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WO2000007596A1 - Water-soluble pharmaceutical formulation for administering sildenafil - Google Patents

Water-soluble pharmaceutical formulation for administering sildenafil Download PDF

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Publication number
WO2000007596A1
WO2000007596A1 PCT/EP1999/005464 EP9905464W WO0007596A1 WO 2000007596 A1 WO2000007596 A1 WO 2000007596A1 EP 9905464 W EP9905464 W EP 9905464W WO 0007596 A1 WO0007596 A1 WO 0007596A1
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Prior art keywords
water
pharmaceutical formulation
soluble pharmaceutical
sildenafil
formulation according
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PCT/EP1999/005464
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German (de)
French (fr)
Inventor
Thomas Strüngmann
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Hexal AG
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Hexal AG
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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence

Definitions

  • the invention relates to a pharmaceutical formulation to be dissolved in water, which contains the phosphodiesterase (PDE) type 5 inhibitor sildenafil or its pharmaceutically acceptable salts as active ingredient.
  • PDE phosphodiesterase
  • Sildenafil [1- (4-ethoxy-3- (6,7-dihydro-1-methyl-7-oxo-3-propyl 1H-pyazolo (4,3-d) pyrimidin-5-yl) phenylsulfonyl) -4-methyl piperazin] is a very selective cyclic guanosine monophosphate (cGMP) -specific phosphodiesterase (PDE) type 5 inhibitor, which was developed for the treatment of both organic and psychologically related impotence.
  • cGMP cyclic guanosine monophosphate
  • PDE phosphodiesterase
  • nitric oxide NO
  • NO nitric oxide
  • cGMP cyclic guanosine monophosphate
  • Sildenafil does not have a direct relaxing effect on the erectile tissue, but it enhances the effect of the nitrogen oxide by inhibiting phosphodieseterase type 5 (PDE 5), which is responsible for the breakdown of cGMP in the erectile tissue.
  • sildenafil of the cGMP levels in the erectile tissue, so that the smooth muscles relax and the blood can penetrate into the erectile tissue.
  • the effect of sildenafil is absent at the recommended dosage but lacks sexual stimulation.
  • sildenafil has been administered orally, in the form of a tablet with an active substance content of 25 mg, 50 mg or 100 mg / day, the bioavailability being only 40%.
  • the active substance content normally administered is 50 mg / day.
  • the tablet should be taken at least one hour, and if fat foods were consumed, 1.5 hours before use. The patient's sexual behavior is therefore somewhat spontaneous, which is a very considerable limitation for them.
  • the object of the invention is to provide a pharmaceutical formulation for the use of sildenafil or its pharmaceutically acceptable salts which can be quickly dissolved in water, in order to achieve the therapeutically effective blood plasma level more quickly and to improve patient compliance by easier intake .
  • the pharmaceutical formulation to be dissolved in water should also be sugar-free.
  • the active ingredient and the sweetener are chemically compatible and are suitable for producing the desired form of the drug and the associated work steps.
  • an orally administrable, water-soluble pharmaceutical formulation which contains, as active ingredient, the phosphodiesterase (PDE) type 5 inhibitor sildenafil or its pharmaceutically acceptable salts.
  • PDE phosphodiesterase
  • Possible salts are the acid addition salts such as the hydrochlorides or the halides, sulfates, phosphates, citrates, acetates, maleates, succinates, fumarates, ascorbates and carbonates.
  • Sildenafil or its pharmaceutically acceptable salts can also be used in combination with other known active compounds, especially specific and non-specific cytochrome P450 (CYP) inhibitors.
  • CYP cytochrome P450
  • sildenafil By combining sildenafil with a CYP inhibitor such as erythromycin, cimetidine, ketoconazole, itraconazole or mibefradil, the concentration in the blood plasma is greatly increased and the breakdown or excretion is delayed. The rapid flooding is thus maintained or accelerated with a reduced amount of sildenafil.
  • a CYP inhibitor such as erythromycin, cimetidine, ketoconazole, itraconazole or mibefradil
  • the amount of sildenafil, preferably in the form of a pharmaceutically acceptable salt, which is used in the pharmaceutical formulation according to the invention to be dissolved in water, can be between 20 to 150 mg and will preferably be in the range from 25 to 100 mg per dosage unit.
  • the pharmaceutical formulation which can be quickly dissolved in water can be in the form of effervescent tablets, granules or tabs.
  • the carbonate and / or the bicarbonate of the alkali and alkaline earth metals in combination with an acid can be used as the carbon dioxide source.
  • the weight ratio of the acid to the carbonate and / or bicarbonate can be between 0.9 and 1.6.
  • sweetener in particular aspartame, cyclamate and saccharin or their sodium salts.
  • binders and lubricants fillers, surfactants, disintegrants, flavoring agents and other customary auxiliaries which are customary for these dosage forms.
  • Effervescent tablet sildenafil citrate 70.23 mg (corresponds to 50 mg sildenafil)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Gynecology & Obstetrics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention relates to a pharmaceutical formulation which can be rapidly dissolved in water and which, as an active constituent, contains the phosphodiesterase (PDE) type 5 inhibitor sildenafil or the pharmaceutically safe salts thereof.

