EP1411894A2 - Pharmaceutical preparations containing ion exchange resins charged with active ingredients - Google Patents

Pharmaceutical preparations containing ion exchange resins charged with active ingredients

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Publication number
EP1411894A2
EP1411894A2 EP02743262A EP02743262A EP1411894A2 EP 1411894 A2 EP1411894 A2 EP 1411894A2 EP 02743262 A EP02743262 A EP 02743262A EP 02743262 A EP02743262 A EP 02743262A EP 1411894 A2 EP1411894 A2 EP 1411894A2
Authority
EP
European Patent Office
Prior art keywords
ion exchanger
pharmaceutical preparation
loaded
preparation according
ion
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP02743262A
Other languages
German (de)
French (fr)
Inventor
Dirk Mertin
Wolfgang Block
Hans-Jürgen HAMANN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer Healthcare AG
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 Bayer Healthcare AG filed Critical Bayer Healthcare AG
Publication of EP1411894A2 publication Critical patent/EP1411894A2/en
Ceased legal-status Critical Current

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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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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

Definitions

  • the present invention relates to pharmaceutical preparations which contain one or more active substances which are bound to an ion exchanger.
  • active substance / ion exchanger particles are smaller than 50 ⁇ m.
  • the abovementioned publication describes formulations of bitter-tasting quinolonecarboxylic acid derivatives which are bound to ion-exchange resins, and the preparation thereof.
  • Weakly acidic cationic types can be considered as ion exchange resins, and their matrix can be gel-like or macroporous.
  • the base monomers for the ion exchangers are polymerizable monomers which can be functionalized to form cation exchange resins by means of corresponding side chains.
  • the ion exchangers are known under the trade names Lewatit ® , Amberlite ® , Purolite ® or Dowex ® . Corresponding formulations are described in veterinary medicine as feed medicines for pigs.
  • formulations containing the loaded cation-exchange resins prepared according to EP-A-295 495 still have disadvantages when administered orally to pets, in particular cats, for example in terms of acceptance. These are attributed to a sandy taste sensation due to ion exchange particles that are larger than approx. 50 ⁇ m.
  • No. 3,138,525 describes the improvement of palatabilty by grinding a strongly acidic ion exchanger loaded with amprotropin.
  • the particle reduction described there to a particle size of 40-250 ⁇ m is not sufficient to improve acceptance in cats.
  • WO 89/12 452 describes the grinding of
  • Cholestyramine a strongly basic ion exchanger, described using a cutting mill.
  • the resulting particles are 75% smaller than 65 ⁇ m and 30% smaller than 30 ⁇ m.
  • Cutting mills are suitable for grinding soft polymers, such as cholestyramine, but not for more brittle brittle polymers such as the cation exchange resins described above.
  • the use of attrition mills has also only been described for the comminution of cholestyramine (EP 26 574).
  • acidic ion exchange resins and their formulations can also be ground using suitable grinding methods in such a way that at least 90% of the particles have a size of less than 50 ⁇ m.
  • Preparations containing these ground ion exchange resins have unexpectedly good technical and pharmaceutical properties and are also well accepted, for example, by pets, especially cats.
  • the invention therefore relates to:
  • Cation exchanger-bound active ingredients characterized in that the loaded cation exchanger is dispersed in a carrier medium and at least 90% of the dispersed ion exchange particles have a size of less than 50 ⁇ m.
  • Particles of at least 90% have a size of less than 50 ⁇ m for the production of pharmaceutical preparations for oral administration.
  • the cationic ion exchange resins can for example be a gel or. have a macroporous matrix.
  • the base monomers for the ion exchangers are polymerizable monomers which can be converted into cation exchange resins by appropriate functionalization. Examples of monomers which may be mentioned are (meth) acrylic acid esters, (meth) acrylonitrile and styrene derivatives. Polyvinyl compounds such as divinylbenzene, ethylene glycol dimethacrylate or methylene bisacrylamide are used as further comonomers for the production of the base polymers. Condensation resins which lead to cation exchangers are also suitable, for example phenol-formaldehyde resins with corresponding functional groups.
  • the ion exchangers that can be used are not new. More detailed information on various types of ion exchangers and their production can be found, for example, in Ullmann's Encyclopedia of Industrial Chemistry (Release 2001, 6th Edition).
  • the preferred macroporous resins can have different pore volumes.
  • the degree of crosslinking of the suitable ion exchange resins should preferably be up to
  • the synthetic resins are usually in grain sizes of 1 to 300 ⁇ m, preferably 10 to 200 ⁇ m.
  • Commercial ion exchange resins are e.g. B. Lewatit ® , Amberlite ® , Dowex ® and Purolite ® .
  • the strongly acidic ion exchangers used are preferably those based on poly (styrene, divinylbenzene) sulfonic acid. Examples include:
  • Amberlite IRP 69 poly (styrene, divinylbenzene) sulfonic acid in the Na form, particle size (before grinding): 10-25%> 75 ⁇ m, max. 1%> 150 ⁇ m, K-
  • Purolite C 100 H MR poly (styrene, divinylbenzene) sulfonic acid in the H form, particle size (before grinding): max. 1%> 150 ⁇ m, exchange capacity: at least 3.2 eq / kg
  • Purolite C 100 MR poly (styrene, divinylbenzene) sulfonic acid in the Na form, corresponds to Amberlite IRP 69
  • Lewatit Catalyst K 1481 poly (styrene, divinylbenzene) sulfonic acid in the H-
  • Lewasorb SW 12 poly (styrene, divinylbenzene) sulfonic acid in the Na form, otherwise corresponds to Lewatit K 1481.
  • Weakly acidic cation exchangers are preferably used as ion exchangers, in particular those based on methacrylic acid-divinylbenzene copolymer. Examples are:
  • Amberlite IRP 64 methacrylic acid-divinylbenzene copolymer in the H form, particle size (before grinding): 15-30%> 75 ⁇ m, max. 1%> 150 ⁇ m, exchange capacity: min. 10 eq / kg
  • Purolite C 1 15 H MR methacrylic acid-divinylbenzene copolymer in the H form, otherwise like Purolite C 1 15 K MR.
  • Lewatit CNP 105 macroporous methacrylic acid-divinylbenzene copolymer in the H form, exchange capacity min. 1, 4 eq / 1.
  • Active pharmaceutical ingredients with a basic function that are capable of binding to cation exchangers can be used. This is particularly useful for drugs that smell unpleasant or lead to an unpleasant taste sensation when administered orally.
  • active substances are quinolone antibiotics, as are disclosed, inter alia, in the following documents: US 4,670,444 (Bayer AG), US 4,472,405 (Riker Labs), US 4,730,000 (Abbott), US 4,861,779 ( Pfizer), U.S. 4,382,892 (Daiichi), U.S. 4,704,459
  • the active substance-loaded ion exchange resins are produced in water or polar organic solvents, such as, for example, alcohols, such as methanol or etha- nol, ketones such as acetone or mixtures thereof. Water is particularly preferred.
  • the ion exchanger and active ingredient are stirred in the medium at room temperature or elevated temperature until the active ingredient is completely bound. The dispersion medium is then separated off by filtration, centrifugation or decanting and the residue is dried.
  • the ion exchanger can be ground in the dry state or preferably by wet grinding, examples of which are air jet grinding and grinding with a bead mill.
  • the ion exchanger can be ground unloaded, but grinding in the loaded state is preferred. For this, the
  • the ion exchanger is dispersed and milled in a suitable carrier together with other auxiliaries, such as wetting agents, preservatives or viscosity-increasing substances.
  • auxiliaries such as wetting agents, preservatives or viscosity-increasing substances.
  • Water, organic solvents, mineral, fatty oils or mixtures thereof, but especially fatty oils, are suitable as carrier liquids.
  • the particles are always smaller than 100 ⁇ m, preferably 75 ⁇ m.
  • the particle sizes specified here are always determined by laser scattered light measurement (e.g. with a Malvern Mastersizer or the like).
  • the pharmaceutical preparation according to the invention owing to the small particle size of the charged ion exchanger [D (0.9) ⁇ 50 ⁇ m], was distinguished by an excellent palatabilty, e.g. in cats.
  • the grinding of the ion exchanger in liquid formulations not only significantly delays the formation of a sediment, but the sediment is also very easy to shake again.
  • the better ability to shake the finely ground ion exchanger in particular was surprising, since Certainly, fine particulate, sedimenting suspensions tend to be poorly redispersible (caking) due to the large specific surface and thus high adhesive forces of the particles.
  • compositions according to the invention are generally suitable for
  • Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon and birds such as Chickens, geese, turkeys, ducks, pigeons and bird species for home and zoo keeping.
  • Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
  • Hobby animals include rabbits, hamsters, guinea pigs, mice, horses, reptiles, appropriate bird species, dogs and cats.
  • Fish should also be mentioned, namely commercial, breeding, aquarium and ornamental fish of all ages that live in fresh and salt water.
