MXPA00007922A - Pharmaceutical combinations containing tramadol - Google Patents

Abstract

The invention relates to the use of pharmaceutical combinations containing as active ingredients tramadol or one of its enantiomers or one of its pharmaceutically acceptable salts and metoclopramide, domperidone or other substances having a prokinetic and antiemetic action or one of their pharmaceutically acceptable salts. Said pharmaceutical combinations are used for the treatment of migraine and migraine-like headaches and for the treatment of pain accompanied by nausea and/or vomiting (for example during chemotherapy) and/or delayed gastric emptying (for example postoperatively in diabetic gastroparesis).

Description

PHARMACEUTICAL COMBINATIONS WITH TRAMADO !. DESCRIPTION OF THE INVENTION The present invention relates to the use of pharmaceutical combinations containing as active ingredients tramadol or one of its enantiomers or one of its pharmaceutically acceptable salts and metoclopramide, domperidon or other substances with prokinetic and antiemetic activity, or one of its pharmaceutically acceptable salts for the treatment of migraine and migraine headaches, as well as for the treatment of pain states that are accompanied by nausea and / or vomiting (for example under chemotherapy) and / or a delayed evacuation of the stomach ( example postoperatively in the case of diabetic gastroparesis). Migraine is a disease with recurrent headache attacks that last for 4-72 hours. Migraine attacks are preponderantly unilateral headaches, which begin in a deaf form to become pulsating medium to strong intensity. The typical concomitant symptoms of migraine are an ultrasusceptibility towards light and noise, paleness of the face, nausea and vomiting with or without focal phenomena such as prodromal state. Migraine (common) without aura differs from migraine (classic) with aura, which in each case begins with a scintillating scotoma. There is a complicated migraine if visual disturbances last for days or if other focal neurological symptoms occur with the special known forms of retinal, basal, ophthalmoplastic, aphasic or hemiplegic migraine. There are several ideas about the pathomechanism of migraine. The old hemodynamic idea according to which the initial neurological symptoms are triggered by a regional intracranial vasoconstriction and the pulsating headache subsequent to an extracranial vasodilatation with channeling of the pain through the ophthalmic nerve and the trigeminal nerve only explains the processes of the migraine in an insufficient form. The regional cerebral blood supply is reduced occipitally in the case of a migraine attack with aura, being that the slow emigration of the cortical oligohemia with transgression of the supply areas of individual arteries induces to believe that not only vasomotor phenomena participate but also electrophysiological according to what is known as "spreading depression" (spreading of depression) (Spierings ELH (1988), Recent advances in the understanding of migraine, Headache 28: 655-658). Other diagnoses lead us to believe that the accompanying headache is not only triggered by an extracranial vasodilation but also by a central reduction of the pain threshold, since in the cells of the spinal cord and brain stem are activated what is known as fast induction genes after noxious excitation (IEG's immediate early genes) (Zimmermann, M. (1995); Neurobiology of Schmerzsystems, Neuroforum 1/95: 34-45). Another theory - the model of neurogenic inflammation - offers the possibility of explaining both the variation in blood flow as well as the increased algesia of the vessels during the migraine attack. According to it, the increase in algesia is caused by an increase in the susceptibility of the perivascular sensory fibers of the trigeminal vascular system. Due to this increase in susceptibility, vascular pulsations that are not normally in a position to trigger painful sensations are powerful algebraic excitations and condition the pulsing pulsating pain of migraine. Neurogenic inflammation is triggered by the noxious stimulation of the perivascular nerve fibers of the meningeal blood vessels. Neuropeptides such as substance P, neurochitin A, and CGRP (calcitonin-related gene peptide) are spilled at the ends of the nerves that are likely to be simultaneously nociceptors, which are in a position to trigger Neurogenic inflammation. It can even be seen that the CGRP appears multiplied in the venous blood of the head. By spilling the neuropeptides a vicious circle is activated: peptide release vasodilation and increased capillary permeability-increased excitation of the nociceptors-increased release of the peptides. The active substances sumatriptan and ergotalcaloid inhibit the release of neuropeptides and thus interrupt the cycle that triggers the pain (Zimmermann, M.; Chronische Sch erzen und ihre Ursachen, Deutsches Arzteblatt 93, Heft 43, 1996: A-2749-2752). Other results induce to believe in a primary neuropathic hypothalamic dysfunction, with vasoactive serotonin that spills in