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EP2954009A1 - Fabrication de matériaux composites inorganiques-organiques par séchage réactif par pulvérisation - Google Patents

Fabrication de matériaux composites inorganiques-organiques par séchage réactif par pulvérisation

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Publication number
EP2954009A1
EP2954009A1 EP14701794.1A EP14701794A EP2954009A1 EP 2954009 A1 EP2954009 A1 EP 2954009A1 EP 14701794 A EP14701794 A EP 14701794A EP 2954009 A1 EP2954009 A1 EP 2954009A1
Authority
EP
European Patent Office
Prior art keywords
phase
calcium
salt
magnesium
liquid phase
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Withdrawn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
EP14701794.1A
Other languages
German (de)
English (en)
Inventor
Andreas Kempter
Max SIEBERT
Heidrun Debus
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.)
BASF SE
Original Assignee
BASF SE
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 BASF SE filed Critical BASF SE
Priority to EP14701794.1A priority Critical patent/EP2954009A1/fr
Publication of EP2954009A1 publication Critical patent/EP2954009A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/02—Compounds of alkaline earth metals or magnesium
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/02—Compounds of alkaline earth metals or magnesium
    • C09C1/021—Calcium carbonates
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/02—Compounds of alkaline earth metals or magnesium
    • C09C1/025—Calcium sulfates
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/02—Compounds of alkaline earth metals or magnesium
    • C09C1/028—Compounds containing only magnesium as metal
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/04—Compounds of zinc

Definitions

  • the present invention relates to a process for the production of inorganic-organic composite materials by reactive spray drying, wherein the organic phase in the composite materials represents at least one organic active ingredient and the inorganic phase is an inorganic salt sparingly soluble under standard conditions , Furthermore, the invention relates to corresponding composite materials and their use.
  • Inorganic-organic materials based on calcium carbonate, in which biomolecules may be embedded, are known per se, the materials being obtained by precipitation processes, and wherein the active substances embedded in the calcium carbonate matrix are water-soluble substances.
  • A. Elabbadi et al., Journal of Microencapsulation, 201 1; 28 (1): 1-9 the microencapsulation of green tea extracts in microparticles of calcium carbonate and phosphates. Fujiwara et al., Chemical Engineering Journal 137 (2008) 14-22, describe the encapsulation of water-soluble biomolecules such as bovine serum albumin in calcium carbonate microcapsules.
  • A.I. Petrov et al., Biotechnol. Prog. 2005, 21, 918-925 describe the embedding or adsorption of water-soluble biomolecules such as bovine serum albumin in calcium carbonate by co-precipitation.
  • US 2009029902 describes complexes of calcium carbonate and proteins with calcium carbonate binding domains.
  • the complexes can be obtained by precipitation from aqueous slurries.
  • WO 2008000042 describes nanoparticulate formulations of sparingly water-soluble active ingredients, wherein the formulations are obtained by grinding the active ingredients with water-soluble inorganic salts.
  • amorphous vitreous products obtained by melting inorganic salt mixtures are mechanically mixed with active substances and granulated.
  • WO 2009077147 describes pharmaceutical formulations obtained by mixing an active ingredient with a particulate basic solid, the basic particulate solid being an alkali or alkaline earth salt.
  • EP-A 1905427 describes the incorporation of active ingredients into an inorganic matrix, with only inorganic salts which are readily soluble in water, such as, for example, sodium carbonate, being described as the inorganic matrix.
  • WO 2012/027378 describes the preparation of particulate active substance preparations, wherein an inorganic carrier such as, for example, calcium carbonate and a hydrophobic pharmaceutical active substance are precipitated together in a mixing chamber.
  • the object of the present invention was to provide a simple and economical process for the preparation of inorganic-organic composite materials containing biologically active substances, which avoids the disadvantages of the prior art.
  • a process for producing composite materials by reactive spray drying comprising a liquid phase A containing inorganic cations and a liquid phase B containing anions which form, with the inorganic cations, a salt insoluble in the liquid phase mixture , sprayed together with a multi-component nozzle, and wherein at least one hydrophobic active ingredient is dissolved in at least one liquid phase, and the salt formed from the cations of phase A and the anions of phase B in the neutral aqueous medium has a solubility of less than 0.02 mol / l.
