EP1962845A2 - Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe - Google Patents

Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe

Info

Publication number
EP1962845A2
EP1962845A2 EP06829659A EP06829659A EP1962845A2 EP 1962845 A2 EP1962845 A2 EP 1962845A2 EP 06829659 A EP06829659 A EP 06829659A EP 06829659 A EP06829659 A EP 06829659A EP 1962845 A2 EP1962845 A2 EP 1962845A2
Authority
EP
European Patent Office
Prior art keywords
tablets
pharmaceutical composition
donepezil hydrochloride
polymorphic form
composition according
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Withdrawn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
EP06829659A
Other languages
German (de)
English (en)
Inventor
Julia Schulze Nahrup
Frank Muskulus
Peter Kraass
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.)
Ratiopharm GmbH
Original Assignee
Ratiopharm GmbH
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
Priority claimed from DE102005060377A external-priority patent/DE102005060377A1/de
Application filed by Ratiopharm GmbH filed Critical Ratiopharm GmbH
Priority to EP06829659A priority Critical patent/EP1962845A2/fr
Publication of EP1962845A2 publication Critical patent/EP1962845A2/fr
Withdrawn legal-status Critical Current

Links

Definitions

  • composition containing donepezil hydrochloride, tablet therefrom and process for its preparation
  • the present invention relates to a pharmaceutical composition containing crystalline Donepezil hydrochloride of the polymorphic form I and which is suitable for direct compression into tablets, as well as tablets obtained from this composition by direct sizing.
  • the present invention relates to tablets in which the donepezil hydrochloride is stable even on storage and does not convert to other polymorphic forms or to the amorphous state.
  • Donepezil hydrochloride (+/-) - 2,3-dihydro-5,6-dimethoxy-2 - [[1- (phenylmethyl) -4-piperidinyl] -methyl] -1H-inden-1-one hydrochloride, shows activity as reversible Acetylcholinesterasehemmer and is used in the treatment of various senile dementia, especially in the prevention and alleviation of Alzheimer's disease use.
  • the structure of Donepezil hydrochloride is as follows:
  • EP 0 296 560 discloses a series of cyclic amine compounds which also include, among others, donepezil hydrochloride for the treatment of age-related dementia.
  • Donepezil hydrochloride has a number of properties that make its formulation into a drug more difficult.
  • a particular difficulty arises in Donepezilhydrochlorid still in that of the compound in addition to an amorphous five crystalline polymorphic forms I to V are known, which are disclosed in the publications WO 97/046526 and WO 97/046527.
  • These references also disclose methods of preparation and characterization of the individual polymorphic forms.
  • the polymorphic forms should be stable upon heating and storage, in particular more stable than the amorphous form.
  • it is also known that in particular the physical stability of the polymorphic form I is problematic, which can pass into the polymorphic form III when heated or stored.
  • EP 1 027 887 discloses pharmaceutical compositions containing amorphous donepezil hydrochloride and a method for stabilizing it by adding a crystallization inhibitor.
  • EP 1 378 238 and WO 2004/071486 disclose pharmaceutical compositions containing Donepezil hydrochloride in amorphous state as a therapeutically active agent for the treatment of dementia or Alzheimer's disease.
  • Medicines containing the active ingredient donepezil may be compressed, e.g. as tablets.
  • the classical process for the production of tablets is a granulation process in which a granulate is produced using a granulating liquid, which is then pressed into tablets.
  • a newer method of making tablets is direct compression.
  • the individual components of the composition to be pressed are mixed without prior granulation and then pressed directly.
  • the Direct compression is an elegant and simple process, but it is difficult to obtain commercially useful tablets which, in addition to sufficient strength, also ensure sufficiently rapid disintegration.
  • Many active ingredients can not be processed by direct compression because they are not compressible without granulation step.
  • WO 2006/045512 published after the priority date of this application, also describes the problem that donepezil hydrochloride must retain its polymorphic form within a drug formulation.
  • WO 2006/045512 solves this problem by formulating either the polymorph I or the polymorph IV to a solid drug with a very specific water content in the range of 3 to 10%.
