EP1556158A1 - Verfahren zur herstellung pulverförmiger wirkstoff-formulierungen mit kompressiblen fluiden - Google Patents

Verfahren zur herstellung pulverförmiger wirkstoff-formulierungen mit kompressiblen fluiden

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Publication number
EP1556158A1
EP1556158A1 EP03809268A EP03809268A EP1556158A1 EP 1556158 A1 EP1556158 A1 EP 1556158A1 EP 03809268 A EP03809268 A EP 03809268A EP 03809268 A EP03809268 A EP 03809268A EP 1556158 A1 EP1556158 A1 EP 1556158A1
Authority
EP
European Patent Office
Prior art keywords
active ingredient
dispersion
active
weight
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Withdrawn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
EP03809268A
Other languages
German (de)
English (en)
French (fr)
Inventor
Bernd Klinksiek
Lars Obendorf
Rainer Bellinghausen
Marcus Eichmann
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
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 Technology Services GmbH filed Critical Bayer Technology Services GmbH
Publication of EP1556158A1 publication Critical patent/EP1556158A1/de
Withdrawn legal-status Critical Current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
    • A61K9/14—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
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • 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
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/003—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic followed by coating of the granules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
    • B01J2/02—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops
    • B01J2/04—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic by dividing the liquid material into drops, e.g. by spraying, and solidifying the drops in a gaseous medium

Definitions

  • the ner driving is a new type of dispersion process for the production of fine particles
  • Active substance particles using CO 2 and for the production of emulsions from highly viscous oils are Active substance particles using CO 2 and for the production of emulsions from highly viscous oils.
  • the ner driving is a further development of the melt dispersion as described in the German patent application with the file number 10 151 392.5.
  • melt dispersion a solid suspension is heated above the melting point of the suspension, then emulsified in fine particles and then rapidly cooled, so that a fine, amorphous dispersion is formed.
  • Emulsification possible at lower temperatures, so more gentle on the product. This effect is probably due to the fact that the compressible fluid dissolves in the active ingredient, the melting temperature is reduced and the viscosity of the melt is reduced.
  • the CO 2 -based ner driving is therefore a conceivable alternative for temperature-sensitive substances for which conventional melt dispersion cannot be used.
  • the supercritical fluid acts as an antisolvent and the particles are generated by precipitation / crystallization from a substance solution (gas anti-solvent, Precipitation with a compressed Fluid Antsolvent, solution enhanced dispersion of solids),
  • the supercritical fluid is a solvent and the particles form when the fluid is released into a container (RESS),
  • the supercritical fluid is dissolved in substance melts or suspensions and fine particles are formed when the substance-fluid mixture is released into a container (Particle Generation from Gas Saturated Solution, Continuous Powder Coating Spraying Process, Concentrated Powder Forni).
  • the mode of operation of the processes can be attributed to phenomena such as solvent properties of the compressed or supercritical fluids, lowering of melting points, lowering of viscosity, increased diffusion and mass transfer coefficients etc. Since there are usually combinations of the phenomena, the processes cannot always be clearly categorized.
  • Marr and Gamse (Chem. Eng. Proc. 2000, 39, 19-28) provide a general overview of the use of supercritical fluids in industrial processes. Bungert et al. Go into the production of microparticles with compressed gases. (Chem. Ing. Tech. 1997, 69, 298-311).
  • a solid is melted under the gas pressure of a compressible fluid that dissolves in the solid and expanded into a spray tower via a nozzle.
  • the micronization takes place through the explosion effect of the compressible fluid dissolved in the melt.
  • the size of the active ingredient particles is in the range of 10 ⁇ m.
  • a solid is first melted individually and then dispersed in supercritical fluids. The micronization also takes place by relaxing in a spray tower.
  • the individual active ingredient particles being encased by a layer of coating material E), in particular polyvinyl alcohol, in particular in an amorphous state 20 and having an average diameter in the range of at most 1 ⁇ m.
  • a layer of coating material E in particular polyvinyl alcohol, in particular in an amorphous state 20 and having an average diameter in the range of at most 1 ⁇ m.
  • the powdered active substance formulations according to the invention can be prepared by adding 25 a) at least one active substance A) which is solid at room temperature, at least one
  • wrapping material E in particular polyvinyl alcohol, optionally in a mixture with other wrapping material E) and optionally additives C),
  • Drying preferably spray drying or freeze drying, particularly preferably spray drying.
