see, for example, 'The United States Pharmacopeia, The National Formulary'; United States Pharmacopeial Convention, Rockville, 1995; pp. 1940-1941), the active substance content is practically unchanged. The degradation product DDVP remains at very low values over the entire course and does not increase.
  • the following table serves to illustrate the stability of Example 1:
  • Tablet strength in the sense of the invention is described in J.Pharmaceut. Be. 1970, 59, 688-91.
  • Friability is less than 1%, preferably less than 0.5%.
  • Friability within the meaning of the invention can be determined using the method described in 'The United States Pharmacopeia, The National Formulary'; United States Pharmaceutical Convention, Rockville, 1995; S. 1981 (USP XXIII).
  • the Bilarcil TM formulation is composed of [% by weight] 62.50 metrifonate, 21.25 microcrystalline cellulose, 12.50 calcium hydrogen phosphate, 1.875 disodium hydrogen phosphate, 1.875 sodium carboxymethyl cellulose
  • Metrifonate is sieved and mixed with other excipients in the following quantities:
  • the mixture is granulated by means of dry compaction (e.g. with a roller compactor) and subsequent comminution (sieve with a mesh size of 1.0 mm).
  • the mixture is then pressed into tablets, e.g. weighing 333 mg (tablet diameter 9 mm).
  • the weight percentages of metrifonate and cellulose are therefore 30.0% and 67.75%, respectively.
  • Typical values for pH and water content of tablets according to the above composition are (measured immediately after manufacture; the pH of a dispersion of the formulation was measured in a 10-fold excess by weight of distilled, non-carbonated Water at 25 ° C):
  • Magnesium stearate 0.25 kg is processed into tablets, for example with a weight of 800 mg (tablet diameter 13 mm), the preparation taking place as described in Examples 1, 2 or 3.
  • the weight percentages of metrifonate and cellulose are therefore 12.5% and 85.25%, respectively.
  • the tablet is coated with a lacquer layer which has the following composition:
  • Color pigments titanium dioxide, iron oxide 20%.
  • the amount of lacquer applied is 2 - 3 mg / cm 2 .

Abstract

The invention relates to new solid metriphonate preparations which contain more than 50 % by weight microcrystalline cellulose and present high stability and improved tabletting and tablet properties. The invention further relates to methods for producing said preparations and to their use.

Description

Neue feste Formulierung von MetrifonatNew solid formulation of metrifonate
Die vorliegende Erfindung betrifft neue feste Zubereitungen von Metrifonat, die eine hohe Stabilität und gleichzeitig verbesserte Tablettier- bzw. Tabletteneigenschaften besitzen, sowie Verfahren zu deren Herstellung und Verwendung.The present invention relates to new solid preparations of metrifonate which have high stability and at the same time have improved tableting or tablet properties, and to processes for their preparation and use.
Metrifonat (auch als Dipterex bekannt) eignet sich u.a. zur Behandlung von Erkrankungen des zentralen Nervensystems wie z.B. Alzheimersche Krankheit, Schizophrenie, Depression, Dyskinesia tarditiva, Amnesie nach Elektrokonvulsionstherapie, Schnarchen oder Schlafapnoe. Darüber hinaus wird die Substanz seit längerem bei der Behandlung der Bilharziose eingesetzt.Metrifonate (also known as Dipterex) is suitable, among other things. for the treatment of diseases of the central nervous system such as Alzheimer's disease, schizophrenia, depression, dyskinesia tarditiva, amnesia after electroconvulsive therapy, snoring or sleep apnea. In addition, the substance has long been used in the treatment of schistosomiasis.
So beschreibt die US-4,950,658 eine in vzvo-Studie, in welcher Metrifonat als Precursor-Substanz zur Behandlung der Alzheimerschen Krankheit eingesetzt wird. Eine Aussage über die Zusammensetzung der durch Injektion und oral verabreichtenFor example, US Pat. No. 4,950,658 describes an in vzvo study in which metrifonate is used as a precursor substance for the treatment of Alzheimer's disease. A statement on the composition of those administered by injection and orally
Formulierungen ist dieser Schrift nicht zu entnehmen.No formulations can be found in this document.
Auch die WO 96/38155 nennt Metrifonat als Precursor bei der Therapie von Erkrankungen des zentralen Nervensystems.WO 96/38155 also mentions metrifonate as a precursor in the therapy of diseases of the central nervous system.
