DE102013009114A1 - Pharmaceutical composition to overcome metabolic problems - Google Patents

Abstract

The invention relates to a pharmaceutical composition for a racemic active substance in which at least 50% of one of the two enantiomers is replaced by a bioequivalent amount of one or more of its metabolites and in particular a pharmaceutical composition containing (-) tramadol and the metabolite (+) demethyltramadol. The invention further relates to methods for producing the above-mentioned pharmaceutical compositions and their use for the treatment of diseases.

Description

The invention relates to a pharmaceutical composition for a racemic active substance in which one of the two enantiomers is replaced by at least 50% by a bioequivalent amount of one or more of its metabolites.

Chiral drugs are of great importance in pharmacotherapy and are also used predominantly in the form of Razemate. Thus, racemic mixtures make up an estimated 10-15% of the drugs on the market. For certain classes of therapeutics, such as β-adrenergic blockers, antiepileptics and oral anticoagulants, nearly 90% of all preparations are racemic mixtures. The frequent use of racemates is based on the fact that animal pharmacology, clinical pharmacology, toxicology and teratology have been performed with the racemate because at the time of drug identification, enantioseparation (or the development of a chiral synthesis) is too difficult, too costly or even impossible.

Razemate as a drug are often against the respective enantiomers of disadvantage, since the individual enantiomers very different properties z. B. in terms of their physiological activity, their mechanism of action, their toxicity and side effects. This is complicated by the fact that they are metabolized in the organism to enantiomeric metabolites, which in turn may have individual properties.

As an example of a very different effect of enantiomers, which also affects the respective metabolites, the tramadol can be used here.

Tramadol is a fully synthetic opioid drug used to treat moderate to severe pain. Tramadol has become an important analgesic because of its good analgesic activity and is marketed worldwide. It is now the world's most widely prescribed opioid ever dar.

The pharmaceutical active ingredient tramadol is usually prepared in the form of its racemate from (+) - tramadol, d. H. (1R, 2R) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) -cyclohexanol and (-) - tramadol, d. H. (1S, 2S) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol used.

The analgesic efficacy of tramadol is based on a complex synergistic interaction of its enantiomers according to a mechanism that includes not only a μ-opioids but also a non-opioid active component. The opioid active component, which makes the essential contribution to the analgesic activity of tramadol, is mainly due to the main metabolite of the (+) - enantiomer, the so-called (+) - O-demethyltramadol. The non-opioid component involves the inhibition of pain transmission in the spinal cord by inhibiting norepinephrine and serotonin uptake. Here, (-) - tramadol is a mild norepinephrine reuptake inhibitor, which has the ability to spinally enhance the descending pain control system.

The (+) - enantiomer of tramadol acts as a weak inhibitor of serotonin reuptake inhibition and may thereby contribute to inhibiting or increasing nociceptive transmission in the spinal cord, as the neurotransmitter serotonin in the spinal cord can both increase and inhibit the transmission of pain. Accordingly, no significant contribution of the serotonin mechanism to tramadol-induced nociception could be demonstrated in animal models ( Desmeules et al., 1996 ). In contrast, the noradrenergic contribution could be demonstrated in animal models as well as in human studies ( Raffa et al., 1992 . Desmeules et al., 1996 . Dayer et al., 1997 . Enggaard et al., 2006 ).

In humans, tramadol is mainly metabolised via N- and O-demethylation and glucuronic acid conjugation of the O-demethylated products. N-demethylation is ensured by the enzyme CYP3A4 and leads to inactive metabolites. The O-demethylation of both tramadol enantiomers is performed by the genetically polymorphic enzyme CYP2D6. O-demethylation of (-) - tramadol leads to the inactive metabolite (-) - M1, whereas O-demethylation of (+) - tramadol leads to the metabolite (+) - M1, which has a strong agonist activity at the μ-opiate receptor.

Noteworthy here is that CYP2D6 has more than 75 allelic variants as a genetically polymorphic enzyme. These variants include point mutations, deletions, insertions or one Gene rearrangement and result in an increase, decrease or a complete loss of CYP2D6 enzyme activity.

Different variants of the chromosome 22q13.1 CYP2D6 gene lead to different phenotypes. Depending on the enzyme activity, a distinction is made between "poor metabolizer" (PM), "intermediate metabolizer" (IM), "fast metabolizer" (EM) and "ultrafast metabolizer" ( "Ultrarapid metabolizer"; UM). The "fast metabolizer" is the norm variant, whereas in the "ultrafast metabolizer" the gene for CYP2D6 is in multiple copies. In return, in the "intermediate metabolizer" the gene function is limited and almost completely absent in the slow type.

International studies have shown significant interethnic differences in the incidence of individual CYP2D6 phenotypes (see 1 ), which are between 0 and 19% for PMs and between 0.9% and 29% (Ethiopia). A typing study by Spartein in the USA showed an extreme variation of the metabolic ratio MR _a within the population (s. 2 ), which is lower by a factor of 10 compared to the average for slow metabolizers and 100 times faster in ultrafast metabolizers (see p. 2 : PM vs. IM vs. AROUND). The occurrence of aberrant CYP2D6 phenotypes is crucial for individualized pharmacotherapy.

Thus, it has been clinically proven that tramadol has a lower analgesic activity in slow metabolizers due to the lack of opioid active component of (+) - demethyltramadol. In addition, slow metabolizers have an increased risk of side effects such as serotonin syndrome and drug interactions.

In contrast, ultrafast metabolizers have an increased risk of sometimes serious side effects, such as respiratory depression, cardiotoxicity, debility, nausea, chronic dizziness or dependence.

In summary, tramadol (as well as many racemic drugs) requires individualized therapy that takes into account their respective metabolism status. One way to minimize the risk is genetic phenotyping to determine an optimized dose. This is time consuming (standard tests up to a week), expensive, requires a special infrastructure and is generally not applicable for the treatment of acute pain.

This is where the invention, which is based on the object to provide a pharmaceutical composition for a racemic active substance, which is at least improved in terms of the above-mentioned disadvantages.

Summary of the invention

• a) ein erstes Enantiomer dieser Wirksubstanz,
• b) optional ein zweites Enantiomer dieser Wirksubstanz, das im äquimolaren Verhältnis zu dem ersten Enantiomer vorliegt,
• c) wenigstens einen Metaboliten des zweiten Enantiomers dieser Wirksubstanz,

wobei das im äquimolaren Verhältnis zum ersten Enantiomer vorliegende zweite Enantiomer zu mindestens 50%, bevorzugt zu mindestens 75%, besonders bevorzugt zu mindestens 80% und insbesondere bevorzugt zu 100% durch eine bioäquivalente Menge eines oder mehrerer dieser Metaboliten ersetzt worden ist.This object is achieved according to the invention by providing a pharmaceutical composition for an active substance present as a racemate, comprising:

• a) a first enantiomer of this active substance,
• b) optionally a second enantiomer of said active substance which is in equimolar ratio to the first enantiomer,
• c) at least one metabolite of the second enantiomer of this active substance,

wherein the second enantiomer present in equimolar ratio to the first enantiomer has been replaced by at least 50%, preferably at least 75%, more preferably at least 80% and most preferably 100% by a bioequivalent amount of one or more of these metabolites.