  • powdered active substance formulations according to the invention are very well suited for the application of the active substances contained therein.
  • An amorphous state in the sense of the invention is understood here to mean that no phase change is discernible in the analysis by means of DSC or that essentially no crystal structure results from X-ray diffraction studies.
  • Suitable fluids D) for the purposes of the invention are, in particular, fluids selected from the group consisting of hydrocarbons having 1 to 6 carbon atoms, in particular methane, ethane, propane, butane, pentane, n-hexane, i-hexane, carbon dioxide, freons, nitrogen, noble gases , gaseous oxides, for example N 2 O, CO 2 , ammonia, alcohols with 1 to 4
  • C atoms in particular methanol, ethanol, isopropanol, n-propanol, butanol, halogenated hydrocarbons or mixtures of the aforementioned substances.
  • the powdered active ingredient formulations according to the invention are considerably more stable than the structurally most similar, known preparations which are accessible by melt dispersion. are in which the individual particles are not encapsulated.
  • the stability of the formulations according to the invention is also unexpected because it was expected that the polyvinyl alcohol layer would dissolve in water and the active ingredient A) would then recrystallize. Contrary to expectations, this effect does not occur.
  • the powdered active substance preparations according to the invention are also notable for a number of advantages.
  • the proportion of active ingredient is very high in comparison to corresponding previously known formulations. This means that a small amount of formulation is sufficient to achieve the desired one
  • the powdered active substance formulations according to the invention can be redispersed without problems before use and the bioavailability of the active components is maintained at the high level achieved after production. Finally, it is favorable that the thermal stress on the active ingredients A) in the preparation of the formulations is even lower than in the process described in DE 10 151 392.5.
  • Active substances A) which are contained in the powdered formulations according to the invention are pharmaceuticals which are solid at room temperature (25 ° C.)
  • Active substances Active substances, agrochemical active substances, vitamins, carotenoids and flavors in question.
  • carotenoids examples include the known, accessible, natural or synthetic representatives of this class of compounds, for example carotene, lycopene, bixin, zeaxanthin, ctryptoxanthin, citranaxanthin, lutein, canthaxanthin,
  • the technically available representatives, such as ß-carotene, canthaxanthin, ß-apo-8'-carotenal, ß-apo-8'-carotenic acid esters are particularly preferred.
  • Retinoids for example all-trans retinoic acid, 13-cis retinoic acid and the esters and amides of this acid, can also be used. Compounds of this type that can be used are described by DL Newton, WR Henderson and MB Sporn in Cancer Research 40, 3413-3425.
  • active pharmaceutical ingredients A) include ibuprofen, clotrimazole, fluconazole, indoxacarb, acetylsalicylic acid and ciprofloxazine.
  • agrochemical active ingredients A are understood to mean all substances customary for plant treatment, the melting point of which is above 20 ° C. Fungicides, bactericides, insecticides, acaricides, nematicides, molluscicides, herbicides and plant growth regulators are preferably mentioned.
  • fungicides are:
  • Tebuconazole Tebuconazole, tecloftalam, tecnazen, tetraconazole, thiabendazole, thicyofen, thiophanate-methyl, thiram, tolclophos-methyl, tolylfluanid, triadimefon, triadimenol, triazoxide, trichlamid, tricyclazole, triflumizol, trifazorolitone, trifoxorinol, trifoxorinol, trifoxorinol, trifoxorinol
  • insecticides examples include acaricides and nematicides.
  • Mecarbam Mevinphos, Mesulfenphos, Metaldehyde, Methacrifos, Methamidophos, Methidathion, Methiocarb, Methomyl, Metolcarb, Milbemectin, Mpnocrotophos,
  • Tebufenozide Tebufenpyrad
  • Tebupirimiphos Teflubenzuron
  • Tefluthrin Temefos
  • Terbam Tetrachlorvmphos
  • Thiacloprid Thiafenox, Thiamethoxam, Thiodicarb, Tliiofanox, Thiomethon, Thuringieninin, Tralomhrhrinin, Tralomhrinin
  • Triarathen Triazuron, Trichlorfon, Triflumuron, Trimethacarb, Vamidothion, XMC, Xylylcarb, Zetamethrin.
  • molluscicides are metaldehyde and methiocarb.