Die Anwendung von Metrifonat und einer Vielzahl weiterer Cholinesterasehemmer bei Schlafstörungen ist in der WO 97/22339 beschrieben.The use of metrifonate and a large number of other cholinesterase inhibitors for sleep disorders is described in WO 97/22339.
Die US-3,111,457 offenbart die orale Verabreichung von Metrifonat an durch innere Parasiten befallene Tiere, insbesondere Pferde. Es wurde gefunden, daß ein Zusatz von etwa bis zu 30 Gew.-% Aluminiumhydroxid zum oral verabreichen Wirkstoff eine retardierende Wirkung hervorruft und der Wirkstoff dadurch geringere Toxizität entfaltet.US 3,111,457 discloses oral administration of metrifonate to internal parasitic animals, particularly horses. It has been found that the addition of approximately up to 30% by weight of aluminum hydroxide to the orally administered active ingredient produces a retarding effect and the active ingredient thereby exhibits less toxicity.
Es ist bekannt, daß sich Metrifonat abhängig von Feuchtigkeit, pH-Wert und/oderIt is known that metrifonate is dependent on moisture, pH and / or
Temperatur zu DDVP [Dimethyl-(2,2-dichlorvinyl)phosphat] umlagert. In der Z. Naturforschg. B Y2 (1957) S.196ff wurde im Rahmen der Untersuchung insektizid wirkender Phosphorsäureester der Zerfall von Metrifonat zu DDVP in Abhängigkeit vom pH- Wert beschrieben. Es wurde gefunden, daß ein derartiger Zerfall nur im pH- Wertbereich von pH 1 bis 5 vermieden werden kann.Temperature rearranged to DDVP [dimethyl (2,2-dichlorovinyl) phosphate]. In the Z. Naturforschg. B Y2 (1957) pp.196ff, the decay of metrifonate to DDVP as a function of pH was described as part of the study of insecticidal phosphoric acid esters. It has been found that such disintegration can only be avoided in the pH range from pH 1 to 5.
1959 beschrieben hierzu Metcalf und Fukuto im J. Economic Entomology 52(1) (1959) S. 44 ff. den Zusammenhang der Umsetzung von Metrifonat zu DDVP und der in v/Yro-Hemmung der Cholinesterase am Modell der Stubenfliege.In 1959, Metcalf and Fukuto in J. Economic Entomology 52 (1) (1959) p. 44 ff. Described the connection between the conversion of metrifonate to DDVP and the in v / yro inhibition of cholinesterase using the housefly model.
Die Deutsche Offenlegungsschrift 25 43 975 beschreibt feste Metrifonat-Zuberei- tungen mit einem Celluloseanteil von 22 bis 25 Gew.-%. Diese festen Zubereitungen sind nur dann stabil gegen Umlagerung oder andersartige Zersetzung, wenn den pH- Wert erhöhende Puffersubstanzen wie Calciumhydrogenphosphat oder Dinatriumhy- drogenphosphat zugegeben werden, so daß eine aus dieser Zubereitung generierte wäßrige Dispersion einen pH- Wert von 6,5 - 7,5 hat. Der Wassergehalt dieser festenGerman Offenlegungsschrift 25 43 975 describes solid metrifonate preparations with a cellulose content of 22 to 25% by weight. These solid preparations are only stable against rearrangement or other types of decomposition if buffer substances such as calcium hydrogen phosphate or disodium hydrogen phosphate which increase the pH are added, so that an aqueous dispersion generated from this preparation has a pH of 6.5-7.5 Has. The water content of this solid
Zubereitung darf jedoch aus Stabilitätsgründen 2,5 Gew.-% nicht überschreiten.However, for reasons of stability, the preparation must not exceed 2.5% by weight.
Eine mikrokristalline Cellulose enthaltende, gegen rheumatische Erkrankungen wirkende Zusammensetzung des strukturell nicht mit Metrifonat verwandten Acetyl- cholinesterasehemmers Galantamin, ist in der WO 97/29750 offenbart.A composition of the acetylcholinesterase inhibitor galantamine which is structurally unrelated to metrifonate and contains microcrystalline cellulose and acts against rheumatic diseases is disclosed in WO 97/29750.
Bekanntermaßen enthält mikrokristalline Cellulose bis zu 6 Gew.-% Wasser und besitzt einen pH- Wert von minimal pH 5 (Angaben und Methode nach 'Europäisches Arzneibuch, Amtliche deutsche Ausgabe; 3. Ausgabe, Deutscher Apotheker Verlag, Stuttgart, 1997; S.665-666.)As is known, microcrystalline cellulose contains up to 6% by weight of water and has a pH of at least pH 5 (information and method according to 'European Pharmacopoeia, Official German Edition; 3rd Edition, Deutscher Apotheker Verlag, Stuttgart, 1997; p.665 -666.)