  • Useful and farmed fish include carp, eel, trout, white fish, salmon, bream, roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), red seabream (Pagurus major ), Seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthead seabream (Sparus auratus), Tilapia spp., Cichlid species such as Plagioscion, Channel catfish.
  • the agents according to the invention are particularly suitable for the treatment of fish fry, for example carp with a body length of 2 to 4 cm.
  • the agents are also very suitable for eel fattening.
  • the preparations according to the invention are preferably used in hobby animals such as hamsters, rabbits, guinea pigs, cats and dogs. They are particularly suitable for use in cats.
  • the application can be prophylactic as well as therapeutic.
  • the preparations according to the invention are preferably administered orally.
  • compositions suitable for animals are e.g. those in which the improvement in taste plays a role in the intake or in which a delayed release of the active ingredient after the application is sought.
  • solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules, or liquid or semi-solid pharmaceutical forms such as suspensions or pastes, e.g. can be used orally.
  • the latter are produced by suspending the resin loaded with active ingredient in a carrier liquid, optionally with the addition of further auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants or light stabilizers.
  • suspensions By adding substances that increase the viscosity, these suspensions can also be used as so-called “semi-solid" preparations, e.g. Ointments are administered.
  • formulations of this type can be used as an oral paste in cats, dogs and horses.
  • the active substance-loading resin is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
  • Inorganic and organic substances serve as such.
  • Inorganic substances are, for example Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.
  • Organic substances are e.g. Sugar, cellulose, food and feed such as milk powder, animal meal, cereal flour and meal, starches.
  • Excipients are preservatives, antioxidants, dyes, which have already been listed above.
  • auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
  • the active substance-loaded resins are distributed as homogeneously as possible in a liquid carrier medium, if appropriate with the aid of other auxiliaries, such as wetting agents, preservatives or viscosity-increasing substances.
  • Carrier liquids are all homogeneous solvents and solvent mixtures, but especially water, paraffin oils and fatty oils, such as. B. Neutral oil.
  • the ion exchanger loaded with the active ingredient is in the invention
  • Preparations preferably in an amount of 1 to 50 wt .-%, particularly preferably 5 to 25 wt .-% based on the total weight of the preparation.
  • the carrier liquid is used in the amount suitable for setting the necessary consistency, usually this is preferably 50 to 99% by weight, particularly preferably 70 to 95% by weight, based on the total weight of the preparation.
  • wetting agents dispersants
  • anionic surfactants including emulsifiers such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt, lignin sulfonates or dioctyl sulfosuccinate
  • cationic surfactants including emulsifiers such as cetyltrimethylammonium chloride
  • Ampholytic surfactants including emulsifiers such as di-Na-N-lauryl- ⁇ -iminodipropionate or lecithin
  • Non-ionic surfactants including emulsifiers, such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, polyethylene-polypropylene block copolymers.
  • emulsifiers such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, polyethylene-polypropylene block copolymers.
  • the nonionic surfactants are particularly preferred.
  • Wetting agents are preferably used in an amount of 0.1 to 10% by weight, particularly preferably 0.5 to 5% by weight, based on the total weight of the preparation.
  • auxiliaries include: • Dyes, ie all dyes approved for use on humans or animals, which can be dissolved or suspended. Dyes are preferably used in an amount of 0.001 to 5% by weight, particularly preferably 0.01 to 2% by weight, based on the total weight of the preparation.
  • Antioxidants such as Sulphites or metabisulphites such as potassium metabisulphite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols. Antioxidants are preferably used in an amount of 0.001 to 5% by weight, particularly preferably 0.01 to 2% by weight, based on the total weight of the preparation.
  • Thickeners or viscosity-increasing substances such as inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates, alginates, gelatin,
  • Polyvinyl pyrrolidone Polyethylene glycols, waxes, gum arabic and xanthan gum or mixtures of the listed substances.
  • Thickeners are preferably used in an amount of 0.01 to 10% by weight, particularly preferably 0.01 to 5% by weight, based on the total weight of the preparation.
  • the preparations according to the invention are preferably liquid or semi-liquid suspensions.
  • these suspensions can also be administered as semi-solid preparations such as pastes.
  • formulations of this type can be used as an oral paste in animals.
  • the active substance-loaded ion exchange resins can be added to the feed as such or in the form of premixes or feed concentrates.
  • Premixes and feed concentrates are mixtures of the active ingredient with a suitable carrier.
  • the carrier substances include the feed materials or mixtures thereof, as well as the inert carrier substances mentioned above.
  • Regulate fluidity and miscibility e.g. Silicas, bentonites, lignin sulfonates.
  • antioxidants such as BHT or preservatives such as sorbic acid or calcium propionate can be added.
  • Liquids such as paraffin oils, vegetable oils and propylene glycols can also be added to the premixes for dust binding.
  • the active substance-loaded resins can be present in the formulations alone or in a mixture with other active substances, mineral salts, trace elements, vitamins, protein substances, colorants, fats or flavorings.
  • the active substance-loaded ion exchange resins can be administered together with the feed.
  • the feed includes single feed of vegetable origin such as hay, beets, cereals, grain by-products, single feed of animal origin such as meat,
  • Fats, milk products, bone meal, fish products furthermore the feed materials such as vitamins, proteins, amino acids, e.g. DL-methionine, salts such as lime and table salt.
  • the feed also includes supplementary, finished and compound feed. These contain feed materials in a composition that provides a balanced diet with regard to energy and protein supply as well as the supply of vitamins,

Abstract

The invention relates to pharmaceutical preparations containing at least one active ingredient which is linked to an ion exchanger. In order to improve the palatability and to increase the stability, at least 90 % of said active ingredient/ion exchanger particles are smaller than 50 νm.

Description

Pharmazeutische Zubereitungen enthaltend wirkstoffbeladene Ionentauscher- harzePharmaceutical preparations containing ion exchanger resins loaded with active substances
Die vorliegende Erfindung betrifft pharmazeutische Zubereitungen, welche einen oder mehrere Wirkstoffe enthalten, die an einen Ionenaustauscher gebunden sind. Zur Verbesserung der Palatabihtät und Erhöhung der Stabilität sind mindestens 90% dieser Wirkstoff/Ionentauscher-Partikel kleiner als 50 μm.The present invention relates to pharmaceutical preparations which contain one or more active substances which are bound to an ion exchanger. To improve palatabilty and increase stability, at least 90% of these active substance / ion exchanger particles are smaller than 50 μm.
Es ist seit langem bekannt, pharmazeutische Wirkstoffe an Ionentauscherharze zu binden, um beispielsweise Wirkstoffe mit ausgeprägtem Eigengeruch besser anwendbar zu machen (CH 383 552). Es ist auch bekannt, pharmazeutische Wirkstoffe an Ionentauscherharze zu binden, um eine gleichmäßige Freigabe des Wirkstoffes über eine längere Zeit zu beeinflussen (DE 30 28 082). Es ist ferner bekannt, anthelmin- tische Wirkstoffe an Ionentauscherharze zu binden, um den Geschmack der Wirkstoffe zu beeinflussen (DE 30 28 082). Durch die Bindung an Ionentauscherharze kann auch der bittere Geschmack von Chinolon- Antibiotika maskiert werden, so dass eine Applikation bei Tieren ermöglicht wird (EP-A-295 495).It has been known for a long time to bind active pharmaceutical ingredients to ion exchange resins, for example to make active ingredients with a distinct intrinsic odor more applicable (CH 383 552). It is also known to bind active pharmaceutical ingredients to ion exchange resins in order to influence a uniform release of the active ingredient over a longer period of time (DE 30 28 082). It is also known to bind anthelmintic active ingredients to ion exchange resins in order to influence the taste of the active ingredients (DE 30 28 082). By binding to ion exchange resins, the bitter taste of quinolone antibiotics can also be masked, so that application to animals is possible (EP-A-295 495).
In der vorgenannten Schrift werden Formulierungen von bitter schmeckenden Chi- noloncarbonsäurederivaten, die an Ionentauscherharze gebunden werden, sowie deren Herstellung beschrieben. Als Ionentauscherharze kommen schwach saure kationische Typen in Frage, wobei deren Matrix gelförmig bzw. makroporös sein kann. Als Basismonomere für die Ionentauscher kommen polymerisierbare Monomere in Betracht, welche durch entsprechende Seitenketten zu Kationentauscherharzen funk- tionalisiert werden können. Die Ionentauscher sind unter den Handelsnamen Lewatit®, Amberlite®, Purolite® oder Dowex® bekannt. Entsprechende Formulierungen sind in der Veterinärmedizin als Fütterungsarzneimittel für Schweine beschrieben. Formulierungen, die die nach EP-A-295 495 hergestellten beladenen Kationentauscherharze enthielten, weisen bei oraler Verabreichung an Haustieren, insbesondere Katzen, jedoch noch Nachteile auf, beispielsweise hinsichtlich der Akzeptanz. Diese werden auf eine sandige Geschmacksempfindung durch Ionentauscherpartikel, die größer als ca. 50 μm sind, zurückgeführt.The abovementioned publication describes formulations of bitter-tasting quinolonecarboxylic acid derivatives which are bound to ion-exchange resins, and the preparation thereof. Weakly acidic cationic types can be considered as ion exchange resins, and their matrix can be gel-like or macroporous. The base monomers for the ion exchangers are polymerizable monomers which can be functionalized to form cation exchange resins by means of corresponding side chains. The ion exchangers are known under the trade names Lewatit ® , Amberlite ® , Purolite ® or Dowex ® . Corresponding formulations are described in veterinary medicine as feed medicines for pigs. However, formulations containing the loaded cation-exchange resins prepared according to EP-A-295 495 still have disadvantages when administered orally to pets, in particular cats, for example in terms of acceptance. These are attributed to a sandy taste sensation due to ion exchange particles that are larger than approx. 50 μm.
