ZA200306529B - Pharmaceutical salts - Google Patents

Pharmaceutical salts Download PDF

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Publication number
ZA200306529B
ZA200306529B ZA2003/06529A ZA200306529A ZA200306529B ZA 200306529 B ZA200306529 B ZA 200306529B ZA 2003/06529 A ZA2003/06529 A ZA 2003/06529A ZA 200306529 A ZA200306529 A ZA 200306529A ZA 200306529 B ZA200306529 B ZA 200306529B
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South Africa
Prior art keywords
alkyl
salt
medicament
meta
pharmaceutical
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ZA2003/06529A
Inventor
Kugelmann Heinrich
Bartholomaus Johannes
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Gruenenthal Chemie
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Publication of ZA200306529B publication Critical patent/ZA200306529B/en

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    • 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
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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]
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/62—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/68—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain with singly-bound oxygen atoms, six-membered aromatic rings and amino groups bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C07D489/04—Salts; Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Description

++. 200376529
Pharmaceutical salts ‘ The present invention relates to pharmaceutical salts of an active compound and at least one sugar i 5 substitute, medicaments comprising these salts, and the use of these salts for the production of medicaments.
On oral administration, a large number of pharmaceutical active compounds having excellent activity lead to a strongly bitter, often nauseating taste sensation in the patient. In some patients, lack of adherence to the dosage instructions and a lack of acceptance of the corresponding medicaments which release such an active compound as early as during taking result from this negative taste experience.
The formulation of pharmaceutical active compounds having very good water solubility to give medicaments frequently causes problems in pharmaceutical practice.
Thus the preparation of pharmaceutical forms having controlled release is often made difficult on account of the very good water solubility of active compound salts. A delaying of the release of these active compounds can in fact be achieved, for example, by coating the pharmaceutical forms with release-delaying film coatings. This manner of delaying the release, however, is associated with a relatively high outlay, since release-delaying film coatings from aqueous coating systems are frequently only an inadequate diffusion barrier for active compounds having very good water solubility. The preparation of these delayed- release active compound preparations therefore requires relatively complicated coating processes with multilayer films. If such release-delaying coatings are applied from organic solvents, the environmental and solvent residue problems associated therewith ) additionally make the preparation of appropriate preparations more expensive.
CONFIRMATION COPY
. x - 2 =
It was therefore the object of the present invention to make available pharmaceutical combinations of active compounds which have no bitter taste. Preferably, the corresponding active compounds should be simpler to formulate and their release should be more effectively delayed.
According to the invention, this object is achieved by the provision of pharmaceutical salts, i.e. physiologically tolerable salts, from a pharmaceutical active compound and at least one sugar substitute.
The present invention therefore relates to pharmaceutical salts of a pharmaceutical active compound and at least one sugar substitute, the respective pharmaceutical salts of a sugar substitute and tramadol, (+)-tramadol, (-)-tramadol, (+)-demethyl- tramadol and (-)-demethyltramadol being excepted.
In a preferred embodiment of the present invention, the solubility of the pharmaceutical salts according to the invention in water is £ 250 mg/ml of water, preferably < 200 mg/ml, particularly preferably < 150 mg/ml, very particularly preferably < 100 mg/ml. This can also be seen in particular in the fact that the water solubility of the pharmaceutical salts according to the invention compared with the water solubility of the best water-soluble salt of the corresponding active compound according to Pharmazeutische Stoffliste [Pharmaceutical Substance List], 12th edition ABDATA
Pharma-Daten-Service, 65735 Eschborn/Taunus, is preferably lowered by at least 50%, preferably by at least 65%, particularly preferably by at least 75%, very particularly preferably by at least 85%, compared with the corresponding hydrochloride. The corresponding literature description is hereby inserted as a reference and is thus regarded as part of the disclosure.
- A - 3 =
According to the invention, suitable sugar substitutes ) are all sugar substitutes which can form a salt with the respective pharmaceutical active compound with ” 5 formation of an at least singly negatively charged form. According to the invention, pharmaceutical salts are also included in which the pharmaceutical active compound has two or more different sugar substitutes as salt components. Preferably, the pharmaceutical salts according to the invention contain saccharin, cyclamate or acesulfam, particularly preferably saccharin, as salt-forming sugar substitutes.
According to the invention, suitable active compounds are all pharmaceutical active compounds which can form a salt in anionic form with the respective sugar substitute(s) with formation of an at least singly positively charged form.
