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WO1994000123A1 - Micro-emulsion of dexniguldipin - Google Patents

Micro-emulsion of dexniguldipin Download PDF

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Publication number
WO1994000123A1
WO1994000123A1 PCT/EP1993/001590 EP9301590W WO9400123A1 WO 1994000123 A1 WO1994000123 A1 WO 1994000123A1 EP 9301590 W EP9301590 W EP 9301590W WO 9400123 A1 WO9400123 A1 WO 9400123A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
preparation according
contained
amount
lecithin
Prior art date
Application number
PCT/EP1993/001590
Other languages
German (de)
French (fr)
Inventor
Rudolf Linder
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to AU44196/93A priority Critical patent/AU4419693A/en
Publication of WO1994000123A1 publication Critical patent/WO1994000123A1/en

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Classifications

    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the invention relates to a pharmaceutical preparation for the intravenous injection of dexniguldipine.
  • the compound (-) - 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid-3-methyl-5- [3- (4.4-diphenyl-l- piperidinyl) -propyl] ester (International Nonproprietary Name: Dexniguldipin) is characterized by its cytostatic activity. It is therefore suitable for the treatment of tumor diseases, in particular for reducing or preventing the formation of metastases and tumor growth.
  • dexniguldipine Because of its poor solubility in aqueous medium (solubility approx. 44 mg / 100 ml water), dexniguldipine has not hitherto been available in the form of injectable preparations with acceptable properties. So far, it has been administered orally. In the case of oral administration, the absorption is subject to undesirable fluctuations. Furthermore, it is hardly possible to achieve sufficiently high blood levels or to maintain them. There is therefore an urgent need for a parenterally administrable preparation.
  • solubilizers such as propylene glycol, polyethylene glycol 400 or substituted cyclodextrins.
  • these preparations show a pronounced intolerance to veins, which means that the indicated administration cannot be carried out over a longer period of time.
  • dexniguldipine When dexniguldipine is incorporated into a fat emulsion, it is possible to use pro 100 ml preparation to dissolve 300 mg of active ingredient. However, the necessary amount of 10 to 20 g of triglycerides per 100 ml of preparation, especially in the case of repeated use, is unacceptable.
  • Microemulsions of active substances for topical preparations.
  • Microemulsions are usually viscous and are therefore particularly suitable as spreadable preparations. They are stable only in certain concentration ranges of the individual auxiliary substances and arise spontaneously without the action of shear forces. Microemulsions are transparent and lead to rapid penetration of the active ingredient through the skin. Microemulsions can also be prepared without an active ingredient.
  • the production of microemulsions is given, for example, in DE-A-3930928 and DE-A-3406497.
  • dexniguldipine in a concentration of 2 g / 100 ml into a very well tolerated parenteral form which, as essential components, in addition to dexniguldipine, a polyoxyethylene polyoxypropylene copolymer, lecithin, a phy ⁇ Siologically compatible organic solvent, a liquid triglyceride and water. If desired, polyvinylpyrrole idone is also included.
  • the invention therefore relates to a pharmaceutical preparation for the intravenous injection of dexniguldipine, characterized in that it contains a polyoxyethylene-polyoxypropylene mixed polymer, lecithin, a physiologically acceptable organic solvent, a liquid triglyceride, polyvinylpyrrolidone and water. Further subject matter of the invention result from the patent claims.
