EP1968555A2 - Masking the taste of powders - Google Patents

Masking the taste of powders

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Publication number
EP1968555A2
EP1968555A2 EP06829765A EP06829765A EP1968555A2 EP 1968555 A2 EP1968555 A2 EP 1968555A2 EP 06829765 A EP06829765 A EP 06829765A EP 06829765 A EP06829765 A EP 06829765A EP 1968555 A2 EP1968555 A2 EP 1968555A2
Authority
EP
European Patent Office
Prior art keywords
solid
microns
coated
coating agent
coated solid
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.)
Withdrawn
Application number
EP06829765A
Other languages
German (de)
French (fr)
Inventor
Rainer Bellinghausen
Daniel Rudhardt
Frank Ridder
Martin Steinbeck
Jesko Zank
Martin Weiss
Olaf Behrend
Udo Van Stiphout
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 Intellectual Property GmbH
Original Assignee
Bayer Technology Services GmbH
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Filing date
Publication date
Application filed by Bayer Technology Services GmbH filed Critical Bayer Technology Services GmbH
Publication of EP1968555A2 publication Critical patent/EP1968555A2/en
Withdrawn legal-status Critical Current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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel, taste-masked powders for inhalation or oral administration, a simple process for their preparation and their use for the application of biologically active substances.
  • bitter-tasting active ingredients usually causes a bad taste during or after inhalation, which often leads to low acceptance of the inhalants among their users. Therefore, masking or flavoring of inhalable powders is desirable.
  • the customer compliance is increased, which has proven itself in oral formulations and has largely prevailed.
  • the taste maskings of inhalants described in the literature are limited to the pulverization of flavors, for example WO2001 / 26630, WO93 / 17663, JP11-106339.
  • microcapsules in the size range above 200 .mu.m can be encapsulated in so-called Wurster coaters in the fluidized bed, for example.
  • the conventional methods are not useful for masking powders with particle sizes (d 50 ) of about 5 microns because they lead to a too thick coating layer.
  • d 50 particle sizes
  • coating tablets usually 2-10 mg of coating material / cm 2 are used, which corresponds to layer thicknesses of 20-100 ⁇ m.
  • a method for the encapsulation of inhalation it is only allowed to build up very thin coating layers, as otherwise the aerodynamic diameter of the particles is changed too much and the encapsulated powder is no longer suitable for inhalation.
  • the aerodynamic diameter of a particle is defined as the diameter of a sphere with the normalized density of 1 g / cm3, which has the same rate of descent as the particle itself.
  • the thin coating layers must lead to a tight sheath, which allows release only after a time of 15-30 minutes, otherwise the desired taste masking is not guaranteed.
  • this object is achieved by a process comprising distributing a pulverulent solid having a mean pond diameter d 50 of from 1 to 40 ⁇ m, preferably 2 to 10 ⁇ m, particularly preferably about 4 to 6 ⁇ m, into a solution of a hydrophobic one Coating agent in a solvent which does not dissolve the powdery solid, and then lowering the temperature of the resulting mixture to precipitate the coated solid and optionally isolating the coated solid.
  • the proportion of the coating agent can be varied.
  • the preferred range is 50 to 99% by weight (based on the sum of pulverulent solid and coating agent), so that layer thicknesses of the coating material 1 to less than 20 .mu.m, preferably 1 to 5 .mu.m and particularly preferably 1 to 3 .mu.m are obtained for the individual particle size ranges ,
  • the inventive method is suitable in principle for all types of powdered solids.
  • active substances ie substances from the range of agents for healing, alleviating or preventing human or animal diseases, such as acidotherapeutic agents, analeptics / antihypoxemics, analgesics / antirheumatics, anthelmintics, antiallergics, antianemics, antiarrhythmics, antibiotics / Anti-infectives, anti-dementia drugs, antidiabetic drugs, antidotes, antiemetics / antivertiginosa, antiepileptics, antihemorrhagics, antihypertensives, antihypoglycemics, antihypotonics, anticoagulants, antifungals, antiparasitic agents, antiprotozoics, antiphlogistics, antitussives / expectorants, arteri sclerosants, broncholytics / antiasthmatics, Cholagoga u
  • Bile Duct Therapeutics cholinergics, corticoids, dermatics, diuretics, circulation-promoting agents, weaners / agents for the treatment of addictions, enzyme inhibitors, preparations b.
  • Enzyme deficiency Transport proteins fibrinolytics, geriatrics, gout, gynecologics, hepatics, hypnotics / sedatives, immunomodulators, cardiacs, coronary agents, laxatives, lipid-lowering agents, local anesthetics / neural therapeutics, gastrointestinal agents, migraine agents, muscle relaxants, ophthalmics, osteoporosis agents / calcium metabolism regulators, otologics, Psychotropic drugs, Rhinologics / Sinusitis agents, Roborantia / Tonics, Thyroid therapeutics, Sexual hormones and others.
  • Boldin, quinolones, ciprofloxacin, felodipine, flurbiprofen, ibuprofen, ketoprofen, macrolides, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, norfloxacin, moxifloxacin, ofloxacin, paclitaxel, praziquantel, sulfonamides and tetracyclines are examples thereof.
  • the coating material is hydrophobic water-repellent materials. As for the purposes of this invention to be understood as hydrophobic are not or only limited water-soluble materials. The coating material must be practically insoluble or at least ⁇ 1000 mg / kg soluble in water at pH 6 to 7.5 at a temperature of 25 ° C. Such hydrophobic materials may be:
  • Waxes with a melting range of 30-180 0 C such as paraffins, natural waxes, bee waxes, canauba wax, saturated hydrocarbons of the form CnH2n + 2, synthetic
  • Waxes Fischer-Tropsch waxes, stearins, macrogol stearate and chemically modified wax types, vinyl polymers, montan ester waxes and montan wax fatty acids.
