WO1997015292A1 - Procede de preparation de formes galeniques solides - Google Patents

Procede de preparation de formes galeniques solides Download PDF

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Publication number
WO1997015292A1
WO1997015292A1 PCT/EP1996/004586 EP9604586W WO9715292A1 WO 1997015292 A1 WO1997015292 A1 WO 1997015292A1 EP 9604586 W EP9604586 W EP 9604586W WO 9715292 A1 WO9715292 A1 WO 9715292A1
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WO
WIPO (PCT)
Prior art keywords
mixing
mixture
melting
active ingredient
acid
Prior art date
Application number
PCT/EP1996/004586
Other languages
German (de)
English (en)
Inventor
Jörg Breitenbach
Axel Paul HÄRTL
Werner Maier
Joerg Rosenberg
Michael Schiessl
Hans Dieter Zettler
Original Assignee
Basf Aktiengesellschaft
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 Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Publication of WO1997015292A1 publication Critical patent/WO1997015292A1/fr

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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
    • A61K9/1682—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
    • 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

Definitions

  • the present invention relates to a process for the production of solid pharmaceutical forms by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one pharmaceutical active ingredient and, where appropriate, customary pharmaceutical additives in the absence of a solvent.
  • the classic processes for producing solid medicament formulations, in particular tablets, are carried out batchwise and comprise several stages.
  • First, the components of the dosage form are conveyed into a suitable container and mixed there with the addition of a solvent to form a kneadable dough.
  • the dough is then granulated, the granules are dried and shaped into the desired medicinal form, for example by compression into tablets.
  • Such methods are described in relevant textbooks and for example in DE-A-41 41 268 and EP-A-590 963.
  • the disadvantage of this process lies in the use of a solvent and in the large number of stages and equipment required.
  • EP-A-337 256 proposes to meter the individual components continuously into the hopper of an extruder. The dosing takes place with the aid of the very precisely working differential dosing scales. Dosing fluctuations can nevertheless not be completely avoided because the differential dosing scales have to be operated volumetrically during filling. As a result, at least some of the pharmaceutical forms obtained do not meet the requirements.
  • EP-A-337 256 Another disadvantage of the process described in EP-A-337 256 is the high outlay for distributing the powdered active ingredient during the mixing process in the plastic zone of the extruder in order to be able to achieve the necessary axial backmixing.
  • the coupling of the melting and mixing process in the extruder requires a relatively long residence time in a zone with high shear in order to achieve sufficient mixing. This can lead to local overheating and damage to the product, especially when using a shear and temperature-sensitive active ingredient.
  • WO-A-94/25008 describes the preparation of an active ingredient-containing solution based on polyvinylpyrrolidone with a low K value in combination with certain esters as plasticizers.
  • the esters under consideration are clear, viscous liquids, with triethyl acetate and glycerol triacetate being preferred.
  • the ester content in this combination is at least 50%.
  • polyvinylpyrrolidone and the active ingredient are processed with heating to form a homogeneous solution.
  • the high proportion of plasticizer in the combination mentioned leads to the so-called cold flow of the solidified solvent system, which is therefore not stable in storage. It is therefore necessary to fill the solution in soft gelatin capsules. The process therefore requires a further step and is not suitable for the production of solid medicament forms.
  • REPLACEMENT BLADE (RULE 26)
  • the present invention is therefore based on the object of providing a simple and gentle process for the production of solid medicament forms, moreover the process should be inexpensive and finally it should allow the medicament forms to be produced reliably with a constant composition.
  • the present invention therefore relates to a process for the production of solid pharmaceutical forms by mixing and melting at least one pharmacologically acceptable polymeric binder, at least one active pharmaceutical ingredient and, if appropriate, customary pharmaceutical additives in the absence of a solvent to give a plastic mixture and shaping the mixture desired dosage form, which is characterized in that the steps of mixing, melting and shaping are carried out continuously and separately from one another.
  • steps which are separate from one another are to be understood to mean that each step is carried out in the apparatus which is optimal for the step in question and the materials used. At least one device is provided for each step.
  • the equipment used for mixing and melting can be the same, the same type or different types. For example, mixing with the aid of a solid mixer or an extruder and melting in a further extruder, which is an identical,
  • REPLACEMENT BLA ⁇ (RULE 26) but extruder operated under different conditions, or be carried out in an extruder of a different type.
  • the components can first be mixed and then melted and homogenized. However, especially when using sensitive active ingredients, it has proven to be preferred to first melt and premix the polymeric binder, if appropriate together with customary pharmaceutical additives, the stirred tanks, stirrers, solid-state mixers etc. optionally being operated alternately and then to mix in (homogenize) the active ingredient or the active ingredients, which can be used in solid form or as a solution or dispersion.