Description

In Wasser zu lösende pharmazeutische Formulierung zur Anwendung von Pharmaceutical formulation to be dissolved in water for the application of

SildenafilSildenafil

Die Erfindung betrifft eine in Wasser zu lösende pharmazeutische Formulierung, die als aktiven Bestandteil den Phosphodiesterase (PDE)-Typ-5-Hemmer Sildenafil oder dessen pharmazeutisch unbedenkliche Salze enthält..The invention relates to a pharmaceutical formulation to be dissolved in water, which contains the phosphodiesterase (PDE) type 5 inhibitor sildenafil or its pharmaceutically acceptable salts as active ingredient.

Sildenafil [l-(4-ethoxy-3-(6,7-dihydro l-methyl-7-oxo-3-propyl lH-pyazolo(4,3-d)pyrimidin- 5-yl)phenylsulfonyl)-4-methyl piperazin] stellt einen sehr selektiven cyclischen- Guanosinmonophosphat (cGMP)-spezifιschen Phosphodiesterase (PDE)-Typ-5-Hemmer dar, der zur Behandlung sowohl von organisch als auch von psychisch bedingter Impotenz entwickelt wurde.Sildenafil [1- (4-ethoxy-3- (6,7-dihydro-1-methyl-7-oxo-3-propyl 1H-pyazolo (4,3-d) pyrimidin-5-yl) phenylsulfonyl) -4-methyl piperazin] is a very selective cyclic guanosine monophosphate (cGMP) -specific phosphodiesterase (PDE) type 5 inhibitor, which was developed for the treatment of both organic and psychologically related impotence.

Der physiologische Mechanismus der Erektion des Penis beinhaltet die Freisetzung von Stickoxid (NO) in den Schwellkörpern während der sexuellen Stimulation. NO aktiviert das Enzym Guanylatcyclase, welches für einen erhöhten Spiegel an cyclischem Guanosinmonophosphat (cGMP ) sorgt. Dieses cGMP ist dafür verantwortlich, daß sich die glatte Muskulatur der Schwellkörper entspannt und somit das Blut in die Schwellkörper eindringen kann, so daß eine Erektion (Gliedsteife) zustande kommt. Sildenafil hat keinen direkten entspannenden Effekt auf die Schwellkö ermuskulatur, sondern es verstärkt die Wirkung des Stickoxides durch eine Hemmung der Phosphodieseterase-Typ-5 (PDE 5), welche für den Abbau von cGMP in den Schwellkörpern verantwortlich ist. Falls durch sexuelle Stimulation eine Freisetzung von NO erfolgt, steigt aufgrund der Hemmung der PDE 5 durch das Sildenafil der cGMP-Spiegel in den Schwellkörpern, so daß sich die glatte Muskulatur entspannt und das Blut in die Schwellkörper eindringen kann. Die Wirkung von Sildenafil bleibt bei empfohlener Dosierung aber fehlender sexueller Stimulierung aus.The physiological mechanism of penile erection involves the release of nitric oxide (NO) in the erectile tissue during sexual stimulation. NO activates the enzyme guanylate cyclase, which ensures an increased level of cyclic guanosine monophosphate (cGMP). This cGMP is responsible for relaxing the smooth muscles of the erectile tissue and thus allowing the blood to penetrate the erectile tissue so that an erection (limb stiffness) occurs. Sildenafil does not have a direct relaxing effect on the erectile tissue, but it enhances the effect of the nitrogen oxide by inhibiting phosphodieseterase type 5 (PDE 5), which is responsible for the breakdown of cGMP in the erectile tissue. If sexual stimulation releases NO, the inhibition increases PDE 5 through the sildenafil of the cGMP levels in the erectile tissue, so that the smooth muscles relax and the blood can penetrate into the erectile tissue. The effect of sildenafil is absent at the recommended dosage but lacks sexual stimulation.