In a further preferred embodiment of the present invention, the salt-forming active compound in the pharmaceutical salt according to the invention is selected from the group consisting of the salt-forming analgesics, antiobesity agents, analeptics, anti- hypoxemics, antirheumatics, opioid antagonists, anthelmintics, antiallergics, antiarrhythmics, anti- biotics, antidementives (nootropics), antidiabetics, antiemetics, antivertiginous agents, antiepileptics, antihypertensives, antihypotensives, antimycotics, antiinflammatories, antitussives, expectorants, arteriosclerosis agents, p-receptor blockers, calcium channel blockers, broncholytics, antiasthmatics, cholinergics, diuretics, circulation-promoting agents, weaning agents, geriatrics, hypnotics, sedatives, immunomodulators, oral therapeutics, pharyngeal therapeutics, coronary agents, hypolipidemics, local anesthetics, neural therapeutics, gastric agents, intestinal agents, migraine agents, muscle relaxants, anesthetics, neuropathy preparations, ophthalmo-
. » logicals, otologicals, Parkinson agents, psycho- pharmaceuticals, rhinologicals, sinusitis agents, ’ spasmolytics, platelet aggregation inhibitors, tuberculosis agents, urologicals and cytostatics. i 5 Particularly preferably, the salt-forming active compound is selected from the group consisting of the salt-forming analgesics, analeptics, antihypoxemics, antiallergics, antiarrhythmics, antiemetics, anti- vertiginous agents, antihypertensives, anti- hypotensives, antitussives, expectorants, f-receptor blockers, calcium channel blockers, ophthalmologicals, otologicals, spasmolytics and urologicals. Very particularly preferably, the salt-forming active compound is selected from the group consisting of the salt-forming analgesics, tramadol, (+)-tramadol, (-)- tramadol, (+)-demethyltramadol and (-)-demethyltramadol being excepted.
If the pharmaceutical active compound is a salt-forming analgesic, it is preferably a salt-forming opioid or a salt-forming opioid analog, such as disclosed in
E. Friderichs, T. Christoph, H. Buschmann, “Analgesics and Antipyretics”; Ullmann’s Encyclopedia of Industrial
Chemistry, Sixth Edition on CD-ROM, Wiley-VCH,
Weinheim, 2000 or in Pharmaceuticals, J.L. McGuire (Editor), Analgesics and Antipyretics, Volume 2, pages 341-434, Wiley-VCH, Weinheim or ephedrine, chloroquine, lidocaine, ethaverine, preglumetacin or triflu- promazine. The corresponding disclosures are hereby inserted as a reference and are thus regarded as part of the present disclosure. Particularly preferably, the salt-forming analgesic is selected from the group consisting of morphine, codeine, ethylmorphine, diacetylmorphine, dihydrocodeine, etorphine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone, pethidine, ketobemidone, fentanyl, alfentanil, remifentanil, sufentanil, levomethadone, levomethadyl, dextro-moramide, dextropropoxyphene, diphenoxylate, piri-tramide, tilidine, buprenorphine,
butorphanol, dezozine, meptazinol, nalbuphine, } nalorphine, pentazo-cine, flupirtin and nefopam or a representative of the group consisting of ephedrine, - chloroquine, lidocaine, ethaverine, preglumetacin and triflupromazine. Very particularly preferably, the salt-forming analgesic is a salt-forming opioid or opioid analog selected from the group consisting of morphine, codeine, hydrocodone, hydromorphone, oxycodone, tilidine, fentanyl and buprenorphine.
Likewise preferably, the salt-forming active compound is a salt-forming compound of 1l-phenyl-3-dimethylamino- propane compounds of the general formula I x R = "1K | CH 3
De v
CH, in which in each case
X is OH, F, Cl, H or an OCOR® group,
R! is a Ci-q4—alkyl group,
R? is H or a Cis-alkyl group and R® is H or a straight- chain C;-4—alkyl group or the radicals R® and R® together form a C4-g-cycloalkyl radical, and if R® is H, R!' is meta-0-Z where Z is H, Ci-z~alkyl,
PO (0-Cj-4-alkyl),, CO(OCji_s—alkyl), CONH-Cg¢H4-(C;i-3—alkyl),
CO-Cg¢Hq-R’, where R’ is ortho-0COC;-s-alkyl or meta- or para-CH,N (R®) , where R® is Ci-4—alkyl or 4-morpholino, or
R* is meta-S-C;-3-alkyl, meta-Cl, meta-F, meta-CR°R!’RM where R%, R!® and RY are H or F, ortho-OH, ortho-0-C,_3—
alkyl, para-F or para-CR°R!°R!! where R®, R!%, R!! are H i or F, or if R® is para-Cl, -F, -OH or -0-C;.;-alkyl, R* is meta-Cl, -F, -OH or -0-C;.-alkyl, or . R! and R® together are 3,4-OCH=CH- or 3,4-OCH=CHO-,
R® is Ci.s—alkyl, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
Preferred 1s a salt-forming compound of l-phenyl-3- dimethylaminopropane compounds of the general formula I in which X is OH, F, Cl or H, R! is a C;4-alkyl group,
R? is H or CH; and R® is H or CH; and if R® is H, R! is meta-0-C,.3-alkyl, meta-OH, meta-8-C;.3-alkyl, meta-F, meta-Cl, meta-CH;, meta-CF,H, meta-CF; or para-CF; or if
R® is a para-Cl or -F, R* is meta-Cl or -F, or R*? and R’ together are 3,4-OCH=CH-.