  • Resins petrochemical origin hydrocarbon resins, polymers of unsaturated aromatic Cg / Cio hydrocarbons with and without phenol, aliphatically modified aromatic C9 / C with an unsaturated aliphatic component, indene-coumarone resins 1 0- hydrocarbons, polymers carbo burly unsaturated aromatic hydrocarbons, phenolmodifiertes indene -Coumarone resin, co-polymer of carbomonomically unsaturated C 9 - / Cio-hydrocarbons with phenol,
  • hydrophobic coating compositions are canauba wax from Baerlocher GmbH and waxes from Sasol Wax GmbH, e.g. the grades 5203, 4110, 6202, 6805, C80 and ClOO, resins and novolac from RÜTGERS Chemicals AG and Ashland-Südchemie-Kernfest GmbH, Eudragite, in particular the E grades ElOO and EPO, from Degussa Röhm, Chitosan from Fa Cognis, hydroxypropyl methylcellulose acetate succinate (AQCOAT) from Shin-Etsu AQOAT.
  • canauba wax from Baerlocher GmbH and waxes from Sasol Wax GmbH e.g. the grades 5203, 4110, 6202, 6805, C80 and ClOO, resins and novolac from RÜTGERS Chemicals AG and Ashland-Südchemie-Kernfest GmbH, Eudragite, in particular the E grades ElOO and EPO, from Degussa Röh
  • Solvents which are suitable for carrying out the process according to the invention are, for example, aromatic or aliphatic hydrocarbons which are liquid at room temperature, in particular linear or cyclic alkanes which may optionally be branched. Also suitable are organic
  • Solvent in particular one selected from the series of short-chain alcohols with 1 to
  • Ethylene glycol 1,2-propylene glycol, short chain ketones of 3 to 10 carbon atoms, e.g. Acetone, 2-butanone, carboxylic acids, e.g. Acetic acid, ethers, e.g. diethyl ether,
  • Tetrahydrofuran or methyl tert-butyl ether esters such as e.g. Methyl acetate, ethyl acetate or
  • Methyl formate e.g. Pyridines, formamides such as e.g.
  • Solvents are n-heptane and methylcyclohexane.
  • the abovementioned solvents can each be used alone or in a mixture.
  • the formation of the coated solid takes place by lowering the temperature (cooling precipitation).
  • the preparation of said mixture is carried out at a temperature of 5O 0 C, preferably from 40 to 100 0 C.
  • the second step it is usually cooled to a temperature of 20 ° C., preferably from 0 to 40 ° C.
  • the concentration of the coating agent in the solvent is usually about 5 to 25%, depending on the solubility also above or below. It should be worked with saturated solutions.
  • the proportion of the pulverulent solid in the said mixture is generally from 1 to 90%, preferably from 5 to 20%.
  • the coated solid particles produced by the process according to the invention have only a very thin coating layer, so that the particle size and in particular the aerodynamic diameter are scarcely changed. Nevertheless, these coated solid particles show successful taste masking.
  • the coated solid particles produced by the process according to the invention are therefore ideally suited for use in dry powder inhalers and oral dosage forms which require efficient taste masking even when bitten or chewed.
  • the small particle size also prevents chewing of the capsule during oral administration. This is particularly advantageous in chewable, veterinary and pediatric applications.
  • Another advantage of oral use is the improved mouthfeel because the small particles are not perceived as particles.
  • the particle sizes of the encapsulated praziquantel are in the range of about 2-9 ⁇ m (dlO and d90, see above). Taste tests show that the bitter taste is not noticed after applying the formulation to the tongue even over a period of 10 minutes. Even chewing the formulation over several minutes does not lead to a release of the taste.
  • Example 2 a to d (Ciprofloxacin with Canauba Wax)
  • the active ingredient content was varied between 5 and 20%:
  • Milled ciprofloxacin having a particle size of 0.5 to 9 ⁇ m were converted into the above-mentioned proportions (based on the coating agent) at 60 ° C.
  • the temperature of the obtained mixture was at 20 0 C with a cooling rate of
  • Example 1 10K / h with constant stirring with a diameter 60mm impeller cooled at 450Upm and the capsules formed by spray drying in a Buechy laboratory spray drier analogous to Example 1 isolated.
  • Example 2a 342 g of methylcyclohexane, 38 g of canauba wax, 2 g of ciprofloxacin 2b: 100 g of methylcyclohexane, 28 g of canauba wax, 7 g of ciprofloxacin 2c: 303 g of heptane, 30 g of canauba wax, 1.6 g of ciprofloxacin 2d: 152 g of heptane, 15 g of canauba wax , 3.8 g of ciprofloxacin
  • An SEM image of the capsules obtained in Example 2a is shown as FIG.
  • the successful taste masking was determined as follows: The coated material was placed on the tongue and rinsed out after about 10 minutes. The strong bitter taste of the drug was not noticed. For comparison, pure drug was tested: the bitter taste occurred very quickly and the taste test had to be stopped prematurely.

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  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Biophysics (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Preparation (AREA)
  • Seasonings (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to novel taste-masked powders that are to be inhaled or administered orally, a simple method for the production thereof, and the use thereof for applying biologically active substances.

Description

Geschmacksmaskierung von PulvernTaste masking of powders
Die vorliegende Erfindung betrifft neue, geschmacksmaskierte Pulver zur Inhalation oder oralen Darreichung, ein einfaches Verfahren zu deren Herstellung und deren Verwendung zur Applikation von biologisch aktiven Stoffen.The present invention relates to novel, taste-masked powders for inhalation or oral administration, a simple process for their preparation and their use for the application of biologically active substances.
Bei der Inhalation bitter schmeckender Wirkstoffe tritt in der Regel ein schlechter Geschmack während oder nach der Inhalation auf, was häufig zu geringer Akzeptanz der Inhalate bei deren Anwendern führt. Daher ist eine Maskierung oder Aromatisierung von inhalierbaren Pulvern wünschenswert. Die Kundenkompliance wird erhöht, was sich bei oralen Formulierungen bewährt und weitestgehend durchgesetzt hat.The inhalation of bitter-tasting active ingredients usually causes a bad taste during or after inhalation, which often leads to low acceptance of the inhalants among their users. Therefore, masking or flavoring of inhalable powders is desirable. The customer compliance is increased, which has proven itself in oral formulations and has largely prevailed.