  • the solid drugs may contain either the polyporphic formone Donepezil hydrochloride I or the polyphenone formone Donepezil hydrochloride IV, and may be prepared in any manner, including an example of direct compression and several examples of a wet granulation process. In the one example in which direct compression is used, it is not specified which polymorphic form of the donepezil is used, and the water content of the prepared tablet was 6 wt%.
  • the object of the invention is to provide a drug containing Donepezilhydrochlorid in which the Donepezil hydrochloride is also in prolonged storage in stable, unchanged form.
  • the polymorphic form of Donepezilhydrochlorids should not change.
  • donepezil hydrochloride of the polymorphic form I is not only extremely well accessible to direct compression with tablets, in particular tablets, especially if it is used in low concentrations, but also in a directly compressed tablet such as a tablet is stable during storage and does not convert to another polymorphic form (especially Form III) or the amorphous form.
  • the Donepezil hydrochloride Form I transforms to a considerable extent in the amorphous form when it is processed by conventional granulation.
  • the invention thus relates to a pharmaceutical composition which is suitable for the preparation of tablets, in particular tablets, by direct compression, containing Donepezil hydrochloride of the polymorphic form I and compressed tablets, in particular tablets, obtained by direct compression of such a composition, a method in which the pharmaceutical Compressive composition, in particular tablets, and the use of Donepezil hydrochloride of the polymorphic form I for the preparation of directly compressed tablets, in particular tablets.
  • compressed is understood to mean in general compressed medicaments, in particular microtablets or tablets.
  • the tablets are preferably tablets.
  • the invention for tablets will be explained in more detail, but the statements apply accordingly to other compresses, such as micro-tablets.
  • the pharmaceutical compositions according to the invention and the compressed tablets according to the invention and in particular the tablets according to the invention are therefore not limited in their water content.
  • the pharmaceutical compositions according to the invention, as well as the compressed tablets according to the invention and especially the tablets according to the invention can have a water content of less than 6%, preferably 5.9% or less, more preferably less than 3%, in particular 2.9%. or less, and more preferably 2.5% or less.
  • compositions compressed tablets and in particular tablets which have a water content of more than 10% by weight, in particular from 10.5% by weight to 20% by weight or from 10.5% by weight to 15% by weight or from 12% by weight to 18% by weight.
  • the water content is determined according to Karl Fischer, the test according to Ph. Eur. 2.5.12, eg on a Karl Fischer titrator Metrohm 7012 KF Titrino or an Aqua 40 from ECH he follows.
  • the above percentages as well as all other percentages in this application are by weight unless otherwise stated or apparent to those skilled in the art.
  • Donepezil hydrochloride of polymorphic form I is known in the art and reference is made in this regard to references WO 97/046526 and WO 97/046527.
  • the polymorphic forms of donepezil hydrochloride can be distinguished principally by X-ray diffractometry, especially when the drug is compressed into a tablet being tested, discrimination is preferably by 13 C solid-state NMR or, more preferably, Raman spectroscopy.
  • the polymorphic forms I and III differ, for example, in the Raman spectra in the frequency range from 1600 to 1800 cm -1 and the distinction in this frequency range is generally still possible if conventional tablet excipients are present of the donepezil hydrochloride are shown in FIGS.
  • donepezil of the polymorphic form I or the polymorphic form III More specifically, it is meant a donepezil with a Raman spectrum as shown in Figures 1 and 2.
  • Table 1 The significant peaks of the Raman spectra are summarized in Table 1 ( ⁇ 2 cm -1 , only characteristic bands were observed which differed in location from the Raman spectra) can distinguish different layers of the other form, congruent bands sin d not listed):
  • Table 2 shows the automatically generated peak list of the upper diffractogram of Figure 4 with an accuracy of ⁇ 0.02 ° 2 theta.
  • ADLAS DPY 321 (Diode Laser Pumped Nd: YAG laser)
  • the Donepezil hydrochloride of polymorphic form I may preferably be present in the composition of the invention in an amount up to 20% by weight, especially up to 10% by weight, more preferably from 1-20% by weight, more preferably 2-10% by weight. -%, preferably 2-5 wt .-%, preferably 2.5-5 wt .-%, wt .-% be contained.
  • the pharmaceutical composition contains conventional additives which are suitable for the production of tablets by direct compression.
