US20110257134A1 - CO-CRYSTALS OF TRAMADOL AND NSAIDs - Google Patents
CO-CRYSTALS OF TRAMADOL AND NSAIDs Download PDFInfo
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- US20110257134A1 US20110257134A1 US13/124,027 US200913124027A US2011257134A1 US 20110257134 A1 US20110257134 A1 US 20110257134A1 US 200913124027 A US200913124027 A US 200913124027A US 2011257134 A1 US2011257134 A1 US 2011257134A1
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- tramadol
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- naproxen
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- RZEKVGVHFLEQIL-UHFFFAOYSA-N CC1=CC=C(C2=CC(C(F)(F)F)=NN2C2=CC=C(S(N)(=O)=O)C=C2)C=C1 Chemical compound CC1=CC=C(C2=CC(C(F)(F)F)=NN2C2=CC=C(S(N)(=O)=O)C=C2)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- TVYLLZQTGLZFBW-UHFFFAOYSA-N COC1=CC(C2(O)CCCCC2CN(C)C)=CC=C1 Chemical compound COC1=CC(C2(O)CCCCC2CN(C)C)=CC=C1 TVYLLZQTGLZFBW-UHFFFAOYSA-N 0.000 description 1
- CMWTZPSULFXXJA-SECBINFHSA-N COC1=CC2=C(C=C1)C=C([C@@H](C)C(=O)O)C=C2 Chemical compound COC1=CC2=C(C=C1)C=C([C@@H](C)C(=O)O)C=C2 CMWTZPSULFXXJA-SECBINFHSA-N 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N COC1=CC2=C(C=C1)C=C([C@H](C)C(=O)O)C=C2 Chemical compound COC1=CC2=C(C=C1)C=C([C@H](C)C(=O)O)C=C2 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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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
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- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
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- 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
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- 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
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- C07C59/40—Unsaturated compounds
- C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
Definitions
- the present invention relates to co-crystals of tramadol and NSAIDs (Non steroidal anti-inflammatory drugs), processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain.
- NSAIDs Non steroidal anti-inflammatory drugs
- Pain is a complex response that has been functionally categorized into sensory, autonomic, motor, and affective components.
- the sensory aspect includes information about stimulus location and intensity while the adaptive component may be considered to be the activation of endogenous pain modulation and motor planning for escape responses.
- the affective component appears to include evaluation of pain unpleasantness and stimulus threat as well as negative emotions triggered by memory and context of the painful stimulus.
- Chronic pain includes neuropathic pain and chronic inflammatory pain, for example arthritis, or pain of unknown origin, as fibromyalgia.
- Acute pain usually follows non-neural tissue injury, for example tissue damage from surgery or inflammation, or migraine.
- Opioids are frequently used as analgesics in pain.
- Derivatives of morphine are indicated for the treatment of moderate to acute pain in human.
- the analgesic effect is obtained through their action on morphinic receptors, preferably the p-receptors.
- morphinic receptors preferably the p-receptors.
- these derivatives of morphine may be mentioned morphine, codeine, pethidine, dextropropoxyphenemethadone, lenefopan and others.
- Tramadol also available as a physiologically acceptable salt, particularly as a chlorohydrate.
- Tramadol whose chemical name is 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol, has the following formula:
- This structure shows two different chiral centers and thus may exist in different diastereoisomers among which the tramadol is the cis-diastereoisomer: (1R,2R), or (1S,2S), both also known as (+)-tramadol and ( ⁇ )-tramadol and both of which contribute in different ways to its activity.
- tramadol is an opioid agonist, whereas clinical experience indicates that it lacks many of the typical side effects of opioids agonist, for example respiratory depression, constipation or tolerance.
- opioids cannot always be given repeatedly or at higher doses as analgesics to treat pain.
- the side effects of opioids are known in the art including e.g. J. Jaffe in “Goodman and Gilman's, The Pharmacological Basis of Therapeutics”, 8 th edition; Gilman et al.; Pergamon Press, New York, 1990, Chapter 22, pages 522-573.
- tramadol base or hydrochloride salt being more active when compared to tramadol base or hydrochloride salt
- the new drugable forms should combine more than one, most of these advantages.
- APIs Active Pharmaceutical Ingredients
- Co-crystals are a specific type of crystalline form which provide a new avenue to modulate the API form and thus to modulate API properties.