US 31 38 525 beschreibt die Verbesserung der Palatabihtät durch Mahlung eines mit Amprotropin beladenen stark sauren Ionentauschers. Allerdings reicht die dort beschriebene Partikelreduktion auf eine Teilchengröße von 40 - 250 μm nicht aus, um die Akzeptanz bei Katzen zu verbessern. In WO 89/12 452 wird die Mahlung vonNo. 3,138,525 describes the improvement of palatabilty by grinding a strongly acidic ion exchanger loaded with amprotropin. However, the particle reduction described there to a particle size of 40-250 μm is not sufficient to improve acceptance in cats. WO 89/12 452 describes the grinding of
Cholestyramin, einem stark basischen Ionentauscher, mittels einer Schneidmühle beschrieben. Die hierbei entstehenden Partikel sind zu 75 % kleiner 65 μm und zu 30 % kleiner 30 μm. Schneidmühlen eignen sich zur Mahlung weicher Polymere, wie Cholestyramin, nicht jedoch für eher sprödbrüchige Polymere wie die oben beschrie- benen Kationentauscherharze. Die Verwendung von Reibmühlen ist ebenfalls nur für die Zerkleinerung von Cholestyramin beschrieben worden (EP 26 574).Cholestyramine, a strongly basic ion exchanger, described using a cutting mill. The resulting particles are 75% smaller than 65 μm and 30% smaller than 30 μm. Cutting mills are suitable for grinding soft polymers, such as cholestyramine, but not for more brittle brittle polymers such as the cation exchange resins described above. The use of attrition mills has also only been described for the comminution of cholestyramine (EP 26 574).
Es wurde nun gefunden, dass auch saure Ionentauscherharze sowie deren Formulierungen mit geeigneten Mahl verfahren so gemahlen werden können, dass mindestens 90 % der Partikel eine Größe von unter 50 μm aufweisen. Zubereitungen, die diese gemahlenen Ionentauscherharze enthalten, besitzen unerwartet gute technische und pharmazeutische Eigenschaften und werden darüber hinaus zum Beispiel von Haustieren, insbesondere Katzen, gut akzeptiert.It has now been found that acidic ion exchange resins and their formulations can also be ground using suitable grinding methods in such a way that at least 90% of the particles have a size of less than 50 μm. Preparations containing these ground ion exchange resins have unexpectedly good technical and pharmaceutical properties and are also well accepted, for example, by pets, especially cats.
Die Erfindung betrifft daher:The invention therefore relates to:
• Eine pharmazeutische Zubereitung, enthaltend einen oder mehrere an einen• A pharmaceutical preparation containing one or more to one
Kationentauscher gebundene Wirkstoffe, dadurch gekennzeichnet, dass der beladene Kationentauscher in einem Trägermedium dispergiert ist und mindestens 90% der dispergierten Ionentauscherpartikel eine Größe von unter 50 μm besitzen.Cation exchanger-bound active ingredients, characterized in that the loaded cation exchanger is dispersed in a carrier medium and at least 90% of the dispersed ion exchange particles have a size of less than 50 μm.
Ein Verfahren zur Herstellung von pharmazeutischen Zubereitungen gemäß Anspruch 1 , bei dem manA process for the preparation of pharmaceutical preparations according to claim 1, in which
(a) entweder den mit Wirkstoff beladenen Ionenaustauscher gegebenenfalls zusammen mit weiteren Hilfsmitteln in einem Träger dispergiert und auf die gewünschte Korngröße mahlt oder(a) either the ion exchanger loaded with active ingredient, if appropriate together with other auxiliaries, dispersed in a carrier and ground to the desired particle size or
(b) den reinen Ionentauscher zunächst auf die gewünschte Korngröße mahlt, ihn mit Wirkstoff belädt und dann den beladenen Ionentauscher in die endgültige Formulierung überführt.(b) first grinds the pure ion exchanger to the desired grain size, loads it with active ingredient and then transfers the loaded ion exchanger into the final formulation.
• Die Verwendung von mit Wirkstoffen beladenen Kationentauschern, deren• The use of cation exchangers loaded with active substances, their
Partikel zu mindestens 90 % eine Größe von unter 50 μm besitzen, zur Herstellung von pharmazeutischen Zubereitungen für die orale Verabreichung.Particles of at least 90% have a size of less than 50 μm for the production of pharmaceutical preparations for oral administration.
Die kationischen Ionenaustauscherharze können beispielsweise eine gelförmige oder. makroporöse Matrix aufweisen. Als Basismonomere für die Ionenaustauscher kommen polymerisierbare Monomere in Betracht, welche durch entsprechende Funktionalisierung zu Kationenaustauscherharzen umgewandelt werden können. Als Monomere seien beispielsweise (Meth)-acrylsäureester, (Meth)-acrylnitril sowie Styrol-Abkömmlinge genannt. Als weitere Comonomere werden zur Herstellung der Basispolymere Polyvinylverbindungen wie beispielsweise Divinylbenzol, Ethylen- glykoldimethacrylat oder Methylenbisacrylamid eingesetzt. Auch Kondensationsharze, die zu Kationenaustauschern führen, sind geeignet, beispielsweise Phenol-Formaldehyd-Harze mit entsprechenden funktioneilen Gruppen. Die verwendbaren Ionenaustauscher sind nicht neu. Nähere Angaben zu verschiedenen Ionenaustauschertypen und ihrer Herstellung finden sich beispielsweise in Ullmann' s Encyclopedia of Industrial Chemistry (Release 2001, 6th Edition). Die bevorzugten makroporösen Harze können unterschiedliche Porenvolumen aufweisen. Der Vernetzungsgrad der geeigneten Ionenaustauscherharze sollte bevorzugt bis zuThe cationic ion exchange resins can for example be a gel or. have a macroporous matrix. The base monomers for the ion exchangers are polymerizable monomers which can be converted into cation exchange resins by appropriate functionalization. Examples of monomers which may be mentioned are (meth) acrylic acid esters, (meth) acrylonitrile and styrene derivatives. Polyvinyl compounds such as divinylbenzene, ethylene glycol dimethacrylate or methylene bisacrylamide are used as further comonomers for the production of the base polymers. Condensation resins which lead to cation exchangers are also suitable, for example phenol-formaldehyde resins with corresponding functional groups. The ion exchangers that can be used are not new. More detailed information on various types of ion exchangers and their production can be found, for example, in Ullmann's Encyclopedia of Industrial Chemistry (Release 2001, 6th Edition). The preferred macroporous resins can have different pore volumes. The degree of crosslinking of the suitable ion exchange resins should preferably be up to
20 % und besonders bevorzugt bis zu 12 % betragen. Die Kunstharze liegen vor der Mahlung üblicherweise in Korngrößen von 1 bis 300 μm, bevorzugt von 10 bis 200 μm vor. Handelsübliche Ionenaustauscherharze sind z. B. Lewatit®, Amberlite®, Dowex® und Purolite®.20% and particularly preferably up to 12%. Before grinding, the synthetic resins are usually in grain sizes of 1 to 300 μm, preferably 10 to 200 μm. Commercial ion exchange resins are e.g. B. Lewatit ® , Amberlite ® , Dowex ® and Purolite ® .