  • Neutral aqueous medium means a pH of 7 +/- 0.5.
  • Aqueous medium preferably means a purely aqueous medium without the presence of other solvents.
  • the solubility refers to the solubility under standard conditions at 20 ° C and 0.101325 MPa.
  • the hydrophobic active ingredient may be dissolved in one of the liquid phases A or B or may be added to the process dissolved in a further liquid phase.
  • composite materials are those materials in which one component is embedded in a matrix of another component. Such composite materials are also referred to in the literature as composites.
  • a hydrophobic organic active substance is embedded in a matrix of a salt of inorganic cations (the "salt matrix"), wherein the salt matrix is amorphous.
  • the hydrophobic active agent is preferably in the amorphous state in this connection, that no more than 5% by weight of the active substance or the salt matrix is present in crystalline form, the determination of this state taking place by means of XRD (X-ray diffraction).
  • Suitable salts according to the invention are, according to the invention, salts which, under certain conditions, comprise contacting at least two liquid phases, of which one phase contains inorganic cations and a second or further phase anions which react with the cations of the other liquid phase Water difficult to form salts, can be obtained.
  • the resulting salts, as defined above, are sparingly soluble in water but readily soluble in an acidic medium, optionally with decomposition.
  • Inorganic cations of the salt matrix according to the invention are metallic cations which are preferably physiologically well tolerated.
  • suitable cations are calcium ions, magnesium ions or zinc ions or mixtures thereof. Particularly preferred are calcium ions.
  • Both inorganic and organic anions come into consideration as counterions of the salt matrix, with the resulting salts being said to be insoluble in a neutral aqueous medium as described.
  • Which anions are suitable depends on the type of cation. For example, some calcium salts are sparingly soluble in water, while the corresponding magnesium salts are readily soluble in water. For all anions listed below, therefore, the solubility of the possible salts is to be determined. This is possible in a simple way for the person skilled in the art, since these are known from the literature.
  • Suitable inorganic anions of the resulting sparingly water-soluble salt matrix are selected from the group consisting of carbonate, phosphate, sulfate or mixed anions such as hydroxyapatite.
  • suitable organic anions of the water-sparingly soluble salt matrix are anions of physiologically compatible organic monobasic or polybasic acids.
  • This embodiment relates to a salt matrix containing calcium salts as sparingly water-soluble salts.
  • Suitable calcium salts are selected from the group consisting of calcium citrate, calcium lactate and calcium oxalate.
  • the liquid phase A which contains the cations of the water-sparingly soluble salt matrix to be formed, is obtained by dissolving corresponding salts which are readily soluble in the chosen medium.
  • Suitable salts are calcium chloride, calcium nitrate, calcium acetate, magnesium chloride, magnesium nitrate, magnesium acetate, magnesium citrate, magnesium lactate, zinc chloride, zinc nitrate or zinc acetate.
  • the salts can, if applicable, also be used in the form of their mono-, di- or semi- hydrate.
  • the salts with which the cations of the water-sparingly soluble salt matrix to be formed in the liquid phase A are introduced as a solution into the process are those which are preferred. example, are readily soluble in water or are readily soluble in organic solvents or organic-aqueous mixtures.
  • the salts with which the anions of the sparingly water-soluble salt matrix to be formed in the liquid phase A are introduced as a solution in the process are readily water-soluble or readily soluble in a hydrophilic organic solvent or readily soluble in aqueous-organic mixtures ammonium salts or alkali metal salts. Furthermore, correspondingly well soluble magnesium salts come into consideration. Suitable salts are above all readily water-soluble carbonates, bicarbonates, sulfates, phosphates, hydrogen phosphates. Also suitable are organic salts such as ammonium, alkali or magnesium salts of citric acid, lactic acid or oxalic acid.
  • the liquid phase B via which the anion component of the water-sparingly soluble salt matrix is introduced, is preferably pure aqueous.