- Co-crystals contain an API and at least one other component which crystallize together. Selection of the other component helps determine whether a co-crystal will form and what properties the co-crystal will have.
- a polymorph, solvate, hydrate or amorphous form of an API can modulate stability, solubility, and hygroscopicity
- a co-crystal can modulate those same properties.
- the main object of the present invention is a co-crystal comprising tramadol either as a free base or as a physiologically acceptable salt and at least one NSAID.
- “Drugable form (of tramadol)” as used herein is defined as any form (salt, amorphous crystal, solution, dispersion, mixture etc,) that tramadol might take which still can be formulated into a pharmaceutical formulation usable as a medicament to treat a disease or a symptom, especially pain.
- Co-Crystal as used herein is defined as a crystalline material comprising two or more compounds at ambient temperature (20 to 25° C., preferably 20° C.), of which at least two are held together by weak interaction, wherein at least one of the compounds is a co-crystal former.
- Weak interaction is being defined as an interaction which is neither ionic nor covalent and includes for example: hydrogen bonds, van der Weals forces, and ⁇ - ⁇ interactions.
- Solvates of tramadol that do not further comprise a co-crystal former are not co-crystals according to the present invention.
- the co-crystals may however, include one or more solvate molecules in the crystalline lattice.
- co-crystal is a multiple component crystal in which all components are solid under ambient conditions when in their pure form. These components consist of a target molecule or ion and a molecular co-crystal former(s); when in a co-crystal, they coexist at a molecular level within a single crystal”.
- Co-crystal former as use herein is defined as a molecule being an active agent selected from NSAIDs, and with which tramadol is able to form co-crystals.
- “Active agents” are APIs which show a pharmaceutical effect and thus can be identified as being pharmaceutically active. In a more narrow sense this definition is encompassing all APIs being marketed or under clinical trial for the treatment of diseases. “Active agents with analgesic activity” are APIs (Active Pharmaceutical Ingredients) which show efficacy in well-known animal models of pain and thus can be identified as being analgesics. In a more narrow sense this definition is encompassing all APIs being marketed or under clinical trial for a labelling including an indication falling under the definition of pain, including also migraine.
- indications might include acute pain, chronic pain, neuropathic pain, hyperalgesia, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy, osteoarthritis or fibromyalgia and all their subforms.
- active agents with analgesic activity include NSAIDs like naproxen or ibuprofen, pregabalin or tramadol and its N-desmethyl-metabolite.
- Pain is defined by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 210). Even though pain is always subjective its causes or syndromes can be classified.
- IASP International Association for the Study of Pain
- allodynia is defined as “a pain due to a stimulus which does not normally provoke pain” (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 210). Even though the symptoms of allodynia are most likely associated as symptoms of neuropathic pain this is not necessarily the case so that there are symptoms of allodynia not connected to neuropathic pain though rendering allodynia in some areas broader than neuropathic pain.
- the IASP further draws the following difference between “allodynia”, “hyperalgesia” and “hyperpathia” (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 212):
- Neurode is defined as “a primary lesion or dysfunction in the nervous system” (IASP, Classification of chronic pain, 2 nd Edition, IASP Press (2002), 211). Neuropathic pain may have central or peripheral origin.
- Sciatica or “sciatic neuritis is defined herein as a set of symptoms including pain that derive from irritation of the sciatic nerve or its roots,
- “Frozen shoulder” or “adhesive capsulitis” is defined herein as a symptom wherein the connective tissue surrounding the shoulder joint or the shoulder capsule itself, is causing chronic pain, becoming inflamed and stiff.
- “Ankylosing spondylitis” or “Morbus Bechterew” is a chronic, inflammatory arthritis and autoimmune disease. It mainly affects joints in the spine and the sacroilium in the pelvis, causing eventual fusion of the spine.
- the NSAID has at least one functional group from the group consisting of ether, thioether, alcohol, thiol, aldehyde, ketone, thioketone, nitrate ester, phosphate ester, thiophosphate ester, ester, thioester, sulfate ester, carboxylic acid, phosphonic acid, phosphinic acid, sulfonic acid, amide, primary amine, secondary amine, ammonia, tertiary amine, thiocyanate, cyanamide, oxime, nitrile, diazo, organohalide, nitro, s-heterocyclic ring, thiophene, n-heterocyclic ring, pyrrole, o-heterocyclic ring, furan, epoxide, peroxide, hydroxamic acid, imidazole, and pyridine;
- the NSAID has at least one functional group from the group consisting of alcohol, thiol, ester, carboxylic acid, primary amine, secondary amine, tertiary amine.