the reduced form of brainstem rafenuclei during the migraine attack plays a decisive role (Ferrari MD et al. (1989): Serotonin metabolism in migraine, Neurology 39: 1239-1242; Pramod R. et al. (1989): 5-HTl-like receptor agonists and the pathophysiology of migraine, Trends in Pharmacological Sciences 10, 200-204). Despite the many hypotheses and conceptions of complicated patterns, until now the pathogenesis of migraine is not understood. Migraine has a multifactorial origin with genetic disposition, trigger mechanisms external (such as alcohol) and internal (such as hormones). It is not a psychosomatic disease even when psychic factors can trigger an attack. For the treatment of migraine a multitude of preparations are known which contain one or several active ingredients in a fixed combination. Generally for the treatment of mild migraine attacks, antiemetics such as metoclopramide or domperidone are recommended alone or in combination with non-opioid analgesics, such as acetylsalicylic acid, paracetamol, ibuprofem or naproxen. In the case of moderately severe to severe migraine attacks, antiemetics are used in combination with ergot alkaloids, such as ergotamine or dihydroergotamine, or sumatriptan as remedies. The frequent side effects of ergotamine and dihydroergotamine are nausea, vomiting, vomiting, headaches, myalgias and a general feeling of cold, that is, symptoms that with the wrong assumption of a prolonged migraine attack can lead to to the repeated ingestion of these preparations and consequently to the overdose. Frequent use can cause permanent headaches that promote the abuse of ergotamine. Serious side effects may include blood supply disorders, coronary heart disease (CHD), occlusion of the arteries (OA), hypertension and chest pain. Ergoalkaloids should not be used during pregnancy and during lactation as well as in children under 12 years of age. Sumatriptan and its derivatives (almotriptan, eletriptan, naratriptan, rizatriptan, zolmitriptan) are very effective remedies for migraine that in the case of oral administration are superior to the individual substances ergotamine, acetylsalicylic acid or metoclopramide. There is a contraindication for sumatriptan in the case of children, during pregnancy and during lactation, in the case of patients older than 65 years and in the case of patients with coronary heart disease. Undesired effects may include sensations of pressure and heat, a general feeling of weakness, feeling of constriction in the chest, hypertension, coronary heart disease (CC), myocardial infarction, angina. Since during the migraine the evacuation of the stomach is inhibited or delayed considerably, and since the stomach is of subordinate importance as a site of resorption of drugs due to the relatively small resorption surface and the vascularization considerably smaller in comparison with the small intestine In the case of a migraine attack there is only an insufficient or very delayed resorption of the analgesic in time. Therefore, the time of evacuation of the stomach plays a very important role in terms of the speed of the entry into action of the analgesic. By means of prokinetics such as metoclopramide or domperidon it is possible to accelerate the evacuation of the stomach and with it the resorption of the analgesic. However, metoclopramide and domperidon not only have their justification in migraine therapy for its prokinetic effects, but also due to its activity against symptoms such as nausea and vomiting., which frequently occur as concomitant symptoms in migraine. Migraine drug therapy is symptomatic in nature, it does not cure the disease. Mixed preparations of non-opioid analgesics and mixed preparations of ergot alkaloids are not recommended because, in the case of prolonged use, especially with daily use, they cause headaches. In addition, damage to the liver and kidney is possible, such as what is known as analgesic nephropathy, as a consequence of the prolonged ingestion of combinations of analgesics. Opioid analgesics are usually not suitable for migraine therapy because of their abuse and potential for dependence. The following combinations are known from the patent literature for the treatment of migraine: paracetamol and metoclopramide (EP 011 489, EP 011 490, US 5 437 874, EP 695 546, EP 774 253) - acetylsalicylic acid or its acetylsalicylate of L-lysine and metoclopramide (EP 606 031) analgesic (as acetylsalicylic acid), antiemetic (such as metoclopramide) and an antacid (CA 20 20 018). The foregoing combinations of analgesics listed in the patent literature are generally suitable for the treatment of mild migraine attacks. For the treatment of moderately severe to severe migraines are not adequate. In the case of severe migraine, ergoalkaloids are usually indicated in combination with an antiemetic or sumatriptan. The disadvantage is that the therapy with ergoalkaloids or sumatriptan can present a multitude of cardiovascular side effects, in part serious, such as angina pectoris, coronary heart disease (CHD), hypertension and myocardial infarction.