  • herbicides examples are:
  • Anilides e.g. Diflufenican and Propanil; Aryl carboxylic acids, e.g. Dichloropicolinic acid, dicamba and picloram; Aryloxyalkanoic acids, e.g. 2,4-D, 2,4-DB, 2,4-DP, fluroxypyr, MCPA, MCPP and triclopyr; Aryloxy-phenoxy-alkanoic acid esters, e.g. Diclofop-methyl, fenoxaprop-ethyl, haloxyfop-methyl and quizalofop-ethyl; Azinones, e.g. Chloridazon and norflurazon; Carbamates, e.g.
  • Ureas e.g. Chlorotoluron, diuron, fluometuron, isoproturon, linuron and methazthiazuron;
  • Hydroxylamines e.g. Alloxydim, clethodim, cycloxydim, sethoxydim and tralkoxydim;
  • Imidazolinones e.g. Imazethapyr, hnazametha- benz, imazapyr and imazaquin;
  • Nitriles e.g. Bromoxyml, dichlobenil and
  • Oxyacetamides such as mefenacet
  • Sulfonylureas such as amidosul- furon, bensulfuron-methyl, chlorimuron-ethyl, chlorosulfuron, cinosulfuron, metsulfuron-methyl, nicosulfuron, primisulfuron, pyrazosulfuron-ethyl, thifensulfuron-methyl, triasulfuron and tribenuron-methyl
  • Thiol carbamates such as butylates, cycloates, dialates, EPTC, esprocarb, molinates, prosulfocarb and triallates
  • Triazines such as atrazine, cyanazine, simazine, simetryne, terbutryne and terbutylazine;
  • Triazinones e.g. Hexazinone, metamitron and metribuzin; Others, such as Aminotriazole, Benfuresate, Bentazone, Cinmethylin, Clomazone, Clopyralid, Difenzoquat, Dithiopyr, Ethofumesate, Fluorochloridone, Glufosinate, Glyphosate, Isoxaben, Pyridate, Quinchlorac, Quinmerac, Sulphosate and Tridiphane.
  • Others such as Aminotriazole, Benfuresate, Bentazone, Cinmethylin, Clomazone, Clopyralid, Difenzoquat, Dithiopyr, Ethofumesate, Fluorochloridone, Glufosinate, Glyphosate, Isoxaben, Pyridate, Quinchlorac, Quinmerac, Sulphosate and Tridiphane.
  • Chlorcholine chloride and ethephon are examples of plant growth regulators.
  • Suitable dispersants B) for the purposes of the invention are all customary nonionic, anionic, cationic and zwitterionic substances with the desired surface-active properties, which are usually used in such preparations. These substances also include reaction products of fatty acids, fatty acid esters, fatty alcohols, fatty amines, alkylphenols or alkyl arylphenols with ethylene oxide and / or propylene oxide, and also their sulfuric acid esters, phosphoric acid monoesters and phosphoric acid di-esters, as well as reaction products of ethylene oxide with propylene oxide Alkyl sulfonates, alkyl sulfates, aryl sulfates, tetra-alkyl-ammonium halides, trialkylaryl-ammonium halides.
  • the dispersants B) can be used individually or in a mixture. Reaction products of castor oil with ethylene oxide in a molar ratio of 1:20 to 1:60, reaction products of C6-C20 alcohols with ethylene oxide in a molar ratio of 1: 5 to 1:50, reaction products of fatty amines with ethylene oxide in a molar ratio of 1: 2 may be mentioned as preferred to 1:20, reaction products of 1 mol of phenol with 2 to 3 mol of styrene and 10 to 50 mol of ethylene oxide, Reaction products of Cg-Ci 2-alkylphenols with ethylene oxide in a molar ratio of 1: 5 to 1:30, alkyl glycosides, Cg-Cig-alkylbenzene-sulfonic acid salts, such as calcium, monoethanolammonium, di-ethanolammonium and tri-ethanolammonium salts ,
  • non-ionic dispersants B are the products known under the names Pluronic® PE 10 100 and Pluronic® F 68 (from BASF) and Atlox® 4913 (from Uniqema). Tristyrylphenyl ethoxylates are also suitable.