The inventors have found that in a racemic active substance, the pharmaceutical composition, the targeted replacement of only one of the two enantiomers by its metabolite leads to a lower-risk drug, which is to develop without much effort.

The fastening device according to the invention combines several decisive advantages over the pharmaceutical compositions known from the prior art.

By replacing one enantiomer with its corresponding metabolite, one circumvents the problem of the variable metabolism of this enantiomer. As a result, one should with the Composition of the invention achieve an efficacy and a side effect profile, as it is observed for the racemic reference composition for the normal metabolizer. In contrast to the racemic comparison composition, the efficacy and the side effects should then be independent of the metabolization status.

Since also the "normal metabolizers" have some variation in the metabolic quotient, the present pharmaceutical composition should have an improved therapeutic index.

Since problems arise in the interaction with other drugs or foods, especially through the metabolization of drugs, the pharmaceutical composition according to the invention is also advantageous in this case since it no longer interacts with the other substances in the metabolic pathway through the use of the metabolite.

Of particular importance here is that one can start from the already approved racemic active ingredients and can optimize them by the composition of the invention. Since an enantiomer is replaced (in whole or in part) by the bioequivalent amount of its metabolite formed in the patient, the regulatory prerequisites for authorization of the composition according to the invention can already be established by a successful bioequivalence study. This is a fast and cost-effective development possible.

Thus, the development of the composition according to the invention is also possible faster than that of an isolated enantiomer (so-called chiral switch).

In summary, the present pharmaceutical composition thus allows individualized therapy, without the need for elaborate and costly patient typing or expensive and costly development of individually adapted dosage forms and / or application schemes.

The pharmaceutical composition according to the invention should therefore significantly improve patient compliance in everyday life.

Detailed description of the invention

• a) ein erstes Enantiomer dieser Wirksubstanz,
• b) optional ein zweites Enantiomer dieser Wirksubstanz, das im äquimolaren Verhältnis vorliegt,
• c) wenigstens einen Metaboliten des zweiten Enantiomers dieser Wirksubstanz, wobei das zweite Enantiomer zu mindestens 50%, bevorzugt zu mindestens 75%, besonders bevorzugt zu mindestens 80% und insbesondere bevorzugt zu 100% durch eine bioäquivalente Menge eines oder mehrerer dieser Metaboliten ersetzt worden ist.

The invention provides in a first aspect a pharmaceutical composition provided for a razemate active substance comprising:

• a) a first enantiomer of this active substance,
• b) optionally a second enantiomer of this active substance, which is present in an equimolar ratio,
• c) at least one metabolite of the second enantiomer of this active substance, wherein the second enantiomer has been replaced by at least 50%, preferably at least 75%, more preferably at least 80% and most preferably 100% by a bioequivalent amount of one or more of these metabolites ,

In a preferred embodiment, the second enantiomer is replaced by exactly one of its metabolites, most preferably the major metabolite of this second enantiomer.

In a further embodiment, in the pharmaceutical composition according to the invention the first and optionally present second enantiomer are contained in non-retarded form and the at least one metabolite in retarded form.

In a further embodiment, in the pharmaceutical composition of the invention both the at least one enantiomer and the at least one metabolite are contained in retarded form, wherein the release of the metabolite is delayed with respect to the first and second enantiomers.

In one embodiment of the invention, the racemic active substance whose enantiomer (s) and metabolite (s) are contained in the pharmaceutical composition is selected from the group comprising acebutolol, acenocoumarol, 3-amino-1-hydroxypyrrolid-2-one (HA- 966), albendazole, albuterol, alogliptin, aprenolol, amphetamine, atamestane, atenolol, atorvastitine, azlocillin, aztreonam, baclofen, bambuterol, benazepril, betaxolol, bicalutamide, bromophenauramine, bufuralol, bupivacaine, captopril, carvedilol, cefalexin, cefaloglycine, cefamandole, cefamandole , Cefapirin, cefazaflur, cefonicid, ceforanide, cefpimizole, Cefradine, Cefroxadine, Ceftezole, Cefuroxime, Chloroquine, Chlorpheniramine, Cilazapril, Clenbuterol, Cloxacillin, Clopidogrel, Cyclophosphamide, Delapril, Dexrazoxane, Disopyramide, Dobutamine, Eflornithine, Enalapril, Esmolol, Ethosuximide, Ethambutol, Felodipine, Fenfluramine, Flecainide, Fluoxetine, Flurbiprofen, Fomocaine, Formoterol, Halofantrine, Hexobarbital, Hydroxychloroquine, Hydroxymebendazole, Idapril, Ifosfamide, Ilaprazole, Indacrinone, Isoprenaline, Ketamine, Ketoconazole, Ketoprofen, Labetalol, Lansoprazole, Loratidine, Losigamon, Lumefantrine, Medetomidine, Mefloquine, Mephobarbital, Methadone, Methamphetamine, Methorphan, 3,4-methylenedioxymethamphetamine (MDMA), mephenytoin, methylphenidate, metoprolol, mianserin, milnacipran, mirtazapine, modafinil, moxalactam, naproxen, nateglinide, nicardipine, nimodipine, nisoldipine, paliperidone, pantoprazole, pentobarbital, pindolol, praziquantel, prilocaine, primaquine, propafenone , Propranolol, Propoxylene, Quinacrine, Rabeprazole, Racecadotril, Racemorphan, Rasagiline , Razoxan, reboxetine, salmeterol, secobarbital, selegiline, sibutramine, sotalol, stiripentol, tafenoquine, tenatoprazole, terbutaline, terfenadine, tetramisole, thiopental, thiohexital, thioridazine, tocainide, tramadol, trimetoquinol, valsartan, verapamil, warfarin, zopiclone and preferably tramadol ,

In one embodiment, the pharmaceutical composition of the invention comprises the enantiomer (S) -sibutramine and the metabolite (R) -dimethylsibutramine.

In one embodiment, the pharmaceutical composition of the invention comprises the enantiomer (+) - perhexiline and the metabolite cis-hydroxy - (-) - perhexiline.

In an alternative embodiment, the pharmaceutical composition according to the invention comprises the enantiomer (-) - perhexiline and the metabolite cis-hydroxy - (+) - perhexiline.