Bisher erfolgt die Verabreichung von Sildenafil oral, in Form einer Tablette mit einem Wirkstoffgehalt von 25 mg, 50 mg oder 100 mg/ Tag, wobei die Bioverfügbarkeit bei nur 40% liegt. Der im Normalfall verabreichte Wirkstoffgehalt beträgt 50 mg/ Tag. Die Tablette sollte, um ihre volle Wirkung zu zeigen, mindestens eine Stunde, bei vorherigem Verzehr von fetten Lebensmitteln 1 ,5 Stunden vor Bedarf eingenommen werden. Das sexuelle Verhalten der Patienten entbehrt somit einer gewissen Spontaneität, was eine doch sehr beträchtliche Einschränkung für diese darstellt.So far, sildenafil has been administered orally, in the form of a tablet with an active substance content of 25 mg, 50 mg or 100 mg / day, the bioavailability being only 40%. The active substance content normally administered is 50 mg / day. To be fully effective, the tablet should be taken at least one hour, and if fat foods were consumed, 1.5 hours before use. The patient's sexual behavior is therefore somewhat spontaneous, which is a very considerable limitation for them.

Die Patienten-Compliance spielt heutzutage eine sehr wichtige Rolle. Der Nachteil der gängigen oralen Darreichungsformen besteht darin, daß ein Großteil der Patienten unfähig ist, diese zu schlucken bzw. ein großer Widerwille gegen diese Art der Darreichungsform besteht.Patient compliance plays a very important role these days. The disadvantage of the conventional oral dosage forms is that a large number of patients are unable to swallow them or there is a great reluctance to use this type of dosage form.

Die Aufgabe der Erfindung ist es nun, eine schnell in Wasser zu lösende pharmazeutische Formulierung zur Anwendung von Sildenafil oder dessen pharmazeutisch unbedenklichen Salzen für alle betroffenen Personen bereitzustellen, um somit schneller den therapeutisch wirksamen Blutplasmaspiegel zu erreichen und die Patienten-Compliance durch leichtere Einnahme zu verbessern.The object of the invention is to provide a pharmaceutical formulation for the use of sildenafil or its pharmaceutically acceptable salts which can be quickly dissolved in water, in order to achieve the therapeutically effective blood plasma level more quickly and to improve patient compliance by easier intake .

Da bei einem sehr großen Anteil der betroffenen Personen der Grund der Impotenz in einer Diabetes-Erkrankung zu suchen ist, sollte die in Wasser zu lösende pharmazeutische Formulierung zudem noch zuckerfrei sein. Dieses ist allerdings nur möglich, wenn der Wirkstoff und der Süßstoff chemisch verträglich und zur Herstellung der gewünschten Form des Arzneimittels und der damit verbundenen Arbeitsschritte geeignet sind.Since the cause of impotence is to be found in a very large proportion of the people affected by diabetes, the pharmaceutical formulation to be dissolved in water should also be sugar-free. However, this is only possible if the active ingredient and the sweetener are chemically compatible and are suitable for producing the desired form of the drug and the associated work steps.

Es wurde nun überraschenderweise gefunden, daß durch die orale Verabreichung mittels einer in Wasser schnell zu lösenden pharmazeutischen Formulierung Sildenafil oder dessen pharmazeutisch wirksame Salze derart gut resorbiert werden, daß schnell ein therapeutisch wirksamer Blutplasmaspiegel erreicht werden kann. Es besteht zudem eine gute chemische Verträglichkeit mit Süßstoffen. Auch bei der Herstellung dieses Gemisches sind keine Einschränkungen zu verzeichnen. Dadurch wird die Flexibilität der betroffenen Personen wesentlich verbessert und eine gewisse Spontaneität ermöglicht, so daß eine freie Gestaltung des Liebesleben kein Problem mehr darstellt.It has now surprisingly been found that oral administration by means of a pharmaceutical formulation which can be quickly dissolved in water means that sildenafil or its pharmaceutically active salts are absorbed so well that a therapeutically effective blood plasma level can be reached quickly. There is also good chemical compatibility with sweeteners. There are no restrictions in the production of this mixture either. This increases the flexibility of the people concerned significantly improved and a certain spontaneity enabled, so that a free design of love life is no longer a problem.