  • polyoxyethylene polyoxypropylene mixed polymer is described in USP XXII under the INN poloxamer.
  • poloxamer 188 is used in a concentration of 2 to 10% by weight, preferably 4-6% by weight.
  • a raw material which contains more than 90% by weight phosphatidylcholine (such as Epikuron 200 from Lucas Meyer) is used as lecithin.
  • the use concentration is 1.5 to 10% by weight, preferably 2.5 to 7.5% by weight.
  • the pharmaceutically acceptable solvents preferably propylene glycol or PEG 400, are used as organic solvents in a concentration of 5 to 40% by weight, preferably 15 to 30% by weight.
  • triglycerides e.g. Neutral oil or soybean oil can be used. It is preferred to use a chain triglyceride (Miglyol 812 from Huls) in a concentration of 2.5 to 10% by weight, preferably 4 to 6% by weight.
  • Polyvinylpyrrolidone used according to the invention has a K value of 11 to 18, preferably 16 to 18 (e.g. Kollidon 17PF from BASF) or alternatively 11 to 14 (Kollidon 12PF from BASF).
  • the use concentration is 1.25 to 10% by weight, preferably 2 to 8% by weight.
  • K values characterize the various polyvinylpyrrolidones and are calculated from their relative viscosities in water according to the Ph. Eur. Or USP monograph "Polyvidonu” or "Povidone”.
  • antioxidants such as e.g. Ascorbyl palmitate, and / or conventional preservatives are added.
  • Glycerin is not suitable as an auxiliary for the purposes of the invention as an alternative to PEG 400 or propylene glycol.
  • the pharmaceutical preparations according to the invention are produced in a manner known per se. For example, dexniguldipine is dissolved together with the lecithin and the liquid triglyceride in the organic solvent.
  • the polyoxyethylene-polyoxypropylene copolymer is dissolved in water, optionally together with the polyvinylpyrrolidone (Kollidon).
  • the two solutions are mixed.
  • the oily phase is roughly dispersed. After adjusting the pH to 5 to 6, the dispersion obtained is sonicated until the preparation has become transparent. If the work was carried out without adding Kollidon, at least 20% by weight of additional water is added. If necessary, the pH value is corrected and possibly sonicated again.
  • the particle size of the inner phase should not exceed 100 nm.
  • the finished preparation is filled into ampoules after sterile filtration.
  • composition for a quantity of 1 liter Composition for a quantity of 1 liter:
  • Epikuron 200, dexniguldipine and neutral oil are dissolved in the stated amount of propylene glycol.
  • Poloxamer 188 and Kollidon 17PF are dissolved in the water for injection purposes.
  • the two solutions are mixed with stirring and the oily phase is roughly dispersed.
  • a pH of 5 to 5 is set with trometamol.
  • the dispersion obtained is then sonicated with an ultrasonic device (Branson Sonifier 450) until the preparation becomes transparent.
  • the pH value is readjusted and if necessary, sonicate again.
  • the particle size of the inner phase must be ⁇ 100 nm.
  • the preparation is sterile filtered and filled into colorless ampoules. Production and filling must take place under nitrogen gassing.
  • Poloxamer 188 50.00 g
  • Lutrol 400 300.00 g
  • the preparation is carried out analogously to Example 1, except that instead of propylene glycol Lu ⁇ trol 400 (polyoxyethylene with an average molecular weight 400 from BASF) is used.
  • propylene glycol Lu ⁇ trol 400 polyoxyethylene with an average molecular weight 400 from BASF
  • the preparation is carried out analogously to Examples 1 and 2. Before sterile filtration, at least 100 ml of water are added for injection purposes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Dispersion Chemistry (AREA)
  • Biophysics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

