WO1993013765A1 - Lecithin-containing solutions with levemopamil - Google Patents

Lecithin-containing solutions with levemopamil Download PDF

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Publication number
WO1993013765A1
WO1993013765A1 PCT/EP1993/000062 EP9300062W WO9313765A1 WO 1993013765 A1 WO1993013765 A1 WO 1993013765A1 EP 9300062 W EP9300062 W EP 9300062W WO 9313765 A1 WO9313765 A1 WO 9313765A1
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WIPO (PCT)
Prior art keywords
levemopamil
solutions
lecithin
phospholipid
solution
Prior art date
Application number
PCT/EP1993/000062
Other languages
German (de)
French (fr)
Inventor
Aktiengesellschaft Knoll
Original Assignee
Rosenberg, Joerg
Binder, Rudolf
Halm, Sabine
Blaich, Guenter
Gruenhagen, Hans-Heinrich
Krause, Hans-Juergen
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Application filed by Rosenberg, Joerg, Binder, Rudolf, Halm, Sabine, Blaich, Guenter, Gruenhagen, Hans-Heinrich, Krause, Hans-Juergen filed Critical Rosenberg, Joerg
Publication of WO1993013765A1 publication Critical patent/WO1993013765A1/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
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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

Definitions

  • Levemopamil is one of these active ingredients (EP 147 707). It is known that the local tolerance of levemopamil can be improved with the help of lipids and phospholipids.
  • Levemopamil can, on the one hand, as described in DE-A-4015108.3, be solubilized in a fat emulsion, as a result of which the local tolerance, tested by intravenous application to the rat, is improved compared to the aqueous solution.
  • the invention relates to a process for the preparation of colloidal aqueous levemopamil solutions, characterized in that a mixture of levemopamil salt, a phospholipid and an isotonizing agent is mixed with water and homogenized
  • the active substance (levemopamil) is used in the form of its salts. Levemopamil hydrochloride is preferred.
  • the active ingredient concentration in the finished solution is 1-20 mg / ml, preferably 3-10 mg / ml. Concentrations of about 5 mg / ml are very particularly preferred.
  • the amount of phospholipid added to the active ingredient is decisive for achieving good local tolerance.
  • the weight ratio of active ingredient to phospholipid is 1: 4 to 1:20, preferably 1: 4 to 1:10. Weight ratios of active ingredient to phospholipid of 1: 5 to are very particularly preferred Suitable phospholipids are natural (ie derived from natural products) or synthetic phospholipids. Preference is given to neutral and / or zwitterionic phospholipids such as the lecithins (phosphatidylcholines), in particular those which contain unsaturated fatty acid residues such as oleic acid and / or linoleic acid. Highly purified egg and soy lecithins containing at least 80% phosphatidylcholine are particularly preferred.
  • levemopamil hydrochloride in the lecithin-containing solutions according to the invention leads to pH values in the weakly acidic range (pH approx. 4-4.5). Despite the relatively acidic pH, these solutions are distinguished by a significantly improved local compatibility after intravenous administration compared to aqueous solutions of the same concentration which do not contain any phospholipid.
  • the local tolerance of the levemopamil hydrochloride solution can be easily increased by increasing the pH up to 7.0.
  • the long-term storage stability of the pH-neutral solutions is worse than that of the weakly acidic solutions, so that the pH-neutral solutions should be stored in a cool place.
  • Another method of improving the storage stability is to freeze-dry the solutions according to the invention. As a result of the very careful removal of the water, a dry preparation (lyophilisate) is formed which can be stored at room temperature. Before use, all that needs to be added is the water removed from the water.
  • the buffer solution can compensate for the low pH values (pH 4-5) of the levemopamil solution caused by the active ingredient (hydrochloride). Buffers which allow a pH of 5-7 in the finished solution are preferred. Phosphate buffers are very particularly preferred. Alkaline pH values above pH 7 are less suitable because the stability of the auxiliary (lecithin) is reduced by hydrolysis. Other auxiliary substances, e.g. Antioxidants can be added (2,6-di-tert-butyl-4-methylphenol) and / or heavy metal chelators such as EDTA (ethylenediamine-tetraacetic acid). The quantities used are based on the dosages that can be used in general in other injection preparations.