- the NSAID has at least one functional group from the group consisting of alcohol, ester, or carboxylic acid.
- the NSAID/s is/are chosen in such a way that if compared to either tramadol alone, or to a mixture of tramadol and the corresponding active agent/s:
- Matture of tramadol and the corresponding active agent/s is defined as a mixture of the active agent or agents in question (the NSAID/s) with tramadol which is only a physical mixture without any coupling forces between the compounds and thus neither includes salts nor another co-crystal.
- the molar ratio between tramadol and the NSAID is different from 1. This might have the advantage of allowing the development of a non-equimolar ratio between tramadol and the active agent/s in a fixed dose with all the advantages of the co-crystal.
- NSAIDs have analgesic activity in a number of pain symptoms, with acetyl salicylic acid known under its trademark aspirin—despite being more than 100 years old—being an outstandingly used pharmaceutical.
- Aspirin other NSAIDs (and COX—INHIBITORS) whose use generally is also centered on anti-inflammatory action like Ibuprofen, naproxen or diclofenac are among the worldwide most frequently applied pharmaceutical compounds.
- COX cyclooxygenase
- Preferred NSAIDs are those with a carboxylic acid function. Preferred examples include salicylates, anthranilates, arylacetic acids/arylalkanoic acids, and arylpropionic acids.
- paracetamol/acetaminophen is to be considered an NSAID.
- paracetamol/acetaminophen is not considered an NSAID and is therefore excluded/disclaimed from the (list of) NSAIDs (Co-crystal formers) according to this invention.
- the NSAID is selected from:
- NSAIDs which have at least one stereogenic center are to be understood as being included herein in their racemic form or as diastereoisomers or enantiomers or mixtures thereof.
- the NSAID is a Coxib, a selective COX-2 inhibitor. Therefore, another preferred embodiment of the invention is a pharmaceutical compound comprising Tramadol and at least one COX-inhibitor selected from an NSAID being a Coxib. Examples of Coxibs are: celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and cimicoxib.
- a pharmaceutical compound comprising tramadol and celecoxib, preferably a pharmaceutical compound comprising (rac)-tramadol.HCl and celecoxib.
- the NSAID is selected from:
- salt is to be understood as meaning any form of tramadol or the NSAID according to the invention in which this assumes an ionic form or is charged and is coupled with a counter-ion (a cation or anion) or is in solution.
- a counter-ion a cation or anion
- complexes of tramadol or the NSAID with other molecules and ions in particular complexes which are complexed via ionic interactions. This also includes physiologically acceptable salt.
- solvate is to be understood as meaning any form of the tramadol or NSAID in which the compound has attached to it via non-covalent binding another molecule (most likely a polar solvent) especially including hydrates and alcohol solvates, e.g. methanol solvate.
- a highly interesting NSAID to be the co-crystal former with tramadol is the marketed drug naproxen.
- the chemical name of its (S)-enantiomer, the marketed (S)-naproxen, is (S)-(6-methoxy-2-naphtyl)propionic acid, and which is also described as a physiologically acceptable salt. It has an empirical formula of C 14 H 14 O 3 , an Mp of 153° C. and a pKa of 4.2.
- NSAID is naproxen, its enantiomers or salts thereof.
- NSAID is (S)-naproxen or (R)-naproxen.
- Another embodiment of the invention relates to a co-crystal according to the invention, wherein the tramadol is ( ⁇ )-tramadol or (+)-tramadol.
- tramadol and especially its enantiomers (+)-tramadol and ( ⁇ )-tramadol form co-crystals with naproxen, especially with (S)-naproxen and (R)-naproxen.
- co-crystals obtained have a specific stoichiometry which depends upon the structure of each co-crystal forming NSAID.
- the molecular ratio between tramadol and naproxen is 1 to 2.
- co-crystal according to the invention is selected from
- the molecular ratio between the tramadol and naproxen is 1:2.
- a co-crystal with a molecular ratio between the tramadol and naproxen of 1:2 comprising ( ⁇ )-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or mixture of enantiomers of these co-crystals
- the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [20] at 4.3, 8.7, 9.5, 10.2, 10.6, 11.3, 12.1, 12.7, 13.2, 13.7, 14.3, 14.6, 14.8, 15.5, 15.7, 16.0, 16.2, 17.0, 17.4, 17.9, 18.1, 18.7, 19.1, 19.4, 19.7, 20.1, 20.5, 20.8, 21.1, 21.4, 21.6 and 21.8 [°].