Überraschenderweise wurde nun gefunden, daß die Stabilität von Metrifonat in festenSurprisingly, it has now been found that the stability of metrifonate in solid
Arzneimittelzubereitungen gleichbleibt, auch wenn der Anteil an mikrokristallinerPharmaceutical preparations remain the same, even if the proportion of microcrystalline
Cellulose auf über 50 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung erhöht wird. Damit steigt der Wassergehalt in der festen Arzneizubereitung auf Werte von größer als 2,5 Gew.-% und der pH- Wert kann unter die im Stand der Technik beschriebene Grenze von pH 6,5 fallen.Cellulose is increased to over 50 wt .-% based on the total weight of the preparation. This increases the water content in the solid pharmaceutical preparation to values greater than 2.5% by weight and the pH can drop below the limit of pH 6.5 described in the prior art.
Durch die Erhöhung des Anteils an mikrokristalliner Cellulose werden aber die Stoff- und Formuliereigenschaften deutlich verbessert.However, increasing the proportion of microcrystalline cellulose significantly improves the properties of the fabric and formulation.
Erfindungsgemäße Stoffeigenschaften von Metrifonat enthaltenden, festen Arzneimittelzubereitungen sind beispielsweise Tabletteneigenschaften wie Bruchfestigkeit, Härte und mechanische Festigkeit von Tabletten, wie z.B. Abrieb.Material properties of solid pharmaceutical preparations containing metrifonate according to the invention are, for example, tablet properties such as breaking strength, hardness and mechanical strength of tablets, such as e.g. Abrasion.
Erfindungsgemäße Formuliereigenschaften sind beispielsweise die Fließfähigkeit von Pulvern, aus denen z.B. Tabletten gepreßt werden können.Formulation properties according to the invention are, for example, the flowability of powders, from which e.g. Tablets can be pressed.
Unter Stabilität des Wirkstoffs wird die Stabilität von Metrifonat in der festen Arzneimittelzubereitung insbesondere gegen Umlagerung zu DDVP verstanden.The stability of the active ingredient means the stability of metrifonate in the solid pharmaceutical preparation, in particular against rearrangement to DDVP.
Eine erfindungsgemäße Arzneimittelzubereitung soll beispielsweise dann als stabil angesehen werden, wenn unter Standardlagerungsbedingungen (z.B. 25°C, 60% relative Luftfeuchte, 3 Jahre, verpackt in Glasflaschen) der Metrifonatgehalt dieser Arzneimittelzubereitung nicht unter 92,5 Gew.-% des Ausgangsgehaltes sinkt und der DDVP-Gehalt nicht höher als auf 0,3 Gew.-% bezogen auf den deklariertenA pharmaceutical preparation according to the invention should, for example, be regarded as stable if the metrifonate content of this pharmaceutical preparation does not fall below 92.5% by weight of the starting content under standard storage conditions (e.g. 25 ° C., 60% relative atmospheric humidity, 3 years, packed in glass bottles) and the DDVP content not higher than 0.3% by weight based on the declared
Metrifonatgehalt in der Arzneimittelzubereitung steigt.Metrifonate content in the pharmaceutical preparation increases.
Feste Arzneimittelformulierungen im Sinne der Erfindung sind Tabletten, Kapseln, Dragees, Pulver und Granulate, bevorzugt Tabletten.Solid pharmaceutical formulations in the sense of the invention are tablets, capsules, dragees, powders and granules, preferably tablets.
Diese festen Arzneimittelformulierungen können in bekannter Weise hergestellt werden, unter Verwendung weiterer inerter, nicht-toxischer, pharmazeutisch geeigneter Zuschlagstoffe, wie z.B. Cellulosederivate (z.B. Methylcellulose), Stärke, Polyvinylpyrrolidon, synthetische Gesteinsmehle (z.B. hochdisperse Kieselsäure, Silikate); Zucker (z.B. Rohr-, Milch- und Traubenzucker), Zuckeralkohole (z.B.These solid drug formulations can be prepared in a known manner using other inert, non-toxic, pharmaceutically acceptable additives such as e.g. Cellulose derivatives (e.g. methyl cellulose), starch, polyvinylpyrrolidone, synthetic rock flour (e.g. highly disperse silica, silicates); Sugar (e.g. cane, milk and dextrose), sugar alcohols (e.g.