Aufgrund der Wasserlöslichkeit wird zudem noch eine angenehme Präsentation des Arzneimittels ermöglicht, insbesondere bei Patienten, die Schwierigkeiten haben normale Tabletten zu schlucken.Due to the water solubility, a pleasant presentation of the drug is also made possible, especially in patients who have difficulty swallowing normal tablets.

Die der Erfindung zugrundeliegende Aufgabe wird nun durch eine oral zu verabreichende, in Wasser zu lösende pharmazeutische Formulierung, die als aktiven Bestandteil den Phosphodiesterase (PDE)-Typ-5-Hemmer Sildenafil oder dessen pharmazeutisch unbedenkliche Salze enthält, gelöst. Als mögliche Salze kommen die Säureadditionssalze wie die Hydrochloride oder die Halogenide, Sulfate, Phosphate, Citrate, Acetate, Maleate, Succinate, Fumarate, Ascorbate sowie Carbonate in Frage.The object on which the invention is based is now achieved by an orally administrable, water-soluble pharmaceutical formulation which contains, as active ingredient, the phosphodiesterase (PDE) type 5 inhibitor sildenafil or its pharmaceutically acceptable salts. Possible salts are the acid addition salts such as the hydrochlorides or the halides, sulfates, phosphates, citrates, acetates, maleates, succinates, fumarates, ascorbates and carbonates.

Sildenafil oder dessen pharmazeutisch unbedenkliche Salze können ferner in Kombination mit weiteren bekannten Wirkstoffen, vor allem spezifischen und unspezifischen Cytochrom P450 (CYP) Inhibitoren, angewendet werden.Sildenafil or its pharmaceutically acceptable salts can also be used in combination with other known active compounds, especially specific and non-specific cytochrome P450 (CYP) inhibitors.

Durch Kombination von Sildenafil mit einem CYP-Inhibitor wie Erythromycin, Cimetidin, Ketoconazol, Itraconazol oder Mibefradil wird die Konzentration im Blutplasma stark gesteigert und der Abbau bzw. die Ausscheidung verzögert. Die schnelle Anflutung wird somit bei einer verringerten Sildenafilmenge trotzdem beibehalten bzw. beschleunigt.By combining sildenafil with a CYP inhibitor such as erythromycin, cimetidine, ketoconazole, itraconazole or mibefradil, the concentration in the blood plasma is greatly increased and the breakdown or excretion is delayed. The rapid flooding is thus maintained or accelerated with a reduced amount of sildenafil.

Die Menge Sildenafil, bevorzugt in der Form eines pharmazeutisch unbedenklichen Salzes, die in der erfindungsgemäßen in Wasser zu lösenden pharmazeutischen Formulierung verwendet wird, kann zwischen 20 bis 150 mg betragen und wird bevorzugt im Bereich von 25 bis 100 mg pro Dosierungseinheit liegen.The amount of sildenafil, preferably in the form of a pharmaceutically acceptable salt, which is used in the pharmaceutical formulation according to the invention to be dissolved in water, can be between 20 to 150 mg and will preferably be in the range from 25 to 100 mg per dosage unit.

Die in Wasser schnell zu lösende pharmazeutische Formulierung kann in der Form von Brausetabletten, Granulat oder Tabs vorliegen.The pharmaceutical formulation which can be quickly dissolved in water can be in the form of effervescent tablets, granules or tabs.

In der Brausetablettenform kann als Kohlendioxidquelle das Carbonat und/ oder das Bicarbonat der Alkali- und Erdalkalimetalle in Verbindung mit einer Säure, z.B. Citronensäure, Ascorbinsäure und/ oder Weinsäure verwendet werden. Dabei kann das Gewichtsverhältnis der Säure zu dem Carbonat und/ oder Bicarbonat zwischen 0,9 und 1,6 liegen.In the effervescent tablet form, the carbonate and / or the bicarbonate of the alkali and alkaline earth metals in combination with an acid, for example citric acid, ascorbic acid and / or tartaric acid, can be used as the carbon dioxide source. The weight ratio of the acid to the carbonate and / or bicarbonate can be between 0.9 and 1.6.