- the 2 ⁇ values were obtained using copper radiation (Cu K ⁇ 1 1.54060 ⁇ ).
- a co-crystal with a molecular ratio between the tramadol and naproxen of 1:2 comprising ( ⁇ )-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or mixture of enantiomers of these co-crystals
- the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3247, 2942, 1699, 1633, 1605, 1583, 1485, 1380, 1271, 1223, 1160, 1029, 851, 789 and 704 cm ⁇ 1 .
- a co-crystal with a molecular ratio between the tramadol and naproxen of 1:2 comprising ( ⁇ )-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or enantiomeric mixtures of these co-crystals
- the co-crystal has a monoclinic unit cell with the following dimensions:
- a co-crystal with a molecular ratio between the tramadol and naproxen of 1:2 comprising ( ⁇ )-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or enantiomeric mixtures of these co-crystals
- the endothermic sharp peak of the co-crystal corresponding to the melting point has an onset at 82° C.
- a co-crystal with a molecular ratio between the tramadol and naproxen of 1:2 comprising ( ⁇ )-tramadol either as a free base or as a physiologically acceptable salt and (S)-naproxen or comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen, or enantiomeric mixtures of these co-crystals
- the endothermic sharp peak of the co-crystal corresponding to the melting point has an onset at 82° C. to 84° C.
- a co-crystal with a molecular ratio between the tramadol and naproxen of 1:2 according to the invention comprising (+)-tramadol either as a free base or as a physiologically acceptable salt and (R)-naproxen is in the form of a methanol solvate.
- the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2 ⁇ ] at 4.1, 6.6, 9.0, 9.2, 10.4, 11.0, 11.5, 12.3, 12.5, 12.7, 13.0, 13.2, 13.8, 14.9, 15.4, 16.2, 17.2, 17.6, 18.1, 18.5, 19.1, 19.3, 19.6, 19.9, 20.1, 20.4, 20.9, 21.0, 21.5, 22.0, 22.3 and 22.6 [°].
- the 2 ⁇ values were obtained using copper radiation (Cu K ⁇ 1 1.54060 ⁇ ).
- the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3523, 3151, 2928, 2861, 2465, 1706, 1632, 1603, 1567, 1485, 1461, 1445, 1417, 1388 and 1362 cm ⁇ 1 .
- tramadol forms co-crystals with (S)-naproxen.
- co-crystals obtained have a specific stoichiometry which depends upon the structure of each co-crystal former.
- the molecular ratio between Tramadol and (S)-naproxen is 1 to 2.
- Coxibs Highly interesting NSAID to be the co-crystal formers with tramadol are the Coxibs. The most important of these is the marketed drug celecoxib. Its chemical name is 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-pyrazol-1-yl]benzenesulfonamide. It has an empirical formula of C 17 H 14 F 3 N 3 O 2 S.
- the NSAID is selected from:
- Another very preferred aspect of the invention relates to a co-crystal according to the invention, wherein the NSAID is celecoxib or salts thereof.
- tramadol and especially the racemate—forms co-crystals with celecoxib.
- co-crystals obtained have a specific stoichiometry which depends upon the structure of each co-crystal forming NSAID.
- the molecular ratio between tramadol and celecoxib is 1 to 1.
- co-crystal according to the invention is selected from
- the molecular ratio between the (rac)-tramadol.HCl and celecoxib is 1:1.
- the co-crystal shows a Powder X-Ray Diffraction pattern with peaks [2 ⁇ ] at 7.1, 9.3, 10.2, 10.7, 13.6, 13.9, 14.1, 15.5, 16.1, 16.2, 16.8, 17.5, 18.0, 19.0, 19.5, 19.9, 20.5, 21.2, 21.3, 21.4, 21.8, 22.1, 22.6, 22.7, 23.6, 24.1, 24.4, 25.2, 26.1, 26.6, 26.8, 27.4, 27.9, 28.1, 29.1, 29.9, 30.1, 31.1, 31.3, 31.7, 32.5, 32.8, 34.4, 35.0, 35.8, 36.2 and 37.2 [°].
- the 2 ⁇ values were obtained using copper radiation (Cu K ⁇ 1 1.54060 ⁇ ).