Auch wenn bei modernen Inhalationsformulierungen die effektive Dosierung außerordentlich hoch ist (»90% des Wirkstoffes erreichen die Lunge), so ist damit die geschmackliche Beeinträchtigung nicht vermieden. Das menschliche Geschmacksempfinden reagiert in der Regel auf extrem kleine Kontaminationen. Daher ist eine Maskierung, die den guten Wirkungsgrad von Dry Powder Inhalern nicht beeinflusst, ein eindeutiger Marktvorteil gegenüber Formulierungen ohne Geschmacks- maskierung.Even though the effective dosage is extremely high in modern inhalation formulations (»90% of the active ingredient reaches the lungs), the impairment of taste is not avoided. The human taste usually reacts to extremely small contaminations. Therefore, masking that does not affect the high efficiency of Dry Powder Inhalers is a clear market advantage over non-flavored formulations.
Die in der Literatur beschriebenen Geschmacksmaskierungen von Inhalaten beschränken sich auf die Pulverisierung von Aromen, so beispielsweise WO2001/26630, WO93/17663, JPl 1-106339.The taste maskings of inhalants described in the literature are limited to the pulverization of flavors, for example WO2001 / 26630, WO93 / 17663, JP11-106339.
Die Verkapselung von größeren Körpern, beispielsweise Tabletten, ist bereits grundsätzlich bekannt. Auch ist bekannt, daß Mikrokapseln im Größenbereich über 200μm beispielsweise in sogenannten Wurster-Coatern in der Wirbelschicht verkapselt werden können.The encapsulation of larger bodies, such as tablets, is already known in principle. It is also known that microcapsules in the size range above 200 .mu.m can be encapsulated in so-called Wurster coaters in the fluidized bed, for example.
Kleinere Korngrößen können durch Kondensation-Verkapselung gecoatet werden, wobei allerdings ein verdampfbares Coating-Material erforderlich ist. (siehe: Ebert, Dau, "Beschichten submikroner Partikeln durch heterogene Kondensation unter Expansion", DFG- Jahresbericht 2003)Smaller grain sizes can be coated by condensation encapsulation, but a vaporizable coating material is required. (see: Ebert, Dau, "Coating of submicron particles by heterogeneous condensation under expansion", DFG Annual Report 2003)
Verkapselungen von Pulvern zum controlled release sind beschrieben in "Controlled dissolution from wax-coated aerosol particles in canine lungs", J. Appl. Physiol. 84(2), 1998, 717-725.Encapsulations of powders for controlled release are described in "Controlled dissolution from wax-coated aerosol particles in canine solutions", J. Appl. Physiol. 84 (2), 1998, 717-725.
Ferner wurden in DE 19753794 Beschichtungen von inhalierbarem Pulver zur Verbesserung der Fließfahigkeit herangezogen, z.B. auf Basis von elektrostatisch aufgeladenem HüllmaterialFurther, in DE 19753794 coatings of inhalable powder have been used to improve flowability, e.g. based on electrostatically charged shell material
Die konventionellen Verfahren sind jedoch nicht brauchbar für die Maskierung von Pulvern mit Partikelgrößen (d50) von etwa 5μm, da sie zu einer zu dicken Coatingschicht fuhren. Beispielsweise werden beim Coaten von Tabletten i.d.R. 2-10mg Coating-Material /cm2 verwendet, was Schichtdicken von 20-1 OOμm entspricht. Ein Verfahren zur Verkapselung von für die Inhalation vorge- sehenen Pulvern darf jedoch nur sehr dünne Coatingschichten aufbauen, da ansonsten der aerodynamische Durchmesser der Teilchen zu stark verändert wird und das verkapselte Pulver dann nicht mehr für die Inhalation tauglich ist. Der aerodynamische Durchmesser eines Partikels ist dabei definiert als der Durchmesser einer Kugel mit der normierten Dichte von 1 g/cm3, welche die gleiche Sinkgeschwindigkeit hat wie der Partikel selber.However, the conventional methods are not useful for masking powders with particle sizes (d 50 ) of about 5 microns because they lead to a too thick coating layer. For example, when coating tablets, usually 2-10 mg of coating material / cm 2 are used, which corresponds to layer thicknesses of 20-100 μm. A method for the encapsulation of inhalation However, it is only allowed to build up very thin coating layers, as otherwise the aerodynamic diameter of the particles is changed too much and the encapsulated powder is no longer suitable for inhalation. The aerodynamic diameter of a particle is defined as the diameter of a sphere with the normalized density of 1 g / cm3, which has the same rate of descent as the particle itself.
Gleichzeitig müssen die dünnen Coatingschichten jedoch zu einer dichten Ummantelung, die eine Freisetzung erst nach einer Zeit von 15-30 min zulässt, fuhren, da anderenfalls die erwünschte Geschmacksmaskierung nicht gewährleistet ist.At the same time, however, the thin coating layers must lead to a tight sheath, which allows release only after a time of 15-30 minutes, otherwise the desired taste masking is not guaranteed.
Andere jüngst entwickelte Verkapselungsmethoden wie Co-Grinding oder Zentrifugalwirbelschichten zeigen entweder schlechte Geschmacksmaskierung oder Probleme z.B. bei hygroskopischen Materialien (Zitronensäure), die zu Agglomeration neigen, wodurch die verkapselten Pulver nicht mehr verarbeitet werden konnten.Other recently developed encapsulation techniques, such as co-grinding or centrifugal fluidization, either show poor taste masking or problems with e.g. in the case of hygroscopic materials (citric acid), which tend to agglomerate, whereby the encapsulated powders could no longer be processed.
Es bestand daher Bedarf an einem Verfahren zur Herstellung von geschmacksmaskierten inhalierbaren Pulvern durch Verkapselung, welches zu einer dünnen jedoch auch dichten Coatingschicht führt und einfach und kostengünstig durchzuführen ist.There was therefore a need for a process for the preparation of taste-masked inhalable powders by encapsulation, which leads to a thin but also dense coating layer and is simple and inexpensive to perform.