Als stark saure Ionenaustauscher werden bevorzugt solche auf Poly(styrol, divinyl- benzol)sulfonsäure-Basis eingesetzt. Als Beispiele seien genannt:The strongly acidic ion exchangers used are preferably those based on poly (styrene, divinylbenzene) sulfonic acid. Examples include:
• Amberlite IRP 69: Poly(styrol, divinylbenzol) sulfonsäure in der Na-Form, Partikelgröße (vor Mahlung): 10-25% > 75 μm, max. 1% > 150 μm, K-• Amberlite IRP 69: poly (styrene, divinylbenzene) sulfonic acid in the Na form, particle size (before grinding): 10-25%> 75 μm, max. 1%> 150 μm, K-
Austausch-Kapazität: 110 - 135 mg/g entsprechend 2,75 - 3,38 eq/kgExchange capacity: 110 - 135 mg / g corresponding to 2.75 - 3.38 eq / kg
• Purolite C 100 H MR: Poly(styrol, divinylbenzol) sulfonsäure in der H-Form, Partikelgröße (vor Mahlung): max. 1% > 150 μm, Austauschkapazität: mindestens 3,2 eq/kg• Purolite C 100 H MR: poly (styrene, divinylbenzene) sulfonic acid in the H form, particle size (before grinding): max. 1%> 150 μm, exchange capacity: at least 3.2 eq / kg
• Purolite C 100 MR: Poly(styrol, divinylbenzol) sulfonsäure in der Na-Form, enspricht Amberlite IRP 69Purolite C 100 MR: poly (styrene, divinylbenzene) sulfonic acid in the Na form, corresponds to Amberlite IRP 69
• Lewatit Catalyst K 1481 : Poly(styrol, divinylbenzol) sulfonsäure in der H-Lewatit Catalyst K 1481: poly (styrene, divinylbenzene) sulfonic acid in the H-
Form, Partikelgröße (vor Mahlung): min. 97% < 30 μm, Austauschkapazität.: 5,0 eq/kgShape, particle size (before grinding): min. 97% <30 μm, exchange capacity .: 5.0 eq / kg
• Lewasorb SW 12: Poly(styrol, divinylbenzol) sulfonsäure in der Na-Form, entspricht ansonsten Lewatit K 1481. Als Ionenaustauscher werden bevorzugt schwach saure Kationentauscher eingesetzt, und zwar insbesondere solche auf Methacrylsäure-Divinylbenzol-Copolymer-Basis. Beispiele sind:• Lewasorb SW 12: poly (styrene, divinylbenzene) sulfonic acid in the Na form, otherwise corresponds to Lewatit K 1481. Weakly acidic cation exchangers are preferably used as ion exchangers, in particular those based on methacrylic acid-divinylbenzene copolymer. Examples are:
• Amberlite IRP 64: : Methacrylsäure-Divinylbenzol-Copolymer in der H- Form, Partikelgröße (vor Mahlung): 15-30% > 75 μm, max. 1% > 150 μm, Austauschkapazität: min. 10 eq/kg• Amberlite IRP 64:: methacrylic acid-divinylbenzene copolymer in the H form, particle size (before grinding): 15-30%> 75 μm, max. 1%> 150 μm, exchange capacity: min. 10 eq / kg
• Purolite C 1 15 K MR: Methacrylsäure-Divinylbenzol-Copolymer in der• Purolite C 1 15 K MR: methacrylic acid-divinylbenzene copolymer in the
Kalium-Form, Partikelgröße (vor Mahlung) max. 1% > 150 μmPotassium form, particle size (before grinding) max. 1%> 150 μm
• Purolite C 1 15 H MR: Methacrylsäure-Divinylbenzol-Copolymer in der H- Form, ansonsten wie Purolite C 1 15 K MR.• Purolite C 1 15 H MR: methacrylic acid-divinylbenzene copolymer in the H form, otherwise like Purolite C 1 15 K MR.
Lewatit CNP 105: makroporöses Methacrylsäure-Divinylbenzol-Copolymer in der H-Form, Austauschkapazität min. 1 ,4 eq/1.Lewatit CNP 105: macroporous methacrylic acid-divinylbenzene copolymer in the H form, exchange capacity min. 1, 4 eq / 1.
Es können pharmazeutische Wirkstoffe mit einer basischen Funktion, die zu einer Bindung an Kationentauscher in der Lage sind, verwendet werden. Sinnvoll ist dies vor allem bei Arzneistoffen, die unangenehm riechen oder bei oraler Applikation zu einer unangenehmen Geschmacksempfindung führen. Als Beispiele für solche Wirkstoffe seien Chinolonantibiotika genannt, wie sie unter anderem in folgenden Dokumenten offenbart sind: US 4 670 444 (Bayer AG), US 4 472 405 (Riker Labs), US 4 730 000 (Abbott), US 4 861 779 (Pfizer), US 4 382 892 (Daiichi), US 4 704 459Active pharmaceutical ingredients with a basic function that are capable of binding to cation exchangers can be used. This is particularly useful for drugs that smell unpleasant or lead to an unpleasant taste sensation when administered orally. Examples of such active substances are quinolone antibiotics, as are disclosed, inter alia, in the following documents: US 4,670,444 (Bayer AG), US 4,472,405 (Riker Labs), US 4,730,000 (Abbott), US 4,861,779 ( Pfizer), U.S. 4,382,892 (Daiichi), U.S. 4,704,459
(Toyama), als konkrete Beispiele seien genannt: Ciprofloxacin, Enrofloxacin, Ibafloxacin, Sarafloxacin, Difloxacin, Binfloxacin, Danofloxacin, Marbofloxacin, Benofloxacin, Ofloxacin, Orbifloxacin, Tosufloxacin, Temafloxacin, Pipemidsäure, Norfloxacin, Pefloxacin, Ofloxacin, Fleroxacin. Weiterhin seien als geeignete Chinolonantibiotika die in WO 97/31001 beschriebenen Verbindungen genannt, insbesondere 8-Cyan-l-cyclopropyl-7-((lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6- fluor-l,4-dihydro-4-oxo-3-chinolincarbonsäure der Formel(Toyama), specific examples are: ciprofloxacin, enrofloxacin, ibafloxacin, sarafloxacin, difloxacin, binfloxacin, danofloxacin, marbofloxacin, benofloxacin, ofloxacin, orbifloxacin, toufloxacin, poxafloxacin, poxafloxacin, poxafloxacin, pentafloxacin, poxafloxacin The compounds described in WO 97/31001 may also be mentioned as suitable quinolone antibiotics, especially 8-cyano-l-cyclopropyl-7 - ((IS, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro-4-oxo-3 -quinoline carboxylic acid of the formula
Darüber hinaus kommen auch andere Wirkstoffe mit einer geeigneten basischenIn addition, other active ingredients come with a suitable basic
Funktion in Frage, wie sie unter anderem in folgenden Dokumenten genannt sind: US 3 536 713, US 3 714 159, US 3 682 930, US 3 177 252; als konkrete Beispiele seien die folgenden Wirkstoffe genannt: Ampicillin, Amoxicillin, Cephazolin, Cefotiam, Ceftizoxim, Cefotaxim, Cefodizim, Ceftriaxon, Ceftazidim, Cefsulodin, Cefalexin, Cefaclor, Cefadroxil, Cefpodoximproxetil, Cefetametpivoxil, Cefixim,Function in question, as mentioned, inter alia, in the following documents: US 3,536,713, US 3,714,159, US 3,682,930, US 3,177,252; The following active substances may be mentioned as concrete examples: ampicillin, amoxicillin, cephazolin, cefotiam, ceftizoxime, cefotaxim, cefodizim, ceftriaxon, ceftazidime, cefsulodin, cefalexin, cefaclor, cefadroxil, cefpodoximetametix, cefpoximetoxametixif
Ceftibuten, Loracarbef, Imipenem, Aztreonam, Streptomycin, Neomycin, Kanamycin, Spectinomycin, Tetracyclin, Oxytetracyclin, Doxycyclin, Minocyclin, Erythromycin, Clarithromycin, Roxithromycin, Azithromycin, Spiramycin, Sulfadiazin, Sulfamethoxazol, Sulfalen, Sulfadoxin, Trimethoprim, Tetroxoprim, Metronidazol, Nimorazol, Tinidazol, Lincomycin, Clindamycin, Vancomycin,Ceftibuten, loracarbef, imipenem, aztreonam, streptomycin, neomycin, kanamycin, spectinomycin, tetracycline, oxytetracycline, doxycycline, minocycline, erythromycin, clarithromycin, roxithromycin, azithromycin, spiramycin, sulfadiazine, sulfamethoxazole, sulfalene, sulfadoxin, trimethoprim, tetroxoprim, metronidazole, nimorazole, Tinidazole, lincomycin, clindamycin, vancomycin,
Teicoplanin, Isoniazid, Pyrazinamid, Ethambutol, Rifampicin, Clotrimazol, Econazol, Isoconazol, Oxiconazol, Bifonazol, Tioconazol, Fenticonazol, Miconazol, Ketoconazol, Itraconazol, Fluconazol, Terbinafin, Naftifin, Amorolfin, Flucytosin, Amphotericin B, Nystatin, Chloroquin, Mefloquin, Chinin, Primaquin, Halofantrin, Proguanil, Pyrimethamin, Melarsoprol, Nifurtimox, Pentamidin, Amantadin,Teicoplanin, isoniazid, pyrazinamide, ethambutol, rifampicin, clotrimazole, econazole, isoconazole, oxiconazole, bifonazole, tioconazole, fenticonazole, miconazole, ketoconazole, itraconazole, fluconazole, terbinafin, quinine, nerbinafin, quinoline, terbinafinine, , Primaquin, halofantrine, proguanil, pyrimethamine, melarsoprol, nifurtimox, pentamidine, amantadine,
Tromantadin, Aciclovir, Ganciclovir, Vidarabin, Didanosin, Zalcitabin, Pyrantel, Mebendazol, Albendazol, Tiabendazol, Diethylcarbamazin, Pyrvinium, Oxamniquin, Ambroxol, Loperamid, Ketotifen, Metoclopramid, Flupirtin.Tromantadine, aciclovir, ganciclovir, vidarabine, didanosine, zalcitabine, pyrantel, mebendazole, albendazole, tiabendazole, diethylcarbamazine, pyrvinium, oxamniquin, ambroxol, loperamide, ketotifen, metoclopramide, flupirtine.