  • phase B may also contain organic solvents.
  • the way in which the salt components of liquid phases A and B are combined depends on the nature of the desired water-sparingly soluble salt matrix. It is obvious that a cation which is introduced in the liquid phase A as a cation-providing component for the water-sparingly soluble salt matrix can not simultaneously serve as a cation of an anion-supplying component dissolved in the liquid phase B.
  • the cations of the liquid phase A must be able to form with the anions of the liquid B in any case a sparingly water-soluble salt having a solubility of less than 0.02 mol / l (at 20 ° C and 0.1 MPa).
  • a magnesium salt such as magnesium chloride can be reacted as cation-delivering salt of phase A with an ammonium carbonate or alkali metal carbonate salt dissolved in phase B to give a corresponding sparingly soluble magnesium carbonate.
  • a calcium salt, such as calcium chloride, as the phase A cationic salt can be reacted with a magnesium salt, such as magnesium citrate, dissolved in phase B to give a corresponding sparingly soluble calcium citrate.
  • Suitable solvents for the various liquid phases to be sprayed are, in addition to water, hydrophilic organic solvents which are immiscible with water indefinitely, such as methanol, ethanol, glycerol, 1,2-propylene glycol, low molecular weight polyethylene glycols such as PEG 200, PEG 300, PEG 600 or , Acetone, acetonitrile, dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, 2-methoxyethanol or tetrahydrofuran. Ethanol is preferably used as the hydrophilic organic solvent.
  • the particular concentration of the starting materials in the solvent depends on the individual case and results from the respective solubilities of the components used.
  • concentrations of 0.1 to 10 mol / l are preferred for the salt component to be used.
  • nenten particularly preferably 0.5 to 2 mol / l.
  • concentration of the hydrophobic active substances in the liquid phase can be 1 to 100 g / l, preferably 10 to 40 g / l.
  • the salt matrix as the target substance of the reactive spray drying is no longer soluble in the mixture of the solvents of the fluid phases and is sparingly soluble in water (less than 0.02 mol / l).
  • the hydrophobic drug component is introduced into the process via an organic solution, and the mixture of all liquid phases constitutes an aqueous-organic solvent mixture.
  • phase A contains a mixture of water and an organic solvent and the hydrophobic active substance
  • phase B is a purely aqueous phase which contains no further solvent.
  • the phases A and B are purely aqueous phases and the hydrophobic active ingredient is introduced in a further liquid phase dissolved in an organic solvent in the spraying process.
  • the phase is a purely aqueous phase and the phase B is an aqueous-organic phase which also contains the hydrophobic active ingredient.
  • hydrophobic active substances can also be introduced into the process. These can be solved together in one phase or introduced via different phases.
  • the hydrophobic active ingredient component is supplied to the spraying process via an aqueous or aqueous-organic phase which additionally contains at least one surfactant.
  • the hydrophobic active ingredient component is contained together with the surfactant in phase A.
  • the hydrophobic active ingredient component is contained together with the surfactant in phase B.
  • the hydrophobic active ingredient component is contained together with the surfactant in an additional liquid phase.
  • the liquid phase containing surfactant and hydrophobic active ingredient is a purely aqueous phase.
  • Suitable surfactants are selected from the group of anionic, cationic, nonionic, and amphiphilic surfactants.
  • Suitable anionic surfactants include. Sodium, potassium, magnesium and calcium salts of fatty acids and fatty acids Suitable anionic surfactants are, for example, sodium lauryl sulfate, ammonium lauryl sulfate, sodium cetyl stearyl sulfate, docusate sodium, docusate potassium or docusate calcium.
  • cetylpyridinium chloride is suitable.
  • suitable surfactants are mono- and diglycerides of fatty acids and edible fatty acids, acetic acid esters, lactic acid esters such as sodium or calcium stearoyl-2-lactate, citric acid esters such as triethyl citrate, tartaric acid esters such as stearyl tartarate, diacetyl tartaric acid esters, mixed acetic and tartaric acid esters , Sugar esters of fatty acids and fatty acids, sugar glycerides, propylene glycol esters of fatty acids, polyglycerol polyricinoleate or propylene glycol esters of fatty acids.