  • the melting takes place in a device customary for this purpose.
  • Extruders or heatable containers with stirrers e.g. Kneader (like the type mentioned below).
  • Kneader like the type mentioned below.
  • a very short and therefore inexpensive extruder is sufficient as the extruder.
  • Suitable devices are described, for example, in "Mixing during the manufacture and processing of plastics", H. Pahl, VDI-Verlag, 1986.
  • Particularly suitable mixing apparatuses are extruders and dynamic and static mixers, as well as stirred tanks, single-shaft agitators with stripping devices, in particular So-called paste agitators, multi-shaft agitators, in particular PDSM mixers, solid matter mixers and preferably mixing-kneading reactors (eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei), double-bowl kneaders (trough mixers) and stamp kneaders (internal mixers) or Rotor / stator systems (eg Dispax from IKA).
  • mixing-kneading reactors eg ORP, CRP, AP, DTB from List or Reactotherm from Krauss-Maffei
  • the polymeric binder is first melted in an extruder and then the active ingredient is mixed in a mixing kneading reactor.
  • REPLACEMENT BLA ⁇ (RULE 26)
  • less sensitive active ingredients can be used to intensively disperse the active ingredient using a rotor / stator system.
  • the mixing device can be fed continuously or discontinuously in the usual manner.
  • Powdered components can be fed in free, e.g. be introduced via a differential metering scale.
  • Plastic masses can be fed in directly from an extruder or fed in via a gear pump, which is particularly advantageous at high viscosities and high pressures.
  • Liquid media can be metered in using a suitable pump unit.
  • all components can be added to the mixing device and then mixed and then passed as a mixture to a melting device. However, it is preferred to first melt the binder, if appropriate together with customary additives, and then to mix in at least one active ingredient in the mixing device. Depending on the consistency of the active ingredient, it can be added using one of the methods described above.
  • the subsequent addition of the active ingredient (and / or other components) is particularly advantageous if the substances are sensitive to shear and temperature, because then the time during which they are subject to the high shear forces and are exposed to high temperatures, is considerably shorter.
  • the outlay for metering the components is reduced in the method according to the invention. Fluctuations in the product quality are avoided, that is, the method according to the invention reliably delivers the desired dosage forms and with the desired specifications.
  • the optimum device can be selected for each stage depending on the component used. A particularly effective mixing effect can therefore be achieved.
  • the process can be carried out very gently. It therefore provides medicinal forms in particular
  • REPLACEMENT BLA ⁇ (RULE 26) high product quality, even when using sensitive materials and active ingredients.
  • the mixture obtained by mixing and melting the binder, the active ingredient and optionally the additive or additives is pasty to viscous (thermoplastic) and therefore also extrudable.
  • the glass transition temperature of the mixture is below the decomposition temperature of all components contained in the mixture.
  • the binder should preferably be soluble or swellable in a physiological environment. Examples of suitable binders are:
  • PVP Polyvinylpyrrolidone
  • NVP N-vin
  • the K values (according to H. Fikentscher, Cellulose-Chemie 13 (1932), pages 58 to 64 and 71 and 74) of the polymers are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35, for PVP> 17, in particular 20 to 35.
  • Preferred polymeric binders are polyvinylpyrrolidone, copolymers of N-vinylpyrrolidone and vinyl esters, polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polymethacrylates, alkyl celluloses and hydroxyalkyl celluloses.
  • the polymeric binder In the total mixture of all components, the polymeric binder must soften or melt in the range from 50 to 180 ° C., preferably 60 to 130 ° C.
  • ERSATZBL ⁇ TT (REGEL26) Schung must therefore be below 180 ° C, preferably below 130 ° C. If necessary, it is reduced by conventional, pharmacologically acceptable plasticizing auxiliaries.
  • the amount of plasticizer is at most 30% by weight, based on the total weight of binder and plasticizer, so that storage-stable pharmaceutical forms are formed which show no cold flow. However, the mixture preferably contains no plasticizer.
  • plasticizers examples include:
  • aromatic carboxylic acid esters eg dialkyl acid phthalates, terephthalic acid phthalates, trimesteric acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, trimellitic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, terephthalic acid phthalates, ter
  • Common pharmaceutical auxiliaries the total amount of which can be up to 100% by weight, based on the polymer, are e.g.
  • Extenders or fillers such as silicates or silica, magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, e.g. the magnesium or calcium salt, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of 0.02 to 5.0, preferably 0.20 to 20% by weight. -%, based on the total weight of the mixture.
  • silicates or silica magnesium oxide, aluminum oxide, titanium oxide, stearic acid or their salts, e.g. the magnesium or calcium salt, methyl cellulose, sodium carboxymethyl cellulose, talc, sucrose, lactose, cereal or corn starch, potato flour, polyvinyl alcohol, in particular in a concentration of 0.02 to 5.0, preferably 0.20 to 20% by weight. -%, based on the total weight of the mixture.
