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WO1999044588A2 - Procede de production de corps moules spheriques solides contenant des principes actifs pharmaceutiques dans une matrice constituee d'un liant - Google Patents

Procede de production de corps moules spheriques solides contenant des principes actifs pharmaceutiques dans une matrice constituee d'un liant Download PDF

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Publication number
WO1999044588A2
WO1999044588A2 PCT/EP1999/001271 EP9901271W WO9944588A2 WO 1999044588 A2 WO1999044588 A2 WO 1999044588A2 EP 9901271 W EP9901271 W EP 9901271W WO 9944588 A2 WO9944588 A2 WO 9944588A2
Authority
WO
WIPO (PCT)
Prior art keywords
melt
matrix
pharmaceutical active
weight
auxiliary
Prior art date
Application number
PCT/EP1999/001271
Other languages
German (de)
English (en)
Other versions
WO1999044588A3 (fr
Inventor
Andreas Kleinke
Thomas Kessler
Jörg Rosenberg
Harald Krull
Gunther Berndl
Werner Maier
Jörg Breitenbach
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
Priority to CA002322629A priority Critical patent/CA2322629A1/fr
Priority to EP99911718A priority patent/EP1059914A2/fr
Publication of WO1999044588A2 publication Critical patent/WO1999044588A2/fr
Publication of WO1999044588A3 publication Critical patent/WO1999044588A3/fr

Links

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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

