EP1863779A1 - Additionssalze des tolperison, verfahren zu deren herstellung und verwendung derselben - Google Patents

Additionssalze des tolperison, verfahren zu deren herstellung und verwendung derselben

Info

Publication number
EP1863779A1
EP1863779A1 EP06722687A EP06722687A EP1863779A1 EP 1863779 A1 EP1863779 A1 EP 1863779A1 EP 06722687 A EP06722687 A EP 06722687A EP 06722687 A EP06722687 A EP 06722687A EP 1863779 A1 EP1863779 A1 EP 1863779A1
Authority
EP
European Patent Office
Prior art keywords
acid
tolperisone
addition salt
syndrome
salt 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Withdrawn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
EP06722687A
Other languages
German (de)
English (en)
French (fr)
Inventor
Rudolf-Giesbert Alken
Frank Schneider
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.)
Birds Pharma GmbH Berolina Innovative
Original Assignee
Birds Pharma GmbH Berolina Innovative
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 Birds Pharma GmbH Berolina Innovative filed Critical Birds Pharma GmbH Berolina Innovative
Publication of EP1863779A1 publication Critical patent/EP1863779A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • 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
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to addition salts of tolperisone,
  • Muscle relaxants (RS) -2,4'-dimethyl-3-piperidinopropiophenone with the empirical formula C 1S H 2S NO.
  • Tolperisone and its salts are used in: painful spasms, muscular tension, cervical syndrome, cervicobrachial syndrome, lumbar syndrome, osteoporosis, arthrosis of the large joints, rheumatic diseases, fibromyalgia syndrome, chronic polyarthritis, occupational disorders. sports-related overloads.
  • Tolperisone remains stable at low pH for a long time. In the basic pH range, color changes occur and the active ingredient is degraded. In order to provide the stability of tolperisone in pharmaceutical preparations, addition salts of tolperisone with pharmaceutically acceptable acids are used.
  • JP 51128418 describes the preparation of the addition salt tolperisone hydrochloride.
  • WO 2004/050648 describes a process for the preparation of addition salts of tolperisone in which 4-methylpropiophenone, piperidine hydrochloride and 1,2-dioxolane and an inorganic acid are used as starting materials.
  • JP 53040779 discloses the preparation of optically active tolperisone. Different pharmacological effects of the enantiomers of tolperisone are described.
  • Tolperisone preparations currently on the market have a maximum shelf life of 3 years. If tolperisone hydrochloride is stored for a long time, loss of hydrochloride may occur due to evaporation. As a result, the desired pH value is not maintained and the stability of the tolperisone is no longer guaranteed.
  • the invention has for its object to provide stable Tolper- rison addition salts available, which in comparison to tolperisone hydrochloride have a greater long-term stability and can be safely used in pharmaceutical preparations.
  • an object of the present invention is the addition salt of tolperisone (2, 4'-dimethyl-3-piperidinopropiophenone) of the formula (A)
  • R is the organic radical of a physiologically acceptable organic acid.
  • R is an aliphatic saturated or unsaturated radical having up to 5 C atoms, which is optionally substituted by one or more hydroxyl, oxo and / or carboxy groups.
  • R is an aryl or aralkyl radical, the radical containing 5 to 9 C atoms and being optionally substituted by one or more hydroxyl and / or carboxy groups
  • the physiologically acceptable organic acid is selected from acetic acid, propionic acid, malonic acid, oxalic acid, gluconic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, pyruvic acid, hydroxybutyric acids, adipic acid, salicylic acid , Phthalic acid, mandelic acid and benzoic acid.
  • the physiologically acceptable organic acid is citric acid.
  • Tolperisone has an asymmetric center in the 2-position, which leads to the corresponding (R) or (S) enantiomers.
  • the present invention thus also relates to all salts according to the invention with organic acids in which the asymmetric center of tolperisone in optically pure or. optically enriched form and all mixtures thereof, including the racemate.
  • a further subject of the present invention is furthermore a process for the preparation of the addition salts according to the invention of 2, 4'-dimethyl-3-piperidinopropiophenone (tolperisone) of the formula (A)
  • tolperisone is added in the solvent 2-propanol to give an addition salt of tolperisone.
  • a method according to the invention wherein citric acid is used as the organic acid. It is preferred that one uses the tolperisone as a race mat. It is particularly preferred that the (S) -enantiomer of tolperisone is used. However, it is also particularly preferred that the (R) -enantiomer of tolperisone is used.
  • physiologically acceptable organic acid is a term familiar to a person skilled in the art. These are to be understood as meaning all organic acids which are physiologically harmless in the concentrations and amounts used in the form of the addition salts, that is to say have, for example, neither toxic, nor irritating, nor otherwise impairing the health of the patient.