Described is a drug preparation for the intravenous injection of dexniguldipin, the preparation being extremely well tolerated. In addition to dexniguldipin, the preparation contains a mixed polymer of polyoxyethylene and polyoxypropylene, lecithin, a physiologically tolerated organic solvent, a liquid triglyceride and water.

Description

DEXNIGULDIPIN MIKROEMULSIONDEXNIGULDIPINE MICROEMULSION
Technisches GebietTechnical field
Die Erfindung betrifft eine Arzneimittelzubereitung zur intravenösen Injek¬ tion von Dexniguldipin.The invention relates to a pharmaceutical preparation for the intravenous injection of dexniguldipine.
Stand der TechnikState of the art
Die Verbindung (-)-l,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl )-pyridin-3,5- dicarbonsäure-3-methyl-5-[3-(4.4-diphenyl-l-piperidinyl)-propyl]ester (In¬ ternational Nonproprietary Name: Dexniguldipin) zeichnet sich durch ihre cytostatische Aktivität aus. Sie eignet sich daher zur Behandlung von Tu¬ morerkrankungen, insbesondere zur Verringerung oder Verhinderung von Meta¬ stasenbildung und des Tumorwachstums.The compound (-) - 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) pyridine-3,5-dicarboxylic acid-3-methyl-5- [3- (4.4-diphenyl-l- piperidinyl) -propyl] ester (International Nonproprietary Name: Dexniguldipin) is characterized by its cytostatic activity. It is therefore suitable for the treatment of tumor diseases, in particular for reducing or preventing the formation of metastases and tumor growth.
Dexniguldipin läßt sich aufgrund seiner Schwerlöslichkeit im wäßrigen Mi¬ lieu (Löslichkeit ca. 44 mg/100 ml Wasser) bisher nicht in Form injizierba¬ rer Zubereitungen mit annehmbaren Eigenschaften zur Verfügung stellen. Es wird daher bislang oral verabreicht. Bei der oralen Verabreichung ist die Resorption unerwünschten Schwankungen unterworfen. Weiterhin ist es kaum möglich, ausreichend hohe Blutspiegel zu erreichen oder aufrecht zu erhal¬ ten. Es besteht daher das dringende Bedürfnis nach einer parenteral appli- zierbaren Zubereitung.Because of its poor solubility in aqueous medium (solubility approx. 44 mg / 100 ml water), dexniguldipine has not hitherto been available in the form of injectable preparations with acceptable properties. So far, it has been administered orally. In the case of oral administration, the absorption is subject to undesirable fluctuations. Furthermore, it is hardly possible to achieve sufficiently high blood levels or to maintain them. There is therefore an urgent need for a parenterally administrable preparation.
Zwar ist es möglich, die Löslichkeit mit Hilfe der üblichen Lösevermittler wie Propylenglykol, Polyethylenglykol 400 oder duch substituierte Cyclodex- trine wesentlich zu erhöhen. Jedoch zeigen diese Zubereitungen eine stark ausgeprägte Venenunverträglichkeit, womit die angezeigte Verabreichung über einen längeren Zeitraum nicht durchführbar ist.It is possible to significantly increase the solubility with the help of the usual solubilizers such as propylene glycol, polyethylene glycol 400 or substituted cyclodextrins. However, these preparations show a pronounced intolerance to veins, which means that the indicated administration cannot be carried out over a longer period of time.
Bei Einarbeitung von Dexniguldipin in eine Fettemulsion ist es möglich, pro 100 ml Zubereitung 300 mg Wirkstoff zu lösen. Jedoch ist die notwendige 'Menge von 10 bis 20 g Triglyceride pro 100 ml Zubereitung, insbesondere bei wiederholter Anwendung, nicht annehmbar.When dexniguldipine is incorporated into a fat emulsion, it is possible to use pro 100 ml preparation to dissolve 300 mg of active ingredient. However, the necessary amount of 10 to 20 g of triglycerides per 100 ml of preparation, especially in the case of repeated use, is unacceptable.