Particularly preferred is a salt-forming compound of 1- phenyl-3-dimethylaminopropane compounds of the general formula I in which the radicals R? and R’® have different meanings and which are present in the form of their diastereomers having the configuration Ia
RS
- NAN
Xo 4
R! “2
HiC CH3 . la
Very particularly preferred is a salt-forming compound of 1l-phenyl-3-dimethylaminopropane compounds of the general formula I, selected from the group consisting of (1RS, 2RS) -3- (3-dimethylamino-1-hydroxy-1,2-dimethyl- propyl) phenol, (-)=(1R,2R) -3-(3-dimethylamino-1l-ethyl-2-methylpropyl) - phenol, (+)-(1S,2S)-3-(3-dimethylamino-l-ethyl-2-methylpropyl) - phenol, (2RS, 3RS) ~1-dimethylamino-3- (3-methoxyphenyl)-2-methyl- pentan-3-o0l, (-)-(1S,2S)-3-(3-dimethylamino-1l-ethyl-1-fluoro- 2-methylpropyl) phenol, (+)-(1R, 2R) -3-(3-dimethylamino-1-hydroxy-1,2-dimethyl- propyl) phenol, : (+)=-(2R,3R) -1-dimethylamino-3- (3-methoxyphenyl) - 2-methylpentan-3-o0l and
(=)=1(2S,38)-1-dimethylamino-3- (3-methoxyphenyl) - 2-methylpentan-3-ol. . The preparation of the salt-forming compounds of 1-phenyl-3-dimethylaminopropane compounds of the general formula I and, if appropriate, the separation into the pure optical antipodes can be carried out according to customary methods known to the person skilled in the art. Preferably, the preparation and, if appropriate, the separation is carried out as described in DE-A-4426245 or EP 0 693 475 Bl, which are hereby inserted as reference and are thus regarded as part of the disclosure.
In a further preferred embodiment of the present invention, the pharmaceutical salt according to the invention contains as a salt-forming active compound a salt-forming compound of 6-dimethylaminomethyl- l-phenylcyclohexane compounds of the general formula 11,
OR¥
R".
CH; nN
R®
CH
R* ’ il in which in each case
RY is H, OH, Cl or F, preferably H, OH or F,
R? and R¥ are identical or different and are H, Cj-4- alkyl, benzyl, CF3, OH, OCH;-C¢Hs, O-C;_4-alkyl, Cl or F
. = 9 = : with the proviso that at least one of the radicals R? or R¥ is H, ; RY is H, CH;, PO(0-Cis-alkyl),, CO(OCi-s—alkyl), CO-NH-
CgHy-Ci-3-alkyl, CO-CgHs—R>, CO-Ci_s-alkyl, CO-CHR® -NHR”' or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group,
R> is OC (0)Ci-3~alkyl in the ortho-position or CH,-
N(R¥), in the meta- or para-position, where R® is Ci-a— alkyl or both radicals R¥ together with N are the 4-morpholino radical, and
R® and R7’ are identical or different and are H or Ci_g— alkyl, . with the proviso that if both radicals R* and R® are
H, RY is not cH; if RY is H, OH or Cl or RY is not H if
RY is OH, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
Preferred are salt-forming compounds of 6- dimethylaminomethyl~1l-phenylcyclohexane compounds of the general formula II, which are present in the configuration as in the general formula IIa, rR? RY . =N08
RY. R
N
7 N\
HaC CHg ila
AMENDED SHEET
10-12-2004 in which the phenyl ring and the dimethylaminomethyl group are 1in each case arranged in an equatorial position to one another.
Particularly preferred is a salt-forming compound of 6-dimethylaminomethyl-l-phenylcyclohexane compounds of the general formula II selected from the group consisting of (-)-(1R,2R) -3- (2-dimethylaminomethylcyclohexyl) phenol, (1RS, 3RS, 6RS)-6-{dimethylaminomethyl)-1~(3-methoxy- phenyl) cyclohexane-1,3-diol and (1RS, 3RS, 6RS)~6~(dimethylaminomethyl)-1- (3-hydroxy- phenyl) cyclohexane-1, 3-diol.
The preparation of the salt-forming compounds of 6-dimethylaminomethyl-1l1-phenylcyclohexane compounds of the general formula II and, if appropriate, the separation into the optically pure antipodes can be carried out according to customary methods known to the person skilled in the art. Preferably, the preparation and, if appropriate, the separation are carried out as described in DE-A-19525137. The corresponding literature description is hereby inserted as reference and is thus regarded as part of the disclosure.