  • the starting materials used are tolperisone as the racemic mixture or an enantiomer of tolperisone, as well as an organic acid and the solvent 2-propanol.
  • the use of the organic acid, (citric acid whose salts are substantially more stable than tolperisone hydrochloride, is advantageous in the process according to the invention.)
  • Citrate is added to the commercial preparations with tolperisone hydrochloride in order to achieve a low pH the use of tolperisone citrate as an active ingredient, eliminates citrate as an excipient.
  • the process according to the invention makes it possible to prepare addition salts of (R) -olperisone, of (S) -tolperisone or of a racemic mixture of both enantiomers. This makes it possible to use the salts of the tolperisone enantiomers both in pure form and in any desired mixture in therapeutic preparations. By using the optically active forms, the selectivity of the pharmacological effects can be increased.
  • Another object of the present invention is the use of an addition salt of the invention for the treatment of painful spasms, muscle tension, cervical syndrome, cervicobrachial syndrome, lumbar syndrome, osteoporosis, arthritis of the large joints, rheumatic diseases, fibromyalgia syndrome, chronic polyarthritis , professional u. sports-related overloads.
  • Another object of the present invention is the use of an addition salt according to the invention for the manufacture of a medicament for the treatment of painful spasms, muscular tension, cervical syndrome, cervicobrachial syndrome, lumbar syndrome, osteoporosis, arthrosis of the large joints, rheumatic diseases, fibromyalgia syndrome, chronic polyarthritis, occupational u. sports-related overloads.
  • An object of the present invention are also medicaments which contain at least one addition salt according to the invention of tolperisone in addition to pharmaceutically acceptable excipients and / or carriers.
  • the present invention also relates, in particular, to pharmaceuticals for oral, rectal, topical (cutaneous, transdermal, local), subcutaneous, intravenous or intramuscular administration, which, in addition to conventional carriers and diluents, contain a compound of the general formula (A) active substance.
  • the Tolperisonsalze invention can be used with organic acid without the use of another penetration enhancer.
  • compositions of the invention are mixed with the usual solid or liquid excipients or diluents. and the commonly used pharmaceutical excipients according to the desired mode of administration with a suitable dosage prepared in a known manner.
  • suitable dosage prepared in a known manner.
  • the preferred formulations consist of a dosage form which is suitable for oral administration.
  • Such administration forms are, for example, tablets, film-coated tablets, dragees, capsules, pills, powders, solutions or suspensions or depot forms.
  • topical application may be in the form of ointments, creams, gels, solutions or patches.
  • parenteral preparations such as injection solutions come into consideration.
  • Further examples of preparations which may be mentioned are suppositories.
  • Corresponding tablets can be prepared, for example, by mixing the active compound with known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and / or Achieve a depot effect such as carboxyl polymethylene, carboxymethylcellulose, Cellu- loseacetatphthalathat or polyvinyl acetate, are obtained.
  • the tablets can also consist of several layers.
  • Coated tablets may accordingly be obtained by coating cores produced analogously to the tablets with agents normally used in tablet coatings, for example polyols. vinylpyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the dragee wrapper can also consist of several layers, wherein the auxiliaries mentioned above in the case of the tablets can be used.
  • Solutions or suspensions with the active ingredient used in the invention may additionally taste-improving agents such as saccharin, cyclamate or sugar and z.
  • B. flavorings such as vanillin or orange extract. They may also contain suspending aids such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates.
  • Active ingredients containing capsules can be prepared, for example, by mixing the active ingredient with an inert carrier such as lactose or sorbitol and encapsulated in gelatin capsules.
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers such as neutral fats or polyethylene glycol or derivatives thereof.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP06722687A 2005-03-21 2006-03-21 Additionssalze des tolperison, verfahren zu deren herstellung und verwendung derselben Withdrawn EP1863779A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102005014080A DE102005014080B4 (de) 2005-03-21 2005-03-21 Additionssalze des Tolperison, Verfahren zu deren Herstellung, Verwendung derselben und diese enthaltende Arzneimittel
PCT/DE2006/000535 WO2006099862A1 (de) 2005-03-21 2006-03-21 Additionssalze des tolperison, verfahren zu deren herstellung und verwendung derselben