- the co-crystal shows a Fourier Transform Infra Red pattern with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1 (m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1 (m), 786.5 (m) 625.9 (m) cm ⁇ 1 .
- the co-crystal has an orthorhombic unit cell with the following dimensions:
- the endothermic sharp peak of the co-crystal corresponding to the melting point has an onset at 164° C.
- Ambient temperature is defined here as a temperature between 20 and 25° C., preferably being 20° C.
- the solvents usable in these processes include water or organic solvents, preferably solvents selected from acetone, isobutyl acetate, acetonitrile, ethyl acetate, 2-butanol, dimethylcarbonate, chlorobenzene, butylether, diisopropylether, dimethylformamide, ethanol, water, hexane (also cyclohexane), isopropanol, methyl ethyl ketone (also methyl isobutyl-ketone), methanol, methyl t-butyl ether, 3-pentanone, toluene and 1,1,1-trichloroethane, most preferably including alcohols, like ethanol. It is preferable—but not necessary—that the solvents in steps (a) and (c) are identical.
- the molecular ratio between tramadol and the NSAID lies between 4:1 to 1:4, preferably from 3:1 to 1:3 and more preferably from 1:1 to 1:2.
- the tramadol-solution in step (b) has a concentration of between 3M and 0.01 M.
- the parts of the co-crystal according to the invention are well-known drugs with analgesic properties sometimes used for a long time worldwide. Due to this a further object of the present invention is a medicament comprising a co-crystal according to the invention.
- the invention also concerns a medicament comprising at least one co-crystal according to the invention as described above and optionally one or more pharmaceutically acceptable excipients.
- the invention also relates to a pharmaceutical composition that comprises a therapeutically effective amount of the co-crystal according to the invention in a physiologically acceptable medium.
- PKPD Pharmacokinetic/Pharmacodynamic
- these co-crystals would be formulated into a convenient pharmaceutical formulation or a medicament. Accordingly, a desirable advantage of a co-crystal of tramadol, would show improved pharmaceutical properties and features, especially when compared to the free base or tramadol hydrochloride.
- the co-crystal of tramadol according to the invention should desirably show at least one, preferably more, of the following features:
- the medicament or pharmaceutical compositions according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
- the medicament of the present invention may for example be administered parenterally, including intramuscular, intraperitoneal, or intravenous injection, transmucosal or sublingual application; or orally, including administration as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or as reconstituted dry powdered form with a liquid medium.
- the medicaments according to the present invention may contain 1-60% by weight of one or more of the co-crystals as defined herein and 40-99% by weight of one or more auxiliary substances (additives/excipients).
- compositions of the present invention may also be administered topically or via a suppository.
- the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
- the daily dosage for humans preferably is in the range of 5 to 500 milligrams of tramadol to be administered during one or several intakes per day.
- a further aspect of the invention relates to the use of co-crystal according to the invention as described above for the treatment of pain, preferably acute pain, chronic pain, neuropathic pain, hyperalgesia, allodynia or cancer pain, including diabetic neuropathy or osteoarthritis or fibromyalgia.
- a further aspect of the invention relates to the use of co-crystal according to the invention as described above for the treatment of pain, preferably acute pain, chronic pain, neuropathic pain, severe to moderate pain, hyperalgesia, allodynia or cancer pain, including diabetic neuropathy, osteoarthritis, fibromyalgia; rheumatoid arthritis, ankylosing spondylitis, frozen shoulder or sciatica.
- these uses are provided for in form of a medicament or a pharmaceutical composition according to the invention as described above.
- Another object of the current invention is a method of treatment of pain, preferably acute pain, chronic pain, neuropathic pain, hyperalgesia, allodynia or cancer pain, including diabetic neuropathy or osteoarthritis or fibromyalgia, by providing to a patient in need thereof a sufficient amount of a co-crystal according to the invention as described above.
- the co-crystal according to the invention is provided in physiologically suitable form like e.g. in form of a medicament or a pharmaceutical composition according to the invention as described above.
- FIG. 1 Powder X-Ray diffraction pattern of ( ⁇ )-tramadol-(S)-naproxen 1:2 co-crystal.
- FIG. 2 DSC analysis of ( ⁇ )-tramadol-(S)-naproxen 1:2 co-crystal.
- FIG. 3 TG analysis of ( ⁇ )-tramadol-(S)-naproxen 1:2 co-crystal.