Es ist bekannt, für topische Präparationen Mikroemulsionen von Wirkstoffen herzustellen. Mikroemulsionen sind üblicherweise viskos und eignen sich deshalb besonders als streichfähige Zubereitungen. Sie sind nur in bestimm¬ ten Konzentrationsbereichen der einzelnen Hilfsstoffe stabil und entstehen spontan ohne Einwirkung von Scherkräften. Mikroemulsionen sind transparent und führen zu einer raschen Penetration des Wirkstoffs durch die Haut. Mi¬ kroemulsionen können auch ohne Wirkstoff hergestellt werden. Die Herstel¬ lung von Mikroemulsionen ist beispielsweise in den DE-A-3930928 und DE-A-3406497 angegeben.It is known to produce microemulsions of active substances for topical preparations. Microemulsions are usually viscous and are therefore particularly suitable as spreadable preparations. They are stable only in certain concentration ranges of the individual auxiliary substances and arise spontaneously without the action of shear forces. Microemulsions are transparent and lead to rapid penetration of the active ingredient through the skin. Microemulsions can also be prepared without an active ingredient. The production of microemulsions is given, for example, in DE-A-3930928 and DE-A-3406497.
Beschreibung der ErfindungDescription of the invention
Aufgabe der vorliegenden Erfindung war es, eine injizierbare Zubereitung für Dexniguldipin zur Verfügung zu stellen, die eine möglichst große Wirk¬ stoffmenge enthält, sich durch eine gute Verträglichkeit auszeichnet und es erlaubt, hohe Dosen Dexniguldipin in einem kleinen Applikationsvolumen zu verabreichen.It was an object of the present invention to provide an injectable preparation for dexniguldipine which contains the largest possible amount of active ingredient, is well tolerated and allows high doses of dexniguldipine to be administered in a small application volume.
Es wurde überraschenderweise gefunden, daß es möglich ist, Dexniguldipin in einer Konzentration von 2 g/100 ml in eine sehr gut verträgliche parentera- le Form einzuarbeiten, die als wesentliche Bestandteile neben Dexniguldi¬ pin, ein Polyoxyethylenpolyoxypropylen-Mischpolymerisat, Lecithin, ein phy¬ siologisch verträgliches organisches Lösungsmittel, ein flüssiges Triglyce- rid und Wasser enthält. Gewünschtenfalls ist außerdem Polyvinylpyrrol idon enthalten.It has surprisingly been found that it is possible to incorporate dexniguldipine in a concentration of 2 g / 100 ml into a very well tolerated parenteral form which, as essential components, in addition to dexniguldipine, a polyoxyethylene polyoxypropylene copolymer, lecithin, a phy¬ Siologically compatible organic solvent, a liquid triglyceride and water. If desired, polyvinylpyrrole idone is also included.
Gegenstand der Erfindung ist deshalb eine Arzneimittelzubereitung zur in¬ travenösen Injektion von Dexniguldipin, dadurch gekennzeichnet, daß ein Po- lyoxyethylenpolyoxypropylen-Mischpoly erisat, Lecithin, ein physiologisch verträgliches organisches Lösungsmittel, ein flüssiges Triglycerid, Poly¬ vinylpyrrolidon und Wasser enthalten sind. -Weitere Erfindungsgegenstände ergeben sich aus den Patentansprüchen.The invention therefore relates to a pharmaceutical preparation for the intravenous injection of dexniguldipine, characterized in that it contains a polyoxyethylene-polyoxypropylene mixed polymer, lecithin, a physiologically acceptable organic solvent, a liquid triglyceride, polyvinylpyrrolidone and water. Further subject matter of the invention result from the patent claims.
Das Polyoxyethylenpolyoxypropylen-Mischpoly erisat ist in der USP XXII un¬ ter dem INN Poloxamer beschrieben. Poloxamer 188 wird erfindungsgemäß in einer Konzentration von 2 bis 10 Gew.-%, vorzugsweise 4 - 6 Gew.-% einge¬ setzt.The polyoxyethylene polyoxypropylene mixed polymer is described in USP XXII under the INN poloxamer. According to the invention, poloxamer 188 is used in a concentration of 2 to 10% by weight, preferably 4-6% by weight.
Als Lecithin wird erfindungsgemäß ein Rohstoff eingesetzt, der mehr als 90 Gew.-% Phosphatidylcholin enthält (wie z.B. Epikuron 200 der Fa. Lucas Meyer). Die Einsatzkonzentration beträgt 1,5 bis 10 Gew.- , vorzugsweise 2,5 bis 7,5 Gew.-%.According to the invention, a raw material which contains more than 90% by weight phosphatidylcholine (such as Epikuron 200 from Lucas Meyer) is used as lecithin. The use concentration is 1.5 to 10% by weight, preferably 2.5 to 7.5% by weight.