Publications (1)

Publication Number Publication Date
EP1863779A1 true EP1863779A1 (de) 2007-12-12

Family

ID=36603305

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06722687A Withdrawn EP1863779A1 (de) 2005-03-21 2006-03-21 Additionssalze des tolperison, verfahren zu deren herstellung und verwendung derselben

Country Status (10)

Country Link
US (1) US20090298893A1 (ja)
EP (1) EP1863779A1 (ja)
JP (1) JP2008537935A (ja)
CN (1) CN101142200A (ja)
AU (1) AU2006226721A1 (ja)
CA (1) CA2602208A1 (ja)
DE (1) DE102005014080B4 (ja)
EA (1) EA200701962A1 (ja)
MX (1) MX2007011523A (ja)
WO (1) WO2006099862A1 (ja)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT505225A1 (de) 2007-04-26 2008-11-15 Sanochemia Pharmazeutika Ag 0erfahren zur herstellung von hoch reinem 2,4'-dimethyl-3-piperidino-propiophenon (tolperison), dieses enthaltende pharmazeutische zusammensetzungen, sowie tolperison enthaltende wirkstoffformulierungen
US20100249423A1 (en) * 2009-03-09 2010-09-30 Sanochemia Pharmazeutika Ag Tolperisone controlled release tablet
CN102311407A (zh) * 2010-06-30 2012-01-11 北京润德康医药技术有限公司 S（+）托哌酮的制备方法及其医药用途
KR101156054B1 (ko) * 2011-09-05 2012-06-20 주식회사 네비팜 안정한 에페리손 함유 서방성 의약조성물

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5527914B2 (ja) * 1973-12-14 1980-07-24
JPS5340779B2 (ja) 1974-06-19 1978-10-28
JPH0720866B2 (ja) * 1987-05-15 1995-03-08 三生製薬株式会社 エペリゾン又はトルペリゾン或いはそれらの塩類含有経皮適用製剤
DE10123129A1 (de) * 2001-05-02 2002-11-14 Berolina Drug Dev Ab Svedala Deuterierte 3-Piperidinopropiophenone sowie diese Verbindungen enthaltende Arzneimittel
AT413539B (de) * 2002-12-05 2006-03-15 Sanochemia Pharmazeutika Ag Verfahren zum herstellen von salzen des tolperison

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006099862A1 *

Also Published As

Publication number Publication date
EA200701962A1 (ru) 2008-04-28
US20090298893A1 (en) 2009-12-03
DE102005014080B4 (de) 2007-11-22
CN101142200A (zh) 2008-03-12
CA2602208A1 (en) 2006-09-28
WO2006099862A1 (de) 2006-09-28
MX2007011523A (es) 2008-01-14
JP2008537935A (ja) 2008-10-02
AU2006226721A1 (en) 2006-09-28
DE102005014080A1 (de) 2006-09-28

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