WO2002019991A1 - Forme pharmaceutique multiparticualire et son procede de preparation - Google Patents

Forme pharmaceutique multiparticualire et son procede de preparation Download PDF

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Publication number
WO2002019991A1
WO2002019991A1 PCT/EP2001/009042 EP0109042W WO0219991A1 WO 2002019991 A1 WO2002019991 A1 WO 2002019991A1 EP 0109042 W EP0109042 W EP 0109042W WO 0219991 A1 WO0219991 A1 WO 0219991A1
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WO
WIPO (PCT)
Prior art keywords
weight
coating
active ingredient
meth
particle
Prior art date
Application number
PCT/EP2001/009042
Other languages
German (de)
English (en)
Inventor
Thomas Beckert
Laetitia Briand
Günter Bergmann
Manfred Assmus
Denis Wouessidijewe
Original Assignee
Röhm GmbH & Co. KG
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 Röhm GmbH & Co. KG filed Critical Röhm GmbH & Co. KG
Priority to AU2001282071A priority Critical patent/AU2001282071A1/en
Publication of WO2002019991A1 publication Critical patent/WO2002019991A1/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50

Definitions

  • the invention relates to a multiparticulate pharmaceutical form and a process for its preparation, as well as the advantageous use of the plasticizer propylene glycol.
  • EP 088 951 describes a method for coating pharmaceutical forms by means of a coating agent dispersed in water.
  • gastric juice-resistant (meth) acrylate copolymers are used as coating agents, which only release a coated active ingredient in the alkaline intestinal area. The release characteristic is strongly dependent on the monomer composition of the respective copolymers.
  • EP 088 951 also describes (eth) acrylate copolymers of 50% by weight methacrylic acid and 50% by weight ethyl acrylate (EUDRAGIT® L100-55).
  • Multiparticulate pharmaceutical forms which are obtained by pressing a binder containing an active ingredient and pellets coated with enteric-resistant (meth) acrylate copolymers are known from Becken et al. (1996), "Compression of enteric-coated pellets to disintegrating tablets", International Journal of Pharmaceutics 143, pp. 13-23.
  • the pressing process proves to be problematic in the production of multiparticulate pharmaceutical forms, since high mechanical loads act on the coated pellets here. This is all the more problematic if (meth) acrylate copolymers with comparatively low film flexibility are to be used for the enteric-coated pellet coatings.
  • Pellet coatings made from (meth) acrylate copolymers made from 50% by weight of methacrylic acid and 50% by weight of ethyl acrylate (EUDRAGIT® L100-55) with elongation at break values of less than 5% despite the addition of 10% by weight of triethyl citrate, according to Beckert et al. when pressing to form cracks.
  • Such cracks in the pellets can cause the active ingredient from the compressed dosage units to be undesirable are already released in the stomach so that the actual gastric juice resistance of this copolymer can no longer come into play.
  • Kollicoat® Who can resist?” (1999) describes enteric copolymers for use as binders and coating agents for pharmaceutical forms.
  • the products named Kollicoat® MAE 30 DP and Kollicoat® MAE 100 P are described as copolymers of 50% by weight methacrylic acid and 50% by weight ethyl acrylate.
  • 10 to 30% coatings are recommended.
  • plasticizers in concentrations of 10 to 25% by weight are recommended.
  • 1, 2 propylene glycol, triethyl citrate, polyethylene glycols and triacetin are mentioned.
  • 15% by weight propylene glycol, based on the dry copolymer substance is listed. Information on the processing of coated particles into multiparticulate dosage forms is not included.
  • WO 96/01624 describes the production of multiparticulate pharmaceutical forms for proton pump inhibitor active substances.
  • a (meth) acrylate copolymer of 50% by weight methacrylic acid and 50% by weight ethyl acrylate (EUDRAGIT® L100-55) in combination with plasticizers, in particular triethyl citrate in concentrations of 30% by weight is used.
  • % used.
  • propylene glycol the application quantities of the coatings are at least 40% by weight. In Example 15, a small application amount is selected at approximately 20% by weight, but this only seems possible because the proportion of pellets in the dosage form is also selected to be low at approximately 23% by weight, so that the mechanical stress on the pellets during Pressing remains low.
  • Multiparticulate drug forms generally offer the advantage of high dosing reliability, since manufacturing-related fluctuations in the coating thickness are averaged by the large number of individual particles and thus statistically balanced. Furthermore, efforts are always made to keep the proportion of substances that are added to a pharmaceutical active ingredient in the formulation of medicaments to a minimum and in particular not to place unnecessary strain on the human organism.
  • the advantage of high dosing security of multiparticulate pharmaceutical forms requires that the coating layers of the particles contained in the production are not damaged by pressing. To be able to guarantee this with some certainty, one must either apply comparatively thick coating layers or else reduce the particle content of the dosage forms. Thick coating layers increase the mechanical strength of the particles. In contrast, lower particle proportions reduce the probability that particles collide during the pressing process and thus mechanically damage one another, since these are then better isolated from one another by the higher proportion of binder.
  • (Meth) acrylate copolymers of 50% by weight methacrylic acid and 50% by weight ethyl acrylate are well suited for many applications as coating and binding agents for enteric drug forms. Because of the high brittleness of this type of copolymer, according to WO 96/01624, when applied in multiparticulate pharmaceutical forms, either application amounts of at least 40% by weight or a combination of a small application amount and at the same time a reduced particle content are selected. Ultimately, both variants represent a compromise, since they run counter to the general requirement to reduce the proportion of excipients in pharmaceutical forms.
  • Multiparticulate pharmaceutical form produced from particles pressed with conventional binders, which contain a pharmaceutical active ingredient and are coated with an enteric coating made from a (meth) acrylate copolymer of 40 to 60% by weight methacrylic acid and 60 to 40% by weight ethyl acrylate .
  • the coating contains more than 15 to 50% by weight of the plasticizer propylene glycol based on the (meth) acrylate copolymer and the particle fraction of the pharmaceutical form is 35-90% by weight when the coating is applied in an amount of more than 15 and up is 38% by weight based on the particle weight.
  • the invention relates to a multiparticulate pharmaceutical form, produced from particles pressed with conventional binders, which contain a pharmaceutical active ingredient and with an enteric coating made from a (meth) acrylate copolymer of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight.
  • % Are coated with ethyl acrylate, the coating containing more than 15 and up to 50, in particular 16 to 28, particularly preferably 17 to 23% by weight of the plasticizer propylene glycol, based on the (meth) acrylate copolymer, and the particle fraction of the pharmaceutical form 35 90, particularly preferably 40 to 70% by weight for an applied amount of the coating of more than 15 and up to 38, particularly preferably from 18 to 36, in particular from 20 to 30% by weight, based on the particle weight.
  • the multiparticulate pharmaceutical form can contain the active substance inside the coated particles in the form of active substance crystals or in the form of pellets coated with the pharmaceutical active substance.
  • the multiparticulate dosage form can e.g. Active substances from the active substance classes proton pump inhibitors, H2-antagonists, anti-rheumatic, pain reliever proteins, antigens, antibodies and / or hormones.
  • the invention also relates to the corresponding process for the production of multiparticulate pharmaceutical forms by pressing pharmaceutically customary binders together with particles containing active ingredient, which are coated with an enteric-resistant (meth) acrylate copolymer from 40 to 60% by weight.