Definitions

  • the present invention relates to a process for the production of solid, spherical shaped articles which contain at least one active pharmaceutical ingredient homogeneously dispersed in a binder matrix by mixing the ingredients to form a melt and subsequent shaping.
  • EP-A 240 904, EP-A 240 906 and EP-A 358105 that pharmaceutical active ingredients can be processed together with polymeric binders by melt extrusion to give various types of solid pharmaceutical forms.
  • the shaping is done by calendering or hot cutting with the help of rotating knives.
  • WO 93/25074 describes the manufacture of crop protection agents by extrusion and shaping using such a rotoformer.
  • the formulations available thereafter are cloudy, mostly soft powder granules.
  • the object of the present invention was to provide a process for the production of solid spherical dosage forms which also enables the processing of low-viscosity melts and which leads to dosage forms with good product properties.
  • a process for the production of solid, spherical shaped bodies which contains at least one active pharmaceutical ingredient homogeneously dispersed in an auxiliary matrix.
  • ten by mixing the ingredients into a melt with subsequent shaping, which is characterized in that at least one active pharmaceutical ingredient with at least one thermoplastically processable matrix auxiliary is processed to a homogeneous melt with a viscosity of less than 5000 mPas, and the melt with the aid a rotating perforated roller forms into drops, which are then solidified by cooling.
  • the process according to the invention is suitable for all active ingredients which do not decompose under the processing conditions.
  • the process according to the invention is suitable, for example, for formulating the following substances or their physiologically acceptable salts, it also being possible to produce the salts in situ in the extruder:
  • Acyclovir aminoglycosides, amphotericin B, azole antifungals, clotrimazole, itraconazole, sepraconazole, clindamycin,
  • Cephalosporins Cephalosporins, chloramphenicol, erythromycin, 5-fluorouracil, etoposide, fluctytosin, ganciclovir, griseofulvin, gyrase inhibitors, isoniacid, lincosamides, mebendazole, mefloquine, metanidazole, nitroimidazole, bionobiocimiminin, rbobi polimiminquin, novobiocimiminquin, platinum - navir, streptomycin, sulfonamides, tetracyclines, trimethoprim, vancomycin, zidovudine;
  • Anti-rheumatic drugs chloroquine, indomethacin, gold compounds, phenylbutazone, oxyphenylbutazone, penicillinamine; Hypnotics
  • Androgens antiandrogens, progestogens, glucocorticoids, estrogens, cortisol, dexamethasone, prednisolone, testosterone, adutinin, oxytocin, somatropin, insulin;
  • Vitamins C, B, A, D, folic acid
  • Solid solutions are familiar to the person skilled in the art (see Chiou and Riegelman, J. Pharm. Sei. JSJ 1281-1302 (1971)). In solid solutions of active pharmaceutical ingredients in polymers or other matrices, the active ingredient is molecularly dispersed in the matrix.
  • Preferred active ingredients are non-steroidal anti-inflammatory drugs, opioids and vitamins. Ibuprofen and tramadol hydrochloride are particularly preferred.
  • the amount of active ingredients in the overall preparation can vary within wide limits depending on the effectiveness, release rate and solubility.
  • the active substance content can be 0.1 to 90, preferably 5 to 70,% by weight, based on the entire preparation. The only condition is that the melts can be processed by the method according to the invention. 25
  • the active ingredient is homogeneously dispersed, preferably as a so-called “solid solution”, i.e. molecularly disperse, in an auxiliary matrix.
  • Suitable structural components for the auxiliary matrix can be polymeric or also low-molecular-weight binders, provided that they can be processed without thermoplastic decomposition and, together with the active ingredient and possibly other additives, result in solid forms which do not tend to cold flow.
  • Suitable polymeric matrix components are, for example:
  • N-vinylpyrrolidone such as polyvinylpyrrolidone (PVP), copolymers of N-vinylpyrrolidone
  • the K values are in the range from 10 to 100, preferably 12 to 70, in particular 12 to 35.
  • the K are -Values particularly preferred in the range of
  • Copolymers of vinyl acetate and crotonic acid, partially saponified polyvinyl acetate or polyvinyl alcohol are preferred.
  • Cellulose derivatives such as cellulose ethers, especially methyl cellulose, ethyl cellulose, hydroxyalkyl celluloses, especially hydroxypropyl cellulose, hydroxyalkyl alkyl celluloses, especially hydroxypropyl methyl cellulose and hydroxypropyl ethyl cellulose.
  • Cellulose esters such as cellulose phthalates, in particular cellulose sulfate phthalate and hydroxypropyl methyl cellulose phthalate, furthermore also mannans, in particular galactomannans.
  • polymeric binders are polymers based on acrylates or methacrylates, for example the polyacrylates and polymethacrylates known as Eurogitite types, copolymers of acrylic acid and methyl methacrylate or polyhydroxyalkyl acrylates or methacrylates.
  • Polylactides polyglycolides, polylactide-polyglycolides, polydioxanes, polyanhydrides, polystyrene sulfonates, polyacetates, polycaprolactones, poly (ortho) esters, polyamines, polyhydroxyalkanoates or alginates are also suitable.
  • Suitable matrix components can also be natural or semisynthetic binders such as starches, degraded starches, for example maltodextrin, and also gelatin, which, depending on requirements, can have a basic or acidic character, chitin or chitosan. Gelatins are preferred.
  • Low molecular weight binders are also suitable according to the invention as matrix auxiliaries, in particular sugar alcohols such as, for example, sorbitol, mannitol, xylitol or, particularly preferably, isomalt. Also preferred is trehalose, which has a cryoprotective effect.
  • Fats or waxes can also be used as binders -eiaag-e-.
  • binders -eiaag-e-.
  • polyethylene glycols or polypropylene glycols with molecular weights in the range from 300 to 100,000 are suitable as binders.
  • binders are the homo- and copolymers of N-vinylpyrrolidone, sugar alcohols and gelatin.
  • Binders are used, in particular also mixtures of thermoplastically processable polymers with sugar alcohols.
  • the binder must soften or melt in the total mixture of all components in the range from 40 to 180 ° C., preferably 60 to 130 ° C.
  • a solvent can also be added to the melt, which in addition to its dissolving properties can also have a softening effect in the melt.
  • Such solvents are above all monohydric or polyhydric alcohols or water or mixtures of alcohols and water. Preferred softening
  • Solvent is water. It may be advisable to add the plasticizing solvent in amounts of 0.5 to 30% by weight. By adding the solvent, the viscosity of the melt can be adjusted in a targeted manner and the tear behavior at the nozzle or nozzle plate can be influenced. When solidifying in the
  • melts are processed whose viscosity at 120 ° C. is less than 5000 mPas, preferably 1000 to 4000 mPas (measured with a rotary viscometer with shear rates in the range from 10