In a further embodiment, the pharmaceutical composition of the invention comprises the enantiomer (2R, 3R) -buproprion and the metabolite (2S, 3S) -hydroxybuproprione.

In a particular embodiment, the pharmaceutical composition according to the invention comprises the enantiomers (1R, 2R) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) -cyclohexanol ((+) - tramadol) and (1S, 2S) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol ((-) - tramadol) and the metabolite (1R, 2R) -3- [2 - [(dimethylamino) methyl] -1-hydroxycyclohexyl] - phenol ((+) - O-demethyltramadol).

The preparation and optionally the purification and / or isolation of the (-) - tramadol can be carried out by customary methods known to the person skilled in the art, such as, for example, In Frankus et al. (Drug Research, Drug Res., 28, pp. 114-121, 1978) . US 3,652,589 or in the EP 0 787715 B1 described. The relevant documents are hereby incorporated by reference and thus are considered part of the disclosure.

In a particularly preferred embodiment, the pharmaceutical composition according to the invention contains the enantiomer ((1S, 2S) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol ((-) - tramadol) and the metabolite (1R, 2R) -3- [2 - [(dimethylamino) methyl] -1-hydroxycyclohexyl] phenol ((+) - O-demethyltramadol), the metabolite ((+) - O-demethyltramadol being substituted for the replaced (+) - enantiomer of the tramadol in a bioequivalent amount and the replaced (+) tramadol was present in equimolar amounts to the (-) - tramadol A bioequivalent amount of the (+) - demethyltramadol with respect to the replaced (+) enantiomer means that the (+) - Demethyltramadol of tramadol is present in a bioequivalent amount to the (+) - enantiomer produced by a normal metabolizer (EM) (+) - demethyltramadol.

In the context of the invention, a "bioequivalent amount" is present if, for the two compositions, the ratio of AUC _0-t and Cmax lies within a confidence interval of 90% in the range between 80 and 125%. The term AUC _0-t stands for the area under the curve (AUC) and denotes the area under the concentration-time curve of a drug in the blood between the time of administration (t = 0) and a Time t. The term Cmax denotes the peak plasma level of the corresponding compound. Other parameters that can be used to assess bioequivalence are the peak plasma level (t _max ), the minimum plasma level (C _min ) and the absorption delay time (t _lag ).

A development of a bioequivalent drug is to be carried out in a very simple form, since it usually requires only a so-called bioequivalence study. This bioequivalence test is conducted as a pharmacokinetic study on volunteers. Two groups receive an equal dose of the test drug or reference product under strictly standardized conditions. At certain intervals, blood samples are taken and analyzed for drug concentration. By the In healthy volunteers, the manageable size of the study, and the restriction to pharmacokinetic data, such a study can be performed quickly, cost-effectively, and with little regulatory effort.

• • Die pharmakologischen/pharmazeutischen Mechanismen sind äquivalent.
• • Die Bioverfügbarkeit des (–) Enantiomers des Tramadols ist gleich.
• • Das (+)-Demethyltramadol ist ein aktiver Bestandteil im razemischen Tramadol und ebenso in der Kombination aus (–)-Tramadol und (+)-Demethyltramadol.

The other regulatory requirements for bioequivalence defined by the EMEA and the FDA are also covered by the combination of (-) - tramadol and (+) - demethyltramadol:

• • The pharmacological / pharmaceutical mechanisms are equivalent.
• • The bioavailability of the (-) enantiomer of tramadol is the same.
• • The (+) - demethyltramadol is an active ingredient in racemic tramadol and also in the combination of (-) - tramadol and (+) - demethyltramadol.

• • Das für Tramadol bestehende Risiko eines Serotonin-Syndroms sollte durch die erfindungsgemäße Kombination nicht mehr auftreten, da auf die serotonerge Aktivität des (+)-Tramadols zurückzuführen ist.
• • Das Risiko für Abhängigkeit und Missbrauch in den ultraschnellen Metabolisierern würde verringert werden.
• • Das Risiko einer unbeabsichtigten Tramadol-Überdosierung in langsamen Metabolisierern würde verringert werden.

The combination of (-) - tramadol and (+) - demethyltramadol according to the invention offers the following advantages in particular:

• • The risk of serotonin syndrome present for tramadol should no longer occur due to the combination according to the invention, since the serotonergic activity of the (+) - tramadol is attributable.
• • The risk of dependency and abuse in the ultrafast metabolizers would be reduced.
• • The risk of inadvertent tramadol overdose in slow metabolizers would be reduced.

All of these advantageous properties, which are associated with a significant clinical benefit, are further arguments that should convince the regulatory authority of a corresponding development.

In a further embodiment, the pharmaceutical composition according to the invention contains the enantiomer ((1S, 2S) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol ((-) - tramadol) in unretarded form and the metabolite ( 1R, 2R) -3- [2 - [(dimethylamino) methyl] -1-hydroxycyclohexyl] phenol ((+) - O-demethyltramadol) in retarded form.

Formulations suitable for sustained release of (-) - tramadol and sustained release of (+) - demethyltramadol may be made by conventional methods known to those skilled in the art, such as e.g. Tie US Pat. Nos. 12 / 225,498 . 12 / 252.117 . 12 / 298.922 . 12 / 336.495 . 12 / 406.272 . 12 / 604.560 . 12 / 644.444 . 5,427,799 . 5,580,578 . 5,591,452 . 6,090,411 . 6,143,327 . 6,245,357 . 6,254,887 . 7,074,430 . 7,611,730 , or US 7,906,141 described. The relevant documents are hereby incorporated by reference and thus are considered part of the disclosure.

In a further embodiment, in the pharmaceutical composition according to the invention, the molar ratio of (-) - tramadol to (+) - O-demethyltramadol is between 1: 1 and 10: 1, preferably between 2: 1 and 8: 1, more preferably between 3 : 1 and 5: 1 and especially 4: 1.

In a particular embodiment, the pharmaceutical composition according to the invention contains 25 mg, 50 mg, 75 mg, 100 mg, 150 mg or 200 mg (-) - tramadol.