Die Herstellung der wirkstoffbeladenen Ionentauscherharze erfolgt in Wasser oder polaren organischen Lösungsmitteln, wie z.B. Alkoholen, wie Methanol oder Etha- nol, Ketonen, wie Aceton oder Gemische derselben. Besonders bevorzugt ist Wasser. Ionentauscher und Wirkstoff werden dabei solange in dem Medium bei Raumtemperatur oder erhöhter Temperatur gerührt, bis der Wirkstoff vollständig gebunden ist. Anschließend wird das Dispergiermedium durch Filtration, Zentrifugation oder Dekantieren abgetrennt und der Rückstand getrocknet.The active substance-loaded ion exchange resins are produced in water or polar organic solvents, such as, for example, alcohols, such as methanol or etha- nol, ketones such as acetone or mixtures thereof. Water is particularly preferred. The ion exchanger and active ingredient are stirred in the medium at room temperature or elevated temperature until the active ingredient is completely bound. The dispersion medium is then separated off by filtration, centrifugation or decanting and the residue is dried.
Die Mahlung des lonentauschers kann im trockenen Zustand oder bevorzugt über eine Nassmahlung erfolgen, als Beispiele seien die Luftstrahlmahlung und die Mahlung mit einer Perlmühle genannt. Der Ionentauscher kann unbeladen gemahlen werden, bevorzugt ist jedoch die Mahlung im beladenen Zustand. Hierzu wird derThe ion exchanger can be ground in the dry state or preferably by wet grinding, examples of which are air jet grinding and grinding with a bead mill. The ion exchanger can be ground unloaded, but grinding in the loaded state is preferred. For this, the
Ionentauscher ggf. zusammen mit weiteren Hilfsmitteln, wie Netzmittel, Konservierungsmittel oder viskositätserhöhende Stoffe, in einem geeigneten Träger dispergiert und vermählen. Als Trägerflüssigkeiten sind Wasser, organische Lösungsmittel, mineralische, fette Öle oder deren Mischungen, insbesondere aber fette Öle geeignet.If necessary, the ion exchanger is dispersed and milled in a suitable carrier together with other auxiliaries, such as wetting agents, preservatives or viscosity-increasing substances. Water, organic solvents, mineral, fatty oils or mixtures thereof, but especially fatty oils, are suitable as carrier liquids.
Die erfindungsgemäß eingesetzten Ionenaustauscher werden so gemahlen, dass 90 % der Partikel kleiner als 50 μm [D(0,9) = 50μm], bevorzugt kleiner 20 μm [D(0,9) = 20 μm], besonders bevorzugt kleiner 10 μm [D(0,9) = 10 μm] sind. Gemäß einer bevorzugten Ausführungsform sind die Partikel stets kleiner als 100 μm, vorzugs- weise 75 μm. Die in hier angegebenen Partikelgrößen sind stets durch Laserstreulichtmessung (z.B. mit einem Malvern Mastersizer o.a.) bestimmt.The ion exchangers used according to the invention are ground in such a way that 90% of the particles are smaller than 50 μm [D (0.9) = 50 μm], preferably smaller than 20 μm [D (0.9) = 20 μm], particularly preferably smaller than 10 μm [ D (0.9) = 10 μm]. According to a preferred embodiment, the particles are always smaller than 100 μm, preferably 75 μm. The particle sizes specified here are always determined by laser scattered light measurement (e.g. with a Malvern Mastersizer or the like).
Überraschenderweise wurde festgestellt, dass sich die erfindungsgemäße pharmazeutische Zubereitung aufgrund der geringen Partikelgröße des beladenen Ionen- tauschers [D(0,9) < 50 μm] durch eine ausgezeichnete Palatabihtät, z.B. bei Katzen, auszeichnet.Surprisingly, it was found that the pharmaceutical preparation according to the invention, owing to the small particle size of the charged ion exchanger [D (0.9) <50 μm], was distinguished by an excellent palatabilty, e.g. in cats.
Darüber hinaus wird in flüssigen Formulierungen durch die Mahlung des lonentauschers nicht nur die Bildung eines Sedimentes deutlich verzögert, sondern das Sediment ist auch sehr leicht wiederaufschüttelbar. Insbesondere die bessere Wieder- aufschüttelbarkeit des fein gemahlenen lonentauschers war überraschend, da üb- licherweise feinpartikuläre, sedimentierende Suspensionen aufgrund der großen spezifischen Oberfläche und somit hohen Adhäsionskräfte der Teilchen zu einer schlechten Redispergierbarkeit (Caking) neigen.In addition, the grinding of the ion exchanger in liquid formulations not only significantly delays the formation of a sediment, but the sediment is also very easy to shake again. The better ability to shake the finely ground ion exchanger in particular was surprising, since Certainly, fine particulate, sedimenting suspensions tend to be poorly redispersible (caking) due to the large specific surface and thus high adhesive forces of the particles.
Die erfindungsgemäßen pharmazeutischen Zubereitungen eignen sich generell für dieThe pharmaceutical preparations according to the invention are generally suitable for
Anwendung bei Mensch und Tier. Bevorzugt werden sie in der Tierhaltung und Tierzucht bei Nutz-, Zucht-, Zoo-, Labor-, Versuchs- und Hobbytieren vorkommen.Use in humans and animals. They will be preferred in animal husbandry and animal breeding for farm, breeding, zoo, laboratory, experimental and hobby animals.
Zu den Nutz- und Zuchttieren gehören Säugetiere wie z.B. Rinder, Pferde, Schafe, Schweine, Ziegen, Kamele, Wasserbüffel, Esel, Kaninchen, Damwild, Rentiere, Pelztiere wie z.B. Nerze, Chinchilla, Waschbär sowie Vögel wie z.B. Hühner, Gänse, Puten, Enten, Tauben und Vogelarten für Heim- und Zoohaltung.Livestock and breeding animals include mammals such as Cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur animals such as Mink, chinchilla, raccoon and birds such as Chickens, geese, turkeys, ducks, pigeons and bird species for home and zoo keeping.
Zu Labor- und Versuchstieren gehören Mäuse, Ratten, Meerschweinchen, Gold- hamster, Hunde und Katzen.Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
Zu den Hobbytieren gehören Kaninchen, Hamster, Meerschweinchen, Mäuse, Pferde, Reptilien, entsprechende Vogelarten, Hunde und Katzen.Hobby animals include rabbits, hamsters, guinea pigs, mice, horses, reptiles, appropriate bird species, dogs and cats.
Weiterhin seien Fische genannt, und zwar Nutz-, Zucht-, Aquarien- und Zierfische aller Altersstufen, die in Süß- und Salzwasser leben. Zu den Nutz- und Zuchtfischen zählen z.B. Karpfen, Aal, Forelle, Weißfisch, Lachs, Brachse, Rotauge, Rotfeder, Döbel, Seezunge, Scholle, Heilbutt, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), Red seabream (Pagurus major), Seabass (Dicentrarchus labrax), Grey mullet (Mugilus cephalus), Pompano, Gilthead seabream (Sparus auratus), Tilapia spp., Cichliden-Arten wie z.B. Plagioscion, Channel catfish. Besonders geeignet sind die erfindungsgemäßen Mittel zur Behandlung von Fischbrut, z.B. Karpfen von 2 bis 4 cm Körperlänge. Sehr gut geeignet sind die Mittel auch in der Aalmast. Bevorzugt werden die erfindungsgemäßen Zubereitungen bei Hobbytieren wie Hamster, Kaninchen, Meerschweinchen, Katzen und Hunden eingesetzt. Insbesondere eignen sie sich für die Anwendung bei Katzen.Fish should also be mentioned, namely commercial, breeding, aquarium and ornamental fish of all ages that live in fresh and salt water. Useful and farmed fish include carp, eel, trout, white fish, salmon, bream, roach, rudd, chub, sole, plaice, halibut, Japanese yellowtail (Seriola quinqueradiata), Japanaal (Anguilla japonica), red seabream (Pagurus major ), Seabass (Dicentrarchus labrax), Gray mullet (Mugilus cephalus), Pompano, Gilthead seabream (Sparus auratus), Tilapia spp., Cichlid species such as Plagioscion, Channel catfish. The agents according to the invention are particularly suitable for the treatment of fish fry, for example carp with a body length of 2 to 4 cm. The agents are also very suitable for eel fattening. The preparations according to the invention are preferably used in hobby animals such as hamsters, rabbits, guinea pigs, cats and dogs. They are particularly suitable for use in cats.
