EP2804593A1 - Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung, enthaltend den wirkstoff rasagilin - Google Patents
Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung, enthaltend den wirkstoff rasagilinInfo
- Publication number
- EP2804593A1 EP2804593A1 EP13702727.2A EP13702727A EP2804593A1 EP 2804593 A1 EP2804593 A1 EP 2804593A1 EP 13702727 A EP13702727 A EP 13702727A EP 2804593 A1 EP2804593 A1 EP 2804593A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- rasagiline
- acid
- salt
- mixture
- pharmaceutically acceptable
- 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- Withdrawn
Links
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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- the present invention relates to a method for
- Rasagiline is the International Nonproprietary Name (INN) for (R) -N-2-propynyl-1-indanamine.
- Rasagiline has the following structural formula:
- Rasagiline is a drug from the group of
- MAO-B Monoamine oxidase B
- CONFIRMATION COPY is based on increasing the dopamine concentration at the central dopaminergic receptors by reducing the degradation of dopamine by inhibiting MAO-B.
- Rasagiline is in the form of tablets under the
- the substance rasagiline is originally disclosed in EP 0 436 492.
- EP 0 812 190 relates to the mesylate salt, the esylate salt and the
- Phosphate salt a benzoate salt, an oxalate salt and a
- Rasagilinhydrogenphosphatsalz of rasagiline and EP 1 987 816 an amorphous adsorbate of a rasagiline salt with at least one water-soluble organic excipient such as povidone.
- EP 0 858 328 relates to a pharmaceutical formulation comprising rasagiline.
- Rasagiline is given in relatively low doses of about 1 mg.
- Solid oral dosage forms such as tablets containing 1 mg rasagiline and of sufficient size for safe handling and more even
- the active ingredient is usually dissolved in a solvent and then first on one
- Object of the present invention is therefore to provide a method of the type mentioned, by means of which solid pharmaceutical compositions containing the
- Rasagiline active ingredient are available in which the rasagiline has an increased stability and the composition can be stored for longer accordingly.
- pharmaceutically acceptable acid is adjusted to a value of less than 3.5, preferably to a value of less than 3.5 to 0.
- compositions of the invention characterized rasagiline by increased stability.
- a pharmaceutically acceptable rasagiline salt is used.
- any Rasagilinsalz can be used that can be formed by reaction of the Rasagilin base with acid or base. According to a preferred embodiment of the
- the rasagiline salt is an acid addition salt of rasagiline.
- the rasagiline is characterized in the resulting composition by a relatively high stability.
- Acid addition salt is different from the corresponding anion of the acid. This will be another
- the anionic component of the salt with the corresponding anion of the acid is considered to be the same if only the degree of protonation of the anionic units is different is.
- the anionic unit HP0 4 2 " to the anionic unit H 2 P0 4 " is considered to be the same.
- the method according to the invention provides that the
- Rasagiline salt is selected from the group consisting of rasagiline tartrate and rasagiline mesylate, the salt particularly preferably rasagiline tartrate, and hereby
- an aqueous solvent is preferably understood as meaning a liquid or a liquid mixture which comprises at least 80% by weight of water, more preferably at least 90% by weight and more preferably at least 95% by weight Water. If the aqueous solvent contains another liquid in addition to water, then this is
- Liquid such as an alcohol or acetone.
- the acid is selected from the group consisting of phosphoric acid (H 3 PO 4 ), benzenesulfonic acid and maleic acid, with phosphoric acid (H 3 PO 4 ) is particularly preferred. It has been found that the stabilizing effect on rasagiline is particularly high when the pH is adjusted by means of one of the acids mentioned.
- the pH of the acid is selected from the group consisting of phosphoric acid (H 3 PO 4 ), benzenesulfonic acid and maleic acid, with phosphoric acid (H 3 PO 4 ) is particularly preferred. It has been found that the stabilizing effect on rasagiline is particularly high when the pH is adjusted by means of one of the acids mentioned.
- Rasagiline salt solution is adjusted to a value of less than 3.5 by means of a pharmaceutically acceptable acid
- the pH is preferably measured using a glass-electrode pH meter from the company Mettler Toledo Model InLab * Routine Pro, after prior calibration.
- Calibration uses standard solutions with known pH. Particularly preferred according to the invention are three standard solutions with pH values of 4.01, 7.0 and 9.21
- buffer solutions can be purchased ready-to-use in the laboratory trade.