  • Suitable nonionic surfactants are, for example, fatty alcohols and sterols, such as cetyl alcohol, stearyl alcohol, cetylstearyl alcohol or cholesterol.
  • Suitable nonionic surfactants are, for example, sorbitan esters, which may also be polyoxyalkylated, for example sorbitan monostearate, sorbitan stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate), polysorbate 21 (polyoxyethylene (4) sorbitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), polysorbate 61 (polyoxyethylene (4) sorbitan monostearate), polysorbate 65 (polyoxyethylene (20) sorbitan tristearate), polysorbate 80 (Polyoxyethylene (20) sorbitan monooleate), polysorbate 81 (polyoxyethylene (5) sorbitan monooleate), polysorbate 85 (polyoxyethylene (20) sorbitan
  • Suitable nonionic surfactants are also sucrose fatty acid esters such as, for example, sucrose stearate, sucrose laurate, sucrose palmitate, sucrose oleate, sucrose caprylate, sucrose decanoate, sucrosemyristate, sucrose pelargonate, sucrose undecanoate, sucrosetridecanoate, sucrose pentadecanoate or sucrose heptadecanoate.
  • sucrose fatty acid esters such as, for example, sucrose stearate, sucrose laurate, sucrose palmitate, sucrose oleate, sucrose caprylate, sucrose decanoate, sucrosemyristate, sucrose pelargonate, sucrose undecanoate, sucrosetridecanoate, sucrose pentadecanoate or sucrose heptadecanoate.
  • polyoxyethylene fatty acid glycerides such as Macrogol-1500- glycerol triricinoleate, Macrogol glycerol hydroxystearate Ph.Eur. (Kolliphor TM RH40), Macrogolglycerolricinoleate Ph.eur. (Kolliphor TM EL), Macrogol 1000 glycerol monolaurate, Macrogol 1000 glycerol monostearate, Macrogol 1000 glycerol monooleate.
  • polyoxyethylene fatty acid esters such as macrogol-15-hydroxystearate (Kolliphor TM HS15), macrogol stearate 400 (Ph.Eur.), Polyoxyl-40-stearate or polyoxyl-50-stearate.
  • polyoxyethylene fatty alcohol ethers such as macrogol lauryl ether, polyoxyethylene ene-23 lauryl ether or polyoxyl-10-oleyl ether.
  • glycerol fatty acid esters such as glycerol monostearate.
  • Suitable amphiphilic surfactants are, for example, poloxamers such as poloxamer 188, poloxamer 237, poloxamer 338 or poloxamer 407, preferably poloxamer 188. Also suitable as amphiphilic surfactants are solubilizing polymers such as Soluplus, a copolymer of PEG 6000, N-vinylcaprolactam and vinyl acetate and in the weight ratio 13 / 57/30. Lecithin is also suitable as an amphiphilic surfactant.
  • sodium lauryl sulfate is a preferred surfactant.
  • the surfactants used are polyoxyethylenated castor oils and hydrogenated castor oils such as Macrogol glycerol hydroxystearate Ph.Eur. or macrogolglycerol ricinoleate Ph. Eur.
  • the surfactant used is tocopherol polyethylene glycol succinate with PEG 1000, 1500 or 2000.
  • the surfactants may be added in amounts of 2 to 50 wt .-%, preferably 5 to 45 wt .-%, based on the amount of active ingredient.
  • Hydrophobic organic active substances may be pharmaceutical or cosmetic active ingredients, crop protection agents, dietary supplements or pigments. Hydrophobic agents have a water solubility of less than 0.1 g / l at 20 ° C and a pressure of 0.101325 MPa.