Die Anwendung kann sowohl prophylaktisch als auch therapeutisch erfolgen.The application can be prophylactic as well as therapeutic.
Die erfindungsgemäßen Zubereitungen werden bevorzugt oral verabreicht.The preparations according to the invention are preferably administered orally.
Für Tiere geeignete Arzneimittelzubereitungen sind z.B. solche, bei denen die Ge- schmacksverbesserung bei der Aufnahme eine Rolle spielt oder bei denen eine verzögerte Wirkstoff-Freisetzung nach der Applikation angestrebt wird.Pharmaceutical preparations suitable for animals are e.g. those in which the improvement in taste plays a role in the intake or in which a delayed release of the active ingredient after the application is sought.
Dies sind z.B. feste Zubereitungen wie Pulver, Premixe oder Konzentrate, Granulate, Pellets, Tabletten, Boli, Kapseln, oder flüssige bzw. halbfeste Arzneiformen wie Suspensionen oder Pasten, die z.B. oral angewendet werden. Letztere werden hergestellt, indem man das wirkstoff eladene Harz in einer Trägerflüssigkeit gegebenenfalls unter Zusatz weiterer Hilfsstoffe wie Netzmittel, Farbstoffe, resorptions- fordernde Stoffe, Konservierungsstoffe, Antioxidantien oder Lichtschutzmittel suspendiert.These are e.g. solid preparations such as powders, premixes or concentrates, granules, pellets, tablets, boluses, capsules, or liquid or semi-solid pharmaceutical forms such as suspensions or pastes, e.g. can be used orally. The latter are produced by suspending the resin loaded with active ingredient in a carrier liquid, optionally with the addition of further auxiliaries such as wetting agents, dyes, absorption-promoting substances, preservatives, antioxidants or light stabilizers.
Durch Zusatz von Substanzen, die die Viskosität erhöhen, können diese Suspensionen auch als sogenannte "halbfeste" Zubereitungen wie z.B. Salben verabreicht werden. Insbesondere können Formulierungen dieser Art als orale Paste bei Katzen, Hunden und Pferden verwendet werden.By adding substances that increase the viscosity, these suspensions can also be used as so-called "semi-solid" preparations, e.g. Ointments are administered. In particular, formulations of this type can be used as an oral paste in cats, dogs and horses.
Zur Herstellung fester Zubereitungen wird das wirkstoffbeladende Harz mit geeigneten Trägerstoffen gegebenenfalls unter Zusatz von Hilfsstoffen vermischt und in die gewünschte Form gebracht.To prepare solid preparations, the active substance-loading resin is mixed with suitable carriers, if appropriate with the addition of auxiliaries, and brought into the desired shape.
Als Trägerstoffe seien genannt alle physiologisch verträglichen Inertstoffe. Als solche dienen anorganische und organische Stoffe. Anorganische Stoffe sind z.B. Kochsalz, Carbonate wie Calciumcarbonat, Hydrogencarbonate, Aluminiumoxide, Kieselsäuren, Tonerden, gefälltes oder kolloidales Siliciumdioxid, Phosphate.All physiologically compatible inert substances may be mentioned as carriers. Inorganic and organic substances serve as such. Inorganic substances are, for example Table salt, carbonates such as calcium carbonate, hydrogen carbonates, aluminum oxides, silicas, clays, precipitated or colloidal silicon dioxide, phosphates.
Organische Stoffe sind z.B. Zucker, Zellulose, Nahrungs- und Futtermittel wie Milchpulver, Tiermehle, Getreidemehle und -schrote, Stärken.Organic substances are e.g. Sugar, cellulose, food and feed such as milk powder, animal meal, cereal flour and meal, starches.
Hilfsstoffe sind Konservierungsstoffe, Antioxidantien, Farbstoffe, die bereits weiter oben aufgeführt worden sind.Excipients are preservatives, antioxidants, dyes, which have already been listed above.
Weitere geeignete Hilfsstoffe sind Schmier- und Gleitmittel wie z.B. Magnesium- stearat, Stearinsäure, Talkum, Bentonite, zerfallsfördernde Substanzen wie Stärke oder quervernetztes Polyvinylpyrrolidon, Bindemittel wie z.B. Stärke, Gelatine oder lineares Polyvinylpyrrolidon sowie Trockenbindemittel wie mikrokristalline Cellulose.Other suitable auxiliaries are lubricants and lubricants such as Magnesium stearate, stearic acid, talc, bentonite, decay-promoting substances such as starch or cross-linked polyvinylpyrrolidone, binders such as e.g. Starch, gelatin or linear polyvinylpyrrolidone and dry binders such as microcrystalline cellulose.
Zur Herstellung von Suspensionen werden die wirkstoffbeladenen Harze in einem flüssigen Trägermedium möglichst homogen verteilt, gegebenenfalls unter Zuhilfenahme von anderen Hilfsstoffen wie Netzmittel, Konservierungsmittel oder viskosi- tätserhöhende Stoffe.To prepare suspensions, the active substance-loaded resins are distributed as homogeneously as possible in a liquid carrier medium, if appropriate with the aid of other auxiliaries, such as wetting agents, preservatives or viscosity-increasing substances.
Als Trägerflüssigkeiten seien genannt alle homogenen Lösungsmittel und Lösungsmittelgemische insbesondere aber Wasser, Paraffinöle und fette Öle, wie z. B. Neutralöl.Carrier liquids are all homogeneous solvents and solvent mixtures, but especially water, paraffin oils and fatty oils, such as. B. Neutral oil.
Der mit dem Wirkstoff beladene Ionenaustauscher ist in den erfindungsgemäßenThe ion exchanger loaded with the active ingredient is in the invention
Zubereitungen vorzugsweise in einer Menge von 1 bis 50 Gew.-%, besonders bevorzugt 5 bis 25 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung enthalten. Die Trägerflüssigkeit wird in der zur Einstellung der nötigen Konsistenz geeigneten Menge eingesetzt, üblicherweise sind das vorzugsweise 50 bis 99 Gew.-%, besonders bevorzugt 70 bis 95 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung.Preparations preferably in an amount of 1 to 50 wt .-%, particularly preferably 5 to 25 wt .-% based on the total weight of the preparation. The carrier liquid is used in the amount suitable for setting the necessary consistency, usually this is preferably 50 to 99% by weight, particularly preferably 70 to 95% by weight, based on the total weight of the preparation.
Als Netzmittel (Dispergiermittel) seien genannt:The following may be mentioned as wetting agents (dispersants):
• anionaktive Tenside einschließlich Emulgatoren wie Na-Laurylsulfat, Fett- alkoholethersulfate, Mono/Dialkylpolyglykoletherorthophosphorsäureester- Monoethanolaminsalz, Ligninsulfonate oder Dioctylsulfosuccinat• anionic surfactants including emulsifiers such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt, lignin sulfonates or dioctyl sulfosuccinate
• kationaktive Tenside, einschließlich Emulgatoren wie Cetyltrimethylammo- niumchlorid• cationic surfactants, including emulsifiers such as cetyltrimethylammonium chloride
• ampholytische Tenside, einschließlich Emulgatoren wie Di-Na-N-lauryl-ß- iminodipropionat oder Lecithin• Ampholytic surfactants, including emulsifiers such as di-Na-N-lauryl-β-iminodipropionate or lecithin
• nicht ionogene Tenside, einschließlich Emulgatoren, wie polyoxyethyliertes Rizinusöl, polyoxyethyliertes Sorbitan-Monooleat, Sorbitan-Monostearat, Glycerinmonostearat, Polyoxyethylenstearat, Alkylphenolpolyglykolether, Polyethylen-Polypropylen-Blockcopolymere.• Non-ionic surfactants, including emulsifiers, such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ether, polyethylene-polypropylene block copolymers.
Besonders bevorzugt sind die nichtionischen Tenside.The nonionic surfactants are particularly preferred.
Netzmittel werden bevorzugt in einer Menge von 0,1 bis 10 Gew.-%, besonders bevorzugt 0,5 bis 5 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung eingesetzt.Wetting agents are preferably used in an amount of 0.1 to 10% by weight, particularly preferably 0.5 to 5% by weight, based on the total weight of the preparation.
Weitere Hilfsstoffe sind z.B.: • Farbstoffe, d.h. alle zur Anwendung am Menschen oder Tier zugelassenen Farbstoffe, die gelöst oder suspendiert sein können. Farbstoffe werden bevorzugt in einer Menge von 0,001 bis 5 Gew.-%, besonders bevorzugt 0,01 bis 2 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung eingesetzt.Other auxiliaries include: • Dyes, ie all dyes approved for use on humans or animals, which can be dissolved or suspended. Dyes are preferably used in an amount of 0.001 to 5% by weight, particularly preferably 0.01 to 2% by weight, based on the total weight of the preparation.