  • Methacrylic acid and 60 to 40% by weight of ethyl acrylate are characterized in that the coating comprises more than 15 and up to 50, in particular 16 to 28, particularly preferably 17 to 23% by weight of the plasticizer propylene glycol, based on the (meth) acrylate Copolymer adds, the particle proportion of the pharmaceutical form sets 35-90% by weight, particularly preferably 40 to 70% by weight, with an application amount of the coating of more than 15 and up to 38, particularly preferably from 18 to 36, in particular from 20 up to 30 wt .-% based on the particle weight.
  • plasticizer propylene glycol in an amount of more than 15 to 50, in particular 16 to 28, particularly preferably 17 to 23 wt .-% in combination with a (meth) acrylate copolymer, from 40 to 60, wt .-% methacrylic acid and 60 to 40% by weight of ethyl acrylate for the production of an active substance-containing, multiparticulate pharmaceutical form with a particle fraction of 35-90, particularly preferably 40 to 70% by weight, with an application amount of the coating of more than 15 and up to 38, particularly preferably of 18 up to 36, in particular from 20 to 30% by weight, based on the particle weight, is an essential element of the invention.
  • (Meth) acrylate copolymers of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight and 60 to 40% by weight of ethyl acrylate are commercially available e.g. B. available as 30 dispersions and well known.
  • the production and processing by spray application is e.g. B. described in EP 088 951.
  • Active substance-containing pellets can be produced by applying active substance by means of a layering process.
  • the active ingredient is used together with other auxiliaries (release agents, if necessary plasticizers) homogenized and dissolved or suspended in a binder (eg EUDRAGIT L 30 D-55).
  • the liquid can be applied to placebo pellets or other suitable carrier materials by means of a fluidized bed process, the solvent or suspending agent being evaporated (literature: International Journal of Pharmaceutics 143, pp. 13-23).
  • a drying step can follow.
  • the active ingredient can be applied in several layers.
  • active ingredients e.g. B. acetylsalicylic acid
  • active ingredient crystals are commercially available in the form of active ingredient crystals and can be used in this form instead of active ingredient-containing pellets.
  • Film coatings on active substance-containing pellets are usually applied in fluidized bed devices. Recipe examples are mentioned in this application. Film formers are usually mixed with plasticizer and release agent by a suitable method. The film formers can be present as a solution or suspension. The auxiliaries for film formation can also be dissolved or suspended. Organic or aqueous solvents or dispersants can be used. Stabilizers can also be used to stabilize the dispersion (example: Tween 80 or other suitable emulsifiers or stabilizers).
  • release agents are glycerol monostearate or other suitable fatty acid derivatives, silica derivatives or talc.
  • plasticizers are propylene glycol, phthalates, polyethylene glycols, sebacates or citrates, as well as other substances mentioned in the literature.
  • a separating layer can be applied between the active substance-containing and gastric juice-resistant layer, which serves to separate the active substance and coating material for the purpose of preventing interactions.
  • This layer can consist of inert film formers (for example HPMC, HPC or (meth) acrylic acid copolymers) or for example talc or other suitable pharmaceutical Substances exist. Combinations of film formers and talc or similar substances can also be used.
  • Mixtures for the production of tablets from coated particles are prepared by mixing the pellets with suitable binders for tabletting, if necessary adding disintegrating substances and if necessary adding lubricants. Mixing can take place in suitable machines. Mixers that damage the coated particles are unsuitable, e.g. B. ploughshare mixer. In order to achieve suitable short disintegration times, a special sequence when adding the auxiliary substances to the coated particles may be necessary. By premixing the coated particle with the lubricant or mold release agent magnesium stearate, its surface can be made hydrophobic and thus sticking can be avoided.
  • Mixtures suitable for tableting usually contain 3 to 15% by weight of a disintegrant, e.g. B. Kollidon CL and z. B. 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate.
  • a disintegrant e.g. B. Kollidon CL and z. B. 0.1 to 1 wt .-% of a lubricant and mold release agent such as magnesium stearate.
  • the proportion of binder is determined by the required proportion of coated particles.
  • Typical binders are e.g. B. Cellactose ® , microcrystalline cellulose, calcium phosphates, Ludipress ® , lactose or other suitable sugars, calcium sulfates or starch derivatives. Substances with a low bulk density are preferred.
  • Typical disintegrants are cross-linked starch or cellulose derivatives, as well as cross-linked polyvinylpyrrolidone. Cellulose derivatives are also suitable. By choosing a suitable binder, the use of disintegrants can be omitted.
  • Typical lubricants and mold release agents are magnesium stearates or other suitable salts of fatty acids or in the literature for this purpose Listed substances (e.g. lauric acid, calcium stearate, talc, etc.).
  • suitable machines e.g. tablet press with external lubrication
  • suitable formulations the use of a lubricant and mold release agent in the mixture can be omitted.
  • a flow improver may be added to the mixture (e.g. highly disperse silica derivatives, talc, etc.).
  • Tableting can be carried out on conventional tablet presses, eccentric or rotary tablet presses, with pressing forces in the range from 5 to 40 kN, preferably 10-20 kN.
  • the tablet presses can be equipped with systems for external lubrication. If necessary, special systems for filling the die are used, which avoid the die filling by means of stirring blades.
  • the amount applied means the proportion of the sprayed dry substance of the functional film-forming polymer in% by weight. It is over 15 to 38, particularly preferably 18 to 36, in particular 20 to 30% by weight, based on the particle weight.
  • the particle fraction is the weight fraction of the coated particles of the total weight of the pharmaceutical form, the compressed table, in% by weight.
  • the particle proportion of the pharmaceutical form is 35-90, particularly preferably 40 to 70% by weight. Particle proportions of 70 to 90% by weight can be achieved in particular if so-called soft cores are used instead of sugar pellets.
  • the multiparticulate pharmaceutical forms obtained, tablets should not be more than 10% (pharmacopoeia request), preferably not more than 7%, particularly preferably not more than 2% in the gastric release test according to USP for 2 hours in artificial gastric juice (pH 1, 0 or pH 1, 2) Release 6% of the active ingredient contained.
  • the state of the particles can e.g. B. can also be examined by scanning electron microscopy.
  • the release test according to USP (according to USP XXIV, method B, modified test for "enteric coated products") is known to the person skilled in the art.
  • the main test conditions are in particular: Paddle method, 100 revolutions per minute, 37 ° C; pH 1, 0 or pH 1, 2 with 0.1 N HCl, pH 6.8 in 0.2 M phosphate buffer and adjustment with 2 N NaOH or with HCl.
  • a particle content of 50% by weight was set equally.
  • the EUDRAGIT® L 30 D-55 used for the spray application is a 30% aqueous dispersion of a copolymer of 50% by weight methacrylic acid and 50% by weight ethyl acrylate.
  • the weight data refer to the dry matter.
  • Placebo pellets e.g. sugar pellets, Werner
  • Placebo pellets 4500.0 g
  • EUDRAGIT® L 30 D-55 dry substance 250.0 g
  • EUDRAGIT® L 30 D-55 dry substance 250.0 g
  • Example 3 comparative example with application amount of coating too low (12.5% by weight)
  • EUDRAGIT® L 30 D-55 dry substance 125.0 g
  • EUDRAGIT® L 30 D-55 dry substance 250.0 g
  • EUDRAGIT® L 30 D-55 dry substance 250.0 g
  • Acetylsalicylic acid crystals 1000.0 g
  • EUDRAGIT® L 30 D-55 dry substance 150.0 g
  • Acetylsalicylic acid crystals 1000.0 g
  • EUDRAGIT® L 30 D-55 dry substance 200.0 g
  • Acetylsalicylic acid crystals 1000.0 g
  • EUDRAGIT® L 30 D-55 dry substance 250.0 g
  • Acetylsalicylic acid crystals 1000.0 g
  • Pharmacopoeia request Less than 10% drug release after 2 hours in 0.1 N HCI.
  • ASS acetylsalicylic acid
  • GMS glycerol monostearate
  • WM / parting agent based on dry polymer substance