Therefore there continues to be a great need for a reliable analgesic which in the case of moderately strong to strong migraine attacks has good activity and few side effects. Accordingly, the task of the present invention is in particular to provide an improved therapeutic preparation for the treatment of moderately severe to severe migraine attacks. Accordingly, the invention relates to the object claimed in the patent claims. Tramadol (1RS, 2RS) -2 [(dimethylamino) methyl] -l- (3-methoxyphenyl) -cyclohexanol is an analgesic which is effective in the case of moderately strong to severe pain. Tramadol belongs to the group of opioids with weak activity. Tramadol is distinguished in comparison with other opioids by a lesser development of tolerance in terms of analgesic activity, by the absence to a large extent of typical side effects of opioids, as well as by a very reduced dependence potential. The analgesic effect of tramadol includes both opioid and non-opioid components, the latter through the release of serotonin (5-HT) and the inhibition of the reuptake of serotonin and norandrenaline in the central nervous system (CNS).

The non-opioid active components contribute substantially to the analgesic activity of tramadol. The reabsorption of norandrenaline is preferentially inhibited by the (-) enantiomer, and the release of serotonin as well as the inhibition of serotonin reuptake from the synaptic interstitium is mainly caused by the (+) enantiomer. Both enantiomers contribute to the analgesic activity in humans. During treatment with tramadol, nausea, vomiting, sweating, dry mouth, dizziness and stupor may occur as undesirable effects. Rarely gastrointestinal disorders or various psychic side effects are observed. The compounds with prokinetic activity whose main representatives are metoclopramide and domperidon increase the tonicity of the sphincter of the lower esophagus and accelerate the evacuation of the stomach and passage through the small intestine. Simultaneously these active ingredients are applied as antiemetics, that is to suppress nausea, the urge to vomit and vomit. Metoclopramide and domperidon are indicated in the case of gastroparesis, which may occur after an operation and in the case of some major diseases (for example, diabetes mellitus and others). They are also administered in the case of functional dyspepsia (irritated stomach), whose origin is supposed to be gastrointestinal motility disorders. They are also indicated for migraine and other algemic diseases that are accompanied by disorders of stomach evacuation. It was surprisingly found that the administration of tramadol in combination with antiemetics of prokinetic activity provides a better remedy for the treatment, in particular, of moderately severe to severe migraine attacks. In general, opioids are not suitable for the treatment of migraine since they suffer from a multitude of side effects and can lead to psychic and physical dependence. In addition, opioids often have a constipating effect, which increases the stomach atony that motivates migraine, and consequently resorption and the entry into action of the analgesic is delayed. One exception among opioid analgesics is tramadol, which does not show these serious side effects, which are typically seen in the use of opioids. Surprisingly it was also found that by the combination according to the invention of tramadol and in particular metoclopramide, the migraine attack can be effectively cut off and the onset of the symptoms of nausea and vomiting prevented. This is all the more surprising because tramadol itself can trigger nausea and vomiting or intensify these concomitant symptoms of migraine. For this reason, tramadol in the past was considered inadequate for the treatment of migraine as monopreparation. Through the combination with metoclopramide it is also possible to provide for the treatment of migraine the analgesic tramadol, very effective in the case of moderately strong and strong pains. Since in the case of migraine, metoclopramide has an analgesic effect of its own, as verified by the placebo-controlled studies, it can be expected that with the simultaneous administration of tramadol and metoclopramide there will also be a synergistic analgesic effect. In addition, the fixed combination can improve the tolerance of tramadol, accelerate the resorption of tramadol in the gastrointestinal tract and prevent the onset of the concomitant symptoms of migraine, which are nausea and vomiting. The tramadol and metoclopramide or domperidone substances as a combination partner in a fixed pharmaceutical preparation are also suitable for their pharmacokinetic and pharmacokinetic properties. The duration of the analgesic activity of tramadol is approximately 4-7 hours with a terminal half-life of approximately 5-6 hours. The duration of the prokinetic activity of metoclopramide and domperidon is approximately 1-2 hours, that of antiemetics approximately 3-5 hours. The half-life is 4-6 hours. In another embodiment of the present invention the combinations may additionally contain non-spheroidal antiphlogistics (FNEAI), such as acetylsalicylic acid, ibuprofen, naproxen or also paracetamol. By this, on the one hand, it is possible to take advantage of various mechanisms of analgesic activity (the central activity of tramadol and the analgesic and inhibitory activity of peripheral and central inflammation of non-spheroidal antiphlogistics) for the treatment of moderately severe to severe migraine attacks. Sual may have significance in the case of migraine-resistant forms of therapy. On the other hand it is possible to reduce the total dose of tramadol and the additional partner with analgesic activity of the combination while preserving the same or better activity on the algesic course, and to reduce or prevent undesirable effects (for example, gastrointestinal discomfort in the case of FNEAI's) by a suitable composition of the combination partner. The combinations indicated are particularly suitable for the treatment of moderately strong to severe migraine headaches or migraine headaches. In addition, these combinations are suitable for the treatment of; moderate to severe strong acute and chronic pain accompanied by nausea and / or vomiting (eg, vomiting conditioned by chemotherapy), acute and chronic pain moderately strong to strong, with simultaneous existence of disorders of stomach evacuation (eg after an operation or in the case of diabetic gastroparesis and others), and - in the case of nausea or vomiting under tramadol therapy. Clinical trials will explain in more detail the effectiveness of the combinations claimed for the treatment of migraine, based on the combination of tramadol and metoclopramide. Eight patients with moderately strong to strong migraine headaches who did not respond sufficiently to treatment with weakly acting analgesics (for example acetylsalicylic acid, ibuprofen or paracetamol) were included in the observation of the application. The intensity of the migraine headaches and the expression of the concomitant symptoms existing before the beginning of the treatment were documented, and the effect was assessed by the patient during the later course of the treatment. The intensity of the pain before and after the ingestion of the medications was measured on an EAV scale of 100 mm in length at 0, 30 min, 1 h, 2 h, 4 h, 6 h and 12 h. The expression of the concomitant symptoms of migraine and its variation after the ingestion of the drugs was documented on a multi-stage verbal evaluation scale. With regard to activity and tolerance, the patient could also issue a global opinion. Of the 8 patients treated, seven were female and one male. The average age of the patients was 44.7 years (35-63 years). Body stature and body weight averaged 169.3 cm (159-186 cm) and 70.4 kg (55-103 kg). All patients met the ICC diagnostic criteria for the diagnosis of migraine and had already suffered at least 5 attacks of migraine lasting 4-72 hours. The location of the headaches was strictly unilateral, the intensity of the headaches increased with the corporal activity. All patients simultaneously suffered from nausea and susceptibility to noise during headache attacks, 28% of patients additionally vomiting, and 43% susceptibility to light. Migraine had been on average 15.3 years (2-38 years); the average frequency of attacks was 4.1 days per month (2-8 days / month). During the period of the investigation, patients suffered 11 acute attacks of migraine that were treated with the free combination of tramadol and metoclopramide. All patients ingested the drugs simultaneously in a single oral dose of 100 mg of tramadol (2 capsules of tramadol AWD with 50 mg of hydrochloride of tramadol) and 10 mg of a solution of metoclopramide (30 drops of a solution of 5 mg of metoclopramide Te mler). Before the documented treatment, the patients indicated that the migraine pains were from strong to very strong. On average, the starting pain was 75 ± 7 mm (62-83 mm) on the EAV scale. Two patients who in each case treated two migraine attacks did not show an improvement of the pain with the treatment and were declared as non-responders.(which do not respond to treatment) and were removed from the analysis. There were 6 patients who treated 7 migraine attacks. For the quantification of headaches, an EAV scale of 100 mm in length was used in this study, which is also generally used in other studies on algesias. Headaches were assessed grossly based on the following classification: 0 mm (grade 0, absence of headache) 1-30 mm (grade 1, slight headache) 31-60 mm (grade 2, pain Semigraves) 61-100 mm (grade 3, strong to very strong headache) In studies on migraine, the percentage of patients in whom over a defined period is usually considered a criterion of success. of time (most of the time after 2 or 4 hours) there is an improvement in the intensity of the headache from 3 or 2 to 1 or 0.