In a further preferred embodiment, the pharmaceutical composition according to the invention contains the following amounts of (-) - tramadol and (+) - demethyltramadol (preferred combinations are highlighted in bold): (-) - Tramadol [mg] (+) - Demethyltramadol [mg] (-) - Tramadol [mg] (+) - Demethyltramadol [mg] 25 3 100 20 25 4 100 21 25 5 100 22 25 6 100 23 25 7 100 24 25 8th 100 25 25 9 100 26 25 10 100 27 25 11 100 28 25 12 100 29 50 6 100 30 50 7 100 31 50 8th 100 32 50 9 100 33 50 10 100 34 50 11 100 35 50 12 100 36 50 13 100 37 50 14 100 38 50 15 100 39 50 16 100 40 50 17 150 30 50 18 150 31 50 19 150 32 50 20 150 33 50 21 150 34 75 15 150 35 75 16 150 36 75 17 150 37 75 18 150 38 75 19 150 39 75 20 150 40 75 21 150 41 75 22 150 42 75 23 150 43 75 24 150 44 75 25 150 45 75 26 150 46 75 27 150 47 75 28 150 48 75 29 150 49 75 30 150 50 100 14 150 51 100 15 150 52 100 16 150 53 100 17 150 54 100 18 150 55 100 19 150 56 100 20 150 57 100 21 150 58 100 22 150 59 100 23 150 60 100 24 150 61 (-) - Tramadol [mg] (+) - Demethyltramadol [mg] (-) - Tramadol [mg] (+) - Demethyltramadol [mg] 200 25 200 54 200 26 200 55 200 27 200 56 200 28 200 57 200 29 200 58 200 30 200 59 200 31 200 60 200 32 200 61 200 33 200 62 200 34 200 63 200 35 200 64 200 36 200 65 200 37 200 66 200 38 200 67 200 39 200 68 200 40 200 69 200 41 200 70 200 42 200 71 200 43 200 72 200 44 200 73 200 45 200 74 200 46 200 75 200 47 200 76 200 48 200 77 200 49 200 78 200 50 200 79 200 51 200 80 200 52 200 81 200 53 200 82

In a further embodiment, the pharmaceutical composition of the invention containing a predetermined mg amount of (-) - tramadol is equivalent to a pharmaceutical composition containing twice the amount of racemic tramadol by the addition of the (+) - demethyltramadol ,

The composition of the invention may also contain at least one of these active components, the (-) - tramadol metabolite or the (-) - enantiomer or the (+) - enantiomer of tramadol, in the form of at least one corresponding physiologically acceptable salt.

Preferably, these physiologically acceptable salts are selected from the group comprising chloride, bromide, sulfate, sulfonate, phosphate, tartrate, teoclate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, diclofenacate, naproxenate, salicylate, acetylsalicylate, glutamate , Fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, besylate, mesylate, saccharinate, cyclamate and acesulfamate, and preferably chloride.

The physiologically tolerable salts or acid addition salts can be obtained by the customary methods known to the person skilled in the art, for example by reacting the (+) - O-demethyltramadol or (-) - tramadol with the corresponding acid, preferably in aqueous solution.

Application form and formulation

The pharmaceutical composition according to the invention is preferably suitable for oral or parenteral, and particularly preferably for oral administration. According to the invention, "orally administrable compositions" mean both those which are absorbed in the mouth area and those which are taken via the mouth but are absorbed only in the gastrointestinal tract.

In a preferred formulation, the pharmaceutical composition of the invention is in the form of syrups, transmucosal therapeutic systems, transdermal therapeutic systems, suspensions, tablets, multilayer tablets, dragees, capsules, suppositories, readily reconstitutable dry preparations or powders. In a particularly preferred embodiment, the medicament according to the invention is in the form of tablets, multilayer tablets, capsules or as a suspension.

Subunits in the context of the present invention are solid formulations which, in addition to the respective active ingredient component, may also contain physiologically acceptable auxiliaries.

In a preferred embodiment of the invention, the pharmaceutical composition according to the invention has separately formulated subunits each containing the at least one enantiomer and the at least one metabolite.

In a particularly preferred embodiment, the metabolite (+) - demethyltramadol and the enantiomer (-) - tramadol are contained in separately formulated subunits.

Preferably, the subunits of the pharmaceutical composition of the invention are in multiparticulate form. Preferred multiparticulate subunits are microtablets, microcapsules, granules, drug crystals or pellets. The multiparticulate subunits are particularly preferably in the form of microtablets, granules or pellets.

The formulation of the multiparticulate forms into the pharmaceutical composition according to the invention can be carried out by customary methods known to the person skilled in the art, for example by filling into capsules or sachets, compressing into tablets or by suspending in hydrophilic or lipophilic liquid.

If the pharmaceutical composition according to the invention is in the form of a multilayer tablet, the subunits may be different layers of a multilayer tablet, preferably the layers of a bilayer tablet, or the multiparticulate subunits may be compressed into such layers.

In a further preferred embodiment of the present invention, the pharmaceutical composition according to the invention may contain the retarded metabolite, which is preferably (+) - demethyltramadol, formulated in subunits which may be u. a. with a coating containing the enantiomer, which is preferably (-) - tramadol.

In addition to the active substance-containing coating and optionally sustained-release coating of at least one metabolite, the subunits may optionally also have at least one further non-retarding coating which is applied as a protective layer directly on the surface of the subunits.

If the multiparticulate subunits are granules or pellets, they preferably have a size in the range from 0.1 to 3 mm, particularly preferably in the range from 0.5 to 2 mm.

If the multiparticulate subunits are in the form of microtablets, they preferably have a diameter of 0.5 to 5 mm, more preferably 1 to 3 mm and most preferably 1 to 2 mm.

If the multiparticulate subunits are active substance crystals or microcapsules, they preferably have a diameter of from 10 μm to 1 mm, particularly preferably from 15 μm to 0.5 mm. Most preferably, the diameter is 30 microns to 200 microns.

Depending on the embodiment, the composition according to the invention may also contain, as further constituents, the customary physiologically compatible auxiliaries known to the person skilled in the art.

If the composition according to the invention is present in the form of tablets or microtablets, these may be further physiologically compatible excipients, preferably microcrystalline cellulose, cellulose ethers, lactose, starch, starch derivatives, sugar alcohols and / or calcium hydrogenphosphate and other customary binders known to the person skilled in the art, flow regulators and / or lubricants and optionally disintegrating agents.

If the composition according to the invention is in the form of pellets or granules, these may contain as further physiologically acceptable excipients preferably microcrystalline cellulose, cellulose ethers, lactose, starch, starch derivatives, sugar alcohols, calcium hydrogenphosphate, fatty alcohols, esters of glycerol and / or fatty acid esters.

If the medicament according to the invention is present in the form of microcapsules, these may contain, depending on the nature of the process used to prepare them, the customary physiologically compatible auxiliaries known to the person skilled in the art.

If the composition according to the invention is in the form of a suspension, this may contain, in addition to the physiologically acceptable suspension medium, further customary physiologically acceptable auxiliaries known to the person skilled in the art, such as, for example, PH regulators, osmolality adjusters, surfactants, viscosity regulators, buffers and / or preservatives.

The preparation of the various formulation forms of the composition according to the invention can be carried out by various methods known to the person skilled in the art. If the medicament according to the invention is present in the form of tablets, these can be prepared, for example, by compressing the granules of the enantiomer prepared by wet, dry or melt granulation and the granules of the metabolite which have been prepared in a suitable manner and optionally retarded with other physiologically acceptable auxiliaries. Furthermore, the tablets may be prepared by compression of multiparticulate optionally coated pellets, drug crystals or microcapsules which are retarded for the metabolite component.