  • Pharmaceutical hydrophobic active substances may be, for example: benzodiazepines, antihypertensives, vitamins, cytostatic agents - especially taxol, anesthetics, neuroleptics, antidepressants, antiviral agents such as anti-HIV agents, antibiotics, antimycotics, antidementia, fungicides, chemotherapeutics, urologics , Platelet aggregation inhibitors, tyrosine kinase inhibitors, sulfonamides, spasmolytics, hormones, immunoglobulins, sera, thyroid therapeutics, psychotropic drugs, Parkinson's and other antihyperkinetics, ophthalmics, neuropathy preparations, calcium metabolism regulators, muscle relaxants, narcosis, lipid lowering, liver therapeutics, coronary agents, cardiacs, immunotherapeutics, regulatory peptides and their Inhibitors, hypnotics, sedatives, gynecologics, gout, fibrinolytics
  • the individual components are dissolved in the appropriate solvents.
  • the different liquid phases are fed separately to the spray nozzle.
  • Suitable spray nozzles are multi-substance nozzles such as two-component nozzles, three-component nozzles or four-component nozzles. Such nozzles can also be designed as so-called “ultrasonic nozzles”.
  • Such nozzles are commercially available per se.
  • a sputtering gas can be supplied.
  • a sputtering gas air or an inert gas such as nitrogen or argon can be used.
  • the gas pressure of the atomizing gas can be up to 1 MPa absolute, preferably 0.12 to 0.5 MPa absolute.
  • ultrasonic nozzles can be operated with or without atomizing gas. In ultrasonic nozzles, the atomization takes place by causing the phase to be atomized to vibrate. Depending on the nozzle size and design, the ultrasonic nozzles can be operated with a frequency of 16 to 120 kHz.
  • the throughput of liquid phase to be sprayed per nozzle depends on the nozzle size.
  • the throughput can be 500 g / h to 1000 kg / h. In the production of commercial quantities, the throughput is preferably in the range of 10 to 1000 kg / h.
  • the liquid pressure may be 0.2 to 20 MPa absolute. If an atomizing gas is used, the liquid can be fed without pressure.
  • the spray drying apparatus is supplied with a drying gas such as air or one of the inert gases mentioned.
  • the drying gas can be supplied in cocurrent or countercurrent to the sprayed liquid, preferably in cocurrent.
  • the inlet temperature of the drying gas may be 120 to 220 ° C, preferably 150 to 200 ° C, the starting temperature 50 to 90 ° C.
  • the magnitudes of spray parameters to be used are critically dependent on the size of the devices.
  • the devices are commercially available and usually orders of magnitude recommended by the manufacturer are recommended.
  • the spraying process is preferably operated so that the average droplet size of the sprayed phases is 10 to 200 ⁇ m.
  • the average droplet size can be determined by means of laser diffraction or high-speed cameras coupled with an image evaluation.
  • the invention relates to a process for the preparation of composite materials by reactive spray drying, wherein a liquid phase A, which contains inorganic cations and a solution of salts of inorganic cations, wherein the salts are selected from the group consisting of calcium chloride, Calcium nitrate, calcium acetate, magnesium chloride, magnesium nitrate, magnesium acetate, magnesium citrate, magnesium lactate, zinc chloride, zinc nitrate and zinc acetate, and a liquid phase B containing anions which form a salt insoluble in the liquid phase mixture with the inorganic cations and a solution of salts selected from the group consisting of ammonium, alkali metal or magnesium salts of acetates, carbonates, hydrogen carbonates, sulfates, phosphates, hydrogen phosphates and hydroxides, sprayed together with at least one multi-fluid nozzle, and wherein at least one hydrophobic W Irkstoff present dissolved in at least one liquid spray phase, and
  • the invention relates to a process for the preparation of composite materials by reactive spray drying, wherein a liquid Phase A, which contains inorganic cations and is a solution of salts of inorganic cations and the salts are selected from the group consisting of calcium chloride, calcium nitrate, calcium acetate, magnesium chloride, magnesium nitrate, magnesium acetate, magnesium citrate, magnesium lactate, zinc chloride, zinc nitrate and Zinc acetate, and a liquid phase B containing anions which, with the inorganic cations, form a salt insoluble in the liquid phase mixture and a solution of salts selected from the group consisting of ammonium, alkali or magnesium salts of acetates, carbonates, Hydrogencarbonaten, sulfates, phosphates, hydrogen phosphates and hydroxides, sprayed together with at least one multi-fluid nozzle, and wherein at least one hydrophobic active ingredient is present together with a surfactant dissolved
  • the invention relates to a process for the preparation of composite materials by reactive spray drying, wherein a liquid phase A, which contains inorganic cations, is used, and wherein the liquid phase A is a solution of salts of inorganic cations, and the salts are selected from the group consisting of calcium chloride and calcium acetate, and a liquid phase B which contains anions which form a salt insoluble in the mixture of the liquid phases with the inorganic cations, and wherein as the liquid phase B a solution of salts selected from among Group consisting of ammonium or alkali metal salts of acetates, carbonates, Hydrgencarbonates, sulfates, phosphates, hydrogen phosphates and hydroxides is used, and wherein the liquid phases A and B and optionally further liquid phases are sprayed together with at least one multi-component nozzle, and wherein at least one H ydrophobic active ingredient is present dissolved in at least one liquid spray phase, and wherein the salt formed
  • the solvents of the liquid phases are preferably water or ethanol or water-ethanol mixtures.