Es wurde nun überraschend gefunden, dass diese Aufgabe gelöst wird durch ein Verfahren, umfassend das Verteilen eines pulverförmigen Feststoffs mit einem mittleren Teichendurchmesser dso von 1 bis 40 μm, vorzugsweise 2 bis 10 μm, besonders bevorzugt ungefähr 4 bis 6 μm in eine Lösung eines hydrophoben Beschichtungsmittels in einem Lösemittel, welches den pulverförmigen Feststoff nicht löst, und dann das Absenken der Temperatur der resultierenden Mischung zum Ausfällen des beschichteten Feststoffs und gegebenenfalls das Isolieren des beschichteten Feststoffs. Dabei kann der Anteil des Beschichtungsmittel variiert werden. Als Vorzugsbereich wird 50 bis 99 Gew.-% (bezogen auf die Summe von pulverfÖrmigem Feststoff und Beschichtungsmittel) angesehen, so dass für die einzelnen Partikelgrößenbereiche Schichtdicken des Beschichtungsmittels 1 bis weniger als 20μm, vorzugsweise 1 bis 5μm und besonders bevorzugt 1 bis 3μm erhalten werden.It has now surprisingly been found that this object is achieved by a process comprising distributing a pulverulent solid having a mean pond diameter d 50 of from 1 to 40 μm, preferably 2 to 10 μm, particularly preferably about 4 to 6 μm, into a solution of a hydrophobic one Coating agent in a solvent which does not dissolve the powdery solid, and then lowering the temperature of the resulting mixture to precipitate the coated solid and optionally isolating the coated solid. In this case, the proportion of the coating agent can be varied. The preferred range is 50 to 99% by weight (based on the sum of pulverulent solid and coating agent), so that layer thicknesses of the coating material 1 to less than 20 .mu.m, preferably 1 to 5 .mu.m and particularly preferably 1 to 3 .mu.m are obtained for the individual particle size ranges ,
Das erfindungsgemäße Verfahren eignet sich prinzipiell für alle Arten von pulverförmigen Feststoffen. Vorzugsweise handelt es sich hierbei um Wirkstoffe, also Stoffe aus der Reihe der Mittel zur Heilung, Linderung oder Abwendung von Krankheiten des Menschen oder des Tieres wie z.B. Acidosetherapeutika, Analeptika/Antihypoxämika, Analgetika/Antirheumatika, Anthelminthika, Antiallergika, Antianämika, Antiarrhythmika, Antibiotika/Antiinfektiva, Antidementiva, Antidiabetika, Antidota, Antiemetika/Antivertiginosa, Antiepileptika, Antihämorrhagika, Antihypertonika, Antihypoglykämika, Antihypotonika, Antikoagulantia, Antimykotika, Antiparasitäre Mittel, Antiprotozoika, Antiphlogistika, Antitussiva/Expektorantia, Arterio- sklerosemittel, Broncholytika/Antiasthmatika, Cholagoga u. Gallenwegstherapeutika, Cholinergika, Corticoide, Dermatika, Diuretika, Durchblutungsfördernde Mittel, Entwöhnungsmittel/Mittel zur Behandlung von Suchterkrankungen, Enzyminhibitoren, Präparate b. Enzymmangel u. Transportproteine, Fibrinolytika, Geriatrika, Gichtmittel, Gynäkologika, Hepatika, Hypnotika/Sedativa, Immunmodulatoren, Kardiaka, Koronarmittel, Laxantia, Lipidsenker, Lokal- anästhetika/Neuraltherapeutika, Magen-Darm-Mittel, Migränemittel, Muskelrelaxanzien, Ophthalmika, Osteoporosemittel/Calciumstoffwechselregulatoren, Otologika, Psychopharmaka, Rhinologika/Sinusitismittel, Roborantia/Tonika, Schilddrüsentherapeutika, Sexualhormone u. ihre Hemmstoffe, Spasmolytika/Anticholinergika, Thrombozytenaggregationshemmer, Tuberkulose- mittel, Umstimmungsmittel, Urologika, Venentherapeutika, Vitamine, Zytostatika, andere antineo- plastische Mittel u. Protektiva.The inventive method is suitable in principle for all types of powdered solids. These are preferably active substances, ie substances from the range of agents for healing, alleviating or preventing human or animal diseases, such as acidotherapeutic agents, analeptics / antihypoxemics, analgesics / antirheumatics, anthelmintics, antiallergics, antianemics, antiarrhythmics, antibiotics / Anti-infectives, anti-dementia drugs, antidiabetic drugs, antidotes, antiemetics / antivertiginosa, antiepileptics, antihemorrhagics, antihypertensives, antihypoglycemics, antihypotonics, anticoagulants, antifungals, antiparasitic agents, antiprotozoics, antiphlogistics, antitussives / expectorants, arteri sclerosants, broncholytics / antiasthmatics, Cholagoga u. Bile Duct Therapeutics, cholinergics, corticoids, dermatics, diuretics, circulation-promoting agents, weaners / agents for the treatment of addictions, enzyme inhibitors, preparations b. Enzyme deficiency Transport proteins, fibrinolytics, geriatrics, gout, gynecologics, hepatics, hypnotics / sedatives, immunomodulators, cardiacs, coronary agents, laxatives, lipid-lowering agents, local anesthetics / neural therapeutics, gastrointestinal agents, migraine agents, muscle relaxants, ophthalmics, osteoporosis agents / calcium metabolism regulators, otologics, Psychotropic drugs, Rhinologics / Sinusitis agents, Roborantia / Tonics, Thyroid therapeutics, Sexual hormones and others. their inhibitors, spasmolytics / anticholinergics, platelet aggregation inhibitors, tuberculosis agents, reprecipitators, urologic agents, vein therapeutics, vitamins, cytostatics, other antineoplastic agents and the like. Protectives.