• Antioxidantien wie z.B. Sulfite oder Metabisulfite wie Kaliummetabisulfit, Ascorbinsäure, Butylhydroxytoluol, Butylhydroxyanisol, Tocopherole. Antioxidantien werden bevorzugt in einer Menge von 0,001 bis 5 Gew.-%, besonders bevorzugt 0,01 bis 2 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung eingesetzt.Antioxidants such as Sulphites or metabisulphites such as potassium metabisulphite, ascorbic acid, butylated hydroxytoluene, butylated hydroxyanisole, tocopherols. Antioxidants are preferably used in an amount of 0.001 to 5% by weight, particularly preferably 0.01 to 2% by weight, based on the total weight of the preparation.
• Verdickungsmittel bzw. viskositätserhöhende Stoffe wie z.B. anorganische Verdickungsmittel wie Bentonite, kolloidale Kieselsäure, Aluminiummono- stearat, organische Verdickungsmittel wie Cellulosederivate, Polyvinylalko- hole und deren Copolymere, Acrylate und Methacrylate, Alginate, Gelatine,Thickeners or viscosity-increasing substances such as inorganic thickeners such as bentonites, colloidal silica, aluminum monostearate, organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates, alginates, gelatin,
Polyvinylpyrrolidon, Polyethylenglykole, Wachse, Gummi arabicum und Xanthan-Gummi oder Gemische der aufgeführten Stoffe. Verdickungsmittel werden bevorzugt in einer Menge von 0,01 bis 10 Gew.-%, besonders bevorzugt 0,01 bis 5 Gew.-% bezogen auf das Gesamtgewicht der Zubereitung eingesetzt.Polyvinyl pyrrolidone, polyethylene glycols, waxes, gum arabic and xanthan gum or mixtures of the listed substances. Thickeners are preferably used in an amount of 0.01 to 10% by weight, particularly preferably 0.01 to 5% by weight, based on the total weight of the preparation.
Bevorzugt handelt es sich bei den erfindungsgemäßen Zubereitungen um flüssige oder halbflüssige Suspensionen.The preparations according to the invention are preferably liquid or semi-liquid suspensions.
Durch Zusatz von Substanzen, die die Viskosität erhöhen, können diese Suspensionen auch als halbfeste Zubereitungen wie z.B. Pasten verabreicht werden. Insbesondere können Formulierungen dieser Art als orale Paste bei Tieren verwendet werden. Weiterhin können die wirkstoffbeladenen lonenaustauscherharze als solche oder in Form von Prämixen oder Futterkonzentraten dem Futter zugesetzt werden.By adding substances that increase the viscosity, these suspensions can also be administered as semi-solid preparations such as pastes. In particular, formulations of this type can be used as an oral paste in animals. Furthermore, the active substance-loaded ion exchange resins can be added to the feed as such or in the form of premixes or feed concentrates.
Prämixe und Futterkonzentrate sind Mischungen des Wirkstoffes mit einem geeig- neten Trägerstoff.Premixes and feed concentrates are mixtures of the active ingredient with a suitable carrier.
Zu den Trägerstoffen zählen die Einzelfuttermittel oder Gemische derselben, sowie die weiter oben genannten inerten Trägerstoffe.The carrier substances include the feed materials or mixtures thereof, as well as the inert carrier substances mentioned above.
Sie können darüber hinaus weitere Hilfsmittel enthalten, wie z.B. Substanzen, die dieThey can also contain other tools, such as Substances the
Fließfähigkeit und Mischbarkeit regulieren, wie z.B. Kieselsäuren, Bentonite, Ligninsulfonate. Darüber hinaus können Antioxydantien wie BHT oder Konservierungsmittel wie Sorbinsäure oder Calciumpropionat hinzugefügt sein. Außerdem können den Prämixen zur Staubbindung Flüssigkeiten wie Paraffinöle, Pflanzenöle, Propylenglykole zugemischt werden.Regulate fluidity and miscibility, e.g. Silicas, bentonites, lignin sulfonates. In addition, antioxidants such as BHT or preservatives such as sorbic acid or calcium propionate can be added. Liquids such as paraffin oils, vegetable oils and propylene glycols can also be added to the premixes for dust binding.
Die wirkstoffbeladenen Harze können in den Formulierungen allein oder in Mischung mit anderen Wirkstoffen, Mineralsalzen, Spurenelementen, Vitaminen, Eiweißstoffen, Farbstoffen, Fetten oder Geschmacksstoffen vorliegen.The active substance-loaded resins can be present in the formulations alone or in a mixture with other active substances, mineral salts, trace elements, vitamins, protein substances, colorants, fats or flavorings.
Die Verabreichung der wirkstoffbeladenen lonenaustauscherharze kann zusammen mit dem Futter erfolgen.The active substance-loaded ion exchange resins can be administered together with the feed.
Zum Futter zählen Einzelfuttermittel pflanzlicher Herkunft wie Heu, Rüben, Ge- treide, Getreidenebenprodukte, Einzelfuttermittel tierischer Herkunft wie Fleisch,The feed includes single feed of vegetable origin such as hay, beets, cereals, grain by-products, single feed of animal origin such as meat,
Fette, Milchprodukte, Knochenmehl, Fischprodukte, ferner die Einzelfuttermittel wie Vitamine, Proteine, Aminosäuren, z.B. DL-Methionin, Salze wie Kalk und Kochsalz. Zum Futter zählen auch Ergänzungs-, Fertig- und Mischfuttermittel. Diese enthalten Einzelfuttermittel in einer Zusammensetzung die eine ausgewogene Ernährung hin- sichtlich der Energie- und Proteinversorgung sowie der Versorgung mit Vitaminen,Fats, milk products, bone meal, fish products, furthermore the feed materials such as vitamins, proteins, amino acids, e.g. DL-methionine, salts such as lime and table salt. The feed also includes supplementary, finished and compound feed. These contain feed materials in a composition that provides a balanced diet with regard to energy and protein supply as well as the supply of vitamins,
Mineralsalzen und Spurenelementen sicherstellen. HerstellungsbeispieleEnsure mineral salts and trace elements. Preparation Examples
Beispiel 1example 1
3,86 kg Enrofloxacin und 19,24 kg Amberlite IRP 64 werden in 76,90 kg gereinigtem Wasser suspendiert und über mindestens 8 Stunden bei Raumtemperatur gerührt. Die Suspension wird in einen Filtertrockner überführt, filtriert und bei 85°C getrocknet. 17,96 kg des so erhaltenen beladenen Ionentauscher werden zusammen mit 60 g kolloidaler Kieselsäure (z.B. Aerosil 200) in 100,40 kg Neutralöl (z.B. Miglyol 812) suspendiert und mit einer Perlmühle (z.B. DynoMill KD 6, W.A. Bachofen AG) vermählen. Mindestens 90 % der resultierenden Partikel sind kleiner als 10 μm.3.86 kg of enrofloxacin and 19.24 kg of Amberlite IRP 64 are suspended in 76.90 kg of purified water and stirred at room temperature for at least 8 hours. The suspension is transferred to a filter drier, filtered and dried at 85 ° C. 17.96 kg of the loaded ion exchanger thus obtained are suspended together with 60 g of colloidal silica (e.g. Aerosil 200) in 100.40 kg neutral oil (e.g. Miglyol 812) and ground using a bead mill (e.g. DynoMill KD 6, W.A. Bachofen AG). At least 90% of the resulting particles are smaller than 10 μm.
Beispiel 2Example 2
5,00 kg 8-Cyan-l-cyclopropyl-7-((lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor- l ,4-dihydro-4-oxo-3-chinolincarbonsäure und 20,00 kg Purolite C 100 H MR werden in 80,00 kg gereinigtem Wasser suspendiert und über mindestens 8 Stunden bei Raumtemperatur gerührt. Nach Sedimentation wird der Überstand abgelassen. Der Rückstand wird mit einem Schaufeltrockner bei 75°C getrocknet. 24,00 kg des so erhaltenen beladenen lonentauschers werden zusammen mit 2,40 kg Aluminium- stearat in 213,60 kg dünnflüssigem Paraffin suspendiert und mit einer Perlmühle (z.B. Drais PM 25 TEX) vermählen. Mindestens 90 % der suspendierten Partikel sind anschließend kleiner als 20 μm.5.00 kg 8-cyano-l-cyclopropyl-7 - ((IS, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid and 20.00 kg of Purolite C 100 H MR are suspended in 80.00 kg of purified water and stirred at room temperature for at least 8 hours. After sedimentation, the supernatant is drained off. The residue is dried with a paddle dryer at 75 ° C. 24.00 kg of the loaded ion exchanger thus obtained are suspended together with 2.40 kg of aluminum stearate in 213.60 kg of low-viscosity paraffin and ground using a bead mill (e.g. Drais PM 25 TEX). At least 90% of the suspended particles are then smaller than 20 μm.