  • the active ingredient is preferably dissolved in ethanol, optionally in the presence of a surfactant, which is preferably a nonionic surfactant, and may be added to phase A or phase B.
  • a surfactant which is preferably a nonionic surfactant, and may be added to phase A or phase B.
  • the ammonium or alkali metal salts of phase B are preferably acetates or carbonates.
  • a nonionic surfactant is used in the liquid phase which contains the hydrophobic active substance, preference is given to using a polyoxyalkylated fatty acid ester, in particular particular macrogol hydroxystearates, macrogol-glycerol hydroxystearates or macrogolglycerolricinoleates.
  • the resulting composite materials represent an amorphous water-sparingly soluble salt matrix in which at least one amorphous hydrophobic active ingredient is embedded. Furthermore, the composite material contains water-soluble salt components.
  • the composite materials according to the invention which are produced by the reactive spraying technique, have particular advantages over the known technologies. Surprisingly, the reaction time can be significantly reduced by the reactive spray drying in comparison to the precipitation.
  • the spray process produces a powder which can be further processed without complicated work-up (filtration, trailing drying).
  • Reactive spray drying has the advantage over the described methods of being based on technology that is scalable and easy to implement under GMP conditions.
  • the composites are particularly suitable for the formulation of poorly soluble active ingredients which have a high melting point (> 180 ° C) and insufficient thermal stability (high temperature decomposition, melt decomposition) and are therefore less suitable for conventional processes such as melt extrusion.
  • the composites show in artificial gastric juice a much faster and more complete release of active substance compared to the crystalline substance.
  • the composite materials are suitable for processing in solid dosage forms.
  • binders such as carboxymethylcellulose Na, hydroxyp- ropylmethylcellulose, homo- and copolymers of N-vinylpyrrolidone such as PVP or copolymers of N-vinylpyrrolidone and vinyl acetate, starches or gelatin ,
  • the powders or granules can be mixed with other excipients or active ingredients and filled into sachets for use as re-dispersible powders.
  • the powders or granules can be filled in hard capsules.
  • flow control agents Alignin 2
  • lubricants such as Mg stearate, Ca stearate, stearic acid, sodium stearyl fumarate, PEG with average molecular weights Mw of 1000-8000
  • disintegrants such as crospovidone or sodium starch glycerol COLAT
  • wetting agents such as Poloxamer 188 or sodium lauryl sulfate can be added to the tableting mixture.
  • the composite materials according to the invention are also suitable for the production of effervescent tablets.
  • the Tablettiermischung is usually added to a effervescent mixture consisting of sodium bicarbonate and an acid (citric acid or tartaric acid).
  • an acid citric acid or tartaric acid
  • the amount of acid in this case is adjusted to the amount of calcium carbonate.
  • Drug release was determined according to USP, chapter ⁇ 71 1>, dissolution, paddle apparatus at 100 rpm. The amount of sample was normalized to 100 mg of active ingredient.