  • the isotonicization of the solution to achieve blood isotonicity can be carried out with the abovementioned buffer or with sodium chloride, but also with other salts, but preferably with carbohydrates such as sucrose and / or maltose. Glycerin is also suitable.
  • the salts or the carbohydrates become the buffer solution in quantities added, which in the finished application solution give Os olarities of about 280 to 400 mOsmol / kg.
  • the batch is homogenized. Preference is given to processes which bring the particle sizes of the colloidal solution to values below 0.2 micrometers (on average), so that the entire formulation can be sterile filtered (so-called sterilization filtration with a 0.2 micrometer filter).
  • a suspension in which the average particle sizes are still in the range of several micrometers is produced using simple dispersing devices which cause the coarse agglomerates to be broken up by knives running at high speed.
  • This suspension is then further homogenized using suitable methods.
  • High-pressure homogenizers which are widely used for the production of emulsions
  • filtration processes in which the suspension is pressed under suitable pressure through suitable membrane filters (extrusion). Both processes allow a gentle reduction of particle sizes to mean values of less than 0.2 micrometers.
  • the finished solutions can thus be sterile filtered, which means that sterilization filtration can take place, which is very important for a pharmaceutical form which is to be administered parenterally.
  • the reduction in particle sizes is still necessary to achieve adequate storage stability. Colloidal solutions with particle sizes in the micrometer range tend to sedimentation and / or flocculation and, moreover, cannot be administered parenterally because of possible embolisms.
  • the finished colloidal solution can be autoclaved in the final container by known methods (typically 20 min at 120 ° C.) without flocculation in the colloidal solution. This sterilization in the final container ensures that the finished dosage form is sterile.
  • the method according to the invention has the advantage of a significantly lower amount of lipid, which must be used for good local tolerance. While the weight ratio of active substance: lipid in the case of the emulsion is 1:11, this value can be reduced to about 1: 6 in the process according to the invention without differences in local tolerance being detectable in animal experiments. As a result, in the case of the method according to the invention, an unnecessarily high lipid load on the patient can be avoided.
  • the transparent, slightly opalescent colloidal solution was passed through a sterile filter (0.2 micrometer).
  • the ampoules were then sterilized in an autoclave for 20 minutes at 120 ° C.
  • the average particle size after autoclaving was 0.082 micrometers (measured by photon correlation spectroscopy).
  • the pH was 6.32.
  • Example 2 The preparation was carried out as in Example 1, but with egg lecithin E 100 (from Lipoid, FRG; same amount as in Example 1).
  • the mean particle sizes after autoclaving were 0.099 micrometers, the pH was 6.18.
  • Example 4 The preparation was carried out as in Example 2, but with a buffer solution which contained 43.15 g of maltrose monohydrate instead of sucrose. The mean particle sizes after autoclaving were 0.089 micrometers, the pH was 6.05. Example 4
  • the preparation was carried out as in Example 3, but without the addition of the phosphate buffer substances.
  • the mean particle sizes after autoclaving were 0.109 micrometers, the pH was 4.15.
  • the preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances.
  • the mean particle sizes after autoclaving were 0.086 microns, the pH was 4.07.
  • the preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances and with 26.0 g glycerol instead of saccharose.
  • the mean particle sizes after autoclaving were 0.046 micrometers, the pH was 4.17.
  • the preparation was carried out as in Example 2, but only with 2.063 g of egg lecithin E 100.
  • the average particle sizes were 0.063 micrometers, the pH was 6.33.
  • Levemopamil hydrochloride was dissolved in water at a concentration of 5.50 mg / ml.
  • Example 2 The formulations of Examples 2, 7 and 8 were administered intravenously at 6 times a day at a dose of 15 mg levemopamil hydrochloride per kg body weight to 6 rats at a rate of 0.6 ml / min. Formulation 8 was only applicable for 2 days, formulation 7 was applicable for 6 days until the occurrence of local incompatibilities made further application impossible. In contrast, the formulation of Example 2 could be administered to the animals over 28 days without local incompatibility reactions occurring.

Abstract

On décrit une solution colloïdale aqueuse de levemopamil obtenue par le fait qu'un mélange contenant de l'hydrochlorure de levemopamil, un phospholipide, un produit d'isotonicité et de l'eau ou une solution tampon est préparé et homogénéisé.An aqueous colloidal solution of levemopamil obtained by the fact that a mixture containing levemopamil hydrochloride, a phospholipid, an isotonic product and water or a buffer solution is prepared and homogenized.

