WO2008064854A1 - Préparation pharmaceutique de tramadol et acétaminophène - Google Patents

Préparation pharmaceutique de tramadol et acétaminophène Download PDF

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Publication number
WO2008064854A1
WO2008064854A1 PCT/EP2007/010275 EP2007010275W WO2008064854A1 WO 2008064854 A1 WO2008064854 A1 WO 2008064854A1 EP 2007010275 W EP2007010275 W EP 2007010275W WO 2008064854 A1 WO2008064854 A1 WO 2008064854A1
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WO
WIPO (PCT)
Prior art keywords
acetaminophen
tramadol
component
solubility
dosage form
Prior art date
Application number
PCT/EP2007/010275
Other languages
German (de)
English (en)
Inventor
Heinrich Kugelmann
Original Assignee
Grünenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Publication of WO2008064854A1 publication Critical patent/WO2008064854A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K9/08—Solutions
    • 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]

Definitions

  • the invention relates to a pharmaceutical composition containing acetaminophen and a tramadol component, wherein the solubility of acetaminophen contained in pure water at 23 ° C is greater than the solubility of acetaminophen in a physical comparison mixture of acetaminophen and the tramadol component with the same relative weight ratio. Furthermore, the invention relates to processes for the preparation of the composition according to the invention and to dosage forms which contain the composition according to the invention. The composition or dosage form according to the invention is particularly suitable for controlling pain.
  • tramadol and its derivatives have an intense bitter taste
  • the active ingredient is usually administered in solid dosage forms. Liquid formulations in which tramadol is dissolved find little acceptance in the patients because of the perceived unpleasant taste.
  • Liquid preparations for the administration of bitter substances are known in the art (see for example EP-A 1 669 090). According to WO 00/12067, the bitter taste of tramadol can be masked by providing it as a saccharinate.
  • Liquid dosage forms have certain advantages over solid dosage forms. Thus, in contrast to larger tablets or capsules, they usually do not cause any difficulty in swallowing, which is particularly advantageous in older patients can. Furthermore, they sometimes have improved pharmacokinetic properties, since the active ingredient is already dissolved and the bioavailability can be improved. In addition, liquid dosage forms can easily be individually dosed, for example by counting the drops from a suitable dosing dispenser.
  • liquid dosage forms are occasionally administered by the patient or caregiver only shortly before administration by dissolution of a solid which i.a. the active ingredient (s) is prepared in a suitable solvent.
  • a solid which i.a. the active ingredient (s) is prepared in a suitable solvent.
  • the solid it is necessary for the solid to have sufficient solubility in the solvent to completely dissolve in a short time.
  • the total volume of the liquid dosage form to be administered should be as small as possible so that the patient does not have to take large amounts of the solution in order to obtain the desired active ingredient dose.
  • the solution can be prepared quickly in a small amount of solvent.
  • compositions containing acetaminophen and a tramadol component which have advantages over the prior art compositions.
  • the compositions should be distinguished by a favorable taste and by an improved solubility of the contained acetaminophen.
  • solids can be prepared from acetaminophen and a tramadol component by certain methods in which the solubility of the acetaminophen contained is greater than the solubility of acetaminophen in the abovementioned physical mixture of acetaminophen and the tramadol component in the same relative weight ratio (comparative physical mixture).
  • the invention relates to a pharmaceutical, preferably solid composition comprising acetaminophen and a tramadol component, wherein the solubility of acetaminophen contained in the pharmaceutical composition in pure water at 23 C C is greater than the solubility of acetaminophen in a physical comparison mixture of acetaminophen and tramadol Component at the same relative weight ratio.
  • the improved solubility of the acetaminophen is preferably brought about by the presence of the tramadol component as such, ie in the pharmaceutical, preferably solid composition preferably no (further) substances are present which have a favorable influence on the solubility of acetaminophen. phen.
  • the solubility of the acetaminophen in the composition according to the invention in pure water at 23 ° C.
  • acetaminophen is preferably greater than the solubility of the acetaminophen in a physical comparison mixture of acetaminophen and the tramadol component at the same relative weight ratio and at the same content of these other materials, which have a favorable influence on the solubility of acetaminophen.
  • a "comparative physical mixture” is a mixture of particles containing acetaminophen and particles containing a tramadol component, the particles containing acetaminophen containing substantially no tramadol component and vice versa.