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une forme pharmaceutique multiparticulaire préparée à partir de particules comprimées avec des agents liants conventionnels, lesdites particules contenant une substance active pharmaceutique et étant recouvertes d'un revêtement résistant au suc gastrique, constitué d'un copolymère (méth)acrylate comprenant de 40 à 60 % en poids d'acide métacrylique et de 60 à 40 % en poids d'éthylacrylate. L'invention se caractérise en ce que, dans le revêtement, plus de 15 % en poids et jusqu'à 50 % en poids du copolymère (méth)acrylate correspondent au plastifiant propylène glycol, et en ce que la proportion en particules de la forme pharmaceutique vaut 35-90 % en poids pour une quantité d'application du revêtement de plus de 15 et jusqu'à 38 % en poids rapportés au poids de la particule. Cette invention concerne également le procédé de préparation correspondant et l'utilisation associée de propylène glycol en tant que plastifiant.
PCT/EP2001/009042 2000-09-07 2001-08-04 Forme pharmaceutique multiparticualire et son procede de preparation WO2002019991A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001282071A AU2001282071A1 (en) 2000-09-07 2001-08-04 Multiparticulate pharmaceutical dosage form and a method for producing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10044299.4 2000-09-07
DE2000144299 DE10044299A1 (de) 2000-09-07 2000-09-07 Multipartikuläre Arzneiform und Verfahren zu ihrer Herstellung