Mannitol, Sorbitol, Xylitol), Sprengmittel (z.B. Natriumcarboxymethylcellulose, quervernetztes Polyvinylpyrrolidon), Schmiermittel (z.B. Magnesiumstearat, Talkum, Stearinsäure), Aromen, Farbstoffe und Geschmackskorrigenzien.Mannitol, sorbitol, xylitol), disintegrants (e.g. sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone), lubricants (eg magnesium stearate, talc, stearic acid), flavors, colorants and taste corrections.
Bevorzugt sind erfindungsgemäße Arzneimittelformulierungen, deren Anteil an mikrokristalliner Cellulose zwischen 60 und 90 Gew.-% beträgt.Preferred pharmaceutical formulations according to the invention are those whose microcrystalline cellulose content is between 60 and 90% by weight.
Der Gewichtsanteil von Metrifonat am Gesamtgewicht der Arzneimittelformulierung beträgt weniger als 50 Gew.-%, bevorzugt 7 - 38,5 Gew.-%.The proportion by weight of metrifonate in the total weight of the pharmaceutical formulation is less than 50% by weight, preferably 7-38.5% by weight.
Der Gewichtsanteil der Zuschlagstoffe am Gesamtgewicht der Arzneimittelformulierung beträgt 0 bis 5 %, bevorzugt 1 ,5 bis 3 %.The proportion by weight of the additives in the total weight of the pharmaceutical formulation is 0 to 5%, preferably 1.5 to 3%.
Besonders bevorzugt sind solche festen Arzneimittelformulierungen, die keine Puffersalze enthalten.Solid pharmaceutical formulations which do not contain buffer salts are particularly preferred.
Puffersalze im Sinne der Erfindung sind beispielsweise Calciumhydrogenphosphat, Natriumdihydrogenphosphat, Dinatriumhydrogenphosphat, Kaliumdihydrogen- phosphat oder Dikaliumhydrogenphosphat, Alkali- und Erdalkalicitrate und -acetate, Alkali-, Erdalkali- und Ammoniumcarbonate, oder Natrium- und Ammoniumchlorid.Buffer salts in the sense of the invention are, for example, calcium hydrogen phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate or dipotassium hydrogen phosphate, alkali and alkaline earth metal citrates and acetates, alkali metal, alkaline earth metal and ammonium carbonates, or sodium and ammonium chloride.
Die festen Arzneimittelformulierungen eignen sich zur Herstellung von Medikamenten, die zur Behandlung von Erkrankungen des zentralen Nervensystems eingesetzt werden können, wie z.B. der Alzheimerschen Krankheit, Schizophrenie, Depression, Dyskinesia tarditiva, Amnesie nach Elektrokonvulsionstherapie, Schnarchen oder Schlafapnoe.The solid drug formulations are suitable for the manufacture of drugs that can be used to treat diseases of the central nervous system, such as Alzheimer's disease, schizophrenia, depression, dyskinesia tarditiva, amnesia after electroconvulsive therapy, snoring or sleep apnea.
Bevorzugt werden diese Medikamente zur Behandlung der Alzheimerschen Krankheit eingesetzt.These drugs are preferably used to treat Alzheimer's disease.
Die erfindungsgemäßen festen Zubereitungen besitzen eine ausgezeichnete chemische Langzeitstabilität. Nach 2 Jahren Lagerung einer festen Zubereitung der Zusammensetzung gemäß Beispiel 1 unter standardisierten Klimabedingungen (siehe z.B. 'The United States Pharmacopeia, The National Formulary'; United States Pharmacopeial Convention, Rockville, 1995; S. 1940 - 1941) ist der Wirkstoffgehalt praktisch unverändert. Das Abbauprodukt DDVP bleibt über den gesamten Verlauf bei sehr niedrigen Werten und erhöht sich nicht. Zur Verdeutlichung der Stabilität von Beispiel 1 dient folgende Tabelle:The solid preparations according to the invention have excellent long-term chemical stability. After 2 years of storage of a solid preparation of the composition according to Example 1 under standardized climatic conditions (see, for example, 'The United States Pharmacopeia, The National Formulary'; United States Pharmacopeial Convention, Rockville, 1995; pp. 1940-1941), the active substance content is practically unchanged. The degradation product DDVP remains at very low values over the entire course and does not increase. The following table serves to illustrate the stability of Example 1:
Figure imgf000007_0001
Figure imgf000007_0001
!) Bestimmung mit HPLC-Methode analog 'Europäisches Arzneibuch, Amtliche deutsche Ausgabe; 3. Ausgabe, Deutscher Apotheker Verlag, Stuttgart, 1997; S.1293-5 !) Determination with HPLC method analogous to 'European Pharmacopoeia, Official German Edition; 3rd edition, Deutscher Apotheker Verlag, Stuttgart, 1997; P.1293-5
2) rF = relative Luftfeuche 2) RH = relative humidity
Bei einer festen Zubereitung von Metrifonat gemäß Beispiel 4 sind nach 3 JahrenWith a solid preparation of metrifonate according to Example 4, after 3 years
Lagerung bei 25°C, 60% rF noch 97,3 % des Wirkstoffs unverändert wiederzufinden; der DDVP-Anteil beträgt 0,02 %.Storage at 25 ° C, 60% rh still 97.3% of the active ingredient unchanged; the DDVP share is 0.02%.