The formulations in the form of pellets may preferably be prepared by extrusion and spheronization, by build-up pelletization or by direct pelletization in a high speed mixer or in the rotor fluidized bed with simultaneous or subsequent retardation of the racemic component. Particularly preferred is the preparation of the pellets by extrusion of wet masses and subsequent spheronization. The enantiomeric component is preferably applied in the form of a coating on the pellets.

The production of microcapsules is carried out by conventional microencapsulation processes, such as. Example, by spray drying, spray solidification or coacervation, wherein for the metabolite component, the desired retardation takes place.

In a preferred embodiment of the composition according to the invention, the retardation of the at least one metabolite, which is preferably (+) - demethyltramadol, is based on a retarding coating, embedding in a retarding matrix, attachment to an ion exchange resin or a combination of at least two of them aforementioned retardation methods.

Preferably, the retarding coating is based on a water-insoluble, optionally modified natural or synthetic polymer or on a natural, semi-synthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these aforementioned components.

As water-insoluble polymers, poly (meth) acrylates, more preferably poly (C1-4) -15-alkyl (meth) acrylates, poly (C1-4) -dialkylamino- (C1-4) -alkyl (meth), are preferably used to prepare a retarding coating ) acrylates and / or their copolymers, most preferably ethyl acrylate / methyl methacrylate copolymers having a molar ratio of the monomers of 2: 1, ethyl acrylate / methyl methacrylate / trimethylammoniumethyl methacrylate chloride copolymers having a molar ratio of the monomers of 1: 2: 0 , 1, ethyl acrylate / methyl methacrylate / Trimethylammoniumethylmethacrylatchlorid copolymers having a molar ratio of the monomers of 1: 2: 0.2 or a mixture of at least two of these polymers mentioned above used as a coating material.

These coating materials are available as 30 wt .-% - aqueous latex dispersions under the name Eudragit RS30D ^®, Eudragit NE30D ^® or Eudragit RL30D ^® available on the market and as such are also used as a coating material is preferred.

Likewise preferably preferred as water-insoluble polymers for the production of the retarding coating in the medicament of the invention are polyvinyl acetates, if appropriate in combination with further auxiliaries. These are available as aqueous dispersion containing 27 wt .-% polyvinyl acetate, 2.5 wt .-% povidone and 0.3 wt .-% sodium lauryl sulfate (Kollicoat SR 30 D ^® ) on the market.

In a further preferred embodiment, the retarding coatings of at least one metabolite, which is preferably (+) - demethyltramadol, are based on water-insoluble cellulose derivatives, preferably alkylcelluloses, such as e.g. As ethyl cellulose, or on cellulose esters, such as. B. cellulose acetate as a coating material. The coatings of ethyl cellulose or cellulose acetate are preferably applied from aqueous pseudolatex dispersion. Aqueous ethyl cellulose pseudolatex dispersions than 30 wt .-% - ige dispersions (Aquacoaf ^®) or as a 25 wt .-% - ige dispersions (Surelease ^®) performed in the market and as such are also used as Oberzugsmaterial preferred.

As natural, semi-synthetic or synthetic waxes, fats or fatty alcohols, the retardant coating of racemic tramadol, preferably on carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate (Compritol AT0888 ^® ), glycerol ditripalmitostearate (Precirol AT05 ^® ), microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or a Mixture of at least two of these components are based.

If the retarding coating is based on a water-insoluble, optionally modified natural and / or synthetic polymer, the coating dispersion or solution may, in addition to the corresponding polymer, have a customary physiologically compatible plasticizer known to the person skilled in the art in order to lower the necessary minimum film temperature.

Suitable plasticizers are, for example, lipophilic diesters of an aliphatic or aromatic dicarboxylic acid with C ₆ -C ₄₀ and an aliphatic alcohol with C ₁ -C ₈ , such as. As dibutyl phthalate, diethyl phthalate, Dibutylsebacat or Diethylsebacat, hydrophilic or lipophilic esters of citric acid, such as. For example, triethyl citrate, tributyl citrate, acetyltributyl citrate or acetyl triethyl citrate, polyalkylene glycols, such as. As polyethylene glycols or propylene glycols, esters of glycerol, such as. B, triacetin, Myvacet ^® (acetylated mono- and diglycerides, C23H440S to C2sH4707), medium chain triglycerides (Miglyol ^®), the above-mentioned process oil acid or mixtures of at least two.

Preferably, aqueous dispersions of Eudragit RS ^® and optionally Eudragit RL ^® triethyl citrate contained as a plasticizer.

Preferably, the retardant coating contains the plasticizer (s) in amounts of from 5 to 50% by weight, more preferably from 10 to 40% by weight and most preferably from 10 to 30% by weight, based on the amount of polymer used. In individual cases, for example, for cellulose acetate and higher amounts of plasticizers, preferably up to 110 wt .-% can be used.

Furthermore, the retardant coating further conventional, known in the art auxiliaries, such as lubricants, preferably talc or glycerol monostearate, color pigments, preferably iron oxides or titanium dioxide, or surfactants such. B. Tween 80 ^® exhibit.

The release profile of the sustained-release tramadol racemate of the medicament according to the invention can be determined by the customary methods known to the person skilled in the art, such as, for example, B. be adjusted by the thickness of the coating or by the use of other excipients as constituents of the coating. Suitable auxiliaries For example, hydrophilic or pH-dependent pore formers, such as. Sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, lactose, polyethylene glycol or mannitol or water-soluble polymers such as e.g. As polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.

The retarding coating can also insoluble or lipophilic excipients, such. B. alkylated silica, the z. B. as Aerosil R972 ^® on the market, or magnesium stearate to further enhance the retardation.

The composition according to the invention itself may also have at least one non-retarding coating. This may be, for example, a taste-improving coating or an enteric coating which dissolves in a pH-dependent manner. By the enteric coating it can be achieved that the corresponding formulation of the composition according to the invention passes through the gastric tract undissolved and the active ingredient components are released only in the intestinal tract. Preferably, the enteric coating dissolves at a pH of between 5 and 7.5.