Table 1: Responders to tramadol-metoclopramide: difference in the intensity of the headache with respect to the starting pain in mm EAV (the values in parentheses reproduce the percentage variation of pain intensity). 00 * missing value On the other hand, according to the aforementioned convention of the opinion on success or effectiveness of the migraine remedies, in Table 2 we have also indicated the success of the treatment as a percentage of the patients who registered an improvement in the degree of intensity from headaches of grade 3 or 2 to grade 1 or 0 (even those who do not respond to treatment). Table 2: improvement in the intensity of headaches from grade 3 or 2 to grade 1 or 0 as a function of time after oral administration of tramadol capsules of 100 mg and 10 mg of metoclopramide solution On average, the headaches in the group of patients responding to treatment had already improved within 30 minutes by 24.3% and after 2 hours by 51.1% in relation to the initial pain, after ingestion of the free combination of tramadol and metoclopramide. After 4 and 6 hours, the reduction in pain intensity was on average 65.6% and 77.5% (see Table 1). For the whole group of treated patients (which includes patients who do not respond to treatment), an effectiveness (improvement in headaches from intense or semi-intense to light or absent) of 25% after 30 minutes and 75% after of two hours (see table 2). In summary it can also be derived from the available data that the combination of tramadol and metoclopramide in the administered dosage can be a very promising alternative to the migraine remedies available so far that are used therapeutically in the case of acute migraine headaches Moderately intense to intense. These combinations can be administered in the form of tablets, effervescent tablets, capsules, granules, powders, delayed tablets, delayed capsules (single or multiple unit formulations), ampoules for intravenous and intramoscular injections, and in the form of solutions of infusions, suspensions, Suppositories and other suitable forms of medication.