Description

Lecithinhaltige Lösungen mit Levemopamil Solutions containing lecithin with levemopamil
Beschreibungdescription
Es wird ein Verfahren zur Herstellung wäßriger, lecithinhaltiger Lösungen mit dem Wirkstoff Levemopamil beschrieben, die mit Hilfe dieses Verfahrens erhaltenen Lösungen und die Verwendung dieser Lösungen zur Herstellung von Arzneimitteln.A process for the preparation of aqueous lecithin-containing solutions with the active ingredient levemopamil is described, the solutions obtained with the aid of this process and the use of these solutions for the production of medicaments.
Eine nicht unbeträchtliche Zahl von Wirkstoffen bereitet bei der Applikation durch das Auftreten lokaler Unverträglichkeiten im Bereich der Applikationsstelle Probleme. Derartige Nebenwirkungen werden insbesondere bei der parenteralen Applikation wäßriger Wirkstofflösungen, z.B. bei der Injektion in die Blutbahn in Form von Venenreizungen erkennbar. Zu diesen Wirkstoffen zählt auch Levemopamil (EP 147 707) . Es ist bekannt, daß mit Hilfe von Lipi- den und Phospholipiden die lokale Verträglichkeit von Levemopamil verbessert werden kann.A not inconsiderable number of active substances causes problems in the application due to the occurrence of local incompatibilities in the area of the application site. Such side effects are particularly noticeable in the parenteral application of aqueous active ingredient solutions, e.g. recognizable in the form of vein irritation when injected into the bloodstream. Levemopamil is one of these active ingredients (EP 147 707). It is known that the local tolerance of levemopamil can be improved with the help of lipids and phospholipids.
Levemopamil kann einerseits, wie in der DE-A-4015108.3 beschrie¬ ben, in einer Fettemulsion solubilisiert werden, wodurch die lo¬ kale Verträglichkeit getestet durch intravenöse Applikation an der Ratte, im Vergleich zur wäßrigen Lösung verbessert wird.Levemopamil can, on the one hand, as described in DE-A-4015108.3, be solubilized in a fat emulsion, as a result of which the local tolerance, tested by intravenous application to the rat, is improved compared to the aqueous solution.
Es wurde nun ein einfaches Verfahren gefunden, das gegenüber dem bekannten Verfahren deutliche Vorteile aufweist.A simple method has now been found which has clear advantages over the known method.
Gegenstand der Erfindung ist ein Verfahren zur Herstellung kol- loidaler wäßriger Levemopamil-Lösungen, dadurch gekennzeichnet, daß man eine Mischung aus Levemopamil-Salz, einem Phospholipid und einem Isotonisierungsmittel mit Wasser versetzt und homogeni¬ siertThe invention relates to a process for the preparation of colloidal aqueous levemopamil solutions, characterized in that a mixture of levemopamil salt, a phospholipid and an isotonizing agent is mixed with water and homogenized
Der Wirkstoff (Levemopamil) wird in Form seiner Salze eingesetzt. Bevorzugt ist das Levemopamil-Hydrochlorid. Die Wirkstoffkonzen- tration in der fertigen Lösung liegt bei 1-20 mg/ml, vorzugsweise bei 3-10 mg/ml. Ganz besonders bevorzugt sind Konzentrationen von etwa 5 mg/ml.The active substance (levemopamil) is used in the form of its salts. Levemopamil hydrochloride is preferred. The active ingredient concentration in the finished solution is 1-20 mg / ml, preferably 3-10 mg / ml. Concentrations of about 5 mg / ml are very particularly preferred.