The enteric coating is preferably based on methacrylic acid / methyl methacrylate copolymers with a molar ratio of the respective monomers of 1: 1 (Eudragit L ^®), methacrylic acid / methyl methacrylate copolymers with a molar ratio of the respective monomers of 1: 2 (Eudragit S ^®), methacrylic acid / ethyl acrylate copolymers with a molar ratio of the respective monomers of 1: 1 (Eudragit L30D-55 ^®), methacrylic acid / MethylacrylatlMethylmethacrylat copolymer having a molar ratio of respective monomers 7: 3: 1 (Eudragit FS ^®), shellac Hydroxypropylmethylcelluloseacetatsuccinate , Celluloseacetatphthalate or a mixture of at least two of these components, which may also be used in combination with the above-mentioned water-insoluble poly (meth) acrylates, preferably in combination with Eudragit NE30D ^® and / or Eudragit RL ^® and / or Eudragit RS ^® ,

The retarding and / or non-retarding coatings can according to the usual, suitable for the respective coating, known in the art methods such. B. by spraying solutions, dispersions or suspensions, by melting or by powder application method. The solutions, dispersions or suspensions may be used in the form of aqueous or organic solutions or dispersions. In this case, aqueous dispersions are preferably used.

As organic solvents, alcohols, for example ethanol or isopropanol, ketones, such as. For example, acetone, esters, for example, ethyl acetate, chlorinated hydrocarbons, such as. For example, dichloromethane can be used, with alcohols and ketones are preferably used. It is also possible to use mixtures of at least two of the abovementioned solvents.

If the composition according to the invention comprises the at least one metabolite, which is preferably the (+) - demethyltramadol, in multiparticulate form, the retarding coating is preferably applied in such a way that the multiparticulate forms containing at least one metabolite after their preparation with the respective retarding polymers and optionally physiologically compatible excipients from aqueous and / or organic media, preferably from aqueous media, coated by means of the fluidized bed process and preferably the coating dries simultaneously at conventional temperatures in the fluidized bed, and optionally, if necessary, tempered and / or a coating of ( -) - Apply tramadol.

Preferably, the coating is dried for poly (meth) acrylate coatings at a supply air temperature in the range of 30 to 50 ° C, more preferably in the range of 35 to 45 ° C.

For coatings based on cellulose, such. As ethyl cellulose or cellulose acetate, the drying is preferably carried out at a temperature in the range of 50 to 80 ° C, more preferably in the range of 55 to 65 ° C.

Wax coatings can be applied by melt coating in the fluidized bed and cooled at temperatures below the respective melting range after coating for complete solidification. The application of wax coatings can also be done by spraying their solutions in organic solvents.

To modify the drug release profile, the composition according to the invention may contain the at least one metabolite, which is preferably the (+) - demethyltramadol, also in a retarding matrix, preferably evenly distributed.

As matrix materials it is possible to use physiologically compatible, hydrophilic materials which are known to the person skilled in the art.

The hydrophilic matrix materials used are preferably polymers, more preferably cellulose ethers, cellulose esters and / or acrylic resins. Very particular preference is given to using as matrix materials ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or derivatives thereof, such as their salts, amides or esters.

Also preferred are matrix materials of hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or mixtures thereof. Mono- or diglycerides of C ₁₂ -C ₃₀ fatty acids and / or C ₁₂ -C ₃₀ fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.

It is also possible to use mixtures of the abovementioned hydrophilic and hydrophobic materials as retarding matrix material.

The preparation of the metabolite present in a retarding matrix, which is preferably the (+) - demethyltramadol, can be carried out by the usual methods known to the person skilled in the art, wherein the formulation with the (+) - demethyltramadol can be carried out to the composition according to the invention as indicated above ,

The total amount of the sustained-release and non-delayed-release active substance to be administered to the patient varies, for example, from As a function of the weight of the patient, the indication and the severity of the pain or the disease. Preferably, the amount to be administered of the sustained-release and non-retarded active ingredient and its release is adjusted so that a dose of the drug must be at most twice, preferably only once a day and at the same time a sufficient immediate effect occurs after administration.

indications

Preferably, the composition of the invention is useful in the control of acute or chronic pain or for the treatment of urinary incontinence, attention deficit syndrome, eating disorders, cough, depression, premature ejaculation, restless leg syndrome or diarrhea. The composition according to the invention is particularly preferably used for combating acute or chronic pain.

The composition of the invention has the advantage that it allows the satisfactory control of very severe pain, with the frequency or strength of any undesirable side effects of tramadol, such as. As nausea, vomiting, sweating, dry mouth, dizziness, cramps or dizziness is reduced or does not occur. The (+) - O-demethyltramadol is available immediately after the application of the drug to the patient (without the previously necessary metabolic activation), so that the composition of the invention is particularly suitable for the treatment of very severe acute pain.

definitions

By the invention, an equimolar ratio means a molarity ratio between two compounds which is between 0.9: 1.1 and 1.1: 0.9 and is preferably 1: 1.

In the context of the invention, a racemate means an equimolar mixture of the two enantiomers of a chiral compound (see IUPAC Rule E-4.5). All racemates thus have an enantiomeric ratio of 1: 1. If different diastereomers occur for a stereoisomeric compound, two of the diastereomers can form a racemate as enantiomers.

A metabolite is defined in the context of the invention as a substance which arises as an intermediate or as a degradation product of an active substance through metabolic processes in the organism.

A major metabolite is defined according to the invention as the metabolite that makes up the largest proportion in the organism in comparison with the other metabolites.

In the following the invention will be explained by means of examples. These explanations are merely exemplary and do not limit the general inventive concept.

EXAMPLES

Example 1:

Production of pellets:

Pellets containing the metabolite (+) - demethyltramadol with an active ingredient content of 55% by weight were prepared by aqueous granulation with microcrystalline cellulose and low-substituted hydroxypropylcellulose and subsequent extrusion and spheronization. The pellets thus obtained were dried, screened to a size of 800-1250 microns and then in the fluidized bed at a supply air temperature of 60 ° C first with 3 wt .-% hydroxypropylmethyl cellulose and talc as a coating and then with 11 wt .-% Surelease ^® E-7-7050 filmed as a retarding coating. The film orders are given in percent by weight, based on the initial weight of the pellets or the coated pellets.

Pellets containing the (-) - enantiomer of tramadol having an active ingredient content of 55% by weight were prepared by aqueous granulation with microcrystalline cellulose and low-substituted hydroxypropyl cellulose followed by extrusion and spheronization. The pellets thus obtained were dried and screened to a size of 800 to 1250 microns. These pellets were then coated with a non-sustained-release coating of hydroxypropyl methylcellulose (Opadry OY 29020 Clear ^®).