  • the preferably solid composition according to the invention is characterized in that at least some particles contain both acetaminophen and the tramadol component. These particles are obtainable, for example, by melt processes or by co-crystallization from suitable solvents.
  • composition according to the invention can be, for example, powders, granules, pellets, etc. If the composition according to the invention is in the form of a suspension, the powder or the granules, pellets, etc. can be suspended in a liquid.
  • the solubility of the contained acetaminophen in pure water at 23 ° C is at least 5%, more preferably at least 10%, more preferably at least 15%, most preferably at least 20%, and most preferably at least 25% greater as the solubility of acetaminophen in a comparative physical mixture of acetaminophen and the tramadol component at the same relative weight ratio.
  • the relative weight ratio of acetaminophen to the tramadol component in the preferably solid composition of the present invention is in the range of 15: 1 to 1: 1, more preferably 14: 1 to 2: 1, and even more preferably 13: 1 to 3: 1.
  • the amount of the tramadol component is the equivalent weight based on the free tramadol base.
  • the tramadol component tramadol hydrochloride has a molecular weight of 299.85 g / mol, whereas the free tramadol base has only 263.38 g / mol. Accordingly, 1.00 g of tramadol hydrochloride corresponds to an equivalent weight of about 0.88 g of the free tramadol base.
  • the solubility of the acetaminophen present in the preferred solid composition of the present invention in pure water at 23 ° C is at least 16.0 mg / g, more preferably at least 16.5 mg / g, even more preferably at least 17.0 mg / g, most preferably at least 17.5 mg / g and in particular at least 18.0 mg / g.
  • in pure water means adding pure water to the composition and determining the solubility of the acetaminophen.
  • the additionally contained in the preferably solid composition tramadol component and optionally further excipients of the composition are then additionally dissolved or suspended in the pure water.
  • acetaminophen in the sense of the description encompasses both the free compound and its pharmaceutically acceptable salts, for example alkali metal and alkaline earth metal salts.
  • the inventive, preferably solid composition contains, besides acetaminophen, a tramadol component.
  • the tramadol component is preferably selected from the group consisting of tramadol, tramadol-N-oxide, O-demethyltramadol, their physiologically acceptable salts and / or stereoisomers, such as (+) - tramadol, (-) - tramadol, ( +) - O-Demethyltramadol, (-) - O-Demethyltramadol or other metabolites, such as the sulfated or glucuronated derivatives of tramadol or O-demethyltramadol.
  • the tramadol component is present as the salt of a sugar substitute.
  • a particularly preferred sugar substitute is saccharin, so that the tramadol component is preferably ( ⁇ ) -tradadol saccharinate, (+) - madolin saccharinate, (-) - tramadol saccharinate, ( ⁇ ) -O- Demethyltramadol saccharinate (+) - O-demethyltramadol saccharinate or (-) - O-demethyltramadol saccharinate.
  • the preferably solid composition according to the invention may contain a further tramadol component and / or conventional pharmaceutical auxiliaries.
  • the composition contains a carrier, preferably SiO 2, wherein the content of the carrier is preferably at most 10.0 wt%, more preferably at most 7.5 wt%, even more preferably at most 5.0 wt%, most preferably at most 2 , 5 wt .-% and in particular at most 2.0 wt .-% is.
  • Preferred carriers are pharmaceutically acceptable metal or semimetal oxides, metal carbonates, in particular alkali metal or alkaline earth metal carbonates, for example CaCO 3 or MgCO 3 .
  • a particularly preferred carrier is SiO 2.
  • the preferably solid composition according to the invention contains macrogol (polyethylene oxide), preferably having an average molecular weight of at least 10,000 g / mol, more preferably at least 20,000 g / mol, even more preferably at least 25,000 g / mol and especially at least 30,000 g / mol (eg macrogol 35,000 ).
  • macrogol polyethylene oxide
  • the inventive, preferably solid composition in addition to acetaminophen and a tramadol component contains no further constituents, ie it consists of the two active ingredients.
  • the inventive, preferably solid composition is particularly advantageous for providing a solution / juice formulation immediately before ingestion by the patient.
  • the composition can be dissolved by the patient in a suitable liquid, for example in water or juice, and then taken.