Als organische Lösungmittel werden die pharmazeutisch annehmbaren Lösungs¬ mittel, vorzugsweise Propylenglykol oder PEG 400, in einer Konzentration von 5 bis 40 Gew.-%, vorzugsweise 15 bis 30 Gew.-%, eingesetzt.The pharmaceutically acceptable solvents, preferably propylene glycol or PEG 400, are used as organic solvents in a concentration of 5 to 40% by weight, preferably 15 to 30% by weight.
Als Triglyceride können erfindungsgemäß z.B. Neutralöl oder Sojaöl verwen¬ det werden. Vorzugsweise wird itte!kettiges Triglycerid (Miglyol 812 der Firma Hüls) in einer Konzentration von 2,5 bis 10 Gew.-%, vorzugsweise 4 bis 6 Gew.-% eingesetzt.As triglycerides according to the invention, e.g. Neutral oil or soybean oil can be used. It is preferred to use a chain triglyceride (Miglyol 812 from Huls) in a concentration of 2.5 to 10% by weight, preferably 4 to 6% by weight.
Erfindungsgemäß verwendetes Polyvinylpyrrolidon hat einen K-Wert von 11 bis 18, vorzugsweise 16 bis 18 (z.B. Kollidon 17PF der Firma BASF) oder alter¬ nativ 11 bis 14 (Kollidon 12PF der Firma BASF). Die Einsatzkonzentration beträgt 1,25 bis 10 Gew.-%, vorzugsweise 2 bis 8 Gew.-%. K-Werte kennzeich¬ nen die verschiedenen Polyvinylpyrrolidone und errechnen sich aus deren re¬ lativen Viskositäten in Wasser nach der Ph. Eur.- oder USP-Monographie "Po- lyvidonu " bzw. "Povidone".Polyvinylpyrrolidone used according to the invention has a K value of 11 to 18, preferably 16 to 18 (e.g. Kollidon 17PF from BASF) or alternatively 11 to 14 (Kollidon 12PF from BASF). The use concentration is 1.25 to 10% by weight, preferably 2 to 8% by weight. K values characterize the various polyvinylpyrrolidones and are calculated from their relative viscosities in water according to the Ph. Eur. Or USP monograph "Polyvidonu" or "Povidone".
Gewünschtenfalls können noch Antioxidantien, wie z.B. Ascorbylpalmitat, und/oder übliche Konservierungsmittel zugegeben werden.If desired, antioxidants such as e.g. Ascorbyl palmitate, and / or conventional preservatives are added.
Als Hilfsstoff für die Zwecke der Erfindung nicht geeignet ist Glycerin als Alternative zu PEG 400 oder Propylenglykol. Die Herstellung der erfindungsgemäßen Arzneimittelzubereitungen erfolgt auf an sich bekannte Weise. Man löst beispielsweise Dexniguldipin zusammen mit dem Lecithin und dem flüssigen Triglycerid in dem organischen Lösungsmit¬ tel. Das Polyoxyethylenpolyoxypropylen-Mischpolymere wird, gegebenenfalls zusammen mit dem Polyvinylpyrrolidon (Kollidon), in Wasser gelöst. Die bei¬ den Lösungen werden vermischt. Die ölige Phase wird grob dispergiert. Nach Einstellen des pH-Wertes auf 5 bis 6 wird die erhaltene Dispersion solange mit Ultraschall beschallt, bis die Zubereitung transparent geworden ist. Falls ohne Zusatz von Kollidon gearbeitet wurde, werden mindestens 20 Gew.-% zusätzliches Wasser hinzugegeben. Erforderlichenfalls wird der pH-Wert korrigiert und eventuell nochmals beschallt. Die Teilchengröße der inneren Phase sollte 100 nm nicht überschreiten. Die fertige Zubereitung wird nach Sterilfiltration in Ampullen abgefüllt.Glycerin is not suitable as an auxiliary for the purposes of the invention as an alternative to PEG 400 or propylene glycol. The pharmaceutical preparations according to the invention are produced in a manner known per se. For example, dexniguldipine is dissolved together with the lecithin and the liquid triglyceride in the organic solvent. The polyoxyethylene-polyoxypropylene copolymer is dissolved in water, optionally together with the polyvinylpyrrolidone (Kollidon). The two solutions are mixed. The oily phase is roughly dispersed. After adjusting the pH to 5 to 6, the dispersion obtained is sonicated until the preparation has become transparent. If the work was carried out without adding Kollidon, at least 20% by weight of additional water is added. If necessary, the pH value is corrected and possibly sonicated again. The particle size of the inner phase should not exceed 100 nm. The finished preparation is filled into ampoules after sterile filtration.
Herstellunqbeispiele:Manufacturing examples:
Beispiel 1example 1
Zusammensetzung für eine Menge von 1 Liter:Composition for a quantity of 1 liter:
Dexniguldipin-Hydrochlorid 21,00 gDexniguldipine hydrochloride 21.00 g
Poloxamer 188 75,00 gPoloxamer 188 75.00 g
