EP1443906A1 - Procede pour former des cristaux de profenes - Google Patents

Procede pour former des cristaux de profenes

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Publication number
EP1443906A1
EP1443906A1 EP02779512A EP02779512A EP1443906A1 EP 1443906 A1 EP1443906 A1 EP 1443906A1 EP 02779512 A EP02779512 A EP 02779512A EP 02779512 A EP02779512 A EP 02779512A EP 1443906 A1 EP1443906 A1 EP 1443906A1
Authority
EP
European Patent Office
Prior art keywords
ibuprofen
additives
surfactants
solvent
profen
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Withdrawn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
EP02779512A
Other languages
German (de)
English (en)
Inventor
Heinz Einig
Bernd W. MÜLLER
Norbert Rasenack
Katrin Friese
Dirk. Franke
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
Publication of EP1443906A1 publication Critical patent/EP1443906A1/fr
Withdrawn legal-status Critical Current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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K9/145—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 organic compounds
    • 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
    • A61K9/146—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 organic macromolecular compounds
    • 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
    • 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]

Definitions

  • the present invention relates to a process for the formation of profen crystals and the use of the profenes thus produced for pharmaceutical dosage forms.
  • the analgesics of the Profene group are poorly water-soluble substances as hydrophobic acidic active substances. This is particularly true in weakly acidic and acidic pH ranges.
  • the slow dissolution rate therefore represents the step that limits bioavailability.
  • Profene have poor flow properties (highly cohesive behavior) and poor tabletting properties (strong adhesion to the stamping tools and poor plastic deformability). These properties lead to tablets or compacts with low strengths, so that in order to equalize the unfavorable pharmaceutical properties in tablet formulations, a high proportion of adjuvants (approx. 30-40%) is usually required, which leads to larger tablets and also to an increase in production costs. Usually, time-consuming and expensive wet granulation is required.
  • the preparation should be designed so that it has the highest possible bioavailability. That means, a tablet should disintegrate quickly in the gastrointestinal tract so that the active ingredient can dissolve quickly.
  • the inactive auxiliaries and the active ingredient should have ideal galenical properties. These are, for example: very good tabletting behavior, good flow behavior, no adhesive behavior (e.g. sticking to stamping tools) and good dissolving behavior.
  • Solvents can achieve improvements in solution speed / solubility (V. Labhasetwar et al., Studies on some crystalline forms of Ibuprofen, Drug Dev. Ind. Pharm. 19 (6), 631-641 (1993)). These are different crystal forms, with polymorphic ibuprofen forms being reported due to the different melting points and IR spectra.
  • the ibuprofen produced according to the invention is not a polymorphic form (identical melting point and identical X-ray diffractograms as the current commercial product).
  • improvements can be made by the method according to the invention achieve the substance properties that have not been achieved with the previously known methods.
  • No. 4,476,248 discloses the crystallization of ibuprofen with the aim of crystallizing cube-shaped to spherical crystals with a larger crystal size and high bulk density. A cooling crystallization from alcoholic solution without the addition of additives is described. A significant increase in the solution speed is not achieved.
  • the object of the present invention was to produce fast-dissolving, free-flowing, readily compressible and tablettable profenes of high purity, which can be directly compressed into tablets with good galenical properties in high active ingredient proportions in mixtures with only a few portions of conventional pharmaceutical auxiliaries without prior granulation.
  • This object was achieved according to the invention by a process for solid formation of profenes, which is characterized in that the solid formation is carried out in the presence of one or more additives.