  • the molds produced by the process according to the invention can furthermore contain customary auxiliaries in the amounts customary for the applications mentioned.
  • auxiliaries are e.g. Fillers, lubricants, mold release agents, plasticizers, blowing agents, stabilizers, dyes, extenders, flow agents and mixtures thereof. In principle, however, these pharmaceutical auxiliaries must not
  • fillers are inorganic fillers such as the 35 oxides of magnesium, aluminum, silicon, titanium etc. in a concentration of 0.02 to 50, preferably from 0.20 to 20% by weight, based on the total weight of the pharmaceutical form.
  • lubricants are stearates of aluminum, calcium 40 and magnesium as well as talc and silicones in a concentration of 0.1 to 5, preferably 0.1 to 3% by weight, based on the total weight of the mold.
  • sodium carboxymethyl starch 45 or crospovidone can be used as decay accelerators.
  • Wetting agents such as sodium lauryl sulfate or sodium docusate can also be used.
  • plasticizers include low molecular weight poly (alkylene oxides), such as poly (ethylene glycols), poly (propylene glycols), poly (ethylene propylene glycols); organic low molecular weight plasticizers such as glycerol, pentaerythritol, glycerol monoacetate, diacetate or triacetate, propylene glycol, sodium diethyl sulfosuccinate etc., added in concentrations of 0.5 to 15, preferably 0.5 to 5% by weight, based on the Total weight of the dosage form.
  • dyes are known azo dyes, organic and inorganic pigments or colorants of natural origin.
  • Inorganic pigments are preferred in concentrations of 0.001 to 10, preferably 0.5 to 3% by weight, based on the total weight of the pharmaceutical form.
  • additives which improve the flow properties of the mixture or act as mold release agents, such as: animal or vegetable fats, preferably in their hydrogenated form, especially those which are solid at room temperature. These fats preferably have a melting point of 50 ° C or higher. Triglycerides of C 12 ", C 14 -, C 6 - and C ⁇ 8 -fatty acids are preferred. The same function can also be performed by waxes such as carnauba wax. These additives can be added alone without the addition of fillers or plasticizers.
  • These fats and Waxes can advantageously be admixed alone or together with mono- and / or diglycerides or phosphatides, especially lecithin
  • the mono- and diglycerides preferably derive from the Fet types described above, ie C i2 -, C 14 -, C ⁇ 6 - and .
  • C ⁇ S fatty acids the total amount of fats, waxes, mono- and diglycerides and / or lecithins is 0.1 to 30, preferably 0.1 to 50 wt -.% based on the total weight of the dosage form.
  • flow regulators e.g. Aerosils or talc are used.
  • Stabilizers can also be added, e.g. Antioxidants, light stabilizers, hydroperoxide destroyers, radical scavengers and stabilizers against microbial attack.
  • auxiliaries are, for example, pentaerythritol and pentaerythritol tetraacetate, polymers such as, for example, polyethylene or polypropylene oxides and their block copolymers (poloxamers), phosphatides such as lecithin, homo- and copolymers of Vinyl pyrrolidones, surfactants such as polyoxyethylene 40 stearate and citric and succinic acid, bile acids, sterols and others, as indicated, for example, by JL Ford, Pharm. Acta Helv. £ 1, 69-88 (1986).
  • the biologically active substance can be mixed with the auxiliaries in a manner known per se.
  • the components can first be mixed and then melted and homogenized. Particularly in the case of active substances which are thermolabile or sensitive to shear forces, it may be advisable to first melt and premix the auxiliary substances and then to mix in the active substance.
  • the melting and mixing takes place in a device which is customary for this purpose.
  • Devices such as those used in plastics technology are generally suitable as mixing and melting devices. Suitable devices are described, for example, in "Mixing in the manufacture and processing of plastics", H. Pahl, VDI-Verlag, 1986. Particularly suitable devices 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, solid mixers and preferably mixing-kneading reactors, double-bowl kneaders (trough mixers), stamp kneaders (internal mixers) or rotor / stator systems.
  • Mixing and melting is particularly preferably carried out in a single or multi-screw extruder, in particular a twin-screw extruder, with kneading chambers also being connected upstream of this.
  • Mixing and melting can also take place in apparatuses in which the energy is supplied in the form of microwaves or ultrasound.
  • the mixing and melting device can be fed continuously or discontinuously in the usual manner.
  • Powdery components can be fed in freely, for example using a differential weigh feeder.
  • Plastic masses can be fed directly from an extruder, for example, or fed in via a gear pump.
  • Liquid components can be metered in using suitable pump units.
  • low-viscosity pastes or gels with a high dispersant content can also be supplied, water being preferably used as the dispersant.
  • the mixtures are preferably processed into melts at temperatures from 20 to 280 ° C., particularly preferably from 25 to 180 ° C.
  • the still thermoplastic melt is divided into drops using rotating perforated rolls, which are then solidified by cooling.
  • the plastic mixture is first extruded into a continuous strand using a suitable extrusion device. Any solvents and residual moisture that may be present can be drawn off during the extrusion by means of a vacuum pump.
  • the shape of the extrusion tool depends on the desired shape.
  • the melt is preferably extruded through round-hole nozzles, the plastic mixture being shaped as a strand with a circular cross section and discharged into the Rotoformer® or into an apparatus suitable for the production of pastilles.
  • the plastic melt is passed through rotating perforated rolls and broken down into drops in this way.
  • the device suitable for pastillation consists of a rotating, heatable roller with openings, which is surrounded by a screen jacket.
  • the roller and screen casing preferably move in opposite directions to one another.
  • the temperature of the extruder zones was (in ° C.): zone 1/80; Zone 2/110; Zone 3/150; Zone 4/150; Zone 6/150; Zone 7/150.
  • the speed of the screws was 70 rpm.
  • the throughput was 20 kg / h with a residence time of 1-2 minutes.
  • the melt emerging at the extruder head through a nozzle was fed into the roller of the Rotofor ers® (type 50.211, Sandvik Process Systems GmbH, Stuttgart) via a gear pump.
  • the Rotoformer consists of a rotating, heated roller that has a screen jacket, from the perforation of which the plastic extrudate was discharged onto a cooled conveyor belt.
  • the distance between that Sieve jacket and the cooling belt was 3 mm.
  • the cooling belt had a length of 4 m with a belt width of 400 mm.
  • the temperature of the roller was kept at 150 to 170 ° C, the belt temperature was set to 20 ° C by means of water cooling and the belt speed was 30 m / min.
  • Temperature of the extruder zones in ° C 20, 80, 120, 80, 80, 80 (nozzle)
  • Hydroxypropylmethylcellulose m.w. with a viscosity of 4000 mPa-s 14% by weight (Methocel® K4M, Colorcon Dow))