Epikuron 200 50,00 gEpikuron 200 50.00 g
Neutralöl 50,00 gNeutral oil 50.00 g
Propylenglycol 200,00 gPropylene glycol 200.00 g
Kollidon 17PF 25,00 gKollidon 17PF 25.00 g
Wasser für Injektionszwecke 889,00 gWater for injections 889.00 g
In der angegeben Menge Propylenglykol werden das Epikuron 200, Dexniguldi¬ pin und Neutralöl gelöst. Im Wasser für Injektionszwecke werden das Poloxa¬ mer 188 und Kollidon 17PF gelöst. Die beiden Lösungen werden unter Rühren gemischt und die ölige Phase grob dispergiert. Man stellt mit Trometamol einen pH von 5 bis 5 ein. Die erhaltene Dispersion wird anschließend so lange mit einem Uϊtraschallgerät (Branson Sonifier 450) beschallt, bis die Zubereitung transparent wird. Es wird der pH-Wert nachjustiert und erfor- derlichenfalls nochmals beschallt. Die Teilchengröße der inneren Phase muß <100 nm sein. Die Zubereitung wird sterilfiltriert und in farblose Ampullen abgefüllt. Herstellung und Abfüllung müssen unter Stickstoffbegasung erfol¬ gen.Epikuron 200, dexniguldipine and neutral oil are dissolved in the stated amount of propylene glycol. Poloxamer 188 and Kollidon 17PF are dissolved in the water for injection purposes. The two solutions are mixed with stirring and the oily phase is roughly dispersed. A pH of 5 to 5 is set with trometamol. The dispersion obtained is then sonicated with an ultrasonic device (Branson Sonifier 450) until the preparation becomes transparent. The pH value is readjusted and if necessary, sonicate again. The particle size of the inner phase must be <100 nm. The preparation is sterile filtered and filled into colorless ampoules. Production and filling must take place under nitrogen gassing.
Beispiel 2Example 2
Menge für einen Ansatz von 1 Liter:Amount for a batch of 1 liter:
Dexniguldipin-Hydrochlorid 20,00 gDexniguldipine hydrochloride 20.00 g
Poloxamer 188 50,00 gPoloxamer 188 50.00 g
Epikuron 200 50,00 gEpikuron 200 50.00 g
Lutrol 400 300,00 gLutrol 400 300.00 g
Neutralöl 50,00 gNeutral oil 50.00 g
Kollidon 17PF 75,00 gKollidon 17PF 75.00 g
Wasser zur Injektion 765,00 gWater for injection 765.00 g
Die Herstellung erfolgt analog Beispiel 1, nur daß statt Propylenglykol Lu¬ trol 400 (Polyoxyethylen mit einem mittleren Molekulargewicht 400 der Firma BASF) verwendet wird.The preparation is carried out analogously to Example 1, except that instead of propylene glycol Lu¬ trol 400 (polyoxyethylene with an average molecular weight 400 from BASF) is used.
Ein Vorteil dieser Injektionslösungen liegt auch darin, daß nach Verdünnen mit handelsüblicher Trägerlösung (Glucose-Lösung 10 %, bzw. Fructose-Lösung 5 %) nach 3 Monaten Lagerung bei Raumtemperatur die Teilchengröße unverän¬ dert bleibt.Another advantage of these injection solutions is that after dilution with a commercially available carrier solution (glucose solution 10% or fructose solution 5%) the particle size remains unchanged after 3 months' storage at room temperature.
Beispiel 3Example 3
Es ist möglich, die in Beispiel 1 und 2 beschriebenen Zubereitungen ohne Zusatz von Polyvinylpyrrolidon herzustellen, wenn diese entsprechend der Herstellungsvorschrift unter Weglassen von Polyvinylpyrrolidon gefertigt werden und anschließend mit Wasser für Injektionszwecke weiter verdünnt werden. Ohne Wasserzugabe tritt bei kein Polyvinylpyrrolidon enthaltenden Mikroemulsionen des Dexniguldipin eine starke Viskositätszunahme auf. Ein Liter enthäl tIt is possible to prepare the preparations described in Examples 1 and 2 without the addition of polyvinylpyrrolidone if they are produced in accordance with the manufacturing instructions with the omission of polyvinylpyrrolidone and then further diluted with water for injection purposes. Without the addition of water, there is a strong increase in viscosity in microemulsions of dexniguldipine which do not contain polyvinylpyrrolidone. One liter contains
Figure imgf000008_0001
Figure imgf000008_0001
Die Herstellung erfolgt analog den Beispielen 1 und 2. Vor Sterilfiltration werden mindestens 100 ml Wasser für Injektionszwecke zugesetzt. The preparation is carried out analogously to Examples 1 and 2. Before sterile filtration, at least 100 ml of water are added for injection purposes.