In a further preferred embodiment of the present invention, the pharmaceutical salt according to the invention contains as a salt-forming active compound a salt-forming compound of l1-phenyl-2-dimethylamino- methylcyclohexan-1-0l compounds of the general formula
III,
+«.20037652¢% rR"
W
Y==7 z/ {
R OH
N
HC” “SCH, im in which in each case
A is O or S,
RY" is H, Ci.g-alkyl, Ci.¢-alkenyl, Cs.;-cycloalkyl or halogenated C,_¢-alkyl, the group —v=2( is the group croft er= 0 ctr a —CH=— or —0— . \ N
R?'" is Cji.¢-alkyl, Cae-alkenyl, Cs.;-cycloalkylmethyl, substituted or unsubstituted phenyl or substituted or unsubstituted benzyl, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar . amounts. - Preferred are salt-forming compounds of 1l-phenyl-2-di- methylaminomethylcyclohexan-1-ol compounds of the general formula III, in which RY" is H, Cij-g—alkyl, 2'- methyl-2’/-propenyl, cyclopentyl or fluoroethyl, with the proviso that RY’ is Cj4-alkyl if A is S,
R*’ is Ci-q—alkyl, Cy-4—alkenyl, cyclopentylmethyl, phenyl, Ci-4-alkoxyphenyl, benzyl, Ci-g—alkylbenzyl, mono- or dihalogenated phenyl or mono- or dihalogenated benzyl.
Particularly preferred are salt-forming compounds of 1-phenyl-2-dimethylaminomethylcyclohexan-1-ol compounds of the general formula III, in which R'" is H, methyl, ethyl, isopropyl, 2’'-methyl-2’-propenyl, cyclopentyl or fluoroethyl, with the proviso that RY" is methyl if A is S,
R¥’ is methyl, propyl, 2’-methylpropyl, allyl, 2’ -methyl-2’ -propenyl, cyclopentylmethyl, phenyl, 3-methoxyphenyl, benzyl, 4-tert-butylbenzyl, 4-chloro- benzyl, 4-fluorobenzyl or 3,4-dichlorobenzyl.
Very particularly preferred are salt-forming compounds of l-phenyl-2-dimethylaminomethylcyclohexan-1-o0l compounds of the general formula III which are present in the configuration of the formula IIIa,

Claims (35)

) CLAIMS: :
1. A pharmaceutical salt of a pharmaceutical active compound and at least one sugar substitute, wherein the salt-forming active compound 1s a salt-forming l-phenyl-3-dimethylaminopropane compound of the general formula I x R Rs = "TK ~ CHj Pes Nn R CH3 in which X is OH, F, Cl, H or an OCOR® group, R' is a Ci-4~alkyl group, R> is H or a Ci-4—alkyl group and R® is H or a straight-chain Cj_4-alkyl group or the radicals R? and R3 together form a C4.;—cycloalkyl radical, and if R® is H, R* is meta-0-Z where Z is H, Ci-3—-alkyl, PO (0-Ci-4—alkyl) 27 CO (0OC;-5—al kyl) ’ CONH-CgH,—- (C1-3— alkyl), CO-CgHs-R’, where R’ is ortho-0COC;_3-alkyl or meta- or para-CH,N (R®) , where R® is Ci-4—alkyl or 4-morpholino, or R? is meta-S-C;_3—alkyl, meta-Cl, meta-F, meta-CR’°R'®R! where R?’, R'?, R' are H or F, ortho-0OH, ortho-0O-C,_3-alkyl, para-F or para- CR°RR!! where R%, RY, R!! are H or F, or if R® is AMENDED SHEET 10-12-2004
: para-Cl, -F, -OH or -0-Cis-alkyl, R' is meta-Cl, -F, -OH or -0-C;-3-alkyl, or R? and R® together are 3,4-OCH=CH- or 3,4-OCH=CHO-,
R® is Ci-3-alkyl, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts, or wherein the the salt-forming active compound is a salt-forming 6-dimethylaminomethyl-1- phenylcyclohexane compound of the general formula II, ORY R" CHa nN RZ CH R® ’ in which
RY is H, OH, Cl or F, R* and R¥ are identical or different and are H, Ci-g—alkyl, benzyl, CFs, OH, OCH,-CgHs, 0-Ci-4—alkyl, : Cl or F with the proviso that at least one of the radicals R?* or R* is H, AMENDED SHEET 10-12-2004
) RY is H, CHs, PO(0O-Ci4-alkyl),, CO(0-Cis-alkyl), CO-NH-Cg¢Hy4-Ci-3—alkyl, CO-CgH,—R>, CO-Cy_s—alkyl, CO- CHR® -NHR”" or an unsubstituted or substituted pyridyl, thienyl, thiazoyl or phenyl group, R> is OC (0)Ci-z3—alkyl in the ortho-position or CHy- N(R¥), in the meta- or para-position, where RY is Cis-alkyl or both radicals R¥® together with N are the 4-morpholino radical, and R® and R7’ are identical or different and are H or Ci-6—alkyl, with the proviso that if both radicals R* and R* are H, RY is not CH; if RY is H, OH or Cl or R* is not H if RY is OH, in the form of their possible stereoisomers as racemates or diastereomerically pure enantiomers | or in the form of mixtures of enantiomers, in which the respective enantiomers are present in nonequimolar amounts.
2. The pharmaceutical salt as claimed in claim 1, characterized in that the solubility of the salt in water is < 250 mg/ml of water.