  • Release medium B like release medium A, but in addition 0.1% by weight of polysorbate 80 was added to the release medium.
  • the amorphous state was determined by XRD.
  • Measuring instrument Diffractometer D 8 Advance with 9-fold sample changer (Fa.Bruker / AXS)
  • Phase A CaC, danazol
  • Phase B Dissolve 0.5 mol / l Na2CC "3 in deionized water
  • the spraying device used was a Büchi device, B290, equipped with a three-component nozzle of the type 0465555
  • Spraying device Buchi B290; Nozzle: outer channel 2.0 mm diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm diameter
  • Atomizing gas nitrogen, 819 l / h
  • Drying gas nitrogen, throughput: 65 m 3 / h
  • the composites were amorphous as determined by XRD.
  • Phase A calcium acetate 0.25 mol / l in deionized water
  • Phase B ammonium acetate 0.25 mol / l, danazol 5 g / l, Kolliphor TM RH40 5% by weight, based on active ingredient
  • ammonium carbonate was dissolved in 150 g of deionized water and mixed with 300 g of the ethanolic solution of active substance. The resulting mixture was stirred at 40 ° C until a clear solution was formed.
  • the nozzle used was a 120 kHz ultrasonic spray-dryer nozzle type 06-04-00445 equipped with a micropore capillary for double-fluid feed type 06-05-00290.
  • Spraying device Buchi B290; Ultrasonic nozzle: two-fluid nozzle, Sonotek, power 5 W Cooling Ultrasonic nozzle with 60%, gas passage, cooling gas nitrogen, nozzle temperature 63 ° C
  • Drying gas nitrogen, throughput: 65 m 3 / h, tower inlet temperature: 130 ° C,
  • the composites were amorphous according to XRD.
  • Release test after 120 min in release medium A, 35% by weight of the danazol was released.
  • Phase A solution of 0.5 mol / L calcium chloride and 10 g / L estradiol in ethanol.
  • Phase B Dissolution of 0.5 mol / l CaCC "3 in deionized water
  • the sprayer used was a Büchi, B290, equipped with a type 0465555 ternary nozzle.
  • Spray parameters spraying device: Buchi B290; Nozzle: outer channel 2.0 mm diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm diameter
  • Atomizing gas nitrogen, 819 l / h
  • Drying gas nitrogen, throughput: 65 m 3 / h
  • Release test after 120 min in release medium B 30 wt .-% of estradiol were released.
  • the composites were amorphous as determined by XRD.
  • Itraconazole-calcium carbonate composite Phase A calcium acetate
  • Phase B Solution of 0.25 mol / l (NH 4 ) 2CO 3 in deionized water.
  • the spraying device used was a Büchi device, B290, equipped with a type 0465555 ternary nozzle
  • Spraying device Buchi B290; Nozzle: outer channel 2.0 mm diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm diameter
  • Atomizing gas nitrogen, 819 l / h
  • Drying gas nitrogen, throughput: 65 m 3 / h
  • Release test after 120 min in release medium A, 30% by weight of itraconazole was released.
  • the composites were amorphous as determined by XRD.
  • Phase A calcium acetate
  • Phase B Solution of 0.25 mol / l (NH 4 ) 2CO 3 in deionized water / acetone (60/40) and 10 g / L naproxen
  • the spraying device used was a Büchi B290 device equipped with a type 0465555 ternary nozzle.
  • Spraying device Buchi B290; Nozzle: outer channel 2.0 mm diameter, inner channel 0.7 mm diameter, gas channel 2.8 mm diameter
  • Atomizing gas nitrogen, 819 l / h
  • Phase A calcium acetate 0.25 mol / l in deionized water
  • Phase B ammonium acetate 0.25 mol / l, celecoxib 5 g / l, 5% by weight Kolliphor TM RH40, based on active ingredient, in a mixture of deionized water and EtOH 1: 2 (waxed ratio).
  • ammonium carbonate was dissolved in 150 g of deionized water and mixed with 300 g of the ethanolic solution of active substance. The resulting mixture was stirred at 40 ° C until a clear solution was formed.