  • a suitable liquid for example in water or juice
  • the invention further relates to a process for the preparation of the above-described pharmaceutical, preferably solid composition comprising one of the two alternatives (ai) and (a 2 )
  • the method according to the invention comprises the step
  • step (b) grinding the solid obtained in step (ai) or (a 2 ).
  • the method according to the invention preferably additionally contains the step:
  • step (c) sieving the ground solid obtained in step (b). Preference is given to sieving through a sieve with a mesh size of ⁇ 400 ⁇ m, more preferably ⁇ 300 ⁇ m, and most preferably ⁇ 200 ⁇ m.
  • Another object of the invention relates to a pharmaceutical, preferably solid composition, which is obtainable by the method described above.
  • the result of the process according to the invention is that the solubility of the acetaminophen contained in the preferably solid composition prepared in this way is greater than the solubility of acetaminophen in a comparative physical mixture of acetaminophen and the tramadol component with the same relative solubility weight ratio.
  • Another object of the invention relates to a dosage form comprising the above-described pharmaceutical composition and a pharmaceutically acceptable carrier.
  • the dosage form according to the invention is present as an aqueous solution or suspension in which the acetaminophen is dissolved.
  • the tramadol component is dissolved therein.
  • the concentration of the dissolved acetaminophen is at least 16.2 mg / g, more preferably at least 16.5 mg / g, even more preferably at least 17.0 mg / g, most preferably at least 17.5 mg / g and especially at least 18.0 mg /G.
  • the pharmaceutically acceptable carrier in this case comprises the solvent, preferably water.
  • an article of the invention relates to a liquid dosage form comprising acetaminophen and a tramadol component, wherein at least the acetaminophen is dissolved and the concentration of the acetaminophen is at least 16.2 mg / g, more preferably at least 16.5 mg / g, even more preferably at least 17, 0 mg / g, most preferably at least 17.5 mg / g and especially at least 18.0 mg / g.
  • the above-described, preferably solid composition according to the invention was preferably used for the preparation of this dosage form.
  • the liquid administration form according to the invention preferably contains macrogol (polyethylene oxide), preferably with an average molecular weight of at least 10,000 g / mol, more preferably at least 20,000 g / mol, even more preferably at least 25,000 g / mol and especially at least 30,000 g / mol (eg Macrogol 35,000 ). It has surprisingly been found that macrogol comparatively high molecular weight suppresses the bitter taste of tramadol. It seems that the macrogol of relatively high molecular weight occupies the taste buds of the tongue and thus suppresses the taste. However, this should not be construed as a commitment to a scientific theory. At the same time, macrogol has a favorable influence on the solubility of the acetaminophen.
  • the liquid dosage form according to the invention is therefore particularly suitable as a juice for oral administration.
  • sweeteners such as saccharin, sodium saccharinate, sodium cyclamate, neohesperidin, sucralose, sugar alcohols such as sorbitol, xylitol, mannitol, etc .; such as sucrose, fructose, etc.
  • Flavoring agents such as sodium chloride, flavors, sodium glutamate
  • Stabilizers and preservatives such as methylparaben, propylparaben, potassium sorbate, benzoic acid derivatives, etc.
  • Antioxidants such as sodium disulfite, ascorbic acid, cysteine, etc.
  • solvents and instability affecting substances such as water, glycerol, propylene glycol, polyethylene glycols, polyethylene glycol derivatives, especially Macrogol 6000 and / or Macrogol 35000, etc.
  • the dosage form of the invention contains no sugars, but sugar substitutes, e.g. Sodium cyclamate, aspartame, neohesperidin, sucralose or mixtures thereof; and / or sugar alcohols, such as sorbitol.
  • sugar substitutes e.g. Sodium cyclamate, aspartame, neohesperidin, sucralose or mixtures thereof; and / or sugar alcohols, such as sorbitol.
  • a particularly preferred liquid administration form according to the invention preferably contains besides acetaminophen and the tramadol component a macrogol or more macrogols (preferably Macrogol 6000 in combination with Macrogol 35000) and a sugar substitute or several sugar substitutes or sugar alcohols (preferably sorbitol, sodium cyclamate, neohesperidin, or their Mixture).
  • the dosage form preferably contains propylene glycol and / or glycerol.