- FIG. 4 Structure of the unit cell of the ( ⁇ )-tramadol-(S)-naproxen 1:2 co-crystal obtained by SCXRD analysis showing four molecules of (S)-naproxen and two molecules of ( ⁇ )-tramadol.
- FIG. 5 Powder X-Ray diffraction pattern of the (+)-tramadol-(R)-naproxen 1:2 methanol solvate co-crystal.
- FIG. 6 DSC analysis of (+)-tramadol-(R)-naproxen 1:2 methanol solvate co-crystal.
- FIG. 7 TG analysis of the (+)-tramadol-(R)-naproxen 1:2 methanol solvate co-crystal.
- FIG. 8 Powder X-Ray diffraction pattern of the (rac)-tramadol.HCl-celecoxib 1:1 co-crystal.
- FIG. 9 DSC analysis of the (rac)-tramadol.HCl-celecoxib 1:1 co-crystal.
- FIG. 10 TG analysis of the (rac)-tramadol.HCl-celecoxib 1:1 co-crystal.
- FIG. 11 Structure of the unit cell of the (rac)-tramadol.HCl-celecoxib 1:1 co-crystal obtained by SCXRD analysis showing two molecules of celecoxib and two molecules of tramadol.
- Powder diffraction patterns were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using Cu K ⁇ -radiation in transmission geometry.
- the system is equipped with a V ⁇ hacek over (A) ⁇ NTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller.
- the FTIR spectra (ATR) of the co-crystal of ( ⁇ )-tramadol-(S)-naproxen were recorded using a Bruker Tensor 27, equipped with a MKII golden gate single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector.
- the spectra were acquired in 32 scans at a resolution of 4 cm ⁇ 1 .
- the sample of ( ⁇ )-tramadol-(S)-naproxen co-crystal (1:2) shows a Fourier Transform Infra Red spectrum (ATR) with absorption bands ⁇ max at 3247, 2942, 1699, 1633, 1605, 1583, 1485, 1380, 1271, 1223, 1160, 1029, 851, 789 and 704 cm ⁇ 1 .
- ATR Fourier Transform Infra Red spectrum
- the endothermic peak of the DSC analysis of ( ⁇ )-tramadol-(S)-naproxen co-crystal (1:2) corresponds to the melting point with an onset at 82° C., see FIG. 2 .
- Thermogravimetric analyses were recorded in a Mettler Toledo SDTA851e. Samples of 3-4 mg were weighted into 40 ⁇ L aluminium crucibles with a pinhole lid, and heated at 10° C./min from 30 to 500° C., under nitrogen (80 mL/min).
- the TG analysis of the ( ⁇ )-tramadol-(S)-naproxen co-crystal (1:2) according to the invention does not show weight loss at temperatures below the melting point (see FIG. 3 ).
- the crystal structure was determined from single crystal X-ray diffraction data.
- the measured crystal obtained from the preparation according to example 1 was selected using a Zeiss stereomicroscope using polarized light and prepared under inert conditions immersed in perfluoropolyether as protecting oil for manipulation.
- (+)-tramadol-(R)-naproxen (1:2) co-crystal obtained according to example 2 was fully characterised by 1 H-NMR, FTIR, powder X-Ray diffraction, DSC and TG.
- (+)-tramadol-(R)-naproxen (1:2) methanol solvate co-crystal obtained according to example 3 was fully characterised by 1 H-NMR, FTIR, powder X-Ray diffraction, DSC and TG (see FIGS. 5 to 8 ).
- Powder X-ray Diffraction (PXRD) Pattern of a (+)-Tramadol-(R)-Naproxen Methanol Solvate (1:2) Co-Crystal See FIG. 5):
- Powder diffraction patterns were acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using Cu K ⁇ -radiation in transmission geometry.
- the system is equipped with a V ⁇ hacek over (A) ⁇ NTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller.
- the FTIR spectra (ATR) of the (+)-tramadol-(R)-naproxen methanol solvate (1:2) co-crystal were recorded using a Bruker Tensor 27, equipped with a MKII golden gate single reflection ATR system, a mid-infrared source as the excitation source and a DTGS detector.
- the spectra were acquired in 32 scans at a resolution of 4 cm ⁇ 1 .
- (+)-tramadol-(R)-naproxen methanol solvate (1:2) co-crystal shows a Fourier Transform Infra Red spectrum (ATR) with absorption bands ⁇ max at 3523, 3151, 2928, 2861, 2465, 1706, 1632, 1603, 1567, 1485, 1461, 1445, 1417, 1388 and 1362 cm ⁇ 1 .