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

Abstract

L'invention concerne un procédé de production de corps moulés sphériques solides contenant au moins un principe actif pharmaceutique homogène en dispersion dans une matrice constituée d'un produit auxiliaire. Selon ce procédé, on mélange les composants pour obtenir une masse en fusion puis on façonne cette masse. Ce procédé est caractérisé en ce que l'on transforme au moins un principe actif pharmaceutique comprenant au moins un produit auxiliaire-matrice thermoplastiquement transformable en une masse en fusion homogène d'une viscosité inférieure à 5000 mPas et en ce que l'on transforme cette masse en fusion en gouttes à l'aide d'un cylindre perceur rotatif. Ces gouttes sont ensuite solidifiées par refroidissement.
PCT/EP1999/001271 1998-03-05 1999-02-26 Procede de production de corps moules spheriques solides contenant des principes actifs pharmaceutiques dans une matrice constituee d'un liant WO1999044588A2 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA002322629A CA2322629A1 (fr) 1998-03-05 1999-02-26 Procede de production de corps moules spheriques solides contenant des principes actifs pharmaceutiques dans une matrice constituee d'un liant
EP99911718A EP1059914A2 (fr) 1998-03-05 1999-02-26 Procede de production de corps moules spheriques solides contenant des principes actifs pharmaceutiques dans une matrice constituee d'un liant