  • additives are usually selected from fillers, binders, disintegrants, lubricants and flow regulators and optionally (but not preferred) other additives.
  • the pharmaceutical composition according to the invention generally contains more than 70% by weight of fillers, in particular 70-95% by weight or 70-90% by weight, preferably 75-95% by weight, or 75-90% by weight. %, more preferably 80-90% by weight or 85 to 95% by weight.
  • the content of disintegrant is usually 1-25 wt .-%, preferably 1-20 wt .-%, in particular 2-15 wt .-%. Suitable ranges for the content of disintegrant are also e.g. 2-5 wt .-% or 7-12 wt .-%.
  • the content of lubricant is usually 0.1-2 wt .-%, preferably 0.2-1, 5 wt .-%, in particular 0.2-1 wt .-%.
  • composition comprises a flow regulator, this is generally present in an amount of 0.1-5 wt.%, Preferably 0.5-5 wt.%, Preferably 1-4 wt. 3 wt .-% present.
  • Fillers may be one or more compounds which provide some of the material to achieve the required and desired total tablet mass. It is possible, inter alia, to use microcrystalline cellulose in various particle sizes, in particular with an average particle size in the range from 20 ⁇ m to 200 ⁇ m, in particular in the range from 50 ⁇ m to 150 ⁇ m, such as e.g. about 100 microns, such as the well-known Avicel products such as Avicel PH-102.
  • Other suitable fillers are e.g. Lactose, cellactose (a mixture of cellulose and lactose), calcium phosphate, dextrose, mannitol, maltodextrin, isomalt optionally also sorbitol or sucrose.
  • fillers care must be taken to use grades suitable for direct compression of tablets. In the case of commercial products, this is stated by the manufacturer or can be checked by simple tests.
  • the most preferred filler is microcrystalline cellulose.
  • Commercial products include Avicel, Vivapur and Emcocel.
  • fillers are water-rich fillers such as calcium sulfate dihydrate, which is commercially available, for example, under the name Compactrol, calcium chloride dihydrate or magnesium trisilicate • xH 2 O.
  • fillers in particular mannitol, sorbitol, isomalt, maltitol and lactitol anhydrate are also preferred as fillers; very particularly preferred according to the invention is the filler mannitol.
  • the quality Pearlitol 400 DC is well suited.
  • the most preferred filler according to the invention is a mixture of microcrystalline cellulose, in particular microcrystalline cellulose and mannitol. This mixture is especially preferred when pharmaceutical compositions according to the invention, compresses and in particular tablets are to be made available, which should have a low water content, in particular one Water content of less than 3%, in particular of 2.9% or less, and more preferably of 2.5% or less.
  • the ratio of microcrystalline cellulose and mannitol is not particularly limited, but more mannitol is preferably used than microcrystalline cellulose, and the ratio is preferably in the range of 1: 1, 1 to 1: 5, more preferably in the range of 1: 2 to 1 : 4th All statements on "ratios" in the context of this application refer to weight ratios, unless otherwise stated or obvious to a person skilled in the art.
  • water-rich formulations ie for compressed tablets such as tablets and microtablets having a water content of more than 10% by weight, in particular from 10.5% by weight to 20% by weight or from 10.5% by weight to 15% Wt .-% or from 12 wt .-% to 18 wt .-%, are particularly preferably used water-rich fillers such as calcium sulfate dihydrate, which is commercially available, for example under the name Compactrol, calcium chloride dihydrate or magnesium trisilicate • xH 2 O.
  • these water-rich fillers in admixture with other fillers, in particular with microcrystalline cellulose such as the Avicel products, for example with Avicel PH 102 used.
  • the ratio of other filler such as microcrystalline cellulose (especially Avicel PH 102) and hydrous filler (such as calcium sulfate dihydrate, calcium chloride dihydrate, or magnesium trisilicate xH 2 O) is not particularly limited, but more water-rich filler is preferably used than other filler such as microcrystalline cellulose , and the ratio is preferably in the range of 1: 1, 1 to 1: 5, more preferably it is about 1: 2 or even in the range of 1: 1, 5 to 1: 3.
  • Disintegrators suitable for direct compression are known in the art. Explosives are often referred to by the English term “Disintegrants”. Disintegrators preferred according to the invention are, for example, crospovidone (Kollidon CL) and starch or pregelatinized starch, in particular the commercial product "Starch 1500". Further suitable starches are commercially available, for example, under the names Lycatab PGS, Prejel and Sepistab ST 200. Furthermore, the known so-called “Super Disintegrants” can be used as croscarmellose sodium (eg Ac-Di-SoI, etc.) and sodium carboxymethyl starch (eg Explotab, Primojel, etc.). Particular preference is given to starches such as Starch 1500.