Als Beispiele genannt seien hierzu Boldin, Chinolone, Ciprofloxacin, Felodipin, Flurbiprofen, Ibuprofen, Ketoprofen, Makrolide, Nicardipin, Nifedipin, Nimodipin, Nisoldipin, Nitrendipin, Norfloxacin, Moxifloxacin, Ofloxacin, Paclitaxel, Praziquantel, Sulfonamide und Tetracycline.Boldin, quinolones, ciprofloxacin, felodipine, flurbiprofen, ibuprofen, ketoprofen, macrolides, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, norfloxacin, moxifloxacin, ofloxacin, paclitaxel, praziquantel, sulfonamides and tetracyclines are examples thereof.
Das Beschichtungsmaterial sind hydrophobe wasserabweisende Materialien. Als im Sinne dieser Erfindung als hydrophob zu verstehen sind auch nicht oder nur begrenzt wasserlösliche Materialien. Das Beschtungsmaterial muss bei einer Temperatur von 25°C in Wasser bei pH 6 bis 7,5 praktisch unlöslich oder zumindest < 1000mg/kg löslich sein. Solche hydrophoben Materialien können sein:The coating material is hydrophobic water-repellent materials. As for the purposes of this invention to be understood as hydrophobic are not or only limited water-soluble materials. The coating material must be practically insoluble or at least <1000 mg / kg soluble in water at pH 6 to 7.5 at a temperature of 25 ° C. Such hydrophobic materials may be:
Wachse mit einem Schmelzbereich von 30-1800C wie Paraffine, Naturwachse, Bienen- wachse, Canaubawachs, gesättigte Kohlenwasserstoffe der Form CnH2n+2, synthetischeWaxes with a melting range of 30-180 0 C such as paraffins, natural waxes, bee waxes, canauba wax, saturated hydrocarbons of the form CnH2n + 2, synthetic
Wachse, Fischer-Tropsch-Wachse, Stearine, Macrogolstearat und chemisch modifizierte Wachstypen, Vinylpolymerisate, Montanesterwachse und Montanwachs-Fettsäuren.Waxes, Fischer-Tropsch waxes, stearins, macrogol stearate and chemically modified wax types, vinyl polymers, montan ester waxes and montan wax fatty acids.
Harze: petrostämmige Kohlenwasserstoffharze, Polymerisate ungesättigter aromatischer Cg- /Cio-Kohlenwasserstoffe mit und ohne Phenol, aliphatisch modifizierte aromatische C9-/C10- Kohlenwasserstoffe mit einer ungesättigten aliphatischen Komponente, Inden-Cumaron- harze, Polymerisate carbostämmiger ungesättigter aromatischer Kohlenwasserstoffe, phenolmodifiertes Inden-Cumaronharz, Co-Polymerisat carbostämmiger ungesättigter C9- /Cio-Kohlenwasserstoffe mit Phenol,Resins: petrochemical origin hydrocarbon resins, polymers of unsaturated aromatic Cg / Cio hydrocarbons with and without phenol, aliphatically modified aromatic C9 / C with an unsaturated aliphatic component, indene-coumarone resins 1 0- hydrocarbons, polymers carbo burly unsaturated aromatic hydrocarbons, phenolmodifiertes indene -Coumarone resin, co-polymer of carbomonomically unsaturated C 9 - / Cio-hydrocarbons with phenol,
Polymethaccrylate und deren CoplymerisatePolymethacyrylates and their copolymers
- Polylactide und Polylactid Glycolid CopolymerisatePolylactides and polylactide glycolide copolymers
Chitosan, Naturprodukte aus chitinhaltigen Naturstoffen und deren chemische Modifikationen - A -Chitosan, natural products of chitin-containing natural products and their chemical modifications - A -
Wasserunlösliche Polyetherverbindungen, PolyetheφolysulfonWater-insoluble polyether compounds, polyether polysulfone
Chemisch modifizierte Cellulosederivate, deren Acetate, Succinate, Sulfonate mit wasserunlöslichen Eigenschaften wie oben beschrieben.Chemically modified cellulose derivatives, their acetates, succinates, sulfonates with water-insoluble properties as described above.
Beispiele für solche hydrophobe Beschichtungsmittel sind Canaubawachs der Firma Baerlocher GmbH sowie Wachse der Fa. Sasol Wax GmbH, z.B. die Typen 5203, 4110, 6202, 6805, C80 und ClOO, Harze und Novolac der Firmen RÜTGERS Chemicals AG und Ashland-Südchemie-Kernfest GmbH, Eudragite, insbesondere die E-Typen ElOO und EPO, der Fa. Degussa Röhm, Chitosan der Fa. Cognis, Hydroxypropylmethylcelluloseacetatsuccinate (AQCOAT) der Fa. Shin-Etsu AQOAT.Examples of such hydrophobic coating compositions are canauba wax from Baerlocher GmbH and waxes from Sasol Wax GmbH, e.g. the grades 5203, 4110, 6202, 6805, C80 and ClOO, resins and novolac from RÜTGERS Chemicals AG and Ashland-Südchemie-Kernfest GmbH, Eudragite, in particular the E grades ElOO and EPO, from Degussa Röhm, Chitosan from Fa Cognis, hydroxypropyl methylcellulose acetate succinate (AQCOAT) from Shin-Etsu AQOAT.
Für die Durchführung des erfindungsgemäßen Verfahrens geeignete Lösemittel sind beispielsweise bei Raumtemperatur flüssige aromatische oder aliphatische Kohlenwasserstoffe, insbesondere lineare oder zyklische Alkane, die gegebenenfalls verzweigt sein können. Ebenfalls geeignet sind organischeSolvents which are suitable for carrying out the process according to the invention are, for example, aromatic or aliphatic hydrocarbons which are liquid at room temperature, in particular linear or cyclic alkanes which may optionally be branched. Also suitable are organic
Lösungsmittel, insbesondere eines ausgewählt aus der Reihe der kurzkettigen Alkohole mit 1 bisSolvent, in particular one selected from the series of short-chain alcohols with 1 to
10 Kohlenstoffatomen, wie z.B. Methanol, Ethanol, 2-Propanol, der kurzkettigen Glykole, wie z.B.10 carbon atoms, e.g. Methanol, ethanol, 2-propanol, short chain glycols, e.g.