3. The pharmaceutical salt as claimed in claim 2, characterized in that the solubility of the salt in water is £ 200 mg/ml. AMENDED SHEET 10-12-2004 i
4. The pharmaceutical salt as claimed in claim 3, ] characterized in that the solubility of the salt in water is £ 150 mg/ml.
5. The pharmaceutical salt as claimed in claim 4, : characterized in that the solubility of the salt in water is £ 100 mg/ml.
6. The pharmaceutical salt as claimed in one of claims 1 to 5, characterized in that the salt- forming sugar substitute is saccharin, cyclamate or acesulfam.
7. The pharmaceutical salt as claimed in claim 6, characterized in that the salt-forming sugar substitute is saccharin.
8. The pharmaceutical salt as claimed in one of claims 1 to 7, characterized in that X is OH, F, Cl or H, R! is a Ci-4-alkyl group, R? is H or CH3 and R?® is H or CH; and if R® is H, R?! is meta-0-C;_;3- alkyl, meta-OH, meta-S-Ci_3—-alkyl, meta-F, meta-Cl, ; meta-CH;, meta-CF;H, meta-CF; or para-CF; or if R’ is a para-Cl or -F, R! is meta-Cl or -F, or R?! and R®> together are 3,4-OCH=CH-.
9. The pharmaceutical salt as claimed in one of claims 1 to 8, characterized in that the radicals R®> and R® have different meanings and the compounds of the general formula I as claimed in claim 1 are present in the form of their diastereomers having the configuration Ia AMENDED SHEET 10-12-2004 oo - 50 - a pi R SX X < H R" J. “2 N pd ~~ HsC CH;
Ia.
10. The pharmaceutical salt as claimed in one of claims 1 to 9, characterized in that the salt- forming 1-phenyl-3-dimethylaminopropane compound is selected from the group consisting of (IRS, 2RS)-3-(3—-dimethylamino~l1-hydroxy-1,2-di- methylpropyl) phenol, (=) -(1R, 2R) -3-(3-dimethylamino-l-ethyl-2-methyl- propyl) phenol, (+)-(1S,2S) -3-(3-dimethylamino-1-ethyl—-2-methyl- propyl) phenol, (2RS, 3RS) -~1-dimethylamino-3- (3-methoxyphenyl) - 2-methylpentan-3-o0l, (-)-(1s,2S)-3-(3-dimethylamino-l-ethyl-1-fluoro- 2-methylpropyl) phenol, (+) -(1R, 2R) -3-(3~dimethylamino-1-hydroxy-1, 2- dimethylpropyl) phenol, AMENDED SHEET 10-12-2004
(+) = (2R, 3R) -1-dimethylamino-3- (3-methoxyphenyl) —- . 2-methylpentan-3-o0l and (-)-(25,3S)-1-dimethylamino-3- (3-methoxyphenyl) —- 2-methylpentan-3-ol.
11. The pharmaceutical salt as claimed in one of claims 1 to 7, characterized in that RY is H, OH or F.
12. The pharmaceutical salt as claimed in claims 1 to 7 or 11, characterized in that the compounds of the general formula II have a configuration in which the phenyl ring and the dimethylaminomethyl group are in each case arranged in an equatorial position to one another.
13. The pharmaceutical salt as claimed in one of claims 1 to 7, 11 or 12, characterized in that the salt-forming 6-dimethylaminomethyl-1- - 20 phenylcyclohexane compound is selected from the group consisting of © (-)-(1R, 2R) -3-(2-dimethylaminomethylcyclohexyl) - phenol, (1RS, 3RS, 6RS) -6- (dimethylaminomethyl) -1- (3- \ methoxyphenyl)cyclohexane-1,3-diol and (1RS, 3RS, 6RS) -6- (dimethylaminomethyl) -1- (3- hydroxyphenyl) cyclohexane-1, 3-diol. AMENDED SHEET 10-12-2004
14. A medicament comprising at least one pharmaceutical . salt as claimed in one of claims 1 to 13 and, optionally, physiologically tolerable excipients.
15. A medicament comprising at least one pharmaceutical salt as claimed in one of claims 1 to 13 for the control of pain.
16. A medicament comprising at least one pharmaceutical salt as claimed in one of claims 1 to 13 for the control of urinary incontinence.
17. The medicament as claimed in one of claims 14 to 16, characterized in that it is present in the form of gels, chewing gums, juices, sprays, tablets, chewable tablets, coated tablets, powders, optionally filled into capsules, easily : reconstitutable dry preparations.
18. The medicament as claimed in claim 17, characterized in that it is present in the form of gels, aqueous or oily juices, sublingual sprays, tablets or chewable tablets.
19. The medicament as claimed in one of claims 14 to 16, characterized in that it is present formulated in multiparticulate form, optionally filled into capsules or compressed to give tablets.
20. The medicament as claimed in claim 19, characterized in that it is present in form of microtablets, microcapsules, granules, active compound crystals or pellets, optionally filled into capsules or compressed to give tablets. AMENDED SHEET 10-12-2004
21. The medicament as claimed in claim 20, characterized . in that is present in the form of microtablets, granules or pellets, optionally filled into capsules or compressed to give tablets. ;
22. The medicament as claimed in one of claims 14 to 21, characterized in that the salt is present at least partially in delayed-release form.