Beispiel 3Example 3
3,50 kg Flupirtin und 5,25 kg Amberlite IRP 69 werden in 40,00 kg Ethanol 50 % (V/V) suspendiert und über mindestens 12 Stunden bei 40°C gerührt. Die Suspension wird in einen Filtertrockner überführt, filtriert und bei 60°C getrocknet. 8,50 kg des beladenen lonentauschers werden mit einer Spiralstrahlmühle (z.B. Alpine 100 AS) vermählen, so dass mindestens 90 % der resultierenden Partikel kleiner 50 μm sind. Der vermahlene Ionentauscher und 0,68 kg Methylcellulose werden anschließend in 30,60 kg gereinigtem Wasser dispergiert.3.50 kg of flupirtine and 5.25 kg of Amberlite IRP 69 are suspended in 40.00 kg of ethanol 50% (v / v) and stirred at 40 ° C. for at least 12 hours. The suspension is transferred to a filter drier, filtered and dried at 60 ° C. 8.50 kg of the loaded ion exchanger are ground with a spiral jet mill (e.g. Alpine 100 AS) so that at least 90% of the resulting particles are smaller than 50 μm. The ground ion exchanger and 0.68 kg of methyl cellulose are then dispersed in 30.60 kg of purified water.
Beispiel 4Example 4
5,00 kg 8-Cyan-l-cyclopropyl-7-((lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor- l,4-dihydro-4-oxo-3-chinolincarbonsäure und 20,00 kg Amberlite IRP 64 werden in 75,00 kg gereinigtem Wasser suspendiert und mit einer Perlmühle (z.B. DynoMill KD 6, W.A. Bachofen AG) vermählen. Anschließend werden 2 kg hochviskose Hydroxyethylcellulose (z.B. Natrosol 250 HX) unter starkem Rühren eingearbeitet, so dass eine Paste entsteht. Mindestens 90 % der suspendierten Partikel sind kleiner als 20 μm.5.00 kg 8-cyano-l-cyclopropyl-7 - ((IS, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid and 20.00 kg of Amberlite IRP 64 are suspended in 75.00 kg of purified water and ground using a bead mill (eg DynoMill KD 6, WA Bachofen AG). Then 2 kg of highly viscous hydroxyethyl cellulose (e.g. Natrosol 250 HX) are worked in with vigorous stirring so that a paste is formed. At least 90% of the suspended particles are smaller than 20 μm.
Beispiel 5Example 5
3,0 kg 8-Cyan-l-cyclopropyl-7-((lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor- l,4-dihydro-4-oxo-3-chinolincarbonsäure und 17,0 kg Amberlite IRP 64 werden in 80 kg gereinigtem Wasser suspendiert und über mindestens 8 Stunden bei Raumtemperatur gerührt. Die Suspension wird in einen Filtertrockner überführt, filtriert und bei 85°C getrocknet. 10,0 kg des so erhaltenen beladenen Ionentauscher werden in 83,0 kg Neutralöl (z.B. Miglyol 812) suspendiert und mit einer Perlmühle (z.B. DynoMill KD 6, W.A. Bachofen AG) vermählen. Mindestens 90 % der resultierenden Partikel sind kleiner als 10 μm. Die vermahlene Suspension wird anschließend durch Zusatz von 7,0 kg Aerosil 200 in einem Homogenisator in eine Paste überführt. 3.0 kg of 8-cyano-1-cyclopropyl-7 - ((IS, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl) -6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid and 17.0 kg of Amberlite IRP 64 are suspended in 80 kg of purified water and stirred at room temperature for at least 8 hours. The suspension is transferred to a filter drier, filtered and dried at 85 ° C. 10.0 kg of the loaded ion exchanger obtained in this way are suspended in 83.0 kg of neutral oil (e.g. Miglyol 812) and ground using a bead mill (e.g. DynoMill KD 6, W.A. Bachofen AG). At least 90% of the resulting particles are smaller than 10 μm. The ground suspension is then converted into a paste by adding 7.0 kg of Aerosil 200 in a homogenizer.

Claims

Patentansprüche claims
1. Pharmazeutische Zubereitung enthaltend einen oder mehrere an einen Kationentauscher gebundene Wirkstoffe, dadurch gekennzeichnet, dass der be- ladene Kationentauscher in einem Trägermedium dispergiert ist und mindestens 90 % der dispergierten Ionenautauscherpartikel eine Größe von unter 50 μm besitzen.1. Pharmaceutical preparation containing one or more active substances bound to a cation exchanger, characterized in that the loaded cation exchanger is dispersed in a carrier medium and at least 90% of the dispersed ion exchanger particles have a size of less than 50 μm.
2. Pharmazeutische Zubereitung gemäß Anspruch 1 , dadurch gekennzeichnet, dass mindestens 90% der dispergierten Ionenautauscherpartikel eine Größe von unter 20 μm besitzen.2. Pharmaceutical preparation according to claim 1, characterized in that at least 90% of the dispersed ion exchange particles have a size of less than 20 microns.
3. Pharmazeutische Zubereitung gemäß Anspruch 1 , dadurch gekennzeichnet, dass der Ionentauscher ein schwach saurer Ionentauscher ist.3. Pharmaceutical preparation according to claim 1, characterized in that the ion exchanger is a weakly acidic ion exchanger.
4. Pharmazeutische Zubereitung gemäß Anspruch 1 in Form einer Suspension.4. Pharmaceutical preparation according to claim 1 in the form of a suspension.
5. Pharmazeutische Zubereitung gemäß Anspruch 1 in Form einer Paste.5. Pharmaceutical preparation according to claim 1 in the form of a paste.
6. Pharmazeutische Zubereitung gemäß Anspruch 1 , dadurch gekennzeichnet, dass der an den Ionentauscher gebundene Wirkstoff ein Chinolon-Anti- biotikum ist.6. Pharmaceutical preparation according to claim 1, characterized in that the active substance bound to the ion exchanger is a quinolone antibiotic.
7. Pharmazeutische Zubereitung gemäß Anspruch 1, dadurch gekennzeichnet, dass der an den Ionentauscher gebundene Wirkstoff Enrofloxacin ist.7. Pharmaceutical preparation according to claim 1, characterized in that the active substance bound to the ion exchanger is enrofloxacin.
8. Pharmazeutische Zubereitung gemäß Anspruch 1, dadurch gekennzeichnet, dass der an den Ionentauscher gebundene Wirkstoff 8-Cyan-l-cyclopropyl-7- ((lS,6S)-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluor-l,4-dihydro-4-oxo-3- chinolincarbonsäure ist. 8. Pharmaceutical preparation according to claim 1, characterized in that the active ingredient bound to the ion exchanger 8-cyano-l-cyclopropyl-7- ((IS, 6S) -2,8-diazabicyclo [4.3.0] nonan-8-yl ) -6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid.
. Verfahren zur Herstellung von pharmazeutischen Zubereitungen gemäß Anspruch 1 , bei dem man, A process for the preparation of pharmaceutical preparations according to claim 1, in which
(a) entweder den mit Wirkstoff beladenen Ionenaustauscher gegebenen- falls zusammen mit weiteren Hilfsmitteln in einem Träger dispergiert und auf die gewünschte Korngröße mahlt oder(a) either the ion exchanger loaded with active ingredient, if appropriate together with other auxiliaries, dispersed in a carrier and ground to the desired particle size or
(b) den reinen Ionentauscher zunächst auf die gewünschte Korngröße mahlt, ihn mit Wirkstoff belädt und dann den beladenen Ionentauscher in die endgültige Formulierung überführt.(b) first grinds the pure ion exchanger to the desired grain size, loads it with active ingredient and then transfers the loaded ion exchanger into the final formulation.
10. Verwendung von mit Wirkstoffen beladenen Kationentauschem, deren Partikel zu mindestens 90 % eine Größe von unter 50 μm besitzen, zur Herstellung von pharmazeutischen Zubereitungen für die orale Verabreichung. 10. Use of cation exchangers loaded with active substances, the particles of which at least 90% have a size of less than 50 μm, for the production of pharmaceutical preparations for oral administration.
EP02743262A 2001-07-17 2002-07-04 Pharmaceutical preparations containing ion exchange resins charged with active ingredients Ceased EP1411894A2 (en)

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PCT/EP2002/007417 WO2003007995A2 (en) 2001-07-17 2002-07-04 Pharmaceutical preparations containing ion exchange resins charged with fluoroquinolone

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DE102012021559A1 (en) 2012-11-02 2014-05-08 Technische Universität Bergakademie Freiberg Preparing sub-micron macroporous ion exchange materials by mechanical grinding, comprises processing product slurry having an average particle size in a stirred ball mill or planetary ball mill at specific process time
US9669010B2 (en) 2012-12-06 2017-06-06 Bio Health Solutions, Llc Treatment for chronic kidney disease
WO2014089526A1 (en) * 2012-12-06 2014-06-12 Bio Health Solutions, Llc Treatment for chronic kidney disease
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