Die dem Wirkstoff zugesetzte Menge Phospholipid ist für das Er¬ reichen einer guten lokalen Verträglichkeit entscheidend. Das Ge¬ wichtsverhältnis von Wirkstoff zu Phospholipid beträgt 1:4 bis 1:20, vorzugsweise 1:4 bis 1:10. Ganz besonders bevorzugt sind Gewichtsverhältnisse von Wirkstoff zu Phospholipid von 1:5 bis Geeignete Phospholipide sind natürliche (d.h. aus Naturstoffen gewonnene) oder synthetische Phospholipide. Bevorzugt sind neu¬ trale und/oder zwitterionische Phospholipide wie die Lecithine (Phosphatidylcholine) , insbesondere solche, die ungesättigte Fettsäurereste wie Ölsäure und/oder Linolsäure enthalten. Ganz besonders bevorzugt sind hochgereinigte Eier- und Sojalecithine, die mindestens 80 % Phosphatidylcholin enthalten.The amount of phospholipid added to the active ingredient is decisive for achieving good local tolerance. The weight ratio of active ingredient to phospholipid is 1: 4 to 1:20, preferably 1: 4 to 1:10. Weight ratios of active ingredient to phospholipid of 1: 5 to are very particularly preferred Suitable phospholipids are natural (ie derived from natural products) or synthetic phospholipids. Preference is given to neutral and / or zwitterionic phospholipids such as the lecithins (phosphatidylcholines), in particular those which contain unsaturated fatty acid residues such as oleic acid and / or linoleic acid. Highly purified egg and soy lecithins containing at least 80% phosphatidylcholine are particularly preferred.
Die Verwendung des Levemopamil-Hydrochlorids führt in den lecithinhaltigen erfindungsgemäßen Lösungen zu pH-Werten im schwach sauren Bereich (pH ca. 4-4,5). Trotz des relativ sauren pH-Werts zeichnen sich diese Lösungen durch eine deutlich verbes¬ serte lokale Verträglichkeit nach intravenöser Applikation gegen¬ über gleichkonzentrierten wäßrigen Lösungen aus, die kein Phos- pholipid enthalten.The use of levemopamil hydrochloride in the lecithin-containing solutions according to the invention leads to pH values in the weakly acidic range (pH approx. 4-4.5). Despite the relatively acidic pH, these solutions are distinguished by a significantly improved local compatibility after intravenous administration compared to aqueous solutions of the same concentration which do not contain any phospholipid.
Die lokale Verträglichkeit der Levemopamil-Hydrochlorid-Lösung läßt sich durch Erhöhung des pH-Wertes auf bis zu 7,0 noch leicht erhöhen. Die Langzeit-Lagerstabilität der pH-neutralen Lösungen ist allerdings schlechter als die der schwach sauren Lösungen, so daß die pH-neutralen Lösungen kühl gelagert werden sollten. Eine andere Methode zur Verbesserung der Lagerstabilität besteht darin, die erfindungsgemäßen Lösungen gefrierzutrocknen. Durch den hiermit sehr schonend erfolgenden Entzug des Wassers entsteht ein Trockenpräparat (Lyophilisat) , das bei Raumtemperatur gela¬ gert werden kann. Vor der Verwendung muß lediglich das zur entzo¬ gene Wasser wieder zugesetzt werden.The local tolerance of the levemopamil hydrochloride solution can be easily increased by increasing the pH up to 7.0. However, the long-term storage stability of the pH-neutral solutions is worse than that of the weakly acidic solutions, so that the pH-neutral solutions should be stored in a cool place. Another method of improving the storage stability is to freeze-dry the solutions according to the invention. As a result of the very careful removal of the water, a dry preparation (lyophilisate) is formed which can be stored at room temperature. Before use, all that needs to be added is the water removed from the water.
Die Pufferlösung kann die durch den Wirkstoff (Hydrochlorid) ver- ursachten niedrigen pH-Werte (pH 4-5) der Levemopamil-Lösung aus¬ gleichen. Bevorzugt sind Puffer, die einen pH-Wert von 5-7 in der fertigen Lösung ermöglichen. Ganz besonders bevorzugt sind Phos¬ phatpuffer. Alkalische pH-Werte über pH 7 sind weniger geeignet, da dadurch die Stabilität des Hilfsstoffs (Lecithin) durch Hydro- lyse herabgesetzt wird. Der Pufferlösung können weitere Hilfs¬ stoffe, z.B. Antioxidantien zugesetzt werden (2,6-Di-tert.bu- tyl-4-methylphenol) und/oder Schwermetallchelatoren wie EDTA (Ethylendiamin-tetraessigsäure) . Die dabei verwendeten Mengen orientieren sich an den in sonstigen InjektionsZubereitungen all- gemein einsetzbaren Dosierungen.The buffer solution can compensate for the low pH values (pH 4-5) of the levemopamil solution caused by the active ingredient (hydrochloride). Buffers which allow a pH of 5-7 in the finished solution are preferred. Phosphate buffers are very particularly preferred. Alkaline pH values above pH 7 are less suitable because the stability of the auxiliary (lecithin) is reduced by hydrolysis. Other auxiliary substances, e.g. Antioxidants can be added (2,6-di-tert-butyl-4-methylphenol) and / or heavy metal chelators such as EDTA (ethylenediamine-tetraacetic acid). The quantities used are based on the dosages that can be used in general in other injection preparations.