23. The medicament as claimed in claim 22, characterized in that delaying of the release is carried out by applying a release-delaying coating, embedding in a release-delaying matrix, binding to an ion- exchange resin or by a combination of at least two of these methods.
24. The medicament as claimed in claim 23, characterized in that the release-delaying coating is based on a water-insoluble, optionally modified natural or synthetic polymer, optionally in combination with a customary plasticizer, or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these components.
25. The medicament as claimed in claim 23, characterized in that the matrix is based on a hydrophilic matrix material.
26. The medicament as claimed in claim 25, characterized in that the hydrophilic matrix material are hydrophilic polymers. AMENDED SHEET 10-12-2004
27. The medicament as claimed in claim 26, characterized . in that the hydrophilic polymers are cellulose ethers, cellulose esters and/or acrylic resins.
28. The medicament as claimed in claim 27, characterized in that the hydrophilic polymers are ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth)acrylic acid and/or their salts, amides and/or esters.
29. The medicament as claimed in claim 23, characterized in that the matrix is based on a hydrophobic matrix material. .
30. The medicament as claimed in claim 29, characterized in that the hydrophobic matrix material are hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or appropriate esters or ethers or their mixtures.
31. The medicament as claimed in claim 30, characterized in that the hydrophobic matrix material are mono- or diglycerides of C;,-C3y fatty acids and/or Cj,- Cio—fatty alcohols and/or waxes or their mixtures.
32. The medicament as claimed in one of claims 14 to 31, characterized in that it has a protective coating.
33. The medicament as claimed in claim 32, characterized in that the protective coating is an enteric protective coating. AMENDED SHEET 10-12-2004
: 34. The use of at least one pharmaceutical salt as v claimed in one of claims 1 to 13 for the production of a medicament for the control of pain.
35. The use of at least one pharmaceutical salt as claimed in one of claims 1 to 13 for the production of a medicament for the treatment of urinary incontinence. AMENDED SHEET 10-12-2004
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Families Citing this family (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PE20030527A1 (en) 2001-10-24 2003-07-26 Gruenenthal Chemie DELAYED-RELEASE PHARMACEUTICAL FORMULATION CONTAINING 3- (3-DIMETHYLAMINO-1-ETHYL-2-METHYL-PROPYL) PHENOL OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME AND ORAL TABLETS CONTAINING IT
SI1443917T1 (en) * 2001-11-07 2006-06-30 Synthon Bv Tamsulosin tablets
DE10163421A1 (en) * 2001-12-21 2003-07-31 Gruenenthal Gmbh Use of (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol as an anti-emetic
DE10224556A1 (en) * 2002-05-31 2004-01-08 Grünenthal GmbH Medicament containing 1-dimethylamino-3- (3-methoxy-phenyl) 2-methyl-pentan-3-ol in various formulations
DE10225315A1 (en) * 2002-06-06 2003-12-24 Gruenenthal Gmbh Active substance salts and esters of 1-dimethylamino-3- (3-methoxyphenyl) -2-methylpentan-3-ol and 3- (3-dimethylamino-1-ethyl-1-hydroxy-2-methylpropyl) - phenol
US7776314B2 (en) 2002-06-17 2010-08-17 Grunenthal Gmbh Abuse-proofed dosage system
EP2255795A1 (en) * 2002-09-28 2010-12-01 McNeil-PPC, Inc. Immediate release dosage form comprising shell having openings therein
LT1562567T (en) 2002-11-22 2017-08-25 Grünenthal GmbH Combination of selected analgesics and cox-ii inhibitors
DE10305984A1 (en) * 2003-02-13 2004-09-02 Helm Ag Salts of organic acids with clopidogrel and their use in the manufacture of pharmaceutical formulations
DE10329386A1 (en) * 2003-06-30 2005-01-20 Novartis Ag Aqueous solution containing opipramol salt, useful for treating depression, also includes a sugar alcohol or synthetic sweetener to improve taste and chemical stability, particularly color