  • the lubricant composition may contain one or more compounds which assist in the preparation and processing of the tablet.
  • Useful lubricants include stearic acid and its derivatives, such as calcium stearate, and especially sodium stearyl fumarate (commercially available, for example, under the name Pruv) and magnesium stearate, glycerol mono-, di-, and especially tristearate, hydrogenated vegetable oil (eg, Lubritab, Dynasan, Sterotex) or a polyethylene glycol (eg Lutrol, Carbowax).
  • the pharmaceutical composition of the invention may comprise one or more flow regulators.
  • Suitable flow control agents are magnesium trisilicate, talc, and especially silica (e.g., Aerosil, especially Aerosil 200).
  • compositions according to the invention may contain other customary pharmaceutically acceptable additives and auxiliaries, but they preferably contain no further excipients apart from those specified above (filler, disintegrants, lubricants and optionally flow regulators).
  • fillers such as microcrystalline cellulose
  • binders can also serve as binders. Also fillers with binder function therefore count in the context of this application to the fillers.
  • the tablet according to the invention is obtained by direct compression of the Donepezil hydrochloride of the polymorphic form I containing pharmaceutical composition.
  • the tablet may be film-coated with one or more coating agents.
  • coating agents are hypromellose (hydroxypropylmethylcellulose), polyvinyl alcohol, sodium carboxymethylcellulose and various combinations thereof.
  • Methacrylic acid polymers with hypromellose and in particular Eudragite are preferred.
  • the coating of the tablets is carried out in the usual way.
  • further customary constituents of tablet coatings such as polyethylene glycol (PEG), talc, or titanium dioxide and optionally lactose may be present in the coating.
  • PEG polyethylene glycol
  • talc polyethylene glycol
  • titanium dioxide optionally lactose
  • the process for preparing the tablets by direct compression of the Donepezil hydrochloride of the polymorphic form I containing pharmaceutical composition can be carried out, for example, as follows:
  • the filler e.g. microcrystalline cellulose
  • the mixing can be done in a conventional mixer, e.g. in a container mixer. Mixing time and speed are chosen depending on the mixer used to ensure adequate mixing. Typical mixing times in a container mixer are in the range of 5 to 30 minutes at 10 to 40 rpm.
  • the tablet weight is not particularly limited, tablets of 100 to 600 mg, e.g. 100 to 200 mg or even 200 to 300 mg or 300 to 400 mg.
  • composition according to embodiment 2 characterized in that it contains 2-10 wt .-% Donepezil hydrochloride of the polymorphic form I.
  • composition according to embodiment 2 or 3 characterized in that it contains 70% by weight or more of a filler, 5-25% by weight of a disintegrant, 0.1-2% by weight of a lubricant and optionally 0, 1-5 wt .-%, preferably 0.5-5 wt .-%, of a flow control agent.
  • composition according to one of embodiments 1 to 4 characterized in that it is the tablet to a tablet.
  • a process for the preparation of Donepezil hydrochloride-containing comprints characterized in that a pharmaceutical composition according to any one of embodiments 1 to 5 is compressed directly.
  • Donepezil hydrochloride of the polymorphic form I for the preparation of compressed by direct compression.
  • composition according to one of embodiments 1 to 8 characterized in that the composition has a water content of more than 10 wt .-%, in particular from 10.5 wt .-% to 20 wt .-%, in particular of 10.5 Wt .-% to 15 wt .-% or from 12 wt .-% to 18 wt .-%, having.
  • composition according to embodiment 13 characterized in that it contains as filler a mixture of microcrystalline cellulose and mannitol.
  • composition according to embodiment 14 characterized in that it contains as filler a mixture of microcrystalline cellulose and one or more fillers selected from calcium sulfate dihydrate, calcium chloride dihydrate and magnesium trisilicate • xH 2 O.
  • FIG. 1 shows the Raman spectrum of the polymorphic form I of FIG. 1
  • FIG. 2 shows the Raman spectrum of the polymorphic form III of FIG
  • FIG. 3 shows a section of the Raman spectra of the polymorphic forms
  • FIG. 4 shows the X-ray diffractograms of two different samples of the
  • FIG. 5 shows the following Raman spectra from top to bottom: tablet according to the invention according to Example 1 after eight months of closed storage under stress conditions at 30 ° C. and 65% relative humidity (a), drug-free and otherwise identical tablet (b), Donepezil hydrochloride of polymorphic form III (c) and donepezil hydrochloride of polymorphic form I (d)