  • the invention also relates to the use of the profenes thus produced for the production of pharmaceutical dosage forms.
  • the method according to the invention provides pure profen that
  • the tablettability can be significantly improved by using the profenes produced according to the invention.
  • the physical admixture of a few percentages (below 10%) of conventional pharmaceutical auxiliaries allows tablets to be pressed directly without further process steps, the physical properties such as pressure force / hardness ratio, friability, proportions of active ingredient and release rate of the active ingredient of the tablets known to date and are clearly superior to the tablets described in the literature.
  • This is achieved by adding water-soluble and / or water-insoluble additives in the formation of solids.
  • suitable solvents or solvent combinations also plays a decisive role here.
  • the addition of additives alone or in combination with suitable solvents leads to an unexpected and surprisingly clearly positive influence on both the dissolution rate and the flow and tableting properties.
  • the additives are no longer contained in the end product or can be almost completely removed with simple washing processes.
  • the additive accordingly causes the formation of a certain crystal habit with a certain surface, which decisively influences the substance properties.
  • Auxiliaries such as explosives, are used. In order to improve the tablettability, higher proportions are usually present. Binders, flow regulators and mold release agents required.
  • the new Profen is particularly suitable for the production of solid dosage forms, such as tablets, which have an active ingredient content of 80 to 98%, preferably 90 to 98%. However, it can also be filled directly into capsules without further processing due to its good flow behavior and fast dissolution rate.
  • Manufacture here does not refer to chemical synthesis, but rather to the subsequent steps of solid production and its extraction, modification and purification.
  • ibuprofen ibuprofen, naproxen, flurbiprofen, ketoprofen, flunoxaprofen, ibufenac, ibuproxam, pirprofen and loxoprofen as well as their hydrates, solvates and physiologically tolerable salts.
  • the invention also relates to the optically active forms, the racemates and the
  • physiologically usable salts are salts with amino acids, e.g. Lysine.
  • Other examples of such salts are alkali metal, alkaline earth metal, ammonium and alkylammonium salts.
  • Pure enantiomers of profenes are obtained either by resolving racemates (via salt formation with optically active bases) or by using optically active starting materials in the synthesis.
  • pharmaceutical dosage form refers to tablets, coated tablets (film, lacquer, sugar coated tablets) and capsules (filled with powder, granules or pellets).
  • pharmaceutical dosage form refers not only to the end product, but also to parts or intermediate products thereof, such as a layer of a multilayer tablet, parts of a capsule filling and the like.
  • Solid formation means, for example, the production of crystals by displacement precipitation, crystallization by cooling the solution (cooling crystallization), evaporative crystallization or spray drying.
  • displacement precipitation describes a process in which the solid formation of the active substance is generated from a solution by adding a non-solvent. It is also possible to lower the temperature or evaporate solvent. The precipitated active ingredient is obtained by filtration and, if necessary, washing with a non-solvent and subsequent drying.
  • the substance properties can be positively influenced by choosing a suitable solvent (preferably organic solvents, such as alcohols, for example isopropanol, if appropriate in a certain mixing ratio with, for example, water).
  • a suitable solvent preferably organic solvents, such as alcohols, for example isopropanol, if appropriate in a certain mixing ratio with, for example, water.
  • the term cooling crystallization describes a process in which the crystals of the active ingredient are generated from a solution in the solvent by lowering the temperature. The active substance produced is obtained by filtration, washing with a non-solvent if possible, filtration and subsequent drying. Another way to crystallize is evaporative crystallization, in which the solvent is removed by evaporation or evaporation.