- the pH of the rasagiline salt solution is adjusted to a value of 3 to 0 by means of the acid, particularly preferably to a value of 2 to 1.
- the adjustment of the pH to a Value in the aforementioned areas causes a particularly strong
- Rasagilinsalz solution further comprises a binder, which is contained in the solution of rasagiline salt. It is particularly preferred that the binder a
- Polyvinylpyrrolidone is.
- the method according to the invention provides that the
- Method further comprises
- Rasagiline salt solution from the vehicle.
- a solid support is used.
- Solid carriers for pharmaceutical applications are known in the art. These are solid substances to which an active substance can be attached, so that the active substance is symbolically "carried" by the substance
- preferred supports are selected from the groups of
- Silicas magnesium oxides, talc, titanium dioxides, clays, zinc oxides, calcium hydrogen phosphates, sugar alcohols,
- Carrier is powdery and that the carrier with the
- Rasagilinsalz solution is added by the Rasagilinsalz- solution and the carrier are combined to obtain a mixture and the mixture is wet granulated by means of the Rasagilinsalz- solution to obtain a granule.
- Carrier comprises or consists of microcrystalline cellulose and / or Na-starch glycolate.
- the method further comprises
- the present invention further relates to a first solid pharmaceutical composition
- Composition is characterized by a relatively high stability of the active ingredient rasagiline.
- the first composition according to the invention can be obtained by the method according to the invention or by simply mixing the rasagiline salt with the acid.
- the composition may be prepared by conventional methods known to those skilled in the art.
- the first composition according to the invention comprises a pharmaceutically acceptable acid having a pKa of less than 3.
- the pKa is based on a temperature of 25 ° C.
- the pKs values may also be below
- the pKs value is to be understood as the pKSi value.
- the rasagiline salt is an acid addition salt.
- the anionic component of the acid addition salt is different from a corresponding anion of the acid.
- rasagiline salt is selected from the group consisting of rasagiline tartrate and rasagiline mesylate, wherein the
- Rasagiline salt is particularly preferred rasagiline tartrate.
- the acid is selected from the group consisting of
- Phosphoric acid H 3 P0 4
- benzenesulfonic acid and maleic acid, wherein the acid is particularly preferably phosphoric acid (H 3 P0 4 ).
- composition according to the invention it is provided that the Rasagilinsalz and the acid to a pharmaceutical
- the rasagiline salt based on the free Rasagilin base and the acid in a molar ratio of 1: 0.5 to 1: 5 in the
- Composition present.
- the rasagiline salt based on the free Rasagilin base and the acid is in a molar ratio of 1: 1.0 to 1: 3 in the composition.
- the present invention further relates to an aqueous
- Rasagilinsalz dissolved wherein the mixture has a pH of less than 3.0.
- the mixture is a useful intermediate for carrying out the process according to the invention.
- the pH of the mixture is adjusted by means of an acid.
- Rasagiline salt is an acid addition salt.
- anionic component of the acid addition salt is different from a corresponding anion of the acid.
- Rasagiline salt is selected from the group consisting of rasagiline tartrate and rasagiline mesylate.
- Rasagiline salt is rasagiline tartrate.
- the acid is selected from the group consisting of phosphoric acid
- the acid is phosphoric acid (H 3 P0 4 ).
- the pH of the mixture is adjusted to a value of 3 to 0 by means of the acid.
- the pH of the mixture is adjusted to a value of 2 to 1 by means of the acid.
- Mixture further comprises a binder which is contained dissolved in the mixture.
- Binder is a polyvinylpyrrolidone.
- the present invention further relates to a second solid pharmaceutical composition obtainable after
- the second composition according to the invention is characterized by a relatively large
- the second solid pharmaceutical composition is preferably characterized in that a suspension thereof obtained by suspending 190 mg of the composition in 10 ml of dist. Water and then 10 minutes
- Ultrasound treatment has a pH of less than 5
- the tablets had the in the
- one tablet was distilled in 10 ml. Suspended water and the resulting suspension for 10 min by means of
- composition of a second embodiment containing 1.44 mg rasagiline (the amount is based on the tartrate salt indicated).