On a suitable capping machine, size 4 hard gelatin capsules containing 26.5 mg of delayed-release pellets containing (+) demethyltramadol (corresponding to 12.5 mg (+) demethyltramadol) and 94 mg of the unretarded pellets containing the (-) enantiomer of tramadol (corresponding to 50 mg (-) tramadol hydrochloride). Composition per capsule: Pellets containing (+) demethyltramadol: 26.5 mg (+) Demethyltramadol hydrochloride 12.5 mg Microcrystalline cellulose 5.4 mg (Avicel PH 105 ^® from FMC) Low substituted hydroxypropyl cellulose 5.11 mg (I-HPC LH 31 ^® from ShinEtsu) hydroxypropyl methylcellulose 0.60 mg Opadry OY 29020 clear ^® (Colorcon) talc 0.2 mg ethylcellulose 2.78 mg 15 Sure / ease E-7-7050 ^® (Colorcon) Pellets containing the (-) - tramadol 94.0 mg (-) - tramadol 50.0 mg Microcrystalline cellulose 21.0 mg (Avicel PH 105 ^® from FMC) Low substituted hydroxypropyl cellulose 20.0 mg (I-HPC LH 31 ^® from ShinEtsu) hydroxypropyl methylcellulose 2.4 mg 25 Opadry OY 29020 clear ^® (Colorcon) talc 0.6 mg

The release of the metabolite and the (-) - tramadol from the pharmaceutical composition according to the invention was determined as follows:
The respective formulation of the inventive composition was in the rotary basket apparatus or Blattrührerapparatur of Pharm. Eur. At a temperature of the release medium of 37 ± 0.5 ° C at a revolution speed of 100 revolutions per minute in the case of Drehkörbchenapparatur or 75 revolutions per minute in the case of Leaf-stirring apparatus was tested for 2 hours in 600 ml of artificial gastric juice at pH 1.2 without enzymes. Subsequently, the formulation was further tested for 8 hours in 600 ml of artificial intestinal juice at pH 7.2 without enzymes. The amount of (+) - tramadol and (-) - tramadol released each time was determined by HPLC. The values shown are the mean values of 6 samples each.

The release profile was determined according to the above-mentioned method in the rotary basket apparatus and is shown in Table 1 below. Tab. 1: Release profile of the capsules from Example 1 Time in minutes Released fraction of (-) - tramadol in mg Released fraction of (+) - demethyltramadol in mg 30 50 0 120 50 1.0 240 50 3.6 360 49 7.4 480 49 10.2 600 50 12.3

Example 2:

Pellets containing the (+) - demethyltramadol and pellets containing the (-) - enantiomer of the tramadol of the compositions given below were prepared and coated analogously to Example 1.

On a suitable capping machine were then size 3 hard gelatin capsules with 52.9 mg of delayed-release pellets containing (+) demethyltramadol (corresponding to 25 mg (+) demethyltramadol) and 188 mg of the unretarded pellets containing the (-) - enantiomer of tramadol (corresponding to 100 mg (-) tramadol hydrochloride). Composition per capsule: Pellets containing (+) demethyltramadol: 52.9 mg (+) Demethyltramadol hydrochloride 25.0 mg Microcrystalline cellulose 10.7 mg (Avicel PH 105 ^® from FMC) Low substituted hydroxypropyl cellulose 10.2 mg (I-HPC LH 31 ^® from ShinEtsu) hydroxypropyl methylcellulose 1.2 mg Opadry OY 29020 clear ^® (Colorcon) talc 0.4 mg ethylcellulose 5.4 mg Sure / ease e-7-7050 ^® (Colorcon) Pellets containing the (-) - tramadol 188.0 mg (-) - tramadol 100.0 mg Microcrystalline cellulose 42.0 mg (Avicel PH 105 ^® from FMC) Low substituted hydroxypropyl cellulose 40.0 mg (I-HPC LH 31 ^® from ShinEtsu) hydroxypropyl methylcellulose 4.8 mg Opadry OY 29020 clear ^® (Colorcon) 1.2 mg talc

The release profile was determined according to the above-mentioned method in the rotary basket apparatus and is shown in Table 2 below. Tab. 2: Release profile of the capsules from Example 2 Time in minutes Released fraction of (-) - tramadol in mg Released fraction of (+) - demethyltramadol in mg 30 99 0 120 100 1.6 240 101 3.9 360 100 15.2 480 101 20.6 600 100 24.5

Example 3:

The metabolite (+) - demethyltramadol hydrochloride is homogeneously mixed with microcrystalline cellulose, hydroxypropylmethylcellulose, fumed silica and magnesium stearate in a cube mixer. (-) - Tramadol hydrochloride is homogeneously mixed with microcrystalline cellulose, fumed silica and magnesium stearate in a cube mixer. The two mixtures are then pressed on a tablet press (Korsch EKO) eccentric to two-layer tablets with a mean diameter of 12 mm, first the 200 mg powder mixture of the first layer are filled into the template, pre-pressed by hand and after addition of the 200 mg mixture of second layer the tablets end-pressed. Composition of the bilayer tablet: 1st shift (+) - Demethyltramadolhydrochlorid 25.0 mg Microcrystalline cellulose (Avicel PH 101 ^® from FMC) 95.0 mg Hydroxypropylmethylcellulose Type 2910, 100,000 mPas 74.0 mg (Metalase 90 SH 100000 ^® ShinEtsu) Colloidal anhydrous silica (Aerosi ^®, Degussa) 3.0 mg magnesium stearate 3.0 mg Total (1st shift) 200 mg 2 layer (-) - tramadol 100.0 mg Microcrystalline cellulose (Avicel PH 101 ^® from FMC) 96.0 mg Colloidal anhydrous silica (Aerosil ^®, Degussa) 2.0 mg magnesium stearate 2.0 mg Total (2nd shift) 200 mg Total (two-layer tablet) 400 mg

Figure legends

1 : Metabolism of tramadol in humans

2 : Incidence of cytochrome P450 CYP2D6 phenotypes in different ethnic groups

3 : The Four Classes of Cytochrome P450 CYP2D6 Enzyme Metabolizers Based on a US Study of Sparteine Metabolism. The median and areas of the metabolic quotient (MR _a ) correspond to a genotype that contains 0.1, 2 or 3 functional genes (see double arrows). A gene dose of ½ indicates a functional gene with decreased activity (eg, CYP2D6 * 41, CYP2D6 * 9, or CYP2D6 * 10). Abbreviations: EM, Fast Metabolizer; IM, intermediary metabolizer; MR, metabolic quotient; PM, slow metabolizer; UM, ultrafast metabolizer (out Bernard et al., 2006 )

Literature:

• Bernard S et al .: "Interethnic differences in genetic polymorphisms of CYP2D6 in the US population: clinical implications.", Oncologist 2006, 11 (2): 126-35 ,
• Dayer P et al: "Pharmacology of tramadol", Drugs 1997, 53 (Suppl. 2): 18-24 ,
• Desmeules J et al .: "Contribution of monoaminergic modulation to the analgesic effect of tramadol", Br. J. Clin. Pharmacol. 41 (1): 7-12
• Enggaard TP et al .: "The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6." Anesth. Analg. 2006, 102 (1): 146-50 ,