In allen Darreichungsformen befinden sich anstatt der Zuckerkomponenten Süßstoff(e) als Süßungsmittel, insbesondere Aspartam, Cyclamat und Saccharin beziehungsweise deren Natriumsalze.In all dosage forms, instead of the sugar components, sweetener (s) are used as sweeteners, in particular aspartame, cyclamate and saccharin or their sodium salts.

Es können zudem die für diese Darrreichungsformen üblichen Binde- und Gleitmittel, Füllstoffe, Tenside, Sprengmittel, Aromastoffe sowie andere übliche Hilfsstoffe zugesetzt werden.It is also possible to add the binders and lubricants, fillers, surfactants, disintegrants, flavoring agents and other customary auxiliaries which are customary for these dosage forms.

Die Erfindung wird durch nachstehende Beispiele näher erläutert, ohne aber denThe invention is illustrated by the following examples, but without the

Erfmdungsumfang damit einzuschränken.To limit the scope of the invention.

Beispiel 1:Example 1:

BrausetabletteEffervescent tablet

Sildenafilcitrat 140,45 mg (entspricht 100 mg Sildenafil)Sildenafil citrate 140.45 mg (corresponds to 100 mg sildenafil)

Citronensäure wasserfrei 1259,54 mg Natriumhydrogencarbonat 1004,00 mgCitric acid anhydrous 1259.54 mg sodium hydrogen carbonate 1004.00 mg

Natriumsulfat wasserfrei 400,00 mgSodium sulfate anhydrous 400.00 mg

Lactose x H2O 150,00 mgLactose x H 2 O 150.00 mg

Macrogol 6000 100,00 mgMacrogol 6000 100.00 mg

Natriumcarbonat wasserfrei 100,00 mg Natriumcyclamat 130,00 mgSodium carbonate anhydrous 100.00 mg sodium cyclamate 130.00 mg

Polyvidon MG 25 000 40,00 mgPolyvidon MG 25,000 40.00 mg

Aroma 16,00 mgAroma 16.00 mg

Simethiconemulsion 0,46 mg Beispiel 2:Simethicone emulsion 0.46 mg Example 2:

BrausetabletteEffervescent tablet

Sildenafilcitrat 140,45 mg (entspricht 100 mg Sildenafil)Sildenafil citrate 140.45 mg (corresponds to 100 mg sildenafil)

Citronensäure wasserfrei 1105,00 mgCitric acid anhydrous 1105.00 mg

Natriumhydrogencarbonat wasserfrei 563,00 mgSodium bicarbonate anhydrous 563.00 mg

Natriumhydrogencarbonat x H2O 150,00 mgSodium bicarbonate x H 2 O 150.00 mg

Weinsäure 200,00 mgTartaric acid 200.00 mg

Natriumcyclamat 65,00 mgSodium cyclamate 65.00 mg

Saccharin-Natrium 40,00 mgSaccharin sodium 40.00 mg

Aroma Orange 100,00 mgAroma Orange 100.00 mg

Beispiel 3:Example 3:

Brausetablette: Sildenafilcitrat 70,23 mg (entspricht 50 mg Sildenafil)Effervescent tablet: sildenafil citrate 70.23 mg (corresponds to 50 mg sildenafil)

Citronensäure wasserfrei 700,00 mgCitric acid anhydrous 700.00 mg

Natriumcarbonat 212,00 mgSodium carbonate 212.00 mg

Natriumhydrogencarbonat 212,00 mgSodium bicarbonate 212.00 mg

Ascorbinsäure 75,00 mg Lactose D 20 182,00 mgAscorbic acid 75.00 mg lactose D 20 182.00 mg

Mannit 182,00 mgMannitol 182.00 mg

Saccharin-Natrium 5,00 mgSaccharin sodium 5.00 mg

PEG 6000 80,00 mgPEG 6000 80.00 mg

Natriumcyclamat 15,00 mg Aroma Himbeere 20,00 mgSodium cyclamate 15.00 mg aroma raspberry 20.00 mg