- ATR Infra Red spectrum
- Thermogravimetric analyses were recorded in a Mettler Toledo SDTA851e. Samples of 3-4 mg were weighted into 40 ⁇ L aluminium crucibles with a pinhole lid, and heated at 10° C./min from 30 to 500° C., under nitrogen (80 mL/min).
- the TG analysis of the (+)-tramadol-(R)-naproxen methanol solvate (1:2) co-crystal according to the invention does show weight loss of 7.2% between 40 and 140° C. followed by decomposition starting at 160° C. (see FIG. 7 ).
- Proton nuclear magnetic resonance analyses were recorded in methanol-d 4 in a Varian Mercury 400 spectrometer, equipped with a broadband probe ATB 1H/19F/X of 5 mm. Spectra were acquired dissolving 5-10 mg of sample in 0.6 mL of deuterated solvent.
- FTIR spectra were recorded using a Thermo Nicolet Nexus 870 FT-IR, equipped with a beamsplitter KBr system, a 35 mW He—Ne laser as the excitation source and a DTGS KBr detector. The spectra were acquired in 32 scans at a resolution of 4 cm 1 .
- the sample shows a Fourier Transform Infra Red spectrum with absorption bands at 3481.6 (m), 3133.5 (m), 2923.0 (m), 2667.7 (m), 1596.0 (m), 1472.4 (m), 1458.0 (m), 1335.1(m), 1288.7 (m), 1271.8 (m), 1168.7 (s), 1237.3 (m), 1168.7 (s), 1122.6 (s), 1100.9 (m), 1042.2 (m), 976.8 (m), 844.6 (m), 820.1(m), 786.5 (m) 625.9 (m) cm ⁇ 1 .
- the novel type of crystal of the present invention is characterized in that the endothermic sharp peak corresponding to the melting point has an onset at 164.44° C. (fusion enthalpy ⁇ 93.56 J/g), measured by DSC analysis (10° C./min) (see FIG. 9 ).
- thermogravimetric analyzer Mettler TGA/SDTA851 e Thermogravimetric analyses were recorded in a thermogravimetric analyzer Mettler TGA/SDTA851 e . A sample of 3.0560 mg was weighed into a 70 ⁇ L alumina crucible with a pinhole lid and was heated at 10° C./min from 30 to 200° C., under nitrogen (50 mL/min).
- the TG analysis of the crystalline form according to the invention shows insignificant weight loss between 30 and 200° C.
- the crystal structure was determined from single crystal X-ray diffraction data.
- the colourless prism used (0.33 ⁇ 0.16 ⁇ 0.11 mm) was obtained from the crystallization of a seeded solution in heptane and IPA of equimolar amounts of (rac)-tramadol hydrochloride and celecoxib.
- FIG. 12 The crystal structure is depicted in FIG. 12 (only half of the unitcell contents is shown, hydrogen atoms have been omitted for clarity; program used: Mercury 2.2, C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de Streek and P. A. Wood, J. Appl. Cryst., 41, 2008, 466-470).
- the objective is to measure plasma exposure in rat of (rac)-tramadol.HCl and celecoxib by means of AUC determination of the co-crystal of (rac)-tramadol.HCl—celecoxib (1:1) of the present invention, and comparing it with each active principle of the co-crystal and the fixed combination of the two active principles.
- Bioavailability of (rac)-tramadol.HCl—celecoxib co-crystal is compared to those obtained after administration of tramadol.HCl plus celecoxib, combined and separately, to rats by oral route.
- Products with an equivalent particle size are orally administered by means of rodent capsules at a dose level of 25 mg/kg of co-crystal and at an equivalent dose level of comparators (11 mg tramadol.HCl/kg, 14 mg celecoxib/kg).
- Blood from rats is extracted at the following time points: predose, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6, 8 and 24 h. Plasma is isolated by centrifugation, purified by SPE and plasma levels are determined by LC-MS-MS. Pharmacokinetic parameters are calculated using non-compartmental pharmacokinetic analysis.
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PCT/EP2009/007451 WO2010043412A1 (en) | 2008-10-17 | 2009-10-16 | Co-crystals of tramadol and nsaids |
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US14/665,055 Abandoned US20150196503A1 (en) | 2008-10-17 | 2015-03-23 | Co-crystals of tramadol and coxibs |
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