  • Lubricants such as aluminum and calcium stearate, talc and silicones, in a concentration of 0.1 to 5, preferably
  • REPLACEMENT BLA ⁇ (RULE 26) 0.1 to 3 wt .-%, based on the total weight of the mixture.
  • Plasticizers such as animal or vegetable fats, especially in hydrogenated form and those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of C 2 -, C
  • Dyes such as azo dyes, organic or inorganic pigments or dyes of natural origin, inorganic pigments in a concentration of 0.001 to 10, preferably 0.5 to 3% by weight, based on the total weight of the mixture, being preferred ;
  • Stabilizers such as antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers, stabilizers against microbial attack.
  • wetting agents, preservatives, disintegrants, adsorbents, mold release agents and blowing agents can also be added (cf. e.g. H. Sucker et al. Pharmaceutical Technology, Thieme-Verlag, Stuttgart 1978).
  • auxiliaries are, for example, pentaerythritol and pentaerythritol tetraacetate, polymers such as e.g. Polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers
  • REPLACEMENT BLA ⁇ (RULE 26) of vinyl pyrrolidone, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others such as those from JL Ford, Pharm. Acta Helv. 6 . 1: 69-88 (1986).
  • compositions in the sense of the invention are understood to mean all substances with a pharmaceutical effect and as few side effects as possible, provided that they do not decompose under the processing conditions.
  • the amount of active ingredient per dose unit and the concentration can vary within wide limits depending on the effectiveness and rate of release. The only condition is that they are sufficient to achieve the desired effect.
  • the active ingredient concentration can thus be in the range from 0.1 to 95, preferably from 20 to 80, in particular 30 to 70% by weight. Combinations of active substances can also be used.
  • Active substances in the sense of the invention are also vitamins and minerals, as well as plant treatment agents and insecticides.
  • the vitamins include the vitamins of the A group and the B group, which in addition to Bi, B 2 , B 6 and B j 2 as well as nicotinic acid and nicotinamide also include compounds with vitamin B properties, such as adenine, choline, pantothenic acid , Biotin, adenylic acid, folic acid, orotic acid, pangamic acid, carnitine, p-aminobenzoic acid, myo-inositol and lipoic acid as well as vitamin C, vitamins of the D group, E group, F group, H group, I- and J group, K group and P group. Active substances in the sense of the invention also include peptide therapeutics.
  • the method according to the invention is for example for processing
  • SPARE BLADE (RULE 26) suitable for the following active ingredients:
  • REPLACEMENT BLA ⁇ (RULE 26) clopramid, metoprolol, miconazole, midazolam, minocycline, minoxidil, misoprostol, morphine, multivitamin mixtures or combinations and mineral salts, N-methylephedrine, naftidrofuryl, naproxen, neomycin, nicardipine, nicergoline, nicotinamide, nicotinamide, nicotinamide, nicotinamide nifedipine, nimodipine, nitrazepam, Ni trendipin, nicillin nizatidine, norethisterone, norfloxacin, norgestrel, nortriptyline, nystatin, ofloxacin, omeprazole, ondansetron, pancreatin, panthenol, pantothenic acid, paracetamol, penicillin G, penicillin V, phenobarbital, P
  • Preferred KirKstoffe are ibuprofen (as racemate, enantiomer or enriched enantiomer), ketoprofen, flurbiprofen, acetylsalicylic acid, verapamil, paracetamol, nifedipine or captopril.
  • solid solutions can be formed.
  • the term “solid solutions” is familiar to the person skilled in the art, for example from the literature cited at the beginning.
  • the active ingredient is molecularly dispersed in the polymer.
  • the mixture obtained is solvent-free, i.e. it contains neither water nor an organic solvent.
  • REPLACEMENT BLA ⁇ (RULE 26)
  • the mixture is shaped by customary methods. Common methods include:
  • Coextrusion of at least two strands and deformation into one of the above-mentioned methods to form an at least two-layer, open or closed dosage form One of the layers contains an active ingredient, the other layer can be free of active ingredient or optionally contain another active ingredient.
  • the layers generally contain different polymeric binders. You will e.g. produced with a slot die or a concentric, circular ring-shaped coextrusion die. Further information can be found in an application which was submitted by the applicant on the same day as the present application.
  • Solid pharmaceutical forms which can be produced by the process according to the invention are, in particular, coated tablets, pellets, granules and tablets.
  • the forms obtained, in particular the granules can then also be ground to powder and used in this form, for example in hard gelatin capsules.
  • Granules can also be compressed into tablets in the usual way.
  • the pharmaceutical forms obtained can also be provided in a conventional manner with film coatings, which the
  • REPLACEMENT BLA ⁇ (RULE 26) Check active ingredient release or cover the taste.
  • Suitable materials for such coatings are polyacrylates, such as the Eudragit types, cellulose esters, such as the hydroxypropyl methyl cellulose phthalates, and cellulose ethers, such as ethyl cellulose, hydroxypropyl methyl cellulose or hydroxypropyl cellulose.
  • the method according to the invention thus also allows the production of pharmaceutical forms by conventional methods, such as pressing granules into tablets, but without the disadvantages of these conventional methods.