Die Isotonisierung der Lösung zur Erzielung der Blutisotonie kann mit dem oben genannten Puffer oder mit Natriumchlorid, aber auch mit anderen Salzen, bevorzugt aber mit Kohlenhydraten wie Saccha- rose und/oder Maltose erfolgen. Auch Glycerin ist geeignet. Die Salze bzw. die Kohlenhydrate werden der Pufferlösung in Mengen zugesetzt, die in der fertigen Applikationslösung Os olaritäten von etwa 280 bis 400 mOsmol/kg ergeben.The isotonicization of the solution to achieve blood isotonicity can be carried out with the abovementioned buffer or with sodium chloride, but also with other salts, but preferably with carbohydrates such as sucrose and / or maltose. Glycerin is also suitable. The salts or the carbohydrates become the buffer solution in quantities added, which in the finished application solution give Os olarities of about 280 to 400 mOsmol / kg.
Nach Herstellen der Gesamtmischung aus Wirkstoff, Phospholipid, Isotonisierungsmittel und Wasser bzw. Pufferlösung wird der An¬ satz homogenisiert. Bevorzugt sind Verfahren, die die Partikel¬ größen der kolloidalen Lösung auf Werte unter 0,2 Mikrometer (im Mittel) bringen, so daß die gesamte Formulierung sterilfiltrier- bar wird (sog. Entkeimungsfiltration mit 0,2 Mikrometer-Filter).After the entire mixture of active ingredient, phospholipid, isotonizing agent and water or buffer solution has been prepared, the batch is homogenized. Preference is given to processes which bring the particle sizes of the colloidal solution to values below 0.2 micrometers (on average), so that the entire formulation can be sterile filtered (so-called sterilization filtration with a 0.2 micrometer filter).
Es hat sich als zweckmäßig erwiesen, die Homogenisierung in zwei Schritten ablaufen zu lassen. Im ersten Schritt wird mit einfa¬ chen Dispergiergeräten, die durch schneilaufende Messer eine Zer¬ kleinerung der groben Agglomerate bewirken, eine Suspension her- gestellt, in der die mittleren Partikelgrößen noch im Bereich von mehreren Mikrometern liegen. Diese Suspension wird dann mit geei¬ gneten Verfahren weiter homogenisiert. Bevorzugt sind Hochdruck- homogenisatoren (die zur Herstellung von Emulsionen weit verbrei¬ tet sind) , aber auch Filtrationsverfahren, bei denen die Suspen- sion unter erhöhtem Druck durch geeignete Membranfilter gedrückt wird (Extrusion) . Beide Verfahren ermöglichen auf schonende Weise eine Reduzierung der Partikelgrößen auf Mittelwerte von unter 0,2 Mikrometer. Die fertigen Lösungen sind somit sterilfiltrier- bar, wodurch eine Entkeimungsfiltration erfolgen kann, die für eine Arzneiform, die parenteral verabreicht werden soll, sehr wichtig ist. Die Reduzierung der Partikelgrößen ist weiterhin zur Erreichung einer ausreichenden Lagerstabilität notwendig. Kolloi¬ dale Lösungen mit Partikelgrößen im Mikrometerbereich neigen zur Sedimentation und/oder Ausflockung und sind zudem wegen möglicher Embolien nicht parenteral applizierbar.It has proven expedient to have the homogenization run in two steps. In the first step, a suspension in which the average particle sizes are still in the range of several micrometers is produced using simple dispersing devices which cause the coarse agglomerates to be broken up by knives running at high speed. This suspension is then further homogenized using suitable methods. High-pressure homogenizers (which are widely used for the production of emulsions) are preferred, but also filtration processes in which the suspension is pressed under suitable pressure through suitable membrane filters (extrusion). Both processes allow a gentle reduction of particle sizes to mean values of less than 0.2 micrometers. The finished solutions can thus be sterile filtered, which means that sterilization filtration can take place, which is very important for a pharmaceutical form which is to be administered parenterally. The reduction in particle sizes is still necessary to achieve adequate storage stability. Colloidal solutions with particle sizes in the micrometer range tend to sedimentation and / or flocculation and, moreover, cannot be administered parenterally because of possible embolisms.
Die fertige kolloidale Lösung kann nach der Homogenisierung und Abfüllung (z.B. in Ampullen) im Endbehältnis durch bekannte Ver¬ fahren autoklaviert werden (typischerweise 20 min bei 120°C) , ohne daß es in der kolloidalen Lösung zu Ausflockungen kommt. Diese Sterilisation im Endbehältnis gewährleistet die Keimfreiheit der fertigen Arzneiform.After homogenization and filling (e.g. in ampoules), the finished colloidal solution can be autoclaved in the final container by known methods (typically 20 min at 120 ° C.) without flocculation in the colloidal solution. This sterilization in the final container ensures that the finished dosage form is sterile.
In Tierversuchen zeigte sich, daß die lokale Verträglichkeit der Formulierungen von dem Gewichtsverhältnis Wirkstoff:Lecithin ab¬ hängig ist. Lösungen, in denen etwa gleiche Gewichtsmengen Wirk¬ stoff und Phospholipid enthalten waren, zeigten im Tierversuch (Ratte) zwar eine Verbesserung der lokalen Verträglichkeit gegen¬ über einer rein wäßrigen Lösung, waren aber deutlich schlechter verträglich als die Formulierungen des erfindungsgemäßen Verfah¬ rens, in denen das Gewichtsverhältnis vorzugsweise bei 1:4 bis 1:10 liegt. Zur Erreichung einer optimalen Verträglichkeit ist daher eine ausreichende Menge Phospholipid nötig.Animal experiments have shown that the local tolerability of the formulations is dependent on the weight ratio of active ingredient: lecithin. Solutions in which approximately equal amounts by weight of active substance and phospholipid were present showed an improvement in the local tolerance compared to a purely aqueous solution in animal experiments (rats), but were significantly less tolerable than the formulations of the method according to the invention in which the weight ratio is preferably 1: 4 to 1:10 lies. A sufficient amount of phospholipid is therefore necessary to achieve optimal tolerance.
Gegenüber 'der Fettemulsionsformulierung der DE-A-4015108.5 be- sitzt das erfindungsgemäße Verfahren den Vorteil einer deutlich niedrigeren Lipidmenge, die für eine gute lokale Verträglichkeit eingesetzt werden muß. Während das Gewichtsverhältnis Wirk¬ stoff:Lipid im Fall der Emulsion 1:11 beträgt, kann dieser Wert beim erfindungsgemäßen Verfahren auf etwa 1:6 gesenkt werden, ohne daß Unterschiede bei der lokalen Verträglichkeit im Tierver¬ such nachweisbar sind. Dadurch kann im Fall des erfindungsgemäßen Verfahrens eine unnötig hohe Lipidbelastung des Patienten vermie¬ den werden.Compared to the fat emulsion formulation of DE-A-4015108.5, the method according to the invention has the advantage of a significantly lower amount of lipid, which must be used for good local tolerance. While the weight ratio of active substance: lipid in the case of the emulsion is 1:11, this value can be reduced to about 1: 6 in the process according to the invention without differences in local tolerance being detectable in animal experiments. As a result, in the case of the method according to the invention, an unnecessarily high lipid load on the patient can be avoided.
Die folgenden Beispiele veranschaulichen die Erfindung.The following examples illustrate the invention.
Beispiel 1example 1
1,375 g Levemopamil-Hydrochlorid, 7,500 g Sojalecithin S 100 (Fa. Lipoid, BRD) und 10 mg 2,6-Di-tert.-butyl-4-methylphenol wurden mit 150 ml Pufferlösung (bestehend aus 550 mg Dinatriu hydrogen- phosphat-Dihydrat, 265 mg Natriumdihydrogen-phosphat-Monohydrat, 43,15 g Saccharose und 100 mg Dinatrium-EDTA in 500 ml Wasser, versetzt. Die Mischung wurde mit einem Ultra-Turrax®-Dispergier- stab 10 min zu einer trüben Suspension zerkleinert und im Meßkol¬ ben mit Pufferlösung auf ein Gesamtvolumen von 250 ml aufgefüllt. Der Ansatz wurde dann im Hochdruckhomogenisator 45 min bei 50°C und 600 bar homogenisiert. Die durchsichtige, schwach opaleszie¬ rende kolloidale Lösung wurde über ein Sterilfilter (0,2 Mikrome- ter) in Ampullen abgefüllt. Die Ampullen wurden anschließend im Autoklaven 20 min bei 120°C sterilisiert. Die mittlere Partikel¬ größe nach dem Autoklavieren lag bei 0,082 Mikrometer (gemessen mit PhotonenkorrelationsSpektroskopie) . Der pH-Wert betrug 6,32.1.375 g levemopamil hydrochloride, 7.500 g soy lecithin S 100 (from Lipoid, Germany) and 10 mg 2,6-di-tert-butyl-4-methylphenol were mixed with 150 ml buffer solution (consisting of 550 mg disodium hydrogen phosphate Dihydrate, 265 mg of sodium dihydrogen phosphate monohydrate, 43.15 g of sucrose and 100 mg of disodium EDTA in 500 ml of water were added, and the mixture was comminuted to a cloudy suspension with an Ultra-Turrax® dispersing rod for 10 minutes and then im The flask was filled with buffer solution to a total volume of 250 ml and the mixture was then homogenized in the high-pressure homogenizer for 45 min at 50 ° C. and 600 bar. The transparent, slightly opalescent colloidal solution was passed through a sterile filter (0.2 micrometer The ampoules were then sterilized in an autoclave for 20 minutes at 120 ° C. The average particle size after autoclaving was 0.082 micrometers (measured by photon correlation spectroscopy). The pH was 6.32.
Beispiel 2Example 2
Die Herstellung erfolgte wie in Beispiel 1, aber mit Eierlecithin E 100 (Fa. Lipoid, BRD; gleiche Menge wie in Bsp. 1) . Die mittle¬ ren Partikelgrößen nach dem Autoklavieren lagen bei 0,099 Mikro- meter, der pH-Wert betrug 6,18.The preparation was carried out as in Example 1, but with egg lecithin E 100 (from Lipoid, FRG; same amount as in Example 1). The mean particle sizes after autoclaving were 0.099 micrometers, the pH was 6.18.
Beispiel 3Example 3
Die Herstellung erfolgte wie in Beispiel 2, aber mit einer Puf- ferlösung, die 43,15 g Maltrose-Monohydrat statt Saccharose ent¬ hielt. Die mittleren Partikelgrößen lagen nach dem Autoklavieren bei 0,089 Mikrometer, der pH-Wert betrug 6,05. Beispiel 4The preparation was carried out as in Example 2, but with a buffer solution which contained 43.15 g of maltrose monohydrate instead of sucrose. The mean particle sizes after autoclaving were 0.089 micrometers, the pH was 6.05. Example 4
Die Herstellung erfolgte wie in Beispiel 3, aber ohne Zusatz der Phosphat-Puffersubstanzen. Die mittleren Partikelgrößen lagen nach dem Autoklavieren bei 0,109 Mikrometer, der pH-Wert betrug 4,15.The preparation was carried out as in Example 3, but without the addition of the phosphate buffer substances. The mean particle sizes after autoclaving were 0.109 micrometers, the pH was 4.15.
Beispiel 5Example 5
Die Herstellung erfolgte wie in Beispiel 2, aber ohne Zusatz der Phosphat-Puffersubstanzen. Die mittleren Partikelgrößen lagen nach dem Autoklavieren bei 0,086 Mikrometer, der pH-Wert betrug 4,07.The preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances. The mean particle sizes after autoclaving were 0.086 microns, the pH was 4.07.