  • the solvent water is preferable. Suitable preservatives are, for example, methylparaben and / or propylparaben.
  • this liquid administration form contains the combination of acetaminophen and a tramidol component according to the invention, the solubility of the acetaminophen contained in the pharmaceutical composition in pure water at 23 ° C. being greater than the solubility of acetaminophen in a physical comparative mixture of acetaminophen and the tramadol component at the same relative weight ratio. Rather, it is also possible in this embodiment that acetaminophen and the tramadol component are present in a physical mixture.
  • this liquid administration form (a) according to the invention has a pleasant taste, without the need for the use of sugar; (b) can be better prepared because of the possibly improved solubility of the acetaminophen; and (c) has a favorable pharmacological profile.
  • the dosage form according to the invention is present as a solid.
  • the solid dosage form or pharmaceutical composition under physiological conditions preferably in artificial gastric juice, after 10 minutes, sets at least 65%, more preferably at least 67.5%, even more preferably at least 70%, most preferably at least 72.5%. and in particular at least 75% of the contained acetaminophen and / or the contained tramadol component.
  • the solid dosage form or pharmaceutical composition under physiological conditions, preferably in artificial gastric juice, at most 80%, more preferably at most 75%, more preferably at most 70%, most preferably at most 65%, and most preferably at most after 30 minutes 60% of the contained acetaminophen and / or the contained tramadol component free.
  • FIGS. 1A and 1B show the release profiles of the compositions according to the invention which have been prepared according to the two alternatives of the method according to the invention (melt, ethanol) in comparison to those compositions in which the active ingredients exist only as a physical comparison mixture (mixing / sieving, Turbula / Mortars ).
  • artificial gastric juice pH 1, 2 was used as the release medium.
  • Figure 1A relates to acetaminophen
  • Figure 1B relates to tramadol.
  • FIGS. 2A and 2B show the release profiles of the compositions according to the invention which have been prepared according to the two alternatives of the method according to the invention (melt, ethanol) in comparison with those compositions in which the active substances are present only as a physical comparison mixture (mixing / sieving, turbulas / mortars) , Pure water was used as the release medium.
  • Figure 2A relates to acetaminophen
  • Figure 2B relates to tramadol.
  • the present solid form of administration contains macrogol (polyethylene oxide), preferably having an average molecular weight of at least 10,000 g / mol, more preferably at least 20,000 g / mol, even more preferably at least 25,000 g / mol and especially at least 30,000 g / mol (eg Macrogol 35000).
  • macrogol polyethylene oxide
  • Another object of the invention relates to the use of an above-described, preferably solid pharmaceutical composition or a solid dosage form described above for preparing a preferably aqueous solution of acetaminophen and the tramadol component.
  • the concentration of the dissolved acetaminophen in the preferably aqueous solution is at least 16.2 mg / g, more preferably at least 16.5 mg / g, even more preferably at least 17.0 mg / g, most preferably at least 17.5 mg / g and in particular at least 18.0 mg / g.
  • Another object of the invention relates to the use of acetaminophen and a tramadol component for the preparation of a previously described pharmaceutical composition or a dosage form described above for controlling pain.
  • the pain is selected from the group consisting of acute pain and chronic pain, especially inflammatory pain or neuropathic pain, where the pain may be weak, moderate, strong or strong.
  • FIGS. 1A acetaminophen, gastric juice
  • 1B tramadol, gastric juice
  • 2A acetaminophen, water
  • 2B tramadol, water
  • the resulting solution was divided into equal portions and mixed with various flavorings.
  • the flavorings used, their respective concentration and the taste impression of the solutions obtained are summarized in the following table:

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Rheumatology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une composition pharmaceutique comprenant de l'acétaminophène et un composant tramadol; la solubilité dans l'eau pure à 23°C de l'acétaminophène contenu dans la composition pharmaceutique est supérieure à la solubilité de l'acétaminophène dans un mélange physique comparable d'acétaminophène et du composant tramadol à un ratio en poids relatif identique.