Besonders hervorzuheben sind jedoch auch die hervorragenden pharmazeutisch- technologischen Eigenschaften der erfindungsgemäßen festen Formulierungen vonOf particular note, however, are the excellent pharmaceutical and technological properties of the solid formulations of
Metrifonat. Verglichen mit den Metrifonat-Tablettenzubereitungen, die in der Deutschen Offen- legungsschrift 25 43 975 beschrieben werden, ergeben sich beispielsweise 2- bis 3- mal größere Tablettenfestigkeiten (Angabe als "tensile strength") und Friabilitäten, die 1/10 und noch weniger betragen. Es zeigt sich sogar, daß die Anforderungen der USP XXIII zur Friabilität (< 1 %; 'The United States Pharmacopeia, The NationalMetrifonate. Compared with the metrifonate tablet preparations described in German Offenlegungsschrift 25 43 975, there are, for example, 2 to 3 times greater tablet strengths (specified as "tensile strength") and friability levels that are 1/10 or less . It even shows that the requirements of USP XXIII on friability (<1%;'The United States Pharmacopeia, The National
Formulary'; United States Pharmacopeial Convention, Rockville, 1995; S. 1981) nur von den erfindungsgemäßen neuen Metrifonat-Formulierungen gehalten werden können.Formulary '; United States Pharmacopeial Convention, Rockville, 1995; S. 1981) can only be kept by the new metrifonate formulations according to the invention.
Bevorzugt sind solche Tabletten, die eine Tablettenfestigkeit (tensile strength) von mehr als 4,0 N/mm2 aufweisen.Preference is given to tablets which have a tensile strength of more than 4.0 N / mm 2 .
Tablettenfestigkeit (tensile strength) im Sinne der Erfindung wird beschrieben in J.Pharmaceut. Sei. 1970, 59, 688-91.Tablet strength (tensile strength) in the sense of the invention is described in J.Pharmaceut. Be. 1970, 59, 688-91.
Ebenso sind solche erfindungsgemäßen Tablettenformulierungen bevorzugt, derenLikewise preferred are tablet formulations according to the invention whose
Friabilität weniger als 1 %, vorzugsweise weniger als 0,5 % beträgt.Friability is less than 1%, preferably less than 0.5%.
Friabilität im Sinne der Erfindung kann nach der Methode bestimmt werden, die in 'The United States Pharmacopeia, The National Formulary'; United States Pharma- copeial Convention, Rockville, 1995; S. 1981 (USP XXIII) beschrieben wird.Friability within the meaning of the invention can be determined using the method described in 'The United States Pharmacopeia, The National Formulary'; United States Pharmaceutical Convention, Rockville, 1995; S. 1981 (USP XXIII).
Die folgende Tabelle zeigt Beispiele, in denen Tabletten mit einem Wirkstoffgehalt von 50 mg und 100 mg verglichen werden. (Tablettierung mittels einer Standard- Exzentertablettenpresse unter jeweils optimierten Bedingungen.)
Figure imgf000009_0001
The following table shows examples in which tablets with an active substance content of 50 mg and 100 mg are compared. (Tableting using a standard eccentric tablet press under optimized conditions.)
Figure imgf000009_0001
1) die Bilarcil™-Formulierung setzt sich zusammen aus [Gew.-%] 62,50 Metrifonat, 21,25 Mikrokristalline Cellulose, 12,50 Calciumhydrogenphosphat, 1,875 Di- natriumhydrogenphosphat, 1,875 Natriumcarboxymethylcellulose 1) The Bilarcil ™ formulation is composed of [% by weight] 62.50 metrifonate, 21.25 microcrystalline cellulose, 12.50 calcium hydrogen phosphate, 1.875 disodium hydrogen phosphate, 1.875 sodium carboxymethyl cellulose
2) bestimmt nach J. Pharmaceut. Sei. 1970, 59, 688-91. 2) determined according to J. Pharmaceut. Be. 1970, 59, 688-91.