DE10333835A1 (en) * 2003-07-24 2005-03-10 Gruenenthal Gmbh Sustained-release drug containing 6-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexane-1,3-diol
DE10361596A1 (en) 2003-12-24 2005-09-29 Grünenthal GmbH Process for producing an anti-abuse dosage form
US20070048228A1 (en) 2003-08-06 2007-03-01 Elisabeth Arkenau-Maric Abuse-proofed dosage form
DE10336400A1 (en) 2003-08-06 2005-03-24 Grünenthal GmbH Anti-abuse dosage form
DE102005005446A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Break-resistant dosage forms with sustained release
DE10356362A1 (en) * 2003-11-28 2005-06-23 Grünenthal GmbH Use of 1-phenyl-3-dimethylamino-propane compounds for the treatment of anxiety disorders
FR2865648B1 (en) * 2004-02-03 2006-06-30 Philippe Perovitch METHOD FOR DIFFUSION OF INSOLUBLE MOLECULES IN AQUEOUS MEDIUM AND COMPOSITION IMPLEMENTING SAID METHOD
DE102004032049A1 (en) 2004-07-01 2006-01-19 Grünenthal GmbH Anti-abuse, oral dosage form
JP4895819B2 (en) * 2004-10-29 2012-03-14 大鵬薬品工業株式会社 Propiverine-containing oral powder granular preparation and its production method
DE102005005449A1 (en) 2005-02-04 2006-08-10 Grünenthal GmbH Process for producing an anti-abuse dosage form
BRPI0502736A (en) * 2005-07-05 2007-02-27 Biolab Sanus Farmaceutica Ltda oral formulations of masked residual flavor ondansetron
US20090104266A1 (en) * 2005-09-15 2009-04-23 Tobias Jung 3-(2-dimethylaminomethylcy clohexyl)phenol retard formulation
US8252329B2 (en) 2007-01-05 2012-08-28 Acelrx Pharmaceuticals, Inc. Bioadhesive drug formulations for oral transmucosal delivery
US8865743B2 (en) * 2006-01-06 2014-10-21 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
US8202535B2 (en) 2006-01-06 2012-06-19 Acelrx Pharmaceuticals, Inc. Small-volume oral transmucosal dosage forms
US8535714B2 (en) 2006-01-06 2013-09-17 Acelrx Pharmaceuticals, Inc. Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain
AU2007247480B8 (en) * 2006-04-28 2013-04-11 Grunenthal Gmbh Pharmaceutical combination comprising 3- (3-dimethylamino-1-ethyl-2-methyl-propyl) -phenol and an NSAID
DE102007022790A1 (en) 2007-05-11 2008-11-20 Grünenthal GmbH Axomadol for the treatment of pain in osteoarthritis
JP2009007311A (en) * 2007-06-29 2009-01-15 Lintec Corp Diphenhydramine-acesulfame adduct, method for producing the same and oral preparation containing the adduct
AU2009207796B2 (en) 2008-01-25 2014-03-27 Grunenthal Gmbh Pharmaceutical dosage form
US8945592B2 (en) 2008-11-21 2015-02-03 Acelrx Pharmaceuticals, Inc. Sufentanil solid dosage forms comprising oxygen scavengers and methods of using the same
US20120064219A1 (en) * 2009-06-08 2012-03-15 Firmenich Sa Extruded particles
NZ596667A (en) 2009-07-22 2013-09-27 Gruenenthal Chemie Hot-melt extruded controlled release dosage form
PT2456424E (en) 2009-07-22 2013-09-30 Gruenenthal Gmbh Oxidation-stabilized tamper-resistant dosage form
EP3597628A1 (en) * 2010-07-23 2020-01-22 Grünenthal GmbH Salts or co-crystals of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol
MX2013002377A (en) 2010-09-02 2013-04-29 Gruenenthal Gmbh Tamper resistant dosage form comprising inorganic salt.
CA2808541C (en) 2010-09-02 2019-01-08 Gruenenthal Gmbh Tamper resistant dosage form comprising an anionic polymer
WO2012051246A1 (en) 2010-10-12 2012-04-19 Ratiopharm Gmbh Tapentadol hydrobromide and crystalline forms thereof
CN107088226A (en) 2011-03-04 2017-08-25 格吕伦塔尔有限公司 The parenteral of tapentadol hydrochloride
RS59491B1 (en) 2011-03-04 2019-12-31 Gruenenthal Gmbh Aqueous pharmaceutical formulation of tapentadol for oral administration
US9446008B2 (en) 2011-03-04 2016-09-20 Gruenenthal Gmbh Semisolid aqueous pharmaceutical composition containing tapentadol
AR087360A1 (en) 2011-07-29 2014-03-19 Gruenenthal Gmbh PROOF OF HANDLING TABLET PROVIDING IMMEDIATE RELEASE OF PHARMACY
MX348054B (en) 2011-07-29 2017-05-25 Gruenenthal Gmbh Tamper-resistant tablet providing immediate drug release.