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• US 3652589 [0037]
• EP 0787715 B1 [0037]
• US 12/225498 [0045]
• US 12/252117 [0045]
• US 12/298922 [0045]
• US 12/336495 [0045]
• US 12/406272 [0045]
• US 12/604560 [0045]
• US 12/644444 [0045]
• US 5427799 [0045]
• US 5580578 [0045]
• US 5591452 [0045]
• US 6090411 [0045]
• US 6143327 [0045]
• US 6245357 [0045]
• US 6254887 [0045]
• US 7074430 [0045]
• US 7611730 [0045]
• US 7906141 [0045]

Cited non-patent literature

• Desmeules et al., 1996 [0008]
• Raffa et al., 1992 [0008]
• Desmeules et al., 1996 [0008]
• Dayer et al., 1997 [0008]
• Enggaard et al., 2006 [0008]
• Frankus et al. (Arzneimittel-Forschung, Drug Res., 28, pp. 114-121, 1978) [0037]
• Bernard et al., 2006 [0121]

Claims (18)

Pharmaceutical composition for an active substance present as a racemate, comprising: a) a first enantiomer of this active substance, b) optionally a second enantiomer of this active substance, which is present in equimolar ratio to the first enantiomer, b) at least one metabolite of the second enantiomer of this active substance, wherein the second enantiomer has been replaced by at least 50%, preferably at least 75%, more preferably at least 80% and most preferably 100% by a bioequivalent amount of one or more of these metabolites. A pharmaceutical composition according to claim 1, wherein the second enantiomer has been replaced by a metabolite which is the major metabolite of this enantiomer. A pharmaceutical composition according to claim 1 or 2, wherein the at least one enantiomer is contained in non-retarded form and the at least one metabolite is in retarded form. A pharmaceutical composition according to claim 1 or 2, wherein the at least one enantiomer and the at least one metabolite are contained in retarded form and wherein the release of the at least one metabolite is retarded to the at least one enantiomer. A pharmaceutical composition according to claims 1 to 4, wherein the racemic active substance is selected from the group comprising acebutolol, acenocoumarol, 3-amino-1-hydroxypyrrolid-2-one (HA-966), albendazole, albuterol, alogliptin, aprenolol, amphetamine, Atamestane, atenolol, atorvastitin, azlocillin, aztreonam, baclofen, bambuterol, benazepril, betaxolol, bicalutamide, bromophenauramine, bufuralol, bupivacaine, captopril, carvedilol, cefalexin, cefaloglycine, cefamandole, cefamandole, cefapirin, cefazaflur, cefonicid, ceforanide, cefpimizole, cefradine, Cefroxadine, Ceftezole, Cefuroxime, Chloroquine, Chlorpheniramine, Cilazapril, Clenbuterol, Cloxacillin, Clopidogrel, Cyclophosphamide, Delapril, Dexrazoxane, Disopyramide, Dobutamine, Eflornithine, Enalapril, Esmolol, Ethosuximide, Ethambutol, Felodipine, Fenfluramine, Flecainide, Fluoxetine, Flurbiprofen, Fomocaine Formoterol, halofantrine, hexobarbital, hydroxychloroquine, hydroxymebendazole, idapril, ifosfamide, ilaprazole, indacrinone, isopre nalin, ketamine, ketoconazole, ketoprofen, labetalol, lansoprazole, loratidine, losigamon, lumefantrine, medetomidine, mefloquine, mephobarbital, methadone, methamphetamine, methorphan, 3,4-methylenedioxymethamphetamine (MDMA), mephenytoin, methylphenidate, metoprolol, mianserin, milnacipran, mirtazapine , Modafinil, Moxalactam, Naproxen, Nateglinide, Nicardipine, Nimodipine, Nisoldipine, Paliperidone, Pantoprazole, Pentobarbital, Pindolol, Praziquantel, Prilocaine, Primaquine, Propafenone, Propranolol, Propoxylene, Quinacrine, Rabeprazole, Racecadotril, Racemorphan, Rasagiline, Razoxan, Reboxetine, Salmeterol , Secobarbital, Selegiline, Sibutramine, Sotalol, Stiripentol, Tafenoquine, Tenatoprazole, Terbutaline, Terfenadine, Tetramisole, Thiopental, Thiohexital, Thioridazine, Tocainide, Tramadol, Trimetoquinol, Valsartan, Verapamil, Warfarin, Zopiclone and preferably tramadol. A pharmaceutical composition according to any one of the preceding claims, wherein it comprises (1S, 2S) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol ((-) - tramadol) and (1R, 2R) -3- [2 - [(dimethylamino) methyl] -1-hydroxycyclohexyl] phenol ((+) - O-demethyltramadol). A pharmaceutical composition according to claim 6, wherein the molar ratio of (-) - tramadol to (+) - O-demethyltramadol is between 1: 1 and 10: 1, preferably between 2: 1 and 8: 1, more preferably between 3: 1 and 5: 1 and in particular 4: 1. A pharmaceutical composition according to claim 7, wherein it contains 25 mg, 50 mg, 75 mg, 100 mg, 150 mg or 200 mg (-) - tramadol. Pharmaceutical composition according to one of the preceding claims, characterized in that at least one of the active ingredient components is in the form of at least one of its corresponding physiologically acceptable salts. The pharmaceutical composition according to claim 7, wherein the physiologically acceptable salt is selected from the group comprising chloride, bromide, sulfate, sulfonate, phosphate, tartrate, teoclate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, diclofenacate, naproxenate , Salicylate, acetylsalicylate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, besylate, mesylate, saccharinate, cyclamate and acesulfamate and preferably the chloride. Pharmaceutical composition according to one of the preceding claims for oral or parenteral, preferably for oral administration. A pharmaceutical composition according to any one of the preceding claims, wherein it comprises the at least one enantiomer and the at least one metabolite, each in separately formulated subunits. A pharmaceutical composition according to claim 12, wherein the subunits are different layers of a multilayer tablet, preferably the layers of a bilayer tablet. A pharmaceutical composition according to claim 12, wherein the subunits are in multiparticulate form, preferably in the form of microtablets, microcapsules, granules, drug crystals or pellets. A pharmaceutical composition according to claim 12, wherein it comprises the at least one metabolite in retarded subunits equipped with a coating containing the at least one enantiomer. A pharmaceutical composition according to any one of claims 3 to 15, wherein the retardation is effected by a retarding coating, by embedding in a retarding matrix, by attachment to an ion exchange resin or a combination of at least two of these retardation methods. A pharmaceutical composition according to claim 16, wherein the retarding coating is based on a water-insoluble optionally modified natural or synthetic polymer or on a natural, semisynthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these components. A pharmaceutical composition according to any one of the preceding claims for use in the treatment of a disease selected from the group comprising acute pain, chronic pain, urinary incontinence, attention deficit syndrome, eating disorders, cough, depression, premature ejaculation, restless leg syndrome or diarrhea.

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