PCT/EP2007/010275 2006-11-28 2007-11-27 Préparation pharmaceutique de tramadol et acétaminophène WO2008064854A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102006056458.8 2006-11-28
DE102006056458A DE102006056458A1 (de) 2006-11-28 2006-11-28 Arzneimittelzubereitung von Tramadol und Acetaminophen

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WO2008064854A1 true WO2008064854A1 (fr) 2008-06-05

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EP2177215A1 (fr) * 2008-10-17 2010-04-21 Laboratorios Del. Dr. Esteve, S.A. Co-cristaux de tramadol et NSAID
WO2010062524A1 (fr) * 2008-10-27 2010-06-03 Alza Corporation Forme posologique orale d'acétaminophène/tramadol à libération prolongée
EP2199274A1 (fr) * 2008-12-16 2010-06-23 Laboratorios Del. Dr. Esteve, S.A. Co-cristaux de tramadol et paracétamol
ES2390897A1 (es) * 2009-08-06 2012-11-19 Laboratorios Del Dr. Esteve, S.A. Compuestos farmacéuticos de O-desmetil-tramadol e inhibidores de la COX
US9562908B2 (en) 2009-11-17 2017-02-07 Asahi Kasei Fibers Corporation Organic colored microparticles, diagnostic reagent kit containing the same, and in vitro diagnosis method
CN110115708A (zh) * 2018-02-07 2019-08-13 保瑞药业股份有限公司 乙酰胺酚及曲马多共溶复方止痛口服液

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US9308196B2 (en) 2012-05-18 2016-04-12 Gruenenthal Gmbh Pharmaceutical composition comprising (1 r,4r) -6'-fluoro-N ,N-dimethyl-4-phenyl-4',9'-d ihydro-3'H-spiro[cyclohexane-1,1'-pyrano-[3,4,b]indol]-4-amine and an oxicam
US8912226B2 (en) 2012-05-18 2014-12-16 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r) -6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4,b]indol]-4-amine and a NSAR
US20130310385A1 (en) 2012-05-18 2013-11-21 Gruenenthal Gmbh Pharmaceutical Composition Comprising (1r,4r)-6'-fluoro-N,N-dimethyl-4-phenyl-4',9'-dihydro-3'H-spiro[cyclohexane-1,1'-pyrano[3,4,b]indol]-4-amine and Antidepressants
US9855286B2 (en) 2012-05-18 2018-01-02 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-fluoro-N,N-di methyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4,b]indol]-4-amine and a salicylic acid component
US20130310435A1 (en) * 2012-05-18 2013-11-21 Gruenenthal Gmbh Pharmaceutical Composition Comprising (1r,4r)-6'-fluoro-N, N-dimethyl-4-phenyl-4,9' -dihydro-3'H-spiro[cyclohexane-1,1' -pyrano[3,4,b]indol]-4-amine and Paracetamol or Propacetamol
US9320729B2 (en) 2012-05-18 2016-04-26 Gruenenthal Gmbh Pharmaceutical composition comprising (1r,4r)-6′-flouro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano-[3,4,b]indol]-4-amine and a propionic acid derivative
TWI620577B (zh) * 2016-11-23 2018-04-11 乙醯胺酚及曲馬多共溶複方止痛口服液
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RU2599717C2 (ru) * 2008-10-17 2016-10-10 Лабораторьос Дель Др. Эстеве, С.А. Сокристаллические формы трамадола и nsaid
WO2010043412A1 (fr) * 2008-10-17 2010-04-22 Laboratorios Del Dr. Esteve, S.A. Co-cristaux de tramadol et d’ains
US11478488B2 (en) 2008-10-17 2022-10-25 Esteve Pharmaceuticals, S.A. Co-crystals of tramadol and coxibs
US10548909B2 (en) 2008-10-17 2020-02-04 Esteve Pharmaceuticals, S.A. Co-crystals of tramadol and coxibs
US10245276B2 (en) 2008-10-17 2019-04-02 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs
US10238668B2 (en) 2008-10-17 2019-03-26 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibis
JP2012505847A (ja) * 2008-10-17 2012-03-08 ラボラトリオス・デル・デエレ・エステベ・エセ・ア トラマドールとｎｓａｉｄとの共結晶
EP2177215A1 (fr) * 2008-10-17 2010-04-21 Laboratorios Del. Dr. Esteve, S.A. Co-cristaux de tramadol et NSAID
AU2009304235B2 (en) * 2008-10-17 2015-05-07 Esteve Pharmaceuticals, S.A. Co-crystals of tramadol and NSAIDs
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