Publications (1)

Publication Number Publication Date
WO2002019991A1 true WO2002019991A1 (fr) 2002-03-14

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DE (1) DE10044299A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2845289A1 (fr) * 2002-10-04 2004-04-09 Ethypharm Sa Spheroides, procede de preparation et compositions pharmaceutiques.
WO2010034425A1 (fr) * 2008-09-24 2010-04-01 Add Technologies Ltd. Comprimés multiparticulaires et leur procédé de fabrication
US9023391B2 (en) 1999-06-22 2015-05-05 Dexcel Ltd. Stable benzimidazole formulation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004046102B4 (de) * 2004-09-23 2009-09-03 Mars Inc. Indikatorgranulat

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004907A1 (fr) * 1994-08-17 1996-02-22 Smithkline Beecham Plc Composition pharmaceutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996004907A1 (fr) * 1994-08-17 1996-02-22 Smithkline Beecham Plc Composition pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DECHESNE, J. P.: "A new enteric tablet of acetylsalicylic acid. I. Technological aspects", INT. J. PHARM. (1987), 37(3), 203-9, XP001022383 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9023391B2 (en) 1999-06-22 2015-05-05 Dexcel Ltd. Stable benzimidazole formulation
FR2845289A1 (fr) * 2002-10-04 2004-04-09 Ethypharm Sa Spheroides, procede de preparation et compositions pharmaceutiques.
WO2004030657A1 (fr) * 2002-10-04 2004-04-15 Ethypharm Spheroides procede de preparation et compositions pharmaceutiques
US9446002B2 (en) 2002-10-04 2016-09-20 Ethypharm Spheroids and multiparticulate tablets comprising them
WO2010034425A1 (fr) * 2008-09-24 2010-04-01 Add Technologies Ltd. Comprimés multiparticulaires et leur procédé de fabrication

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Publication number Publication date
AU2001282071A1 (en) 2002-03-22
DE10044299A1 (de) 2002-03-21

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