3) bestimmt nach 'The United States Pharmacopeia, The National Formulary'; United States Pharmacopeial Convention, Rockville, 1995; S. 1981 (USP XXIII) Herstellungsbeispiele 3) determined according to 'The United States Pharmacopeia, The National Formulary'; United States Pharmacopeial Convention, Rockville, 1995; P. 1981 (USP XXIII) Manufacturing examples
Beispiel 1example 1
Metrifonat wird gesiebt und in folgenden Mengen mit weiteren Hilfsstoffen gemischt:Metrifonate is sieved and mixed with other excipients in the following quantities:
Metrifonat 30,0 kgMetrifonate 30.0 kg
Mikrokristalline Cellulose 28,8 kg Natriumcarboxymethylcellulose 1,2 kgMicrocrystalline cellulose 28.8 kg sodium carboxymethyl cellulose 1.2 kg
Die Mischung wird mittels Trockenkompaktierung (z.B. mit einem Walzenkompaktor) und anschließender Zerkleinerung (Sieb mit Maschenweite 1 ,0 mm) granuliert.The mixture is granulated by means of dry compaction (e.g. with a roller compactor) and subsequent comminution (sieve with a mesh size of 1.0 mm).
Zu diesem Granulat werden weiterhin gegeben und gemischt:The following are further added to these granules and mixed:
Mikrokristalline Cellulose 38,95 kgMicrocrystalline cellulose 38.95 kg
Natriumcarboxymethylcellulose 0,80 kgSodium carboxymethyl cellulose 0.80 kg
Magnesiumstearat 0,25 kg.Magnesium stearate 0.25 kg.
Anschließend wird die Mischung zu Tabletten gepreßt, z.B. mit einem Gewicht von 333 mg (Tablettendurchmesser 9 mm).The mixture is then pressed into tablets, e.g. weighing 333 mg (tablet diameter 9 mm).
Die Gewichtsanteile von Metrifonat und Cellulose betragen demnach 30,0 % bzw. 67,75 %.The weight percentages of metrifonate and cellulose are therefore 30.0% and 67.75%, respectively.
Typische Werte für pH und Wassergehalt von Tabletten gemäß obengenannter Zusammensetzung (Masse 167 mg, entsprechend 50 mg Metrifonat pro Tablette) sind (gemessen unmittelbar nach Herstellung; gemessen wurde der pH- Wert einer Dispersion der Formulierung in einem 10-fachen Gewichtsüberschuß von destilliertem, kohlensäurefreiem Wasser bei 25°C):
Figure imgf000011_0001
Typical values for pH and water content of tablets according to the above composition (mass 167 mg, corresponding to 50 mg metrifonate per tablet) are (measured immediately after manufacture; the pH of a dispersion of the formulation was measured in a 10-fold excess by weight of distilled, non-carbonated Water at 25 ° C):
Figure imgf000011_0001
Beispiel 2Example 2
Wie Beispiel 1, jedoch werden alle Komponenten zusammengemischt und direkt zu Tabletten verarbeitet.Like example 1, but all components are mixed together and processed directly into tablets.
Metrifonat 30,00 kgMetrifonate 30.00 kg
Mikrokristalline Cellulose 67,75 kgMicrocrystalline cellulose 67.75 kg
Natriumcarboxymethylcellulose 2,00 kgSodium carboxymethyl cellulose 2.00 kg
Magnesiumstearat 0,25 kg.Magnesium stearate 0.25 kg.
Beispiel 3Example 3
Wie Beispiel 2, jedoch werden alle Komponenten - mit Ausnahme von Magnesiumstearat - gemischt, per Trockenkompaktierung und anschließender Zerkleinerung granuliert. Nach Zumischung von Magnesiumstearat wird tablettiert.Like example 2, but all components - with the exception of magnesium stearate - are mixed, granulated by dry compaction and subsequent comminution. After adding magnesium stearate, the tablets are tabletted.