  • dispersants B examples include copolymers
  • Ethylene oxide and propylene oxide reaction products of tristyrylphenol with ethylene oxide and / or propylene oxide, such as tristyrylphenol ethoxylate with an average of 24 ethylene oxide groups, tristyrylphenol ethoxylate with an average of 54 ethylene oxide groups or tristyrylphenol ethoxylate propoxylate with an average of 6 ethylene oxide and 8 propylene oxide groups , further phosphated or sulfated
  • Tristyrylphenol ethoxylates such as phosphated tristyrylphenol ethoxylate with an average of 16 ethylene oxide groups, sulfated tristyrylphenol ethoxylate with an average of 16 ethylene oxide groups or ammonium salt of phosphated tristyrylphenol ethoxylate with an average of 16 ethylene oxide groups, and also lipoids, such as phospholipid sodium Glycolate or lecithin, and also liguinsulfonates.
  • substances with wetting agent properties can also be used.
  • Shell material E) in the sense of the invention are in particular polyvinyl alcohol, polyvinylpyrrolidone, saccharides, preferably glucose, oligomeric saccharides, in particular disaccharides, particularly preferably cane sugar, or polysaccharides.
  • polyvinyl alcohol means both water-soluble polymerization products of vinyl alcohol and water-soluble, partially saponified polymers of vinyl acetate.
  • Polyvinyl alcohol with an average molecular weight (number average) of 10,000 to 200,000 is preferred.
  • Clariant product known under the trade name Mowiol® 3-83.
  • a partially saponified polyvinyl acetate with an average molecular weight (number average) of 13,000 to 130,000 and an acetate group content of between 1 and 28%.
  • polyvinyl alcohols obtained by partial saponification of polyvinyl acetate with a degree of hydrolysis of 72 to 99 mol% and a viscosity of 2 to 40 mPa.s, particularly preferably between 3 and 18 mPa.s, measured on a 4 % aqueous solution at 20 ° C. Both individual partially saponified polyvinyl acetates and mixtures can be considered.
  • additives C which may be included in the inventive formulations, are penetration enhancers, defoamers, antifreeze agents, preservatives, dyes, redispersing, disintegrating agents, inert 'filler materials and film-forming substances in question.
  • R represents straight-chain or branched alkyl having 4 to 20 carbon atoms
  • AO stands for an ethylene oxide residue, a propylene oxide residue, a butylene oxide residue or for mixtures of ethylene oxide and propylene oxide residues and
  • n stands for numbers from 2 to 30.
  • a particularly preferred group of penetration requirements are alkanol alkoxylates of the formula
  • n stands for numbers from 2 to 20.
  • CH 3 p stands for numbers from 1 to 10
  • q stands for numbers from 1 to 10.
  • EO stands for -CH 2 -CH 2 -O-
  • CH 3 r stands for numbers from 1 to 10
  • s stands for numbers from 1 to 10.
  • alkanol alkoxylates of the formula CH 3 - (CH2) t-CH2-O - (- CH 2 -CH2-O-) u -H (Id) in which
  • u stands for numbers from 6 to 17.
  • R preferably for butyl, i-butyl, n-pentyl, i-pentyl, neopentyl, n-hexyl, i-hexyl, n-octyl, i-octyl, 2-ethyl-hexyl, nonyl, i-nonyl, decyl, n -Dodecyl, i-dodecyl, lauryl, myristyl, i-tridecyl, trimethyl-nonyl, palmityl, stearyl or eicosyl.
  • alkanol alkoxylate of the formula (Ic) is 2-ethylhexyl alkoxylate of the formula
  • EO stands for -CH 2 -CH 2 -O-
  • alkanol alkoxylates of the formula (Id) are compounds of this formula in which
  • u stands for numbers from 7 to 9.
  • the above formulas generally define the alkanol alkoxylates. These substances are mixtures of substances of the specified type with different chain lengths. Average values are therefore calculated for the lidices, which can also deviate from whole numbers.
  • Examples include alkanol alkoxylate of the formula (Id), in which
  • u stands for the average value 8.4.
  • alkanol alkoxylates of the formulas given are generally known or can be prepared by known methods (cf. WO 98-35 553 A1,
  • Defoamers are all substances which can normally be used for this purpose in agrochemical compositions. Silicone oils and magnesium stearate are preferred.
  • Cold stabilizers are all substances which can normally be used for this purpose in agrochemical compositions. Examples include urea, glycerin and propylene glycol. All substances that can normally be used for this purpose in agrochemical compositions of this type are suitable as preservatives. Examples include Preventol® (Bayer AG) and Proxel®.