  • solvent describes a liquid in which the active ingredient dissolves sufficiently.
  • solvent for example, ethanol, methanol, propanol, isopropanol, acetone or acetonitrile.
  • non-solvent describes a liquid in which the active ingredient has only a low solubility, such as long-chain alcohols, but also water. The liquid thus serves as a precipitant.
  • suitable solvents preferably organic solvents, such as, for example, alcohols, for example 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, ethanol, methanol or
  • suitable solvents preferably organic solvents, such as, for example, alcohols, for example 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, ethanol, methanol or
  • non-solvents such as water, aqueous solutions of acids or organic solvents
  • Organic solvents are preferably used which, in the presence of profenes, form a mixture gap with the non-solvent over a certain concentration range.
  • Profen crystals are formed by first dissolving Profen in a suitable solvent with the addition of additives.
  • the solubility is then reduced, for example by lowering the temperature (cooling crystallization), by evaporating the solvent (evaporative crystallization) or by adding a suitable non-solvent and, if appropriate, a second additive dissolved therein (displacement precipitation).
  • a particularly free-flowing, tablettable and rapidly soluble solid is formed when solvents and non-solvents form a mixture gap over a certain concentration range in the presence of profen and when the crystals formed are given sufficient time to grow.
  • the solid formation is preferably carried out after the displacement precipitation.
  • the formation of solids by cooling and / or evaporation crystallization can be carried out batchwise or continuously.
  • the formation of solids by adding a non-solvent (displacement precipitation) is preferably carried out as a semi-batch process, the profen being introduced into the solvent and the non-solvent being metered in.
  • a suitable stirrer generates a shear field that is as homogeneous as possible with sufficiently high shear (specific stirring power in the range from 0.2 to 2 W / kg, preferably 0.5 to 1.5 W / kg).
  • Multi-stage stirrers and / or stirrers without sharp edges can be used for this.
  • a combination of different stirrer types also makes sense (for example, an impeller stirrer in combination with axially conveying stirrer stages). It makes sense to choose a sufficiently long dosing time for the non-solvent (dosing time between 30 min and 300 min, preferably between 40 and 210 min).
  • the temperature is generally selected in the range from 10 ° C. to 80 ° C., preferably in the range from 15 ° C. to 60 ° C.
  • the solution or suspension can be cooled at the same time or a part of the solvent can be evaporated.
  • Suitable additives according to the invention are, for example, the following surfactants
  • Partial fatty acid esters of polyoxyethylene sorbitan such as polyethylene glycol (20) sorbitan monolaurate, monopalmitate, monostearate, monooleate; Polyethylene glycol (20) sorbitan tristearate and trioleate; Polyoxyethylene (5) sorbitan monooleate; Polyoxyethylene (4) sorbitan monolaurate (also called polysorbate)
  • Polyoxyethylene fatty alcohol ethers such as, for example, polyoxyethylene (4) lauryl ether, polyoxyethylene (23) lauryl ether, polyoxyethylene (10) cetyl ether, polyoxyethylene (20) cetyl ether, polyoxyethylene (10) stearyl ether, polyoxyethylene (20) stearyl ether, Polyoxyethylene (10) oleyl ether, polyoxyethylene (20) oleyl ether (also called macrogol fatty acid ether)
  • Polyoxyethylene fatty acid esters such as polyoxyethylene stearate Ethoxylated triglycerides, such as polyoxyethylene glycerol fatty acid esters, such as, for example, polyoxyethylene glycerol monoisostearate,
  • Sugar esters such as, for example, sucrose monolaurate, sucrose monopalmitate, sucrose monostearate, sucrose monomyristate, sucrose monooleate
  • Alkali soaps fatty acid salts
  • fatty acid salts such as sodium laurate, palmitate, stearate, oleate
  • Ionic and zwitterionic surfactants e.g. B. betaines, such as cocobetaine