  • FIG. 6 shows the relevant section of the Raman spectrum of FIG. 5, enlarged in the range 1600 to 1800 cm -1 .
  • FIG. 7 shows from top to bottom the following Raman spectra, wherein in each case only the enlarged range of 1600 to 1800 cm -1 is represented: Tablet according to Comparative Example 1 immediately after preparation (a) drug-free and otherwise to (a) identical tablet ( b) Donepezil hydrochloride of polymorphic form III (c) and donepezil hydrochloride of polymorphic form I (d).
  • Donepezil hydrochloride of polymorphic form I was prepared according to the disclosure of WO 97/46527.
  • the X-ray diffraction pattern is shown in FIG. 4 (upper diagram) and the essential peak positions are shown in Table 2.
  • the ingredients of the following table were used to prepare a pharmaceutical composition suitable for direct compression.
  • the preparation of the pharmaceutical composition was as follows: 1) sieving the Donepezil hydrochloride of polymorphic Form I over a 0.355 mm sieve,
  • composition thus obtained was compressed in the usual way using a Korscheko tablet press directly to 9 mm biconvex tablets with 280 mg tablet weight.
  • the tablets thus prepared were stored closed at 30 ° C. and 65% relative humidity (stress conditions) for 8 months and then examined by Raman spectroscopy.
  • the spectra are given in FIGS. 5 and 6. It has been shown that even after 8 months of storage under stress conditions, the donepezil hydrochloride is still present in the polymorphic form I, while substantial amounts of the amorphous form or the polymorphic form III could not be detected.
  • the spectrum corresponded to the Raman spectrum recorded immediately after production (not shown).
  • Granules were prepared in the usual way and then pressed into tablets.
  • Tablets were prepared as follows: 1. Avicel PH102 was presented and then the Donepezil hydrochloride and Starch 1500 were added and mixed in a container mixer for 9 minutes at 23 rpm.
  • the mixture was deagglomerated over a 0.600 mm sieve and re-mixed for 22 minutes at 23 rpm.
  • Magnesium stearate was also deagglomerated over a 0.600 mm sieve and added to the mixture. It was mixed again for 4 minutes at 23 rpm.
  • the mixture was excellently compressed into tablets, especially for the 5 mg tablets 3.35 ⁇ 0.20 mm in height and 120 N ⁇ 10 N in hardness.
  • the tablet showed a fast and excellent release profile.
  • the donepezil hydrochloride of the polymorphic form I in the tablet is physically stable.
  • the mixture was excellently compressed into tablets, in particular for the 5 mg tablets with a height of 3.50 ⁇ 0.20 mm and a hardness of 70 N ⁇ 10 N.
  • the tablet showed a fast and excellent release profile.
  • the donepezil hydrochloride of the polymorphic form I in the tablet is physically stable.
  • Example 1 further tablets were produced with a weight of about 280 mg.
  • the exact compositions are summarized in the following table.
  • the preparation of the tablets was done by sieving the donepezil hydrochloride (polymorph I) through a 0.355 mm sieve.
  • the Avicel was submitted, then the Donepezil hydrochloride was added, then the remaining substances without the magnesium stearate, and mixed for 5 minutes in the Turbula mixer (1 L vessel).
  • the mixture was sieved through a 0.8 mm sieve, returned to the mixing vessel, and mixed for an additional 15 minutes.
  • the magnesium stearate was over 0.355 mm sieved and mixed for another 3 minutes.
  • the mixture was pressed on a KorschEKO press into 9 mm biconvex tablets.
  • the tablets showed excellent breaking strength, friability and an excellent disintegration time of generally less than one minute.
  • the water content of the resulting tablets was determined according to Karl Fischer at 13O 0 C, and it was 2.1 ⁇ 0.1%
  • the tablets showed excellent breaking strength, friability and an excellent disintegration time of generally less than 1 minute.
  • Drug release (900 ml 0.1 mol HCl, pH 1, 0.37 ° C, 50 rpm, USP paddle device) was above 80% after 5 minutes.
  • the tablets showed excellent breaking strength, friability and an excellent disintegration time of generally less than 1 minute. After three weeks of storage at 5O 0 C and 75% relative humidity in a sealed glass vessel itself showed no change in the polymorphic form. Furthermore, only donepezil hydrochloride of the polymorphic form I was present.
  • Example 1 tablets were prepared with a composition as shown in the following table.
  • Donepezil hydrochloride was of polymorphic form I:
  • the water content was determined according to Karl Fischer at 130 0 C.
  • the tablets showed excellent breaking strength, friability and an excellent disintegration time of generally less than 1 minute.
  • the chemical stability was very good.