Beispiel 4Example 4
Die Zubereitung entsprechend folgender Zusammensetzung:The preparation according to the following composition:
Metrifonat 12,50 kgMetrifonate 12.50 kg
Mikrokristalline Cellulose 85,25 kgMicrocrystalline cellulose 85.25 kg
Natriumcarboxymethylcellulose 2,00 kgSodium carboxymethyl cellulose 2.00 kg
Magnesiumstearat 0,25 kg wird zu Tabletten verarbeitet, z.B. mit einem Gewicht 800 mg (Tablettendurchmesser 13 mm), wobei die Herstellung gemäß Beschreibung der Beispiele 1, 2 oder 3 erfolgt.Magnesium stearate 0.25 kg is processed into tablets, for example with a weight of 800 mg (tablet diameter 13 mm), the preparation taking place as described in Examples 1, 2 or 3.
Bei Herstellung entsprechend der Reihenfolge in Beispiel 1 werden zum Trocken- kompaktieren folgende Mengen verarbeitet:When manufactured according to the order in Example 1, the following quantities are processed for dry compacting:
Metrifonat 12,5 kg Mikrokristalline Cellulose 12,0 kgMetrifonate 12.5 kg microcrystalline cellulose 12.0 kg
Natriumcarboxymethylcellulose 0,5 kg.Sodium carboxymethyl cellulose 0.5 kg.
Die weitere Zugabe der Bestandteile ist wie folgt:The further addition of the components is as follows:
Mikrokristalline Cellulose 73,25 kgMicrocrystalline cellulose 73.25 kg
Natriumcarboxymethylcellulose 1,50 kg Magnesiumstearat 0,25 kg.Sodium carboxymethyl cellulose 1.50 kg magnesium stearate 0.25 kg.
Die Gewichtsanteile von Metrifonat und Cellulose betragen demnach 12,5 % bzw. 85,25 %.The weight percentages of metrifonate and cellulose are therefore 12.5% and 85.25%, respectively.
Typische Werte von Tabletten gemäß o.g. Zusammensetzung (Masse 80 mg, entsprechend 10 mg Metrifonat pro Tablette) sind beispielsweise pH = 6,7; Wassergehalt = 4,4 %. Beispiel 5Typical values of tablets according to the above composition (mass 80 mg, corresponding to 10 mg metrifonate per tablet) are, for example, pH = 6.7; Water content = 4.4%. Example 5
Wie Beispiele 1 - 4, jedoch wird die Tablette in einem weiteren Prozeßschritt mit einer Lackschicht überzogen, die folgende Zusammensetzung hat:Like Examples 1-4, but in a further process step the tablet is coated with a lacquer layer which has the following composition:
Hydroxypropylmethylcellulose 60 %Hydroxypropylmethyl cellulose 60%
Macrogol 20 %Macrogol 20%
Farbpigmente (Titandioxid, Eisenoxid) 20 %.Color pigments (titanium dioxide, iron oxide) 20%.
Die Lackauftragsmenge beträgt 2 - 3 mg/cm2. The amount of lacquer applied is 2 - 3 mg / cm 2 .

Claims

Patentansprüche: Claims:
1. Feste Arzneimittelformulierung enthaltend Metrifonat und mikrokristalline Cellulose, dadurch gekennzeichnet, daß der Anteil an mikrokristalliner Cellu- lose mehr als 50 Gew.-% bezogen auf das Gesamtgewicht der Arzneimittelformulierung beträgt.1. Solid pharmaceutical formulation containing metrifonate and microcrystalline cellulose, characterized in that the proportion of microcrystalline cellulose is more than 50% by weight, based on the total weight of the pharmaceutical formulation.
2. Feste Arzneimittelformulierung nach Anspruch 1, dadurch gekennzeichnet, daß der Anteil an mikrokristalliner Cellulose 60 bis 90 Gew.-% beträgt.2. Solid pharmaceutical formulation according to claim 1, characterized in that the proportion of microcrystalline cellulose is 60 to 90 wt .-%.
3. Feste Arzneimittelformulierung nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß diese Formulierung keine Puffersalze enthält.3. Solid pharmaceutical formulation according to claim 1 or 2, characterized in that this formulation contains no buffer salts.
4. Feste Arzneimittelformulierung nach Ansprüchen 1 bis 3, dadurch gekenn- zeichnet, daß die feste Arzneimittelformulierung eine Tablette ist.4. Solid pharmaceutical formulation according to claims 1 to 3, characterized in that the solid pharmaceutical formulation is a tablet.