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE1998109242 DE19809242A1 (de) 1998-03-05 1998-03-05 Verfahren zur Herstellung von festen, sphärischen Formkörpern, enthaltend pharmazeutische Wirkstoffe in einer Bindemittelmatrix
DE19809242.3 1998-03-05

Publications (2)

Publication Number Publication Date
WO1999044588A2 true WO1999044588A2 (fr) 1999-09-10
WO1999044588A3 WO1999044588A3 (fr) 1999-10-28

Family

ID=7859688

Family Applications (1)

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PCT/EP1999/001271 WO1999044588A2 (fr) 1998-03-05 1999-02-26 Procede de production de corps moules spheriques solides contenant des principes actifs pharmaceutiques dans une matrice constituee d'un liant

Country Status (4)

Country Link
EP (1) EP1059914A2 (fr)
CA (1) CA2322629A1 (fr)
DE (1) DE19809242A1 (fr)
WO (1) WO1999044588A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070254028A1 (en) * 2004-08-12 2007-11-01 Reckitt Benckiser Healthcare (Uk) Limited Granules Comprising a Nsaid and a Sugar Alcohol Made by Melt Extrusion
US20100179182A1 (en) * 2003-02-03 2010-07-15 Rama Ali Abu Shmeis Pharmaceutical formulation

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19943501A1 (de) * 1999-09-10 2001-03-15 Basf Ag Unterwassergranulation wirkstoffhaltiger Schmelzen
US20010036959A1 (en) * 2000-04-03 2001-11-01 Gabel Rolf Dieter Carvedilol-hydrophilic solutions
GB0113841D0 (en) * 2001-06-07 2001-08-01 Boots Co Plc Therapeutic agents
DE102007061408A1 (de) 2007-12-11 2009-06-18 Sandvik Materials Technology Deutschland Gmbh Verfahren und Tropfenformer zum Herstellen von Pastillen sowie Verfahren zum Herstellen eines schwefelhaltigen Düngers

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3139920A1 (de) * 1981-10-08 1983-04-28 Nittner, Erich, Dr., 8280 Kreuzlingen "mittel in granulatform auf basis von polysaccharid-gummen, verfahren zu seiner herstellung und verwendung"
DE3813756C1 (fr) * 1988-04-23 1989-03-02 Santrade Ltd., Luzern, Ch
TW230742B (fr) * 1992-06-16 1994-09-21 Du Pont
DE4225730C2 (de) * 1992-08-04 2003-04-30 Merz Pharma Gmbh & Co Kgaa Verfahren zur Herstellung von festen Arzneiformkörpern mit protrahierter 2-Stufen-Freisetzung
DE19536394A1 (de) * 1995-09-29 1997-04-03 Basf Ag Feste Arzneiformen, erhältlich durch Extrusion einer Isomalt enthaltenden Polymer-Wirkstoff-Schmelze
DE19753300A1 (de) * 1997-12-01 1999-06-02 Basf Ag Verfahren zur Herstellung von festen Dosierungsformen

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100179182A1 (en) * 2003-02-03 2010-07-15 Rama Ali Abu Shmeis Pharmaceutical formulation
US20070254028A1 (en) * 2004-08-12 2007-11-01 Reckitt Benckiser Healthcare (Uk) Limited Granules Comprising a Nsaid and a Sugar Alcohol Made by Melt Extrusion

Also Published As

Publication number Publication date
CA2322629A1 (fr) 1999-09-10
EP1059914A2 (fr) 2000-12-20
WO1999044588A3 (fr) 1999-10-28
DE19809242A1 (de) 1999-09-09

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