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Abstract

L'invention concerne une composition pharmaceutique adaptée à la production de comprimés par compression directe et contenant de l'hydrochlorure de donépézil de forme polymorphe I. La forme polymorphe I d'hydrochlorure de donépézil contenue dans le comprimé obtenu par compression directe est stable, même en cas de stockage prolongé.
EP06829659A 2005-12-16 2006-12-15 Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe Withdrawn EP1962845A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06829659A EP1962845A2 (fr) 2005-12-16 2006-12-15 Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE102005060377A DE102005060377A1 (de) 2005-12-16 2005-12-16 Pharmazeutische Zusammensetzung enthaltend Donepezilhydrochlorid, Tablette hieraus und Verfahren zu deren Herstellung
PCT/EP2006/007990 WO2007073782A1 (fr) 2005-12-16 2006-08-11 Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe
PCT/EP2006/012122 WO2007073888A2 (fr) 2005-12-16 2006-12-15 Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe
EP06829659A EP1962845A2 (fr) 2005-12-16 2006-12-15 Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe

Publications (1)

Publication Number Publication Date
EP1962845A2 true EP1962845A2 (fr) 2008-09-03

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ID=39665999

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06829659A Withdrawn EP1962845A2 (fr) 2005-12-16 2006-12-15 Composition pharmaceutique contenant de l'hydrochlorure de donepezil, comprime a base de cette composition et procede de production associe

Country Status (1)

Country Link
EP (1) EP1962845A2 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
G ZHANG: "Phase transformation considerations during process development and manufacture of solid oral dosage forms", ADVANCED DRUG DELIVERY REVIEWS, vol. 56, no. 3, 23 February 2004 (2004-02-23), pages 371 - 390, XP055003708, ISSN: 0169-409X, DOI: 10.1016/j.addr.2003.10.009 *

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