  • the surfactants without a PEG chain especially the sugar esters and the fatty acid salts, particularly preferably sucrose monolaurate.
  • the HLB value of the surfactants used should be> 8 with water as the non-solvent, since with the more lipophilic surfactants a higher proportion of surfactant can remain in the end product, which leads to increased agglomeration. It is particularly surprising to observe that surfactants that are only present during the manufacture of the drug but are then largely removed by washing permanently change the galenical properties of the drug. An accelerated release by surfactants - if they are present in the end product - is obvious. Profen produced by the process presented here contains practically no surfactant. Surprisingly, however, an increase in the release rate was nevertheless found through the novel process for solid formation. The formation of a readily flowable product when surfactants are added is also surprising, since surfactants actually form one
  • Non-surfactants can also be used as additives. For example, the following are:
  • Dextrans such as dextran 20, 60, 200
  • Polyvinyl alcohol-polyethylene glycol graft copolymer e.g. Kollicoat ® IR
  • HES Hydroxyethyl starch
  • Cellulose ethers such as, for example, hydroxypropyl cellulose HPC or hydroxyethyl cellulose, HEC
  • the additives can be dissolved or emulsified in the solvent or non-solvent.
  • the profenes produced by the process according to the invention have an in vitro release (phosphate buffer pH 7.4 according to USP XXIV using the paddle process at 100 rpm) of> 70%, preferably of> 90%, within 5 minutes.
  • a further increase in the positive effects on the physicochemical properties of the active ingredient can be achieved by combining several additives.
  • Both several surfactants and several non-surfactants and combinations thereof can be used here, preferably the combination of an additive from the group of surfactants with an additive from the group of non-surfactants, particularly preferably the combination of sugar residue / non-surfactant leads to a considerable increase in the solution speed.
  • a combination of sucrose monolaurate with dextran 200, trehalose, Kollicoat ® IR is preferably, hydroxy ethyl starch, P ⁇ vidon or hydroxypropylcellulose, or a combination of Tween 80 with, for example dextran used 200th
  • the profenes produced by the process according to the invention have an in vitro release (phosphate buffer pH 7.4; USP XXIV) of> 70%, preferably> 90% (Table 3).
  • the active ingredient with modified galenical properties (attributable to modifications in surface and habit) produced by the process described here can be used to produce powder mixtures for direct tableting with an active ingredient content of> 90%.
  • ⁇ m following is called an example of a recipe that can be tableted by way of direct compression without the use of additional auxiliary techniques:
  • the average particle size of the profen used does not play a decisive role; it should preferably have an average particle size of 10 to 100 ⁇ m.
  • Dry binders (approx. 4%), such as microcrystalline cellulose (Avicel ® )
  • Disintegrants such as cross-linked sodium carboxymethylcellulose (AcDiSol ® ), starch derivatives, cross-linked PVP
  • Flow regulating agents 0.2 to 0.5%), such as highly disperse silicon dioxide (Aerosil ® ). In most cases, due to the good flow properties, an additional flow control agent can be dispensed with.
  • Lubricants 0.1 to 0.5%), such as. B. magnesium stearate, calcium stearate, stearic acid, derivatives of stearic acid (z. B. Precirol ® ), talc, higher molecular weight polyethylene glycols. Due to the low adhesiveness of the profen produced by this process, the proportion of lubricant • can be significantly reduced compared to conventional recipes are primarily used to lubricate the tablet press.
  • excipient proportions mentioned here relate to the part of the dosage form which contains the active ingredient.
  • a possibly additionally applied coating, which mostly serves to cover the taste of the very bitter active ingredient, is not taken into account.
  • One or more further active ingredients can also be added to the pharmaceutical dosage forms.