Claims

Patentansprüche Claims
1. Arznei ittelzubereitung zur intravenösen Injektion von Dexniguldipin, dadurch gekennzeichnet, daß ein Polyoxyethylenpolyoxypropylen-Mischpolyme- risat, Lecithin, ein physiologisch verträgliches organisches Lösungsmittel, ein flüssiges Triglycerid und Wasser enthalten sind.1. Pharmaceutical preparation for intravenous injection of dexniguldipine, characterized in that it contains a polyoxyethylene polyoxypropylene mixed polymer, lecithin, a physiologically compatible organic solvent, a liquid triglyceride and water.
2. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet daß zusätzlich Polyvinylpyrrol idon enthalten ist.2. Pharmaceutical preparation according to claim 1, characterized in that polyvinylpyrrole idon is additionally contained.
3. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß das Polyoxyethylenpolyoxypropylen-Mischpolymerisat in einer Menge von 2 bis 10 Gew.-% enthalten ist.3. Pharmaceutical preparation according to claim 1, characterized in that the polyoxyethylene polyoxypropylene copolymer is contained in an amount of 2 to 10 wt .-%.
4. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß das Lecithin in einer Menge von 1 bis 10 Gew.-% enthalten ist.4. Pharmaceutical preparation according to claim 1, characterized in that the lecithin is contained in an amount of 1 to 10 wt .-%.
5. Arzneimittelzubereitung nach Anspruch 4, dadurch gekennzeichnet, daß das Lecithin mehr als 90 Gew.-% Phosphatidylcholin enthält.5. Pharmaceutical preparation according to claim 4, characterized in that the lecithin contains more than 90 wt .-% phosphatidylcholine.
6. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß das organische Lösungsmittel in einer Menge von 5 bis 40 Gew.-% enthalten ist.6. Pharmaceutical preparation according to claim 1, characterized in that the organic solvent is contained in an amount of 5 to 40 wt .-%.
7. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß als organisches Lösungsmittel Propylenglykol und/oder Polyethylenglykol enthalten sind.7. Pharmaceutical preparation according to claim 1, characterized in that propylene glycol and / or polyethylene glycol are contained as the organic solvent.
8. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß das Triglycerid in einer Menge von 2,5 bis 10 Gew.-% enthalten ist.8. Pharmaceutical preparation according to claim 1, characterized in that the triglyceride is contained in an amount of 2.5 to 10 wt .-%.
9. Arzneimittelzubereitung nach Anspruch 1, dadurch gekennzeichnet, daß als Triglycerid Neutralöl und/oder Sojaöl enthalten sind.9. Pharmaceutical preparation according to claim 1, characterized in that neutral oil and / or soybean oil are contained as triglyceride.
10. Arzneimittelzubereitung nach Anspruch 2, dadurch gekennzeichnet, daß das Polyvinypyrrolidon in einer Menge von 1,25 bis 10 Gew.-% enthalten ist. 10. Pharmaceutical preparation according to claim 2, characterized in that the polyvinypyrrolidone is contained in an amount of 1.25 to 10 wt .-%.
11. Arzneimittelzubereitung nach Anspruch 2, dadurch gekennzeichnet, daß das Polyvinylpyrrolidon einen K-Wert von 11 bis 14 aufweist.11. Pharmaceutical preparation according to claim 2, characterized in that the polyvinylpyrrolidone has a K value of 11 to 14.
12. Arzneimittel nach Anspruch 2, dadurch gekennzeichnet, daß das Polyvi- nylpyrroldon einen K-Wert von 16 bis 18 aufweist. 12. Medicament according to claim 2, characterized in that the polyvinyl pyrrone has a K value of 16 to 18.
PCT/EP1993/001590 1992-06-24 1993-06-22 Micro-emulsion of dexniguldipin WO1994000123A1 (en)