Beispiel 6Example 6
Die Herstellung erfolgte wie in Beispiel 2, aber ohne Zusatz der Phosphat-Puffersubstanzen sowie mit 26,0 g Glycerin statt Saccha¬ rose. Die mittleren Partikelgrößen lagen nach dem Autoklavieren bei 0,046 Mikrometer, der pH-Wert betrug 4,17.The preparation was carried out as in Example 2, but without the addition of the phosphate buffer substances and with 26.0 g glycerol instead of saccharose. The mean particle sizes after autoclaving were 0.046 micrometers, the pH was 4.17.
Beispiel 7 (Vergleichsbeispiel)Example 7 (comparative example)
Die Herstellung erfolgte wie in Beispiel 2, aber nur mit 2,063 g Eierlecithin E 100. Die mittleren Partikelgrößen lagen bei 0,063 Mikrometer, der pH-Wert betrug 6,33.The preparation was carried out as in Example 2, but only with 2.063 g of egg lecithin E 100. The average particle sizes were 0.063 micrometers, the pH was 6.33.
Beispiel 8 (Vergleichsbeispiel)Example 8
Levemopamil-Hydrochlorid wurde in einer Konzentration von 5,50 mg/ml in Wasser gelöst.Levemopamil hydrochloride was dissolved in water at a concentration of 5.50 mg / ml.
Beispiel 9Example 9
Die Formulierungen der Beispiele 2, 7 und 8 wurden lx täglich in einer Dosis von 15 mg Levemopamil-Hydrochlorid pro kg Körperge¬ wicht 6 Ratten intravenös mit einer Geschwindigkeit von 0,6 ml/ min verabreicht. Die Formulierung 8 war nur 2 Tage, die Formulie¬ rung 7 war 6 Tage lang applizierbar, bis das Auftreten lokaler Unverträglichkeiten eine weitere Applikation unmöglich machte. Dagegen konnte den Tieren die Formulierung des Beispiels 2 über 28 Tage verabreicht werden, ohne daß lokale Unverträglichkeits¬ reaktionen auftraten. The formulations of Examples 2, 7 and 8 were administered intravenously at 6 times a day at a dose of 15 mg levemopamil hydrochloride per kg body weight to 6 rats at a rate of 0.6 ml / min. Formulation 8 was only applicable for 2 days, formulation 7 was applicable for 6 days until the occurrence of local incompatibilities made further application impossible. In contrast, the formulation of Example 2 could be administered to the animals over 28 days without local incompatibility reactions occurring.

Claims

Pa en ansprüche Pa en claims
1. Verfahren zur Herstellung kolloidaler wäßriger Levemopamil- Lösungen, dadurch gekennzeichnet, daß man eine Mischung aus einem Levemopamil-Salz, einem Phospholipid und einem Isotoni¬ sierungsmittel mit Wasser versetzt und homogenisiert.1. A process for the preparation of colloidal aqueous Levemopamil solutions, characterized in that a mixture of a Levemopamil salt, a phospholipid and an Isotoni¬ sierungsmittel mixed with water and homogenized.
2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man der Mischung aus Levemopamil-Salz, Phospholipid und Isotoni¬ sierungsmittel einen Puffer zugibt.2. The method according to claim 1, characterized in that the mixture of levemopamil salt, phospholipid and Isotoni¬ sierungsmittel a buffer is added.
3. Lösung, erhältlich gemäß Anspruch 1 oder 2. 3. Solution obtainable according to claim 1 or 2.
PCT/EP1993/000062 1992-01-21 1993-01-14 Lecithin-containing solutions with levemopamil WO1993013765A1 (en)

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SI9300468A (en) * 1992-10-14 1994-06-30 Hoffmann La Roche Injectable composition for the sustained release of biologically active compounds

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WO1992001441A1 (en) * 1990-07-21 1992-02-06 Knoll Aktiengesellschaft Stable formulation of active substance
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EP0366990A2 (en) * 1988-10-29 1990-05-09 A. Nattermann & Cie. GmbH Stable parenteral solution of 2-phenyl-1.2-benzisoselenazol-3(2H)-one and process for producing the same
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WO1992001441A1 (en) * 1990-07-21 1992-02-06 Knoll Aktiengesellschaft Stable formulation of active substance
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WO2001060337A1 (en) * 2000-02-14 2001-08-23 The Procter & Gamble Company Compositions for topical delivery of a pharmaceutically active agent having reduced oxidation

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