  • PLURONIC® F 68 Oxirane, methyl, block polymer with oxirane
  • PREVENTOL® D2 B enzylhemiformal
  • PROXEL®GXL 1,2-benzisothiazol-3 (2H) -one
  • SOPROPHOR® FLK Polyethylene glycol mono [tris ( ⁇ -methyl) phenyl] ether phosphate potassium salt.
  • Suitable dyes are all substances which can normally be used for this purpose in agrochemical compositions. Titanium dioxide may be mentioned as an example,
  • redispersants are all substances which can normally be used for this purpose in solid agrochemical compositions. Surfactants, swelling agents and sugar are preferred. Lactose, urea, polyethylene glycol and tetramethylolpropane may be mentioned as examples.
  • Suitable so-called disintegrants are substances which are suitable for accelerating the disintegration of the powder formulations according to the invention when mixed with water. Salts such as sodium chloride and potassium chloride are preferred.
  • Inert fillers are all commonly used for this purpose e.g. substances which can be used in agrochemical compositions and which do not function as thickeners. Inorganic particles, such as carbonates, silicates and oxides, and also organic substances, such as urea-foam aldehyde condensates, are preferred. Examples include kaolin, rutile, silicon dioxide, so-called highly disperse
  • Water-soluble substances that are usually used for this purpose in active substance formulations are suitable as film-forming substances.
  • Gelatin, water-soluble starch and water-soluble copolymers of polyvinyl alcohol and polyvinylpyrrolidone are preferred.
  • the content of the individual components in the powdered active ingredient formulations can be varied within a substantial range. So that is
  • solid active ingredients A) preferably from 10 to 50% by weight, preferably from 15 to 40% by weight, of dispersant B) preferably from 5 to 50% by weight, preferably from 7.5 to 40% by weight,
  • shell material E in particular polyvinyl alcohol, preferably from 10 to 30% by weight, preferably from 15 'to 30% by weight and
  • additives C preferably from 0 to 50% by weight, preferably from 0 to 40% by weight.
  • the powdered active substance formulations according to the invention consist of a large number of individual particles containing active substance and dispersing agent, which are surrounded by a shell made of shell material E), in particular of polyvinyl alcohol.
  • the shell can also contain other water-soluble, film-forming substances.
  • the particles are in the amorphous state and have an average diameter in the nanometer range. The average particle diameter
  • (Number average) of the particles is preferably 10 to 1000 nm, preferably 40 to 500 nm.
  • step (a) is carried out in particular by suspending finely divided, optionally pre-ground active ingredient A) and dispersing agent B) and optionally additives C) in water with stirring. It is generally carried out at a temperature of 10 ° C to 30 ° C, preferably at room temperature.
  • step (b) of the process the resulting suspension is mixed with a compressible fluid D) under pressure.
  • the process is preferably carried out at a pressure of 50,000 to 500,000 hPa, preferably 70,000 to 300,000 hPa.
  • the temperature can correspond to the temperature of the suspension preparation from step (a) of the process, or else can be chosen higher or lower.
  • step (c) of the method is that the solid components used in forming the disperse phase liquid supply and an emulsion is formed, in which the components tröpfchenfb 'RMIG in the water phase dispersed are.
  • the procedure is generally carried out at a temperature below the melting point (under normal conditions) of the particular active substance, in the case of active substance mixtures of the solid having the highest melting point, preferably at a temperature of 40 ° C. to 220 ° C., preferably 50 ° C. to 220 ° C.
  • the mixture is preferably heated so quickly that an emulsion is only briefly present. In the short term this means, for example, in the range of a few milliseconds.
  • step (d) of the process according to the invention e.g. with the help of a jet disperser or other high pressure homogenizer or one
  • Homogenizer based on the rotor / stator principle, homogenized in such a way that a finely divided dispersion is created.
  • the homogenization in the homogenizer or jet disperser is generally carried out at a temperature of 40 ° C to 220 ° C.
  • the pressure is generally applied to the homogenizer, preferably at a pressure difference of 40,000 hPabis 1,600,000 hPa, particularly preferably from 50,000 bPa to 1,000,000 hPa.
  • the very fine-particle dispersion produced is encapsulated in step e) for encapsulation with an aqueous solution of the coating material E), preferably in a container. concentration of 10 to 50 wt .-%, preferably with polyvinyl alcohol, optionally with additives C).
  • step e) of the method according to the invention the dispersion from step d) is suddenly expanded, as a result of which the compressible fluid D) escapes and contributes to the tearing of the particles formed, and preferably at the same time, preferably spray drying with a dry gas, in particular with dry air or inert gas, particularly preferably subjected to nitrogen or an inert gas.
  • the temperature can be varied within a wide range. Preferably carried out at a drying gas inlet temperature of 100 ° C to 200 ° C, more preferably from 120 ° C to 180 ° C, 'and a drying gas outlet temperature of 50 ° C to 100 ° C, preferably from 60 ° C to 90 ° C ,
  • step d) To remove the water contained in step d) by freeze-drying. This method is expediently used when the active compounds are unstable at higher temperatures.
  • Both spray drying and freeze drying preferably work in such a way that only a very low residual moisture remains in the powder formulation. In general, it is dried until the residual moisture is below
  • Residual moisture here means a content of volatile compounds such as
  • step d) If polyvinyl alcohol is already added as additive C) in step a) when carrying out the process according to the invention, it is not necessary to add this capsule-forming shell material E) in step d).
  • Another object of the invention is therefore an alternative method for
  • the process according to the invention can be carried out either continuously or batchwise.
  • a new apparatus is preferably used to carry out the method according to the invention
  • a pump which is suitable for introducing a compressible fluid D) under pressure into a pressure-resistant container provided with an agitator, which is connected via a pump suitable for generating pressure to a heat exchanger to which a jet disperser or homogenizer is connected which leads a pipe which can be closed by a valve back into the container and from which a pipe leads to a metering pump and, if appropriate, is connected to a mixing container and a spray dryer is connected to the pipeline leading therefrom.
  • FIG. 1 Equipment suitable for the process is shown in FIG. 1.
  • FIG. 1 In this figure:
  • valve 7 cooler in the cooling circuit
  • the heat exchanger 4 is a device that is fast
  • the jet disperser 5 is constructed in such a way that the incoming emulsion is dispersed through a nozzle.
  • the fineness of the dispersion produced depends on the homogenization pressure and the nozzle used. The smaller the nozzle bore, the finer the dispersion obtained. In general, nozzles are used whose bores are between 0.1 and 1 mm, preferably between 0.2 and 0.7 mm.
  • the pump 9 is a metering device which is connected to the pipeline leading away from the cooling circuit. An additional mixing tank with agitator can also be installed at this point in the apparatus.
  • the spray dryer 10 is a device of this type, which is designed in such a way that the dispersion can be expanded and thus the compressible fluid D) can escape, and that the water can be extracted from the aqueous solution entering.
  • the spray dryer can also be replaced by a freeze dryer.
  • the procedure is in particular that in the first step one or more solid active ingredients A) with a crystalline structure and, if appropriate, additives C) in a one-piece state in container 2 in a mixture of water and Dispersant B) suspended.
  • the components can be put together in the pre-ground state. Alternatively, however, it is also possible to comminute the components after mixing using a rotor / stator disperser, a colloid mill or a bead mill.
  • a compressible fluid D is added to the container 2 under pressure under pressure.
  • the dispersion produced in this way is conveyed by the pump 3 via the heat exchanger 4 into the downstream jet disperser 5.
  • the pump also has the task of building up the necessary dispersion pressure.
  • the dispersion in the heat exchanger 4 is quickly heated to a temperature above the melting point of the solid phase, so that an emulsion is formed for a short time. This is then homogenized in fine particles in the jet disperser 5 and cooled immediately after passage through the jet disperser in the cooling circuit system 7/8. To keep the cooling time as short as possible, the dispersion is passed into the cooler 7 and recirculated with the pump 8 at about ten times the pumping current based on the dispersion stream leaving the disperser. Through the cooling loop, quenching ensures that the emulsion cools down in a period of milliseconds and the active substance particles solidify amorphously.
  • an aqueous solution of polyvinyl alcohol and optionally further coating materials and / or other additives C) is added to the dispersion of amorphous particles via the metering pump 9.
  • aqueous solution of polyvinyl alcohol and optionally further coating materials and / or other additives C is added to the dispersion of amorphous particles via the metering pump 9.
  • the pre-stabilized solution is then immediately introduced into the spray dryer 10 and expanded, where the compressible fluid D) escapes and the
  • Dispersion is removed from the water and the active ingredient particles are encapsulated by the enveloping material.
  • a free-flowing powder is created in each case.
  • the particle size depends on the atomization conditions in the jet disperser.
  • a partial flow is removed between the jet disperser 5 and the cooling circuit 7/8 and returned to the container 2 via the valve 6.
  • This circulation system makes it possible to homogenize the dispersion several times over the jet disperser. In the circular mode of operation, the
  • the powder formulations according to the invention are stable even after prolonged storage. They can be converted into homogeneous spray liquids by stirring them into water. These spray liquids are used within the application area of application by customary known methods, for example by spraying, pouring or injecting. It is also possible to granulate the powders, process them into tablets, pastes or other dosage forms.
  • the application rate of the powder formulations according to the invention can be varied within a substantial range. It depends on the active ingredients A) present and on their content in the formulations.
  • Active ingredients A can be applied in a particularly advantageous manner with the aid of the powder formulations according to the invention.
  • the active ingredients contained are easily bio-available xmd develop a biological effectiveness that is significantly better than that of conventional formulations in which the active components are in a crystalline state.
  • FIG. 1 The invention is explained in more detail below using FIG. 1 as an example.
  • Example 2 In a container 2, 2.8 kg of a suspension consisting of
  • capsule material 21.6 parts by weight of capsule material (25% by weight dissolution of Mowiol® 3-83 polyvinyl alcohol from Clariant in water),

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EP03809268A 2002-10-18 2003-10-06 Verfahren zur herstellung pulverförmiger wirkstoff-formulierungen mit kompressiblen fluiden Withdrawn EP1556158A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10248619 2002-10-18
DE10248619A DE10248619A1 (de) 2002-10-18 2002-10-18 Verfahren zur Herstellung pulverförmiger Wirkstoff-Formulierungen mit kompressiblen Fluiden
PCT/EP2003/011023 WO2004037402A1 (de) 2002-10-18 2003-10-06 Verfahren zur herstellung pulverförmiger wirkstoff-formulierungen mit kompressiblen fluiden

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EP1556158A1 true EP1556158A1 (de) 2005-07-27

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US (1) US20040076670A1 (ja)
EP (1) EP1556158A1 (ja)
JP (1) JP2006502859A (ja)
CN (1) CN1705507B (ja)
AU (1) AU2003276054A1 (ja)
DE (1) DE10248619A1 (ja)
WO (1) WO2004037402A1 (ja)

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PL2061427T3 (pl) * 2006-09-15 2011-12-30 Echo Pharmaceuticals Bv Granulat zawierający substancję farmaceutycznie aktywną i emulgator oraz sposób jego wytwarzania
JP2010503664A (ja) * 2006-09-15 2010-02-04 エコ・ファーマシューティカルズ・ビー．ブイ． 水不溶性医薬活性物質の舌下、頬若しくは経口投与のための医薬投薬単位
JP5004333B2 (ja) * 2006-12-08 2012-08-22 日機装株式会社 ナノオーダ粒子製造装置
HU230862B1 (hu) * 2008-04-28 2018-10-29 DARHOLDING Vagyonkezelő Kft Berendezés és eljárás nanorészecskék folyamatos üzemű előállítására
ES2342140B1 (es) * 2008-12-30 2011-05-17 Consejo Superior Investigacion Procedimiento para la obtencion de micro- o nanoparticulas solidas
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EP2611529B1 (en) 2010-09-03 2019-01-23 Bend Research, Inc. Spray-drying method
AU2011301966B2 (en) * 2010-09-17 2015-06-04 Dow Agrosciences Llc Liquid agricultural formulations of improved stability
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US9827191B2 (en) 2012-05-03 2017-11-28 The Johns Hopkins University Compositions and methods for ophthalmic and/or other applications
CN103920641B (zh) * 2013-01-12 2016-12-28 唐山兴铭科技有限公司 一种生产纳米颗粒的工业化装置及其工艺
EP3197442B1 (en) 2014-09-26 2019-07-03 The Cleveland Clinic Foundation Treating and preventing disease with tma and tmao lowering agents
JP6650933B2 (ja) 2014-10-31 2020-02-19 ベンド リサーチ， インコーポレイテッド マトリックス中に分散された活性薬剤ドメインを形成するためのプロセス
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CN1705507A (zh) 2005-12-07
US20040076670A1 (en) 2004-04-22
AU2003276054A1 (en) 2004-05-13
JP2006502859A (ja) 2006-01-26
DE10248619A1 (de) 2004-04-29
CN1705507B (zh) 2010-05-26
HK1085962A1 (en) 2006-09-08
WO2004037402A1 (de) 2004-05-06

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