Delayed forms of medication may contain the active ingredients in a fully or partially delayed form with or without an initial dose ratio. The active ingredients can exist together or in formulations partially or totally independent of each other, so that an independent or stepwise administration is also possible. If these completely independent formulations exist, they adapt to one another and contain the respective active ingredients in the dosage unit in the same quantities and proportions by weight corresponding to those existing in the combined mixture. In these pharmaceutical compositions the active ingredients may also exist in the form of their pharmaceutically applicable salts. Pharmaceutical compositions for oral administration are preferred, in which the indicated combinations are contained. For the preparation of the pharmaceutical preparations containing these combinations, the active ingredients are formulated in the desired manner in the amounts indicated with vehicles and / or diluents and / or physiologically acceptable auxiliary substances. Examples for the carrier and auxiliary substances are gelatin, natural sugars such as sucrose or lactose, lecithin, pectin, starch (for example corn starch or amylase), cyclodextrin and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic , alginic acid, tylose, talc, lycopodium, silicic acid, calcium hypophosphate, cellulose, cellulose derivatives such as methyloxpylcellulose, methylcellulose, hydroxpylmethylcellulose, hydroxpylmethylcellulose phthalate, fatty acids with 12 to 22 carbon atoms, emulsifiers, oils and fats, in particular also glyceric esters and polyglycerol esters of vegetable origin from saturated fatty acids, mono- or polyvalent alcohols and polyglycols such as polyethylene glycols, saturated or unsaturated aliphatic fatty acid esters with 2 to 22 carbon atoms, with monovalent aliphatic alcohols with 1 to 20 carbon atoms or polyvalent alcohols such as glyc oles, glycerin, diethylene glycol, propylene glycol 1,2, sorbitol, mannitol. Additional auxiliary substances also include substances which promote disintegration (known as disintegrants), crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, microcrystalline cellulose. Likewise, known wrapping substances can be used. Polymers as well as copolymers of acrylic acid and / or methacrylic acid and / or its esters, ceina, ethylcellulose, ethylcellulose succinate, shellac. Plasticizers for the surrounding substances may be considered: Citric acid and tartaric acid ester, glycerin and glycerin ester, polyethylene glycol of various chain lengths. For the preparation of solutions or suspensions, for example, water or physiologically acceptable organic solvents such as alcohols or fatty alcohols are suitable. For liquid preparations, the use of preservatives such as potassium sorbate, methyl-4-hydroxybenzoate or propyl-4-hydroxybenzoate, antioxidants such as ascorbic acid and flavor improvers such as peppermint oil may be required. In preparing the preparations, known and common solubility promoters or emulsifiers such as polyvinylpyrrolidone and polysorbate 80 can be used. For other examples of the vehicle and auxiliary substances that are considered, we also refer to the book "Lexikon der Hilfsstoffe für Pharmazie , Kosmetik an angrenzende Gebiete "by Dr. HP Fiedler. In pharmaceutical preparations containing the combinations of antiemetics of prokinetic activity and tramadol, the ratio should be from 1: 4 to 1: 10. These pharmaceutical preparations usually contain as individual doses 5-80 mg of an antiemetic or of a its salts and 50-400 mg of tramadol or one of its salts. In this the daily dose should preferably contain 20-80 mg of antiemetic and 200-400 mg of tramadol. The daily doses mentioned can be applied depending on the therapeutic indication either in the form of a single administration of the total amount or in the form of 2 to 4 partial doses per day. An administration of 2 to 4 times per day is generally preferred. The following examples should further explain the invention and therefore do not represent a definitive enumeration. Example 1 Preparation of a metoclopramide solution. 802.4 g of purified water are placed in a suitable vessel and, under stirring, they are added and stirred until all the components are dissolved. 4.7 g of metoclopramide hydrochloride-1-H20, 0.1 g of ascorbic acid, 170.1 g of sorbitol, 2.8 g of potassium sorbate and a pressure consisting of 18.9 g of 96% ethanol (v / v), 0.7 g of methyl-4-hydroxybenzoate and 0.3 g of propyl-4-hydroxybenzoate. The solution is filtered through a suitable filter.