Compritol 20,00 mgCompritol 20.00 mg

Beispiel 4:Example 4:

Brausetablette: Sildenafilcitrat 70,23 mg (entspricht 50 mg Sildenafil)Effervescent tablet: sildenafil citrate 70.23 mg (corresponds to 50 mg sildenafil)

Citronensäure wasserfrei 1500,00 mgCitric acid anhydrous 1500.00 mg

Natriumcarbonat 630,00 mgSodium carbonate 630.00 mg

Natriumhydrogencarbonat 70,00 mg Ascorbinsäure 75,00 mg Flow-Lac 100 820,00 mg Saccharin-Natrium 5,00 mg PEG 6000 150,00 mg Natriumcyclamat 50,00 mg Aroma Erdbeere 25,00 mg Compritol 20,00 mgSodium bicarbonate 70.00 mg Ascorbic acid 75.00 mg Flow-Lac 100 820.00 mg saccharin sodium 5.00 mg PEG 6000 150.00 mg sodium cyclamate 50.00 mg Flavor strawberry 25.00 mg Compritol 20.00 mg

Beispiel 5: TabsExample 5: Tabs

Sildenafilcitrat 70,23 mg (entspricht 50 mg Sildenafil)Sildenafil citrate 70.23 mg (corresponds to 50 mg sildenafil)

Erdbeeraroma 22,50 mgStrawberry flavor 22.50 mg

S accharin-Natrium 15,00 mgS accharin sodium 15.00 mg

Lactose x H2O 15,00 mg mikrokristalline Cellulose 101,00 mgLactose x H 2 O 15.00 mg microcrystalline cellulose 101.00 mg

Crospovidon 12,50 mgCrospovidone 12.50 mg

Macrogol 4000 2,00 mgMacrogol 4000 2.00 mg

Magnesiumstearat 1,00 mg disperses Siliciumdioxid 1,00 mgMagnesium stearate 1.00 mg disperse silicon dioxide 1.00 mg

Beispiel 6:Example 6:

TabsTabs

Sildenafilcitrat 140,45 mg (entspricht 100 mg Sildenafil)Sildenafil citrate 140.45 mg (corresponds to 100 mg sildenafil)

Citronenaroma 0,85 mg Vanillearoma 3,35 mgLemon aroma 0.85 mg vanilla aroma 3.35 mg

Saccharin-Natrium 2,50 mgSaccharin sodium 2.50 mg

Lactose x H2O 16,70 mg mikrokristalline Cellulose 47,50 mgLactose x H 2 O 16.70 mg microcrystalline cellulose 47.50 mg

Maisstärke 4,00 mg Saccharin-Natrium 2,50 mgCorn starch 4.00 mg saccharin sodium 2.50 mg