Priority Applications (1)

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AU44196/93A AU4419693A (en) 1992-06-24 1993-06-22 Micro-emulsion of dexniguldipin

Applications Claiming Priority (2)

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DEP4220616.2 1992-06-24
DE19924220616 DE4220616C2 (en) 1992-06-24 1992-06-24 Dexniguldipine for intravenous administration

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024193A1 (en) * 1994-03-10 1995-09-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Topical preparations
US5601856A (en) * 1993-09-08 1997-02-11 Rieter Automatik Gmbh Spinning beam
US5631373A (en) * 1993-11-05 1997-05-20 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones
US6949257B2 (en) 1998-05-26 2005-09-27 Novartis Ag Pharmaceutical compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102014015625A1 (en) 2014-10-16 2016-04-21 Gonzalo Urrutia Desmaison Solubilizing compositions

Citations (2)

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Publication number Priority date Publication date Assignee Title
WO1989007443A1 (en) * 1988-02-19 1989-08-24 Byk Gulden Lomberg Chemische Fabrik Gmbh Optically pure r-(-)-niguldipine and its derivatives for treating tumorous diseases
WO1991015485A1 (en) * 1990-04-10 1991-10-17 Byk Gulden Lomberg Chemische Fabrik Gmbh Novel pyridine esters

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989007443A1 (en) * 1988-02-19 1989-08-24 Byk Gulden Lomberg Chemische Fabrik Gmbh Optically pure r-(-)-niguldipine and its derivatives for treating tumorous diseases
WO1991015485A1 (en) * 1990-04-10 1991-10-17 Byk Gulden Lomberg Chemische Fabrik Gmbh Novel pyridine esters

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5601856A (en) * 1993-09-08 1997-02-11 Rieter Automatik Gmbh Spinning beam
US5631373A (en) * 1993-11-05 1997-05-20 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University And The University Of Oregon, Eugene Oregon Alkyl, azido, alkoxy, and fluoro-substituted and fused quinoxalinediones
WO1995024193A1 (en) * 1994-03-10 1995-09-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Topical preparations
US6949257B2 (en) 1998-05-26 2005-09-27 Novartis Ag Pharmaceutical compositions

Also Published As

Publication number Publication date
AU4419693A (en) 1994-01-24
DE4220616C2 (en) 1994-12-22
DE4220616A1 (en) 1994-01-05

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