Abstract

L'invention concerne un procédé de préparation de formes galéniques solides par mélange et fusion d'au moins un liant polymère pharmaceutiquement acceptable, d'au moins un principe actif pharmaceutique et éventuellement d'additifs pharmaceutiques classiques, en l'absence de solvant, pour obtenir un mélange plastique et par moulage pour donner au mélange la forme galénique voulue. Les différentes étapes du procédé (mélange, fusion, moulage) sont effectuées en continu, séparément les unes des autres. Ce procédé permet d'obtenir des formes galéniques de haute qualité, selon un mode de production aisé qui n'altère pas les produits.
PCT/EP1996/004586 1995-10-23 1996-10-22 Procede de preparation de formes galeniques solides WO1997015292A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19539362.7 1995-10-23
DE1995139362 DE19539362A1 (de) 1995-10-23 1995-10-23 Verfahren zur Herstellung von festen Arzneiformen

Publications (1)

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WO1997015292A1 true WO1997015292A1 (fr) 1997-05-01

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PCT/EP1996/004586 WO1997015292A1 (fr) 1995-10-23 1996-10-22 Procede de preparation de formes galeniques solides

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DE (1) DE19539362A1 (fr)
WO (1) WO1997015292A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2795326B1 (fr) † 1999-06-28 2001-08-31 Adir Composition pharmaceutique solide thermoformable a liberation controlee

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4413350A1 (de) * 1994-04-18 1995-10-19 Basf Ag Retard-Matrixpellets und Verfahren zu ihrer Herstellung

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4413350A1 (de) * 1994-04-18 1995-10-19 Basf Ag Retard-Matrixpellets und Verfahren zu ihrer Herstellung

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DE19539362A1 (de) 1997-04-24

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