- the tablets had the in the
- microcrystalline cellulose 5.26 g highly dispersed
- one tablet was distilled in 10 ml. Suspended water and the resulting suspension for 10 min by means of
- the tablets had the in the
- one tablet was distilled in 10 ml. Suspended water and the resulting suspension for 10 min by means of
- the preparation of the tablets was carried out as follows
- one tablet was distilled in 10 ml. Suspended water and the resulting suspension treated for 10 minutes by means of ultrasound. The resulting suspension had a pH of 7.1.
- the tablets were finely pulverized and the
- the tablets had the in the
- microcrystalline 62 41 carrier / filler cellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Psychology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102012000786A DE102012000786A1 (de) | 2012-01-18 | 2012-01-18 | Verfahren zur Herstellung einer festen pharmazeutischen Zusammensetzung, enthaltend den Wirkstoff Rasagilin |
PCT/DE2013/000024 WO2013107441A1 (de) | 2012-01-18 | 2013-01-16 | Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung, enthaltend den wirkstoff rasagilin |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2804593A1 true EP2804593A1 (de) | 2014-11-26 |
Family
ID=47665777
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP13702727.2A Withdrawn EP2804593A1 (de) | 2012-01-18 | 2013-01-16 | Verfahren zur herstellung einer festen pharmazeutischen zusammensetzung, enthaltend den wirkstoff rasagilin |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP2804593A1 (de) |
DE (1) | DE102012000786A1 (de) |
RU (1) | RU2014128296A (de) |
WO (1) | WO2013107441A1 (de) |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL92952A (en) | 1990-01-03 | 1994-06-24 | Teva Pharma | R-enantiomers of n-propargyl-1-aminoindan compounds, their preparation and pharmaceutical compositions containing them |
SE9301112D0 (sv) * | 1993-04-02 | 1993-04-02 | Orion-Yhtymae Oy | A new composition |
IL111240A (en) | 1993-10-18 | 2001-10-31 | Teva Pharma | Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them |
IL115357A (en) | 1995-09-20 | 2000-01-31 | Teva Pharma | Stable compositions containing N-propargyl-1-aminoindan and polyhydric alcohols |
AU771490B2 (en) * | 1995-09-20 | 2004-03-25 | Teva Pharmaceutical Industries Ltd. | Stable compositions containing N-propargyl-1-aminoidan |
DE19743323C2 (de) * | 1997-09-30 | 2000-05-25 | Iip Inst Fuer Ind Pharmazie Fo | Feste Arzneimittelzusammensetzung auf der Grundlage von Selegilin |
EP1892233A1 (de) * | 2006-08-18 | 2008-02-27 | Ratiopharm GmbH | Neue Salze des Wirkstoffs Rasagilin |
EP1987816A1 (de) | 2007-04-30 | 2008-11-05 | Ratiopharm GmbH | Adsorbate eines Rasagilinsalzes mit einem wasserlöslichen Hilfsstoff |
DE102008064061A1 (de) * | 2008-12-19 | 2010-06-24 | Ratiopharm Gmbh | Feste Zusammensetzung mit dem Wirkstoff Rasagilin |
WO2010111264A2 (en) * | 2009-03-24 | 2010-09-30 | Dr. Reddy's Laboratories Ltd. | Rasagiline formulations |
WO2011010324A1 (en) * | 2009-07-23 | 2011-01-27 | Alkem Laboratories Ltd. | Oral pharmaceutical composition of rasagiline and process for preparing thereof |
WO2011095985A2 (en) | 2010-02-02 | 2011-08-11 | Glenmark Generics Limited | Rasagiline salts and processes for the preparation thereof |
WO2011121607A2 (en) | 2010-03-29 | 2011-10-06 | Cadila Healthcare Limited | Rasagiline and its pharmaceutically acceptable salts |
-
2012
- 2012-01-18 DE DE102012000786A patent/DE102012000786A1/de not_active Ceased
-
2013
- 2013-01-16 WO PCT/DE2013/000024 patent/WO2013107441A1/de active Application Filing
- 2013-01-16 EP EP13702727.2A patent/EP2804593A1/de not_active Withdrawn
- 2013-01-16 RU RU2014128296A patent/RU2014128296A/ru unknown
Non-Patent Citations (2)
Title |
---|
None * |
See also references of WO2013107441A1 * |
Also Published As
Publication number | Publication date |
---|---|
RU2014128296A (ru) | 2016-03-10 |
WO2013107441A1 (de) | 2013-07-25 |
DE102012000786A1 (de) | 2013-07-18 |
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