Filling the solution: The solution is filled into suitable dropper bottles in a suitable filling machine. Example 2 Preparation of the tramadol solution 484.2 g of purified water are placed in a suitable container and under agitation are added and stirred until all the components are dissolved, 100.0 g of tramadol hydrochloride, 1.5 g of potassium sorbate, 161.8 g of 96% ethanol (v / v), 124.5 g of propylene glycol 1.2, 200.0 g of crystalline sugar, 1.0 g of polysorbate 80 and 1.0 g of peppermint oil. The solution is filtered through a suitable filter.

Filling the solution: The solution is filled into suitable dropper bottles in a suitable filling machine. Example 3 Tramadol-metoclopramide delayed pellets Preparation of nuclei containing the active ingredient About 1000 g of neutral pellets of suitable size (eg , with a diameter of between 0.5 and 0.6 mm), in the grapple tank apply with approximately 2200 g of a 15% solution of ethylcellulose / shellac (6: 4) in an approximately 96% ethanol-water mixture (V / V), 4824 g of a mixture of tramadol-hydrochloride hydrochloride-l-H20 methocroplamide-aerosil3 200, The obtained cores are dried and then sieved (0.8-1.4 mm). Application of the membrane About 6.15 kg of the active substance-containing nuclei prepared in this way a membrane is applied by adding 470 g of a 15% solution of ethylcellulose / shellac (6: 4) in an ethanol-water mixture at approximately 96% (V / V). As a disintegrating agent, 700 g of talc are dusted.

Release of the active ingredient The in vitro release of tramadol hydrochloride from the delayed pellets according to example 3 is determined according to USP 23 / NF 18 in apparatus 3. The temperature of the release agent is 37 ° C, the number of runs of the test tubes is 20 runs / minute and the amount of the test solution per research interval is 175 ml. The investigation is started with the test solution pH 1.5, after the first hour the test tubes are changed to respectively 175 ml of test solution pH 4.5, after the second hour to a test solution pH 6.9, after the fourth hour to a new test solution pH 6.9, after the sixth hour to a test solution pH 7.2 and after the eighth hour to a test solution pH 7.5. The amount of active principle released that is found in the solvent in the previously mentioned instants is determined photo-spectrometrically. The following release values were determined for tramadol hydrochloride: The in vitro release curve of the delayed pellets is shown in Figure 1.

EXAMPLE 4 Capsule of tramadol-metoclopramide Preparation of the capsule filling mass. 323 g of tramadol hydrochloride, 6.5 g of metoclopramide hydrochloride-1-H20, 597 g of calcium hypophosphate are screened and mixed in a suitable mixer. 0.5 g of Aerosil®200 and 1.0 g of magnesium stearate.

Preparation of the capsules: The filling mass of the capsules is filled into hard gelatin capsules of suitable size, in a suitable capsule filling machine with the nominal filling weight of 155 mg. Example 5 Effervescent tablet of tramadol + metoclopramide Preparation of the powder mixture: Sift and mix in a suitable mixer 251 g of tramadol hydrochloride, 25 g of hydrochloride-1-H20 of metoclopramide, 4 g of Aerosil®200, 50 g of Aspartam®, 100 g of crospovidone, 700 g of microcrystalline cellulose, 819.5 g of lactose monohydrate, 37.5 g of aroma (for example strawberry), 10 g of sodium dodecylsulfate and 3 g of magnesium stearate.

Preparation of the tablets: The powder mixture is compressed into tablets (400 mg nominal) by using a suitable tableting machine.

Claims (1)

1. CLAIMS Use of pharmaceutical combinations comprising at least one prokinetically active antiemetic or its pharmaceutically acceptable salts and tramadol, its enantiomers or pharmaceutically acceptable salts for the preparation of a medicament for the treatment of migraine or migraine headaches. Use according to claim 1, characterized in that the pharmaceutical combinations contain as antiemetic metoclopramide, domperidon or 5-HT3 antagonