WO2003011459A1 - Method for producing pharmaceutical preparations - Google Patents

Method for producing pharmaceutical preparations Download PDF

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Publication number
WO2003011459A1
WO2003011459A1 PCT/EP2002/007863 EP0207863W WO03011459A1 WO 2003011459 A1 WO2003011459 A1 WO 2003011459A1 EP 0207863 W EP0207863 W EP 0207863W WO 03011459 A1 WO03011459 A1 WO 03011459A1
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WO
WIPO (PCT)
Prior art keywords
particles
dispersion
ion exchanger
pharmaceutical preparations
ion
Prior art date
Application number
PCT/EP2002/007863
Other languages
German (de)
French (fr)
Inventor
Thomas Rheinländer
Gül CAGLAR
Original Assignee
Institut für Diagnostikforschung GmbH an der Freien Universität Berlin
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 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin filed Critical Institut für Diagnostikforschung GmbH an der Freien Universität Berlin
Priority to JP2003516683A priority Critical patent/JP2004535907A/en
Priority to EP02747467A priority patent/EP1463583A1/en
Publication of WO2003011459A1 publication Critical patent/WO2003011459A1/en
Priority to NO20040312A priority patent/NO20040312L/en

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D57/00—Separation, other than separation of solids, not fully covered by a single other group or subclass, e.g. B03C
    • B01D57/02—Separation, other than separation of solids, not fully covered by a single other group or subclass, e.g. B03C by electrophoresis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J39/00—Cation exchange; Use of material as cation exchangers; Treatment of material for improving the cation exchange properties
    • B01J39/04—Processes using organic exchangers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J41/00—Anion exchange; Use of material as anion exchangers; Treatment of material for improving the anion exchange properties
    • B01J41/04—Processes using organic exchangers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J47/00—Ion-exchange processes in general; Apparatus therefor
    • B01J47/12—Ion-exchange processes in general; Apparatus therefor characterised by the use of ion-exchange material in the form of ribbons, filaments, fibres or sheets, e.g. membranes

Definitions

  • the invention relates to a new method for producing pharmaceutical
  • the pharmaceutical preparation being in the form of a dispersion, the particles present in the dispersion having a charge distribution and at least some of the particles present in the dispersion being separated off with the aid of ion exchangers or by means of electrophoretic separation processes. Furthermore, directions for carrying out the driving are disclosed. Furthermore, pharmaceutical preparations, which can be obtained with the aid of the ner process, and their use are described.
  • compositions can be in the form of dispersions, e.g. as parenteral fat emulsions or crystal suspensions.
  • Magnetic dispersions are used as contrast agents in nuclear magnetic resonance imaging (see, for example, EP 186 616, US 5,328,681, US 5,424,419, US 5,766,572).
  • International application WO 98/05430 describes a process for separating magnetic materials from pharmaceutical preparations and agents produced by this process. It is shown that magnetite dispersions in which certain magnetic particles are selected are particularly well suited for magnetic resonance angiography.
  • ion exchangers in connection with pharmaceuticals is proposed for special applications.
  • ion exchangers are proposed in a separate container (WO 9823375).
  • ion exchange resins are proposed for the delayed release of active substances such as pharmaceuticals, which are loaded with the active substance and are also covered or loaded with an oppositely charged polymer (DE 19619313).
  • the object of the present invention is to provide a further process by means of which the preparation of pharmaceutical preparations from dispersions is possible.
  • the new manufacturing process does not separate dispersions with the help of a magnetic filter, but with the help of ion exchangers or by electrophoresis.
  • dispersions in the method according to the invention are not separated by magnetic forces, but by electrostatic forces.
  • the method is therefore not restricted to magnetic materials like the method described in WO 98/05430.
  • the method according to the invention requires that the particles to be selected are electrostatically charged.
  • the charge of the particles contributes to the stabilization of the dispersion and is therefore present in most cases or a desired effect. It stems from bound or adsorbed ions, amino acids, proteins, lipids, lipoproteins, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates, glycoproteins, natural or synthetic polymers and their derivatives, activated carbons,
  • Silicon compounds and / or surface-active substances such as surfactants.
  • the particles can be or are combined with structure-specific substances, some of which also have a stabilizing effect.
  • structure-specific substances include antibodies, antibody fragments, agonists specifically binding to receptors such as cytokines, lymphokines, endothelins or their antagonists, other specific peptides or proteins, receptors, enzymes, enzyme substrates, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates or lipoproteins.
  • Preferred structure-specific substances are those whose binding constant is in the range from 10 5 to 10 15 1 / mol.
  • the structure-specific substances can be marked with the particles using common methods. An alternative is the binding via antibodies which are directed against the surface of the particles, for example against the shell material.
  • particles in pharmaceutical preparations in the form of dispersions for example in magnetite dispersions or ultrasound contrast medium dispersions, have a charge distribution, i.e. ions with a different number of elementary charges are present (single, double, triple charged, etc.) side by side in the dispersion.
  • the separation of such dispersions with the aid of the method according to the invention therefore leads to new pharmaceutical preparations which have an altered charge distribution.
  • the separation after the charge also allows an influence on the in vivo pharmacokinetic properties of the pharmaceutical preparations.
  • Particles in magnetite dispersions are magnetic, particles in ultrasound contrast medium dispersions are usually filled with a gas.
  • the particles to be selected advantageously have a size of less than 10 ⁇ m. Particle sizes from 1 to 100 nm are particularly preferred.
  • a device suitable for carrying out the method according to the invention consists of a separation space which contains an ion exchanger and has an inlet and outlet. Special configurations of such a device are shown in FIG. 1.
  • (1) denotes a separation space
  • (3) an ion exchange membrane
  • (4) a frit or a filter
  • each a connection (6) the inflow and (7) the outflow.
  • FIG. (8) A device integrated in an infusion set is shown schematically in FIG. (8) should denote the infusion container.
  • the device can also be designed as a front filter for an infusion or injection set.
  • ion exchangers All common commercially available ion exchangers can be considered as ion exchangers.
  • the most common ion exchangers are gel-like, the ions having to diffuse through the gel with a porosity of, for example, 3 nm to the exchanger groups. Macroporous ion exchangers with pores in the range of approximately 100 nm can also be used. Ion exchangers in which the exchanger groups sit on tentacles are preferred. Ion exchange membranes can also be used.
  • Displacement salts or an electrophoresis buffer that may be used choose that the ions and salts are physiologically compatible and can remain in the products.
  • electrophoresis is possible as free or carrier electrophoresis, e.g. as gel and paper electrophoresis.
  • the method according to the invention is particularly suitable for the production of
  • Contrast medium dispersions e.g. Magnetic resonance or
  • the dispersions modified in this way can be used for certain diagnostic questions (e.g.
  • the method is also suitable for separating disruptive foreign particles from pharmaceutical preparations.
  • Ultrafiltered magnetite suspension (produced according to US 4101435, Ex. 7) in 10 mM sodium acetate buffer pH 5 [zeta potential: -27 mV, 70 nm particle diameter (photon correlation spectroscopy (PCS)), rl: 20 l / mmol Fe / s, r2: 160 1 / mmolFe / s (magnetic resonance (MR)), 5 mT / mol Fe (magnetic relaxometry (MRX) according to DE 19503664, solid), 1.1 mT / mol Fe (MRX liquid)] is on the paper MN 866 from Macherey-Nagel von dripped away from the anode.
  • PCS photon correlation spectroscopy
  • the supernatant is dialyzed (-35 mV, 76 nm, 22/167 l / mmol / s, 5.2 / 1.1 mT / mol).
  • the exchanger beads are shaken overnight with 1 M NaCl and the supernatant is dialyzed (-16 mV, 67 nm, 18/69 l mmol s, 1.2 / 0.3 mT / mol).
  • a suitable ion exchanger is filled into a container with two connections and at least one filter frit (see FIG. 1). If the ion exchanger is suspended in a saline solution, the solution is then replaced by rinsing with water.
  • Ion exchange attachment according to Example 3, filled with 1 ml of weak tentacle anion exchanger Fractogel EMD DMAE 650 S from Merck, and filled with dist. Rinsed water. The pass only has a count rate of 0.4 kCps. This reflects the separation of the charged particles.

Abstract

The invention relates to a novel method for producing pharmaceutical preparations or intermediate products thereof, whereby the pharmaceutical preparation is provided in the form of a dispersion, the particles contained in the dispersion have a charge distribution, and at least a portion of the particles contained in the dispersion are separated out with the aid of ion exchangers or by electrophoretic separating methods. Devices for carrying out the method are also disclosed in addition to pharmaceutical preparations, which can be obtained by using said method, as well as the use thereof.

Description

Verfahren zur Herstellung pharmazeutischer ZubereitungenProcess for the preparation of pharmaceutical preparations
Die Erfindung betrifft ein neues Verfahren zur Herstellung pharmazeutischerThe invention relates to a new method for producing pharmaceutical
Zubereitungen oder deren Zwischenprodukten, wobei die pharmazeutische Zubereitung als Dispersion vorliegt, die in der Dispersion vorliegenden Partikel eine Ladungsverteilung aufweisen und zumindest ein Teil der in der Dispersion vorliegenden Partikel mit Hilfe von Ionenaustauschern oder durch elektrophoretische Trennverfahren abgetrennt werden. Weiter werden Norrichtungen zur Durchführung des Nerfahrens offenbart. Ferner werden pharmazeutische Zubereitungen, welche mit Hilfe des Nerfahrens erhältlich sind, sowie deren Verwendung beschrieben.Preparations or their intermediates, the pharmaceutical preparation being in the form of a dispersion, the particles present in the dispersion having a charge distribution and at least some of the particles present in the dispersion being separated off with the aid of ion exchangers or by means of electrophoretic separation processes. Furthermore, directions for carrying out the driving are disclosed. Furthermore, pharmaceutical preparations, which can be obtained with the aid of the ner process, and their use are described.
Pharmazeutische Zubereitungen können in Form von Dispersionen vorliegen, z.B. als parenterale Fettemulsionen oder Kristallsuspensionen. In der Kernresonanztomographie werden Magnetitdispersionen als Kontrastmittel eingesetzt (siehe z.B. EP 186 616, US 5,328,681, US 5,424,419, US 5,766,572). In der internationalen Anmeldung WO 98/05430 werden ein Verfahren zur Abtrennung magnetischer Materialien aus pharmazeutischen Zubereitungen sowie nach diesem Verfahren hergestellte Mittel beschrieben. Es wird gezeigt, daß Magnetitdispersionen, bei denen bestimmte magnetische Partikel selektiert werden, für die Magnetresonanzangiographie besonders gut geeignet sind.Pharmaceutical preparations can be in the form of dispersions, e.g. as parenteral fat emulsions or crystal suspensions. Magnetic dispersions are used as contrast agents in nuclear magnetic resonance imaging (see, for example, EP 186 616, US 5,328,681, US 5,424,419, US 5,766,572). International application WO 98/05430 describes a process for separating magnetic materials from pharmaceutical preparations and agents produced by this process. It is shown that magnetite dispersions in which certain magnetic particles are selected are particularly well suited for magnetic resonance angiography.
Weiterhin ist bereits bekannt, daß sich Ionen bis hin zu hochmolekularen Biomolekülen wie Proteinen durch Ionenaustausch oder Elektrophorese trennen lassen (Schwedt, Analytische Chemie, Thieme Verlag, 1995, 301 ff + 365 ff). In der Technik werden zur elektrostatischen bzw. -phoretischen Separation von Mineralien, Verunreinigungen, Wertstoffen usw. die Partikel allerdings vorher aufgeladen durch Ionenbombardment, kapazitive Induktion oder Kontaktelektrifizierung (Bronkala, UUmann's Encyclopedia of Industrial Chemistry (5. Ed.) B2, 20-1, VCHFurthermore, it is already known that ions up to high molecular weight biomolecules such as proteins can be separated by ion exchange or electrophoresis (Schwedt, Analytische Chemie, Thieme Verlag, 1995, 301 ff + 365 ff). In technology, however, the particles are charged beforehand by ion bombardment, capacitive induction or contact electrification for the electrostatic or -phoretic separation of minerals, impurities, valuable materials, etc. (Bronkala, UUmann's Encyclopedia of Industrial Chemistry (5th ed.) B2, 20-1 , VCH
Weinheim 1990). Die Trennung von Partikeln im Mikrometerbereich erfolgt trocken, im Νanometerbereich naß. Mit der Dielektrophorese hingegen können prinzipell alle ungeladene, aufgrund ihrer Polarisierbarkeit mit elektrischen Gleich- wie Wechselfeldern getrennt werden.Weinheim 1990). Particles in the micrometer range are dry and wet in the Νanometer range. In principle, with dielectrophoresis everyone can uncharged, due to their polarizability with electrical DC and AC fields.
Für spezielle Anwendungen wird der Einsatz von Ionenaustauschern im Zusammenhang mit Pharmazeutika vorgeschlagen. So werden zur Änderung des pH-Werts von pH- empfindlichen pharmazeutischen Lösungen von deren Lagerungs-pH auf einen geeigneten Verabreichungs-pH Ionenaustauscher in einem separaten Behältnis vorgeschlagen (WO 9823375). Weiterhin werden für die verzögerte Abgabe von Wirkstoffen wie Pharmazeutika Ionenaustauscherharze vorgeschlagen, die mit Wirkstoff beladen und ferner mit einem entgegengesetzt geladenen Polymer bedeckt oder beladen werden (DE 19619313).The use of ion exchangers in connection with pharmaceuticals is proposed for special applications. To change the pH of pH-sensitive pharmaceutical solutions from their storage pH to a suitable administration pH, ion exchangers are proposed in a separate container (WO 9823375). Furthermore, ion exchange resins are proposed for the delayed release of active substances such as pharmaceuticals, which are loaded with the active substance and are also covered or loaded with an oppositely charged polymer (DE 19619313).
Aufgabe der vorliegenden Erfindung ist es, ein weiteres Verfahren bereitzustellen, mit dessen Hilfe die Herstellung pharmazeutischer Zubereitungen aus Dispersionen gelingt.The object of the present invention is to provide a further process by means of which the preparation of pharmaceutical preparations from dispersions is possible.
Diese Aufgabe wird mit dem neuen Verfahren zur Herstellung pharmazeutischer Zubereitungen gemäß Patentanspruch 1 gelöst.This object is achieved with the new method for producing pharmaceutical preparations according to claim 1.
Das neue Herstellungsverfahren trennt Dispersionen nicht mit Hilfe eines magnetischen Filters, sondern mit Hilfe von Ionenaustauschern oder durch Elektophorese auf.The new manufacturing process does not separate dispersions with the help of a magnetic filter, but with the help of ion exchangers or by electrophoresis.
Im Gegensatz zu dem aus WO 98/05430 bekannten Verfahren werden Dispersionen bei dem erfindungsgemäßen Verfahren nicht durch magnetische Kräfte, sondern durch elektrostatische Kräfte getrennt. Das Verfahren ist daher nicht wie das in WO 98/05430 beschriebene Verfahren auf magnetische Materialien beschränkt. Allerdings erfordert das erfindungsgemäße Verfahren, daß die zu selektierenden Partikel elektrostatisch geladen sind.In contrast to the method known from WO 98/05430, dispersions in the method according to the invention are not separated by magnetic forces, but by electrostatic forces. The method is therefore not restricted to magnetic materials like the method described in WO 98/05430. However, the method according to the invention requires that the particles to be selected are electrostatically charged.
Die Ladung der Partikel trägt zur Stabilisierung der Dispersion bei und ist daher in den meisten Fällen vorhanden bzw. ein erwünschter Effekt. Sie rührt von gebundenen oder adsorbierten Ionen, Aminosäuren, Proteinen, Lipiden, Lipoproteinen, Nukleotiden, Ribonukleinsäuren, Desoxyribonukleinsäuren, Kohlenhydraten, Glycoproteinen, natürlichen oder synthetischen Polymeren sowie deren Derivate, Aktivkohlen,The charge of the particles contributes to the stabilization of the dispersion and is therefore present in most cases or a desired effect. It stems from bound or adsorbed ions, amino acids, proteins, lipids, lipoproteins, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates, glycoproteins, natural or synthetic polymers and their derivatives, activated carbons,
Siliziumverbindungen und/oder grenzflächenaktiven Substanzen wie Tensiden her.Silicon compounds and / or surface-active substances such as surfactants.
Die Partikel können mit strukturspezifischen Substanzen kombiniert sein oder werden, welche teilweise ebenfalls stabilisierend wirken. Solche strukturspezifischen Substanzen sind u.a. Antikörper, Antikörperfragmente, spezifisch an Rezeptoren bindende Agonisten wie Zytokine, Lymphokine, Endotheline oder deren Antagonisten, sonstige spezifische Peptide oder Proteine, Rezeptoren, Enzyme, Enzymsubstrate, Nukleotide, Ribonukleinsäuren, Desoxyribonukleinsäuren, Kohlenhydrate oder Lipoproteine. Als strukturspezifische Substanzen werden diejenigen bevorzugt, deren Bindungskonstante im Bereich von 105 - 1015 1/mol liegt. Die strukturspezifischen Substanzen lassen sich mit Hilfe geläufiger Verfahren mit den Partikeln markieren. Eine Alternative ist die Bindung über Antikörper, die gegen die Oberfläche der Partikel gerichtet sind, z.B. gegen das Hüllmaterial.The particles can be or are combined with structure-specific substances, some of which also have a stabilizing effect. Such structure-specific substances include antibodies, antibody fragments, agonists specifically binding to receptors such as cytokines, lymphokines, endothelins or their antagonists, other specific peptides or proteins, receptors, enzymes, enzyme substrates, nucleotides, ribonucleic acids, deoxyribonucleic acids, carbohydrates or lipoproteins. Preferred structure-specific substances are those whose binding constant is in the range from 10 5 to 10 15 1 / mol. The structure-specific substances can be marked with the particles using common methods. An alternative is the binding via antibodies which are directed against the surface of the particles, for example against the shell material.
Im Gegensatz zu biochemischen Molekülen wie Proteinen, wo alle Moleküle eines Proteins unter gleichen Bedingungen dieselbe Ladung aufweisen, besitzen Partikel in pharmazeutischen Zubereitungen in Form von Dispersionen, beispielsweise in Magnetitdispersionen oder Ultraschallkontrastmitteldispersionen, eine Ladungsverteilung, d.h., es liegen Ionen mit einer unterschiedlichen Anzahl an Elementarladungen (einfach, doppelt, dreifach geladen usw.) nebeneinander in der Dispersion vor. Die Auftrennung derartiger Dispersionen mit Hilfe des erfinderischen Verfahrens führt daher zu neuen pharmazeutischen Zubereitungen, die eine veränderte Ladungsverteilung aufweisen. Da die Aufnahme parenteral in den Menschen oder das Tier eingebrachter Partikel in das monozytäre Phagozytensystem (MPS) bzw. in andere Körperteile u.a. von deren Ladung abhängt, erlaubt die Separation nach der Ladung auch eine Einflußnahme auf die in-vivo pharmakokinetischen Eigenschaften der pharmazeutischen Zubereitungen.In contrast to biochemical molecules such as proteins, where all molecules of a protein have the same charge under the same conditions, particles in pharmaceutical preparations in the form of dispersions, for example in magnetite dispersions or ultrasound contrast medium dispersions, have a charge distribution, i.e. ions with a different number of elementary charges are present (single, double, triple charged, etc.) side by side in the dispersion. The separation of such dispersions with the aid of the method according to the invention therefore leads to new pharmaceutical preparations which have an altered charge distribution. Since the uptake of particles introduced parenterally into humans or animals into the monocytic phagocyte system (MPS) or into other parts of the body depending on their charge, the separation after the charge also allows an influence on the in vivo pharmacokinetic properties of the pharmaceutical preparations.
Partikel in Magnetitdispersionen sind magnetisch, Partikel in Ultraschallkontrastmitteldispersionen sind in der Regel mit einem Gas gefüllt. Die zu selektierenden Partikel weisen vorteilhafterweise eine Größe von kleiner als 10 μm auf. Besonders bevorzugt sind Partikelgrößen von 1 bis 100 nm.Particles in magnetite dispersions are magnetic, particles in ultrasound contrast medium dispersions are usually filled with a gas. The particles to be selected advantageously have a size of less than 10 μm. Particle sizes from 1 to 100 nm are particularly preferred.
Eine zur Durchführung des erfindungsgemäßen Verfahrens geeignete Vorrichtung besteht aus einem Separationsraum, welcher einen Ionenaustauscher enthält und einen Zu- und Ablauf hat. Spezielle Ausgestaltungen einer solchen Vorrichtung sind in Fig. 1 gezeigt. Dabei bezeichnet (1) einen Separationsraum, (2) Ionenaustauscherpartikel, (3) eine Ionenaustauschermembran, (4) eine Fritte bzw. einen Filter, (5) jeweils einen Anschluß, (6) den Zufluß und (7) den Abfluß.A device suitable for carrying out the method according to the invention consists of a separation space which contains an ion exchanger and has an inlet and outlet. Special configurations of such a device are shown in FIG. 1. Here, (1) denotes a separation space, (2) ion exchange particles, (3) an ion exchange membrane, (4) a frit or a filter, (5) each a connection, (6) the inflow and (7) the outflow.
In Fig. 2 ist schematisch eine in ein Infüsionsbesteck integrierte Vorrichtung gezeigt. (8) soll dabei den Infusionsbehälter bezeichnen.A device integrated in an infusion set is shown schematically in FIG. (8) should denote the infusion container.
Die Vorrichtung kann auch als Vorsatzfilter für ein Infusions- oder Injektionsbesteck ausgeführt werden.The device can also be designed as a front filter for an infusion or injection set.
Als Ionenaustauscher kommen alle gängigen handelsüblichen Ionenaustauscher in Betracht. Die gebräuchlichsten Ionenaustauscher sind gelförmig, wobei die Ionen durch das Gel mit einer Porosität von beispielsweise 3 nm zu den Austauschergruppen diffundieren müssen. Es können auch makroporöse Ionenaustauscher verwendet werden, welche Poren im Bereich von ca. 100 nm aufweisen. Bevorzugt sind Ionenaustauscher, bei denen die Austauschergruppen auf Tentakeln sitzen. Weiter können auch Ionenaustauschermembranen verwendet werden. Ferner gibt es schwache/starke Ionenaustauscher. Schwache Ionenaustauscher enthalten schwache Säure- oder Basegruppen wie z.B. R-COOH, starke Ionenaustauscher enthalten starke Säure- oder Basegruppen wie z.B. R-SO3 ". Zur vollständigen Entfernung aller geladenen Verbindungen ist der Einsatz von Anionen- und Kationenaustauscher erforderlich.All common commercially available ion exchangers can be considered as ion exchangers. The most common ion exchangers are gel-like, the ions having to diffuse through the gel with a porosity of, for example, 3 nm to the exchanger groups. Macroporous ion exchangers with pores in the range of approximately 100 nm can also be used. Ion exchangers in which the exchanger groups sit on tentacles are preferred. Ion exchange membranes can also be used. There are also weak / strong ion exchangers. Weak ion exchangers contain weak acid or base groups such as R-COOH, strong ion exchangers contain strong acid or base groups such as R-SO 3 " . The complete removal of all charged compounds requires the use of anion and cation exchangers.
Die Einstellung eines bestimmten pH-Wertes für die Trennung kann von Vorteil sein. Außerdem ist es vorteilhaft, die Gegenionen der Ionenaustauscher und dieSetting a certain pH value for the separation can be advantageous. It is also advantageous to use the counterions of the ion exchanger and the
Verdrängungssalze bzw. einen gegebenenfalls verwendeten Elektrophoresepuffer so zu wählen, daß die Ionen und Salze physiologisch verträglich sind und in den Produkten verbleiben können.Displacement salts or an electrophoresis buffer that may be used choose that the ions and salts are physiologically compatible and can remain in the products.
Beim elektrophoretischen Trennverfahren ist die Elektrophorese als freie oder Trägerelektrophorese möglich, wie z.B. als Gel- und Papierelektrophorese.In the electrophoretic separation process, electrophoresis is possible as free or carrier electrophoresis, e.g. as gel and paper electrophoresis.
Das erfindungsgemäße Verfahren eignet sich besonders zur Herstellung vonThe method according to the invention is particularly suitable for the production of
Kontrastmitteldispersionen, wie z.B. Magnetresonanz- oderContrast medium dispersions, e.g. Magnetic resonance or
Ultraschallkontrastmitteldispersionen. Dabei werden bereits vorhandene Magnetresonanz- bzw. Ultraschallkontrastmitteldispersionen mit dem erfindungsgemäßen Verfahren behandelt. Durch die Selektion bestimmter Partikel werden die physikalischenUltrasound contrast agent dispersions. Already existing magnetic resonance or ultrasound contrast medium dispersions are treated with the method according to the invention. By selecting certain particles, the physical
Eigenschaften der Kontrastmitteldispersionen verändert. Die so veränderten Dispersionen können für bestimmte diagnostische Fragestellungen eingesetzt werden (z.B.Properties of the contrast medium dispersions changed. The dispersions modified in this way can be used for certain diagnostic questions (e.g.
Kernresonanz- Angiographie) .Nuclear magnetic resonance angiography).
Darüber hinaus eignet sich das Verfahren auch zur Abtrennung störender Fremdpartikel aus pharmazeutischen Zubereitungen.In addition, the method is also suitable for separating disruptive foreign particles from pharmaceutical preparations.
Die nachfolgenden Beispiele erläutern die Erfindung, ohne sie auf diese beschränken zu wollen. The following examples illustrate the invention, without wishing to restrict it thereto.
Beispiel 1example 1
Trennung geladener Partikel aus einer Dispersion geladener Partikel mittels ElektrophoreseSeparation of charged particles from a dispersion of charged particles using electrophoresis
Ultrafiltrierte Magnetitsuspension (hergestellt nach US 4101435, Beisp. 7) in 10 mM Natriumacetatpuffer pH 5 [Zetapotential: -27 mV, 70 nm Partikeldurchmesser (Photonenkorrelationsspektroskopie (PCS)), rl: 20 l/mmol Fe/s, r2: 160 1/mmolFe/s (Magnetresonanz (MR)), 5 mT/mol Fe (Magnetrelaxometrie (MRX) gemäß DE 19503664, fest), 1, 1 mT/mol Fe (MRX flüssig)] wird auf das Papier MN 866 von Macherey-Nagel von der Anode abgewandt getropft. Bei 20 V/cm wird ein Teil der Partikel zur Anode hin abgelenkt, so daß die Partikel am Ende der Laufstrecke an verschiedenen Ausgängen aufgefangen werden können. Es wird eine kaum abgelenkte Fraktion (-23 mV, 60 nm, 5,1/0,7 mT/mol) sowie eine zur Anode hin abgelenkte erhalten (-25 mV, 60 nm, 5,4/0,8 mT/mol).Ultrafiltered magnetite suspension (produced according to US 4101435, Ex. 7) in 10 mM sodium acetate buffer pH 5 [zeta potential: -27 mV, 70 nm particle diameter (photon correlation spectroscopy (PCS)), rl: 20 l / mmol Fe / s, r2: 160 1 / mmolFe / s (magnetic resonance (MR)), 5 mT / mol Fe (magnetic relaxometry (MRX) according to DE 19503664, solid), 1.1 mT / mol Fe (MRX liquid)] is on the paper MN 866 from Macherey-Nagel von dripped away from the anode. At 20 V / cm, some of the particles are deflected towards the anode, so that the particles can be collected at various outlets at the end of the run. A fraction which is hardly deflected (-23 mV, 60 nm, 5.1 / 0.7 mT / mol) and one which is deflected towards the anode are obtained (-25 mV, 60 nm, 5.4 / 0.8 mT / mol ).
Beispiel 2Example 2
Trennung geladener Partikel aus einer Dispersion geladener Partikel mit einem starkem IonenaustauscherSeparation of charged particles from a dispersion of charged particles with a strong ion exchanger
Zu 5 ml ultrafiltrierter Magnetitsuspension [Zetapotential: -34 mV, 70 nm Partikeldurchmesser (PCS), rl: 20 l/mmol/s, r2: 160 l/mmol/s (MR). , 5 mT/mol (MRX fest), 1,1 mT/mol (MRX flüssig)] wird 1 ml entsalzter starker Tentakelanionentauscher Fractogel EMD TMAE 650 S von Merck gegeben, mit dest. Wasser verdünnt und 1 h geschüttelt. Der Überstand wird dialysiert (-35 mV, 76 nm, 22/167 l/mmol/s, 5,2/1,1 mT/mol). Die Austauscherbeads werden über Nacht mit 1 M NaCl geschüttelt und der Überstand dialysiert (-16 mV, 67 nm, 18/69 l mmol s, 1,2/0,3 mT/mol). Beispiel 3To 5 ml of ultrafiltered magnetite suspension [Zeta potential: -34 mV, 70 nm particle diameter (PCS), rl: 20 l / mmol / s, r2: 160 l / mmol / s (MR). , 5 mT / mol (MRX solid), 1.1 mT / mol (MRX liquid)], 1 ml of desalted strong tentacle anion exchanger Fractogel EMD TMAE 650 S from Merck is added, with dist. Diluted water and shaken for 1 h. The supernatant is dialyzed (-35 mV, 76 nm, 22/167 l / mmol / s, 5.2 / 1.1 mT / mol). The exchanger beads are shaken overnight with 1 M NaCl and the supernatant is dialyzed (-16 mV, 67 nm, 18/69 l mmol s, 1.2 / 0.3 mT / mol). Example 3
IonenaustauschervorsatzIonenaustauschervorsatz
In einen Behälter mit zwei Anschlüssen und mindestens einer Filterfritte (siehe Fig. 1) wird geeigneter Ionenaustauscher gefüllt. Falls der Ionenaustauscher in einer Salzlösung suspendiert vorliegt, wird die Lösung anschließend durch Spülen mit Wasser ersetzt.A suitable ion exchanger is filled into a container with two connections and at least one filter frit (see FIG. 1). If the ion exchanger is suspended in a saline solution, the solution is then replaced by rinsing with water.
Beispiel 4Example 4
Abtrennung geladener Partikel aus einer Dispersion mittels IonenaustauschervorsatzSeparation of charged particles from a dispersion using an ion exchange attachment
50 μl einer negativ geladenen Latexsuspension in 10 ml dest. Wasser ergeben am PCS eine Zählrate von 615 kCps. 2 ml dieser Lösung werden auf einen50 μl of a negatively charged latex suspension in 10 ml dist. Water gives a count rate of 615 kCps at the PCS. 2 ml of this solution are added to one
Ionenaustauschervorsatz gemäß Beispiel 3, gefüllt mit 1 ml schwachem Tentakelanionentauscher Fractogel EMD DMAE 650 S von Merck, gegeben und mit dest. Wasser gespült. Der Durchlauf weist nur noch eine Zählrate von 0,4 kCps auf. Dies spiegelt die Abtrennung der geladenen Partikel wider.Ion exchange attachment according to Example 3, filled with 1 ml of weak tentacle anion exchanger Fractogel EMD DMAE 650 S from Merck, and filled with dist. Rinsed water. The pass only has a count rate of 0.4 kCps. This reflects the separation of the charged particles.
Beispiel 5Example 5
Trennung geladener Partikel aus einer Dispersion geladener Partikel mit IonenaustauschervorsatzSeparation of charged particles from a dispersion of charged particles with an ion exchange attachment
1 ml Magnetitsuspension [Zetapotential: -31 mV, 66 nm Partikeldurchmesser (PCS), rl: 20 l/mmol/s, r2: 160 l/mmol/s (MR), 5 mT/mol (MRX fest), 1,1 mT/mol (MRX flüssig)] wird auf einen Ionenaustauschervorsatz gemäß Beispiel 4 gegeben. Danach wird mit dest. Wasser gespült, bis der aufgefangene Auslauf nicht mehr braun ist. Der Auslauf wird dialysiert (-30 mV, 66 nm, 24/170 l/mmol/s, 7/1,7 mT/mol). Anschließend wird mit 10 mM NaOH (pH 12) gespült und der Auslauf aufgefangen.1 ml magnetite suspension [zeta potential: -31 mV, 66 nm particle diameter (PCS), rl: 20 l / mmol / s, r2: 160 l / mmol / s (MR), 5 mT / mol (MRX solid), 1.1 mT / mol (MRX liquid)] is added to an ion exchange attachment according to Example 4. After that, dist. Rinse water until the spout is no longer brown. The outlet is dialyzed (-30 mV, 66 nm, 24/170 l / mmol / s, 7 / 1.7 mT / mol). It is then rinsed with 10 mM NaOH (pH 12) and the spout is collected.
Dieser wird mit HCl neutralisiert und dialysiert (-21 mV, 52 nm, 19/80 l/mmol/s, 1,9/0,3 mT/mol). This is neutralized with HCl and dialyzed (-21 mV, 52 nm, 19/80 l / mmol / s, 1.9 / 0.3 mT / mol).

Claims

Patentansprüche claims
1. Verfahren zur Herstellung pharmazeutischer Zubereitungen oder deren Zwischenprodukten, wobei die pharmazeutische Zubereitung als Dispersion vorliegt, die in der Dispersion vorliegenden Partikel eine Ladungsverteilung aufweisen und zumindest ein Teil der in der Dispersion vorliegenden Partikel mit Hilfe von Ionenaustauschern oder durch elektrophoretische Trennverfahren abgetrennt werden.1. A process for the preparation of pharmaceutical preparations or their intermediates, the pharmaceutical preparation being in the form of a dispersion, the particles present in the dispersion having a charge distribution and at least some of the particles present in the dispersion being separated using ion exchangers or by electrophoretic separation processes.
2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß die Partikel magnetische Partikel sind.2. The method according to claim 1, characterized in that the particles are magnetic particles.
3. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß die Partikel gasgefüllte Partikel sind.3. The method according to claim 1, characterized in that the particles are gas-filled particles.
4. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß die Partikel störende Fremdpartikel sind. 4. The method according to claim 1, characterized in that the particles are disruptive foreign particles.
5. Verfahren gemäß einem der vorangegangenen Ansprüche, dadurch gekennzeichnet, daß die Partikelgröße der zu selektierenden Partikel unter 10 μm liegt. 5. The method according to any one of the preceding claims, characterized in that the particle size of the particles to be selected is less than 10 microns.
6. Vorrichtung zur Durchführung des Verfahrens gemäß Anspruch 1, dadurch gekennzeichnet, daß die Vorrichtung aus einem Separationsraum besteht, welcher einen Ionenaustauscher enthält und einen Zu- und Ablauf hat. 6. Device for performing the method according to claim 1, characterized in that the device consists of a separation room which contains an ion exchanger and has an inlet and outlet.
7. Vorrichtung gemäß Anspruch 6, dadurch gekennzeichnet, daß der Ionenaustauscher ein starker oder schwacher Anionen- und/oder Kationenaustauscher ist.7. The device according to claim 6, characterized in that the ion exchanger is a strong or weak anion and / or cation exchanger.
8. Vorrichtung gemäß Anspruch 6 oder 7, dadurch gekennzeichnet, daß der Ionenaustauscher ein Tentakelionenaustauscher ist.8. The device according to claim 6 or 7, characterized in that the ion exchanger is a tentacle ion exchanger.
9. Vorrichtung gemäß einem der Ansprüche 6 bis 8, dadurch gekennzeichnet, daß der Ionenaustauscher eine Ionenaustauschermembran ist.9. Device according to one of claims 6 to 8, characterized in that the ion exchanger is an ion exchange membrane.
10. Vorrichtung gemäß einem der Ansprüche 6 bis 9, dadurch gekennzeichnet, daß der Ionenaustauscher mit physiologisch verträglichen Gegenionen vorbelegt ist bzw. die Verdrängung adsorbierter Ionen mit physiologisch verträglichen Salzen erfolgt.10. Device according to one of claims 6 to 9, characterized in that the ion exchanger is pre-populated with physiologically compatible counterions or the displacement of adsorbed ions with physiologically compatible salts.
11. Vorrichtung gemäß einem der Ansprüche 6 bis 10, dadurch gekennzeichnet, daß sie in ein Injektions- oder Infusionsbesteck integriert ist.11. The device according to one of claims 6 to 10, characterized in that it is integrated in an injection or infusion set.
12. Vorrichtung gemäß einem der Ansprüche 6 bis 10, dadurch gekennzeichnet, daß sie in Form eines Vorsatzfilters für ein Infusions- oder Injektionsbesteck ausgeführt ist. 12. The device according to one of claims 6 to 10, characterized in that it is designed in the form of a front filter for an infusion or injection set.
13. Vorrichtung gemäß einem der Ansprüche 6 bis 12, dadurch gekennzeichnet, daß die13. The device according to one of claims 6 to 12, characterized in that the
Vorrichtung steril ist.Device is sterile.
14. Pharmazeutische Zubereitungen erhältlich durch ein Verfahren gemäß Anspruch 1.14. Pharmaceutical preparations obtainable by a process according to claim 1.
15. Kontrastmittel für die Magnetresonanzdiagnostik erhältlich durch Behandlung magnetischer Partikelsuspensionen nach dem Verfahren gemäß Anspruch 1.15. Contrast agent for magnetic resonance diagnostics obtainable by treating magnetic particle suspensions by the method according to claim 1.
16. Kontrastmittel für die Ultraschalldiagnostik erhältlich durch Behandlung von Ultraschallkontrastmittelsuspensionen nach dem Verfahren gemäß Anspruch 1.16. Contrast agents for ultrasound diagnostics obtainable by treatment of ultrasound contrast agent suspensions by the method according to claim 1.
17. Verwendung von Zubereitungen gemäß Anspruch 14 als Kontrastmittel. 17. Use of preparations according to claim 14 as a contrast agent.
PCT/EP2002/007863 2001-07-26 2002-07-15 Method for producing pharmaceutical preparations WO2003011459A1 (en)

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JP2003516683A JP2004535907A (en) 2001-07-26 2002-07-15 How to make a formulation
EP02747467A EP1463583A1 (en) 2001-07-26 2002-07-15 Method for producing pharmaceutical preparations
NO20040312A NO20040312L (en) 2001-07-26 2004-01-23 Process for the preparation of pharmaceutical preparations

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DE10137515A DE10137515A1 (en) 2001-07-26 2001-07-26 Production of pharmaceutical preparations in charged particle dispersion form, e.g. contrast agent dispersion, including separation of particles using ion exchangers or by electrophoresis
DE10137515.8 2001-07-26

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2004745A (en) * 1977-09-30 1979-04-11 Farmaceutici Italia Injectable suspensions of drug- containing liposomes.
JPS6014984A (en) * 1983-07-07 1985-01-25 Asahi Chem Ind Co Ltd Method for removing ion and fine particle
US4844882A (en) * 1987-12-29 1989-07-04 Molecular Biosystems, Inc. Concentrated stabilized microbubble-type ultrasonic imaging agent
EP0580878A1 (en) * 1992-06-01 1994-02-02 BASF Aktiengesellschaft The use of dispersions of magneto-ionic particles as MRI contrast media
US5503723A (en) * 1995-02-08 1996-04-02 Eastman Kodak Company Isolation of ultra small particles
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
DE19624426A1 (en) * 1996-06-19 1998-01-02 Christian Bergemann Magnetic particle for transport of diagnostic or therapeutic agent
WO1998005430A1 (en) * 1996-08-05 1998-02-12 Schering Aktiengesellschaft Process and device for separating magnetic materials from pharmaceutical compositions, their starting or intermediate products and agents produced by means of this device
US6080571A (en) * 1994-03-22 2000-06-27 The Immune Response Corporation Highly efficient production and isolation of viral particles utilizing tentacle anion exchange

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2004745A (en) * 1977-09-30 1979-04-11 Farmaceutici Italia Injectable suspensions of drug- containing liposomes.
JPS6014984A (en) * 1983-07-07 1985-01-25 Asahi Chem Ind Co Ltd Method for removing ion and fine particle
US4844882A (en) * 1987-12-29 1989-07-04 Molecular Biosystems, Inc. Concentrated stabilized microbubble-type ultrasonic imaging agent
EP0580878A1 (en) * 1992-06-01 1994-02-02 BASF Aktiengesellschaft The use of dispersions of magneto-ionic particles as MRI contrast media
US6080571A (en) * 1994-03-22 2000-06-27 The Immune Response Corporation Highly efficient production and isolation of viral particles utilizing tentacle anion exchange
US5560932A (en) * 1995-01-10 1996-10-01 Nano Systems L.L.C. Microprecipitation of nanoparticulate pharmaceutical agents
US5503723A (en) * 1995-02-08 1996-04-02 Eastman Kodak Company Isolation of ultra small particles
DE19624426A1 (en) * 1996-06-19 1998-01-02 Christian Bergemann Magnetic particle for transport of diagnostic or therapeutic agent
WO1998005430A1 (en) * 1996-08-05 1998-02-12 Schering Aktiengesellschaft Process and device for separating magnetic materials from pharmaceutical compositions, their starting or intermediate products and agents produced by means of this device

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 198510, Derwent World Patents Index; Class B06, AN 1985-058824, XP002221145 *

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