5. Feste Arzneimittelformulierung nach Anspruch 4, dadurch gekennzeichnet, daß die Tablette eine Tablettenfestigkeit (tensile strength) von mehr als 4,0 N/mm2 aufweist.5. Solid pharmaceutical formulation according to claim 4, characterized in that the tablet has a tablet strength (tensile strength) of more than 4.0 N / mm 2 .
6. Feste Arzneimittelformulierung nach Anspruch 4 oder 5, dadurch gekennzeichnet, daß die Tablette eine Friabilität von weniger als 1 %, vorzugsweise weniger als 0,5 % aufweist.6. Solid pharmaceutical formulation according to claim 4 or 5, characterized in that the tablet has a friability of less than 1%, preferably less than 0.5%.
7. Verfahren zur Herstellung einer festen Arzneimittelformulierung gemäß den7. Process for the preparation of a solid pharmaceutical formulation according to
Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß Metrifonat mit mikrokristalliner Cellulose und gegebenenfalls weiteren Zuschlagstoffen kompak- tiert, zerkleinert und nach Zugabe von weiterer mikrokristalliner Cellulose und gegebenenfalls weiteren Zuschlagstoffen tablettiert wird. Claims 1 to 6, characterized in that metrifonate is compacted with microcrystalline cellulose and optionally further additives, comminuted and tabletted after addition of further microcrystalline cellulose and optionally further additives.
8. Verfahren zur Herstellung einer festen Arzneimittelformulierung gemäß den Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß Metrifonat mit mikrokristalliner Cellulose und gegebenenfalls weiteren Zuschlagstoffen gemischt und direkt tablettiert wird.8. A process for the preparation of a solid pharmaceutical formulation according to claims 1 to 6, characterized in that metrifonate is mixed with microcrystalline cellulose and optionally further additives and is tabletted directly.
9. Verfahren zur Herstellung einer festen Arzneimittelformulierung gemäß den Ansprüchen 1 bis 6, dadurch gekennzeichnet, daß Metrifonat mit mikrokristalliner Cellulose und gegebenenfalls weiteren Zuschlagstoffen kompak- tiert, zerkleinert und anschließend, gegebenenfalls nach Zumischung weiterer Zuschlagstoffe, tablettiert wird.9. A process for the preparation of a solid pharmaceutical formulation according to claims 1 to 6, characterized in that metrifonate is compacted with microcrystalline cellulose and optionally further additives, comminuted and then, optionally after admixing further additives, is tabletted.
10. Verwendung einer festen Arzneimittelformulierung gemäß Ansprüchen 1 bis 6 zur Herstellung eines Medikaments zur Behandlung von Erkrankungen des zentralen Nervensystems.10. Use of a solid pharmaceutical formulation according to claims 1 to 6 for the manufacture of a medicament for the treatment of diseases of the central nervous system.
11. Verwendung einer festen Arzneimittelformulierung gemäß den Ansprüchen 1 bis 6 zur Herstellung eines Medikaments zur Behandlung der Alzheimerschen Krankheit. 11. Use of a solid pharmaceutical formulation according to claims 1 to 6 for the manufacture of a medicament for the treatment of Alzheimer's disease.
PCT/EP1999/009769 1998-12-15 1999-12-10 New solid metriphonate formulations WO2000035459A1 (en)

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HU226642B1 (en) * 2001-12-17 2009-05-28 Egis Gyogyszergyar Nyilvanosan Amlodipine bezylate tablets having extended stability and process for producing the same

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4834977A (en) * 1987-03-06 1989-05-30 Sumitomo Chemical Company, Limited Poison bait for control of noxious insects
WO1990006122A1 (en) * 1988-12-06 1990-06-14 The Board Of Trustees Of Southern Illinois University Method of medical treatment of alzheimer's disease
US5629300A (en) * 1992-05-26 1997-05-13 Bayer Aktiengesellschaft Drug containing (-)-metriphonate
EP0879596A2 (en) * 1991-05-14 1998-11-25 Ernir Snorasson Use of cholinesterase inhibitors to reduce benzodiazepine side effects

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4834977A (en) * 1987-03-06 1989-05-30 Sumitomo Chemical Company, Limited Poison bait for control of noxious insects
WO1990006122A1 (en) * 1988-12-06 1990-06-14 The Board Of Trustees Of Southern Illinois University Method of medical treatment of alzheimer's disease
EP0879596A2 (en) * 1991-05-14 1998-11-25 Ernir Snorasson Use of cholinesterase inhibitors to reduce benzodiazepine side effects
US5629300A (en) * 1992-05-26 1997-05-13 Bayer Aktiengesellschaft Drug containing (-)-metriphonate

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