Ethylenglykol, 1 ,2-Propylenglykol, der kurzkettigen Ketone mit 3 bis 10 Kohlenstoffatomen, wie z.B. Aceton, 2-Butanon, Karbonsäuren, wie z.B. Essigsäure, Ether, wie z.B. Diethylether,Ethylene glycol, 1,2-propylene glycol, short chain ketones of 3 to 10 carbon atoms, e.g. Acetone, 2-butanone, carboxylic acids, e.g. Acetic acid, ethers, e.g. diethyl ether,
Tetrahydrofuran oder Metyl-tert-butylether, Ester wie z.B. Methylacetat, Ethylactetat oderTetrahydrofuran or methyl tert-butyl ether, esters such as e.g. Methyl acetate, ethyl acetate or
Ameisensäuremethylester, heterozyklische Amine wie z.B. Pyridine, Formamide wie z.B.Methyl formate, heterocyclic amines, e.g. Pyridines, formamides such as e.g.
Dimethylformamid, oder auch n-Methylpyrrolidon oder Dimethylsulfoxid Besonders bevorzugteDimethylformamide, or n-methylpyrrolidone or dimethylsulfoxide Particularly preferred
Lösemittel sind n-Heptan und Methyl-Cyclohexan. Die zuvor genannten Lösungsmittel können jeweils allein oder in Mischung zur Anwendung kommen.Solvents are n-heptane and methylcyclohexane. The abovementioned solvents can each be used alone or in a mixture.
Nach Herstellung einer Mischung aus pulverförmigem Feststoff, Lösemittel und Beschichtungsmittel erfolgt die Bildung des beschichteten Feststoffs durch eine Absenkung der Temperatur (Kühlungsfällung). Typischerweise erfolgt die Herstellung der besagten Mischung bei einer Temperatur von 5O0C , vorzugsweise von 40 bis 1000C.After preparation of a mixture of pulverulent solid, solvent and coating agent, the formation of the coated solid takes place by lowering the temperature (cooling precipitation). Typically, the preparation of said mixture is carried out at a temperature of 5O 0 C, preferably from 40 to 100 0 C.
Zur Durchführung der Kühlungsfällung wird im zweiten Schritt üblicherweise auf eine Temperatur von 200C gekühlt, vorzugsweise von 0 bis 40 0C.To carry out the cooling precipitation, in the second step it is usually cooled to a temperature of 20 ° C., preferably from 0 to 40 ° C.
Die Konzentration der Beschichtungsmittels im Lösemittel beträgt üblicherweise etwa 5 bis 25%, je nach Löslichkeit auch darüber oder darunter. Es sollte mit gesättigten Lösungen gearbeitet werden. Der Anteil des pulverförmigen Feststoffs an der besagten Mischung liegt in der Regel bei 1 bis 90%, vorzugsweise 5 bis 20%.The concentration of the coating agent in the solvent is usually about 5 to 25%, depending on the solubility also above or below. It should be worked with saturated solutions. The proportion of the pulverulent solid in the said mixture is generally from 1 to 90%, preferably from 5 to 20%.
Die Isolierung des beschichteten Feststoffs nach erfolgter Bildung geschieht durch bekannte Methoden, beispielsweise durch Sprühtrocknung. Die nach dem erfindungsgemäßen Verfahren hergestellten beschichteten Feststoffpartikel weisen überraschenderweise eine lediglich sehr dünne Coatingschicht auf, so daß die Partikelgröße und insbesondere der aerodynamische Durchmesser kaum verändert werden. Gleichwohl zeigen diese beschichteten Feststoffpartikel eine erfolgreiche Geschmacksmaskierung. Die nach dem erfindungs- gemäßen Verfahren hergestellten beschichteten Feststoffpartikel sind daher ideal geeignet für den Einsatz in Dry Powder Inhalern und oralen Darreichungsformen, die auch bei Biss oder kauen einer effizienten Geschmacksmaskierung bedürfen.The isolation of the coated solid after the formation by known methods, for example by spray drying. Surprisingly, the coated solid particles produced by the process according to the invention have only a very thin coating layer, so that the particle size and in particular the aerodynamic diameter are scarcely changed. Nevertheless, these coated solid particles show successful taste masking. The coated solid particles produced by the process according to the invention are therefore ideally suited for use in dry powder inhalers and oral dosage forms which require efficient taste masking even when bitten or chewed.
Die kleine Partikelgröße verhindert zudem bei der oralem Darreichungsform ein Zerbeißen der Kapsel beim Kauen. Dies ist besonders vorteilhaft bei Anwendungen als Kautablette sowie bei Tier- und Kinderarzneimitteln.The small particle size also prevents chewing of the capsule during oral administration. This is particularly advantageous in chewable, veterinary and pediatric applications.
Ein weiterer Vorteil bei oraler Anwendung ist das verbesserte Mundgefühl, da die kleinen Partikel nicht als Partikel wahrgenommen werden.Another advantage of oral use is the improved mouthfeel because the small particles are not perceived as particles.
Die Erfindung soll durch die nachfolgenden Beispiele illustriert werden, ohne sie jedoch dadurch zu beschränken. The invention will be illustrated by the following examples without, however, limiting it.
BeispieleExamples
Beispiel 1 (Praziquantel mit Wax C80)Example 1 (Praziquantel with Wax C80)
2,8 g gemahlenes Praziquantel mit einer Teilchengröße von < 10μm (Korngrößenverteilung nach2.8 g of ground praziquantel with a particle size of <10 μm (particle size distribution after
Verkapselung: d90=9,0μm; dlθ=l,5μm, Feststoff dispergiert in Myritol, 120" Ultraschall, Malvern Master Sizer, Linse 100mm) wurden bei 70°C in eine Lösung von 22,2g Wax C80Encapsulation: d90 = 9.0μm; dlθ = 1, 5μm, solids dispersed in Myritol, 120 "ultrasound, Malvern Master Sizer, 100mm lens) were placed at 70 ° C in a solution of 22.2g Wax C80
(kommerziell erhältlich von Sasol Wax GmbH) in 200g Heptan eingerührt. Anschließend wurde die Temperatur der erhaltenen Mischung auf 2O0C abgekühlt mit einer Abkühlrate von 10K/h unter(commercially available from Sasol Wax GmbH) in 200 g of heptane. Subsequently, the temperature of the resulting mixture was cooled to 2O 0 C with a cooling rate of 10K / h under
Rühren mit einer Mizerscheibe Duchmesser 57mm mit 500Upm und die gebildeten Kapseln durchStir with a Mizer disc diameter 57mm at 500 rpm and the capsules formed by
Sprühtrocknung in einem Buechy-Laborsprühtrockner mit einer pneumatischen Düse mit Durch- messer 0,5mm bei einer Zulufttemperatur von 14O0C und einer Ablufttemperatur von 800C isoliert.Spray drying in a Buechy laboratory spray dryer with a pneumatic nozzle with a diameter of 0.5 mm at an inlet air temperature of 14O 0 C and an exhaust air temperature of 80 0 C isolated.
Die Partikelgrößen des verkapselten Praziquantels liegen im Bereich von ca. 2-9μm (dlO und d90, s.o.). Geschmackstests zeigen, dass der bittere Geschmack nach Auflegen der Formulierung auf die Zunge auch über einen Zeitraum von 10 Minuten nicht bemerkt wird. Auch kauen der Formulierung über mehrere Minuten führt nicht zu einer Freisetzung des Geschmacks.The particle sizes of the encapsulated praziquantel are in the range of about 2-9μm (dlO and d90, see above). Taste tests show that the bitter taste is not noticed after applying the formulation to the tongue even over a period of 10 minutes. Even chewing the formulation over several minutes does not lead to a release of the taste.
Beispiel 2 a bis d (Ciprofloxacin mit Canaubawachs)Example 2 a to d (Ciprofloxacin with Canauba Wax)
Auch hier wird gemahlener Wirkstoff in eine Wachslösung eingerührt und die Temperatur gesenkt, so dass das Wachs ausfällt. Die Isolierung erfolgte wieder durch Sprühtrocknung.Again, ground active ingredient is stirred into a wax solution and the temperature is lowered so that the wax precipitates. The isolation was again by spray drying.
Der Wirkstoffgehalt wurde zwischen 5 und 20% variiert:The active ingredient content was varied between 5 and 20%:
Gemahlenes Ciprofloxacin mit einer Teilchengröße von 0,5 bis 9μm (dlO und d90 in Q3-Ver- teilung) wurden in den genannten Anteilen (bezogen auf das Beschichtungsmittel) bei 600C in eineMilled ciprofloxacin having a particle size of 0.5 to 9 μm (d10 and d90 in Q3 distribution) were converted into the above-mentioned proportions (based on the coating agent) at 60 ° C.
Lösung von Canaubawachs (kommerziell erhältlich von Firma Baerlocher GmbH) eingerührt.Solution of Canaubawachs (commercially available from Baerlocher GmbH) stirred.
Anschließend wurde die Temperatur der erhaltenen Mischung auf 200C mit einer Abkühlrate vonSubsequently, the temperature of the obtained mixture was at 20 0 C with a cooling rate of
10K/h unter ständigem Rühren mit einem Impeller Durchmesser 60mm mit 450Upm abgekühlt und die gebildeten Kapseln durch Sprühtrocknung in einem Buechy-Laborsprühtrockner analog zu Beispiel 1 isoliert.10K / h with constant stirring with a diameter 60mm impeller cooled at 450Upm and the capsules formed by spray drying in a Buechy laboratory spray drier analogous to Example 1 isolated.
2a: 342 g Methylcyclohexan, 38 g Canaubawachs, 2 g Ciprofloxacin 2b: 100 g Methylcyclohexan, 28 g Canaubawachs, 7 g Ciprofloxacin 2c: 303 g Heptan, 30 g Canaubawachs, 1,6 g Ciprofloxacin 2d: 152 g Heptan, 15 g Canaubawachs, 3,8 g Ciprofloxacin Eine REM-Aufnahme der in Beispiel 2a erhaltenen Kapseln ist als Figur 1 aufgeführt. Die erfolgreiche Geschmacksmaskierung wurde wie folgt festgestellt: Das gecoatete Material wurde auf die Zunge gelegt und nach ca. 10min ausgespült. Der stark bittere Geschmack des Wirkstoffes wurde nicht bemerkt. Zum Vergleich wurde auch reiner Wirkstoff getestet: der bittere Geschmack trat sehr schnell auf und der Geschmackstest musste vorzeitig beendet werden.2a: 342 g of methylcyclohexane, 38 g of canauba wax, 2 g of ciprofloxacin 2b: 100 g of methylcyclohexane, 28 g of canauba wax, 7 g of ciprofloxacin 2c: 303 g of heptane, 30 g of canauba wax, 1.6 g of ciprofloxacin 2d: 152 g of heptane, 15 g of canauba wax , 3.8 g of ciprofloxacin An SEM image of the capsules obtained in Example 2a is shown as FIG. The successful taste masking was determined as follows: The coated material was placed on the tongue and rinsed out after about 10 minutes. The strong bitter taste of the drug was not noticed. For comparison, pure drug was tested: the bitter taste occurred very quickly and the taste test had to be stopped prematurely.
Beispiel 3 (nicht erfindungsgemäß)Example 3 (not according to the invention)
Es wurden nach den bekannten Verfahren Koazervate von Praziquantel mit den gängigen Verkapselungsmitteln Gelatine und CMC hergestellt und gehärtet. Diese wiesen jedoch in Wasser eine schnellere Freisetzung auf als der ungecoatete Wirkstoff, es konnte keine Geschmacks- maskierung erzielt werden. Coazervates of praziquantel with the common encapsulating agents gelatin and CMC were prepared and cured according to the known methods. However, these showed a faster release in water than the uncoated active ingredient, no taste masking could be achieved.

Claims

Patentanspriiche Patentanspriiche
1. Beschichteter Feststoff umfassend einen pulverförmigen Feststoff mit einem Partikeldurchmesser von 1 bis 40 μm, bevorzugt 2 bis 10 μm und besonders bevorzugt 4 bis 6 μm und eine Beschichtung aus einem hydrophoben Hüllmaterial mit einem Anteil 50 bis 99 Gew.-% (bezogen auf die Summe von pulverförmigem Feststoff und Beschichtungsmittel)1. Coated solid comprising a powdery solid having a particle diameter of 1 to 40 microns, preferably 2 to 10 microns and more preferably 4 to 6 microns and a coating of a hydrophobic shell material in a proportion of 50 to 99 wt .-% (based on the Sum of powdery solid and coating agent)
2. Beschichteter Feststoff gemäß Anspruch 1 , dadurch gekennzeichnet, dass die Schichtdicken des Beschichtungsmittelsl bis weniger als 20 μm, vorzugsweise 1 bis 5 μm und besonders bevorzugt 1 bis 3 μm beträgt.2. Coated solid according to claim 1, characterized in that the layer thicknesses of the coating agent is up to less than 20 microns, preferably 1 to 5 microns and more preferably 1 to 3 microns.
3. Beschichteter Feststoff gemäß Anspruch 1, dadurch gekennzeichnet, dass der pulverfÖrmige Feststoff ein Wirkstoff ist.3. Coated solid according to claim 1, characterized in that the pulverulent solid is an active ingredient.
4. Verfahren zur Herstellung von beschichteten Feststoffen gemäß einem der Ansprüche 1 bis 3, umfassend das Verteilen eines pulverförmigen Feststoffs mit einem mittleren Teichendurchmesser d50 von 1 bis 40 μm in einer Lösung eines hydrophoben Beschichtungsmittels in einem Lösemittel, welches den pulverförmigen Feststoff nicht löst, und dann das Absenken der Temperatur der resultierenden Mischung zum Ausfällen des beschichteten Feststoffs und gegebenenfalls das Isolieren des beschichteten Feststoffs.4. A process for producing coated solids according to any one of claims 1 to 3, comprising distributing a powdery solid having a mean pond diameter d 50 of 1 to 40 microns in a solution of a hydrophobic coating agent in a solvent which does not dissolve the powdery solid, and then lowering the temperature of the resulting mixture to precipitate the coated solid and, optionally, isolating the coated solid.
5. Verfahren gemäß Anspruch 2, dadurch gekennzeichnet, dass der pulverfÖrmige Feststoff ein Wirkstoff ist.5. The method according to claim 2, characterized in that the pulverulent solid is an active ingredient.
6. Verfahren gemäß einem der Ansprüche 4 oder 5, dadurch gekennzeichnet, dass das hydro- phobe Beschichtungsmittel ein Wachs mit einem Schmelzpunkt von 30-1000C, vorzugsweise von 50-700C ist.6. The method according to any one of claims 4 or 5, characterized in that the hydrophobic coating agent is a wax having a melting point of 30-100 0 C, preferably from 50-70 0 C.
7. Verfahren gemäß einem der Ansprüche4 bis 6, dadurch gekennzeichnet, dass das Lösemittel Heptan oder Methyl-Cyclohexan ist.A process according to any one of claims 4 to 6, characterized in that the solvent is heptane or methylcyclohexane.
8. Verfahren gemäß einem der vorstehenden Ansprüche 2 bis 8, dadurch gekennzeichnet, dass die Herstellung der Mischung bei etwa 600C erfolgt und die Mischung anschließend auf etwa 2O0C abgekühlt wird.8. The method according to any one of the preceding claims 2 to 8, characterized in that the preparation of the mixture is carried out at about 60 0 C and the mixture is then cooled to about 2O 0 C.
9. Verfahren gemäß einem der vorstehenden Ansprüche 2 bis 9, dadurch gekennzeichnet, dass das Isolieren des beschichteten Feststoffs durch Sprühtrocknung erfolgt.9. The method according to any one of the preceding claims 2 to 9, characterized in that the isolation of the coated solid takes place by spray drying.
10. Verwendung eines beschichteten Feststoffs nach einem der Ansprüche 1 bis 3 als Pulver- Inhalat oder als orale Dareichungsform. 10. Use of a coated solid according to one of claims 1 to 3 as a powder inhalant or as an oral dosage form.
EP06829765A 2005-12-24 2006-12-20 Masking the taste of powders Withdrawn EP1968555A2 (en)

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AU2006331009A1 (en) 2007-07-05
HN2008000964A (en) 2013-03-11
GT200800126A (en) 2010-06-25
JP2009521419A (en) 2009-06-04
CU23877B1 (en) 2013-04-19
TNSN08284A1 (en) 2009-10-30
KR20120006085A (en) 2012-01-17
UA93072C2 (en) 2011-01-10
RU2440103C2 (en) 2012-01-20
WO2007073911A2 (en) 2007-07-05
BRPI0620618A2 (en) 2011-11-16
AU2006331009B2 (en) 2012-10-04
JP2013144695A (en) 2013-07-25
SV2009002971A (en) 2009-04-28
WO2007073911A3 (en) 2007-08-23
DE102005062270A1 (en) 2007-06-28
IL192085A0 (en) 2008-12-29
ECSP088577A (en) 2008-07-30
JP5275039B2 (en) 2013-08-28
CN101346133A (en) 2009-01-14
ZA200805498B (en) 2009-11-25
MA30072B1 (en) 2008-12-01
US20090269411A1 (en) 2009-10-29
MY149601A (en) 2013-09-13
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NZ569279A (en) 2011-06-30
KR20080081021A (en) 2008-09-05
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RU2008130171A (en) 2010-01-27
CA2634481A1 (en) 2007-07-05

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