  • the nozzle used was a 120 kHz ultrasonic spray-dryer nozzle type 06-04-00445, from SonoTek, USA, equipped with a Micropore capillary for double-fluid feed, type 06-05-00290.
  • Spraying device Buchi B290; Ultrasonic nozzle: two-fluid nozzle, Sonotek, power 5 W Cooling Ultrasonic nozzle with 60% gas passage, cooling gas nitrogen, nozzle temperature 52 ° C
  • Drying gas nitrogen, throughput: 65 m 3 / h, tower inlet temperature: 132 ° C,
  • Release test after 120 min in release medium A, 20% by weight of the celecoxib were released.
  • the composites were amorphous according to XRD.
  • Comparative Example I Spraying of pure danazol As spraying solution, a solution obtained analogously to Example 2, Phase B, was sprayed under the spraying conditions given in Example 2.
  • Release test after 120 min in release medium A containing 0.1% by weight of polysorbate 80, 5 to 6.5% by weight of danazol were released.
  • Comparative Example II Danazole-calcium carbonate composite prepared by precipitation in a mixing chamber according to WO 2012/027378 Release test: after 120 min in release medium A containing 0.1% by weight of polysorbate 80, 8% by weight of the danazol were liberated.
  • the products had significant levels of crystalline calcium carbonate according to XRD.
  • the plasma levels were determined as follows:
  • Each of the 5 dogs received the test substances in the same order with a break of 14 days after each application.
  • the formulations were administered as a physical mixture of 70% test substance, 15% Avicel PH 101 (FMC BioPolymer) and 15% Kollidon CL (BASF SE) in hard gelatin capsules (Torpac Inc., USA # 11).
  • the dose was 30 mg / kg and was individually related to the current body weight for each animal and each time of application.
  • the dogs got the capsules sober.
  • the blood was taken 3, 60, 90 min, 2,4,8 and 24 hours after the application. Water was present ad libitum, the feeding took place 4 hours after the application.
  • the plasma concentration of the drug is indicated in the figure in ng / ml.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un procédé de fabrication de matériaux composites par séchage réactif par pulvérisation. Pour cela, on pulvérise conjointement, à l'aide d'au moins une buse multiple, une phase liquide A contenant des cations inorganiques et une phase liquide B contenant des anions qui forment avec les cations inorganiques un sel insoluble dans le mélange des phases liquides. Au moins une substance active hydrophobe est dissoute dans au moins une phase de pulvérisation liquide et le sel formé à partir des cations de la phase A et des anions de la phase B présente en milieu aqueux neutre une solubilité inférieure à 0,02 mol/l.
EP14701794.1A 2013-02-08 2014-01-31 Fabrication de matériaux composites inorganiques-organiques par séchage réactif par pulvérisation Withdrawn EP2954009A1 (fr)

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EP14701794.1A EP2954009A1 (fr) 2013-02-08 2014-01-31 Fabrication de matériaux composites inorganiques-organiques par séchage réactif par pulvérisation

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EP13154684 2013-02-08
EP14701794.1A EP2954009A1 (fr) 2013-02-08 2014-01-31 Fabrication de matériaux composites inorganiques-organiques par séchage réactif par pulvérisation
PCT/EP2014/051921 WO2014122077A1 (fr) 2013-02-08 2014-01-31 Fabrication de matériaux composites inorganiques-organiques par séchage réactif par pulvérisation

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US9138381B2 (en) 2013-02-08 2015-09-22 Basf Se Production of inorganic-organic composite materials by reactive spray-drying
EP2899162A1 (fr) 2014-01-22 2015-07-29 Basf Se Synthèse et utilisation d'accélérateurs de durcissement à base de CaSO4
JP2019167319A (ja) * 2018-03-26 2019-10-03 株式会社親広産業 糖消費促進剤
CN109111762A (zh) * 2018-10-09 2019-01-01 河南骏化发展股份有限公司 一种油墨用改性纳米碳酸钙的制备方法

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