AU2013225106B2 (en) 2012-02-28 2017-11-02 Grunenthal Gmbh Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer
RS57913B1 (en) 2012-04-18 2019-01-31 Gruenenthal Gmbh Tamper resistant and dose-dumping resistant pharmaceutical dosage form
US10064945B2 (en) 2012-05-11 2018-09-04 Gruenenthal Gmbh Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc
JP6466417B2 (en) 2013-05-29 2019-02-06 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング A tamper-resistant dosage form with a bimodal release profile
JP6445537B2 (en) 2013-05-29 2018-12-26 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Tamper-resistant dosage forms containing one or more particles
EP2808319A1 (en) 2013-05-31 2014-12-03 Arevipharma GmbH 3-[3-(Dimethylamino)-1-ethyl-2-methylpropyl]phenol resin complex
JP6449871B2 (en) 2013-07-12 2019-01-09 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Anti-modified dosage form containing ethylene-vinyl acetate polymer
BR112016010482B1 (en) 2013-11-26 2022-11-16 Grünenthal GmbH PREPARATION OF A PHARMACEUTICAL COMPOSITION IN POWDER BY MEANS OF CRYOMING
EP2942054A1 (en) * 2014-05-09 2015-11-11 G.L. Pharma GmbH Slow-release pharmaceutical formulation
WO2015173195A1 (en) 2014-05-12 2015-11-19 Grünenthal GmbH Tamper resistant immediate release capsule formulation comprising tapentadol
JP2017516789A (en) 2014-05-26 2017-06-22 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Multiparticulates protected against ethanol overdose
RU2588840C1 (en) * 2015-03-26 2016-07-10 Общество с ограниченной ответственностью ООО "ВАЛЕНТА-ИНТЕЛЛЕКТ" Tablet quetiapine with prolonged release and synthesis method thereof
JP6923447B2 (en) 2015-03-27 2021-08-18 グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング Stable formulation for parenteral administration of tapentadol
EA035434B1 (en) 2015-04-24 2020-06-15 Грюненталь Гмбх Tamper-resistant dosage form with immediate release and resistance against solvent extraction
US10842750B2 (en) 2015-09-10 2020-11-24 Grünenthal GmbH Protecting oral overdose with abuse deterrent immediate release formulations
US9833408B1 (en) * 2016-07-28 2017-12-05 Allen Greenspoon Orally administrable formulation
AU2017329964B2 (en) 2016-09-23 2022-10-06 Grünenthal GmbH Stable formulation for parenteral administration of Tapentadol
WO2018153947A1 (en) 2017-02-23 2018-08-30 Grünenthal GmbH Tapentadol as local anesthetic
DE202020104285U1 (en) 2020-07-24 2020-12-18 Grünenthal GmbH Ethyl cellulose-coated particles containing a salt of tapentadol and phosphoric acid

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4362730A (en) * 1980-08-25 1982-12-07 Heinrich Mack Nachf. Chem-Pharm. Fabrik Vincamine saccharinate and a pharmaceutical composition containing it dissolved therein
DE3113132A1 (en) * 1981-04-01 1982-10-21 Heinrich Mack Nachf., 7918 Illertissen VINCAMINE CYCLAMATE, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THIS
DE3639901A1 (en) * 1986-11-22 1988-06-01 Bayer Ag SACCHARINE SALTS FROM SUBSTITUTED AMINES
DE3639903A1 (en) * 1986-11-22 1988-06-01 Bayer Ag SACCHARINE SALTS OF AMINOMETHYLHETEROCYCLEN
DE3639902A1 (en) * 1986-11-22 1988-06-01 Bayer Ag SACCHARINE SALTS FROM SUBSTITUTED HYDROXYPROPYLAMINES
US6077822A (en) * 1993-09-14 2000-06-20 Dumex-Alpharma A/S Drug salts
DE4426245A1 (en) * 1994-07-23 1996-02-22 Gruenenthal Gmbh 1-phenyl-3-dimethylamino-propane compounds with pharmacological activity
DE19525137C2 (en) * 1995-07-11 2003-02-27 Gruenenthal Gmbh 6-Dimethylaminomethyl-1-phenyl-cyclohexane compounds as intermediates for the preparation of pharmaceutical agents
DE19601744C2 (en) * 1996-01-19 1998-04-16 Gruenenthal Gmbh Process for the preparation of the enantiomers of O-demethyltramadol
EP1136498A1 (en) * 1996-10-18 2001-09-26 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hepatitis c virus NS3 protease
CN1348363A (en) * 1998-08-27 2002-05-08 布里斯托尔-米尔斯·斯奎布公司 Novel pharmaceutical salt form
ES2226886T3 (en) * 1999-08-31 2005-04-01 Grunenthal Gmbh FORM OF ADMINISTRATION OF DELAYED ACTION CONTAINING SQUARINATE OF TRAMADOL.
DE19947747A1 (en) * 1999-10-05 2001-04-12 Gruenenthal Gmbh Treatment of urinary incontinence using (+)-tramadol, O-demethyl-tramadol or O-demethyl-N-mono-desmethyl-tramadol, having strong effect on bladder function without side-effects or analgesic action
DE10013259A1 (en) * 2000-03-17 2001-09-20 Nutrinova Gmbh New stable complexes of acesulfame with trace elements e.g. zinc or copper, useful as taste-masked form of trace elements for use in foods, feedstuffs, pharmaceuticals or cosmetics
DE10013712A1 (en) * 2000-03-20 2001-09-27 Nutrinova Gmbh Nicotine salts with improved taste, process for their preparation and their use
DE10059412A1 (en) * 2000-11-30 2002-06-13 Gruenenthal Gmbh Use of 1-phenyl-3-dimethylamino-propane compounds for the treatment of urinary incontinence
DE10130298A1 (en) * 2001-06-22 2003-01-23 Nutrinova Gmbh Antimicrobial acesulfame complexes, process for their preparation and their use

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