Citronensäure wasserfrei 1,70 mgCitric acid anhydrous 1.70 mg

Magnesiumstearat 0,90 mg Magnesium stearate 0.90 mg

Claims

Patentansprüche claims 1. In Wasser zu lösende pharmazeutische Formulierung mit einem Gehalt an dem Phosphodiesterase (PDE)-Typ-5-Hemmer Sildenafil oder dessen pharmazeutisch unbedenklichen Salzen.1. Water-soluble pharmaceutical formulation containing the phosphodiesterase (PDE) type 5 inhibitor sildenafil or its pharmaceutically acceptable salts. 2. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 1, gekennzeichnet durch Sildenafil als Wirkstoff.2. Water-soluble pharmaceutical formulation according to claim 1, characterized by sildenafil as an active ingredient. 3. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 1, gekennzeichnet durch das Citrat, Hydrochlorid, Halogenid, Sulfat, Phosphat, Acetat, Maleat, Succinat, Ascorbat oder Carbonat von Sildenafil als Wirkstoff, insbesondere Sildenafilcitrat.3. Water-soluble pharmaceutical formulation according to claim 1, characterized by the citrate, hydrochloride, halide, sulfate, phosphate, acetate, maleate, succinate, ascorbate or carbonate of sildenafil as an active ingredient, in particular sildenafil citrate. 4. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 1, 2 oder 3, gekennzeichnet durch Sildenafil oder eines seiner pharmazeutisch verträglichen Salze als4. Water-soluble pharmaceutical formulation according to claim 1, 2 or 3, characterized by sildenafil or one of its pharmaceutically acceptable salts as Wirkstoff in Kombination mit weiteren Wirkstoffen.Active ingredient in combination with other active ingredients. 5. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 4, gekennzeichnet durch mindestens einen weiteren Wirkstoff, der die Sildenafil- Wirkung verstärkt, insbesondere spezifische und unspezifische Cytochrom P450- Inhibitoren. 6. In Wasser zu lösende pharmazeutische Formulierung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch einen Wirkstoffgehalt von 20 bis 150 mg.5. Water-soluble pharmaceutical formulation according to claim 4, characterized by at least one further active ingredient which enhances the sildenafil effect, in particular specific and non-specific cytochrome P450 inhibitors. 6. Water-soluble pharmaceutical formulation according to one of the preceding claims, characterized by an active ingredient content of 20 to 150 mg. 7. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 6, gekennzeichnet durch einen Wirkstoffgehalt von 25 bis 100 mg.7. Water-soluble pharmaceutical formulation according to claim 6, characterized by an active ingredient content of 25 to 100 mg. 8. In Wasser zu lösende pharmazeutische Formulierung nach einem der vorangegangenen Ansprüche, gekennzeichnet dadurch, daß diese in Form von schnell löslichen8. Water-soluble pharmaceutical formulation according to one of the preceding claims, characterized in that it is in the form of quickly soluble Brausetabletten, Granulat oder Tabs vorliegen kann. Effervescent tablets, granules or tabs can be present. . In Wasser zu lösende pharmazeutische Formulierung nach einem der vorangegangenen. Pharmaceutical formulation to be dissolved in water according to one of the preceding Ansprüche, gekennzeichnet dadurch, daß die Brausetablettenform als Kohlendioxidquelle das Carbonat und/oder Bicarbonet der Alkali- oder Erdalkalimetalle in Verbindung mitClaims, characterized in that the effervescent tablet form as the carbon dioxide source, the carbonate and / or bicarbonet of the alkali or alkaline earth metals in combination with Säure enthalten kann. 10. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 9, gekennzeichnet durch Citronen-, Ascorbin- und/oder Weinsäure. 11. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 9 oder 10, gekennzeichnet durch ein Gewichtsverhältnis zwischen Säure und Carbonat und/ oderMay contain acid. 10. Water-soluble pharmaceutical formulation according to claim 9, characterized by citric, ascorbic and / or tartaric acid. 11. Water-soluble pharmaceutical formulation according to claim 9 or 10, characterized by a weight ratio between acid and carbonate and / or Bicarbonat von 0,9 bis 1,6. 12. In Wasser zu lösende pharmazeutische Formulierung nach einem der vorangegangenenBicarbonate from 0.9 to 1.6. 12. Pharmaceutical formulation to be dissolved in water according to one of the preceding Ansprüche, gekennzeichnet durch Süßstoff als Ersatz der Zuckerkomponente.Claims characterized by a sweetener as a substitute for the sugar component. 13. In Wasser zu lösende pharmazeutische Formulierung nach Anspruch 12, gekennzeichnet durch Aspartam, Cyclamat, Saccharin und/ oder deren Natriumsalze.13. Water-soluble pharmaceutical formulation according to claim 12, characterized by aspartame, cyclamate, saccharin and / or their sodium salts. 14. In Wasser zu lösende pharmazeutische Formulierung nach einem der vorangegangenen Ansprüche, gekennzeichnet durch den möglichen Zusatz von bekannten Binde- und14. Water-soluble pharmaceutical formulation according to one of the preceding claims, characterized by the possible addition of known binding and Gleitmitteln, Füllstoffen, Tensiden, Sprengmitteln, Aromastoffen sowie anderen üblichen Hilfsstoffen. Lubricants, fillers, surfactants, disintegrants, flavorings and other common auxiliaries.
PCT/EP1999/005464 1998-07-31 1999-07-30 Water-soluble pharmaceutical formulation for administering sildenafil Ceased WO2000007596A1 (en)

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DE19834507.0 1998-07-31

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EP1469852A4 (en) * 2002-01-04 2009-12-02 Ford Henry Health System DONORS OF NITROGEN MONOXIDE FOR THE TREATMENT OF DISEASES AND INJURIES
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