  • active ingredients can be, for example: pseudoephedrine, ephedrine, phenylpropanolamine, tripolidine, acetylcysteine, ambroxol, azelaic acid, dehydrocodeine, hydrocodone or caffeine. Salts of these compounds are preferred if the active substance is not in the form of a solid crystal.
  • the proportion of the other active ingredient (s) in the pharmaceutical dosage form can be between 0.5 and 70% by weight of the profene, depending on the strength of the active ingredient and the desired effect.
  • ibuprofen 80 g are dissolved in 100 ml of isopropanol at 40 ° C. 3 g of sucrose monolaurate are added as an additive. It is then precipitated by adding ice water (450 ml / stirrer speed 200 rpm) for 70 min; cooling to 10 ° C takes place during this process. The crystals are collected by filtration, washed with ice water (3 x 150 ml) and dried in vacuo. It forms a fine, loose, free-flowing product that is neither used for
  • ibuprofen dissolved in 100 ml of isopropanol at 40 ° C.
  • 3 g of sucrose monolaurate are added as an additive. It is then precipitated by adding ice water (450 ml / stirrer speed 200 rpm) for 70 min; cooling to 10 ° C takes place during this process.
  • the crystals are collected by filtration, washed with ice water (3 x 150 ml) and dried in vacuo. 3 g of the product are washed again with water (10 x 50 ml). It forms a fine, loose, free-flowing product that is neither used for Adhesion still tends to cohesion.
  • ibuprofen 80 g are dissolved in 100 ml of isopropanol at 40 ° C. 3 g of sucrose monolaurate are added as an additive. It is then precipitated (70 min) by adding ice water (450 ml) to which 8 g of dextran 200 are added. During this process, it cools down to 10 ° C. The crystals are collected by filtration, washed with ice water (3 x 150 ml) and dried in vacuo. A fine, loose, free-flowing product is formed which is neither prone to adhesion nor cohesion.
  • the crystals are collected by filtration, washed with ice water (3 x 150 ml) and dried in vacuo. A fine, loose, free-flowing product is formed which is neither prone to adhesion nor cohesion.
  • powder dissolution pure active substance
  • a 100% release was found (in phosphate buffer pH 7.4 USP XXIV) after ⁇ 30 seconds.
  • the merchandise currently available only dissolves to ⁇ 20% after 2 minutes; 100% resolution is only achieved after> 15 min.
  • Ibuprofen was precipitated from 2-propanol with water in a discontinuously operated stirred kettle using saccharose monolaurate and Klucel LF on a 3 1 scale.
  • a double-walled glass container with three baffles and an inclined-blade turbine was used as the stirring element.
  • a specific stirring power of 0.25 W / kg was entered. 411 g of ibuprofen were introduced and dissolved in 936 g of a solution of 2-propanol and sucrose monolaurate (1.0% by weight
  • Ibuprofen was precipitated from 2-propanol with water in a discontinuously operated stirred kettle using sucrose monolaurate and Klucel LF on a 3 1 scale.
  • a double-walled glass container with three baffles and an inclined-blade turbine was used as the stirring element.
  • a specific stirring power of 1 W / kg was entered.
  • 414 g of ibuprofen were introduced and dissolved in 943 g of a solution of 2-propanol and sucrose monolaurate (1.0% by weight of sucrose monolaurate in the solution).
  • At 20 ° C was 3780 g IR solution added within 70 min a 0.24 wt .-% water / Kollicoat ®.
  • the solid was separated off on a suction filter and washed with water. The crystals are very free-flowing and show a good dissolution rate. After 5 and 8 minutes, 87 and 95% of the active ingredient are dissolved.
  • ibuprofen 80 g ibuprofen are dissolved in 100 ml isopropanol at 40 ° C. 3 g of sucrose monolaurate are added as an additive. Then add ice water (450 ml / stirrer
  • the tablets pressed by direct tabletting meet the requirements of Ph. Eur .; the maximum deviation when determining the uniformity of the mass is 0.9%.
  • the tablet surface is even.
  • the ibuprofen produced according to the invention is therefore suitable for direct tableting (with a high active ingredient content of> 90%). Due to the good flow properties of the active ingredient, the proportion of Aerosil can be further reduced. A reduction in the proportion of lubricant (magnesium stearate) is also possible. 5 When the release behavior was determined (in phosphate buffer pH 7.4 USP XXIV) a 100% release was found after 2 minutes (including the disintegration time of ⁇ 30 sec).

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un procédé pour former des cristaux de profènes, caractérisé en ce que la solidification est provoquée par un procédé de précipitation par déplacement, de cristallisation par refroidissement, de cristallisation par évaporation, ou par une combinaison de ces procédés, en présence d'un ou de plusieurs additifs. L'invention concerne par ailleurs l'utilisation des profènes ainsi produits dans des formulations pharmaceutiques.
EP02779512A 2001-11-06 2002-10-25 Procede pour former des cristaux de profenes Withdrawn EP1443906A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10153934A DE10153934A1 (de) 2001-11-06 2001-11-06 Verfahren zur Kristallisation von Profenen
DE10153934 2001-11-06
PCT/EP2002/011999 WO2003039513A1 (fr) 2001-11-06 2002-10-25 Procede pour former des cristaux de profenes

Publications (1)

Publication Number Publication Date
EP1443906A1 true EP1443906A1 (fr) 2004-08-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP02779512A Withdrawn EP1443906A1 (fr) 2001-11-06 2002-10-25 Procede pour former des cristaux de profenes

Country Status (14)

Country Link
US (1) US20050003000A1 (fr)
EP (1) EP1443906A1 (fr)
JP (1) JP2005512994A (fr)
KR (1) KR20050039732A (fr)
CN (1) CN1585630A (fr)
BR (1) BR0213878A (fr)
CA (1) CA2464756A1 (fr)
DE (1) DE10153934A1 (fr)
HU (1) HUP0402006A2 (fr)
IL (1) IL161406A0 (fr)
MX (1) MXPA04004236A (fr)
NO (1) NO20041850L (fr)
RU (1) RU2004117167A (fr)
WO (1) WO2003039513A1 (fr)

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CZ297830B6 (cs) * 2005-08-30 2007-04-11 I.Q.A., A. S. Zpusob výroby jemne krystalické smesi obsahující nesteroidní protizánetlivé lécivo, jemne krystalická smes pripravitelná tímto zpusobem a pevný farmaceutický prostredek tuto smes obsahující
DK2043637T3 (da) 2006-07-18 2012-05-07 Horizon Pharma Usa Inc Fremgangsmåder og medikamenter til administrering af ibuprofen
ATE516013T1 (de) * 2007-07-06 2011-07-15 Basf Corp Gastroretentive zusammensetzung auf basis eines wasserlöslichen reaktionsprodukts eines vinylgruppen enthaltenden vorläufers
ATE545411T1 (de) * 2008-03-25 2012-03-15 Formac Pharmaceuticals N V Herstellungsverfahren für feststoffdispersionen
EP2374478B1 (fr) * 2008-12-04 2017-08-23 Next 21 K.K. Complexes d'inclusion contenant d'un ains et d'saccharide pour atténuer les dommages occasionnés à la muqueuse gastro-intestinale
US20120135955A1 (en) * 2009-07-24 2012-05-31 The University Of Tokyo External Preparation Containing NSAIDs And Method For Producing The External Preparation
JP5750856B2 (ja) * 2010-10-04 2015-07-22 ライオン株式会社 固形医薬組成物及び医薬製剤
US9248139B2 (en) * 2011-12-21 2016-02-02 Bristol-Myers Squibb Company Co-processing method and formulations for HIV attachment inhibitor prodrug compound and excipients
LT3258920T (lt) 2015-02-17 2023-07-25 Universiteit Gent Kieta farmacinė dozavimo forma, tinkanti tirpinti geriamajame vandenyje ir vartoti kaip geriamąjį vaistinį tirpalą
CN106397181B (zh) * 2016-09-08 2019-01-01 山东理工大学 一种通过添加十二烷基硫酸钠自水溶液中制备长针状布洛芬晶体的方法
CN106518655B (zh) * 2016-09-08 2019-01-04 山东理工大学 一种通过添加晶形控制剂自水溶液中制备片状布洛芬晶体的方法
CN110627629A (zh) * 2019-10-15 2019-12-31 山东新华制药股份有限公司 一种多级连续反应结晶生产布洛芬的方法
JP2023084097A (ja) * 2021-12-06 2023-06-16 花王株式会社 芳香族ヒドロキシカルボン酸結晶の製造方法

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BR0213878A (pt) 2004-08-31
IL161406A0 (en) 2004-09-27
CN1585630A (zh) 2005-02-23
US20050003000A1 (en) 2005-01-06
DE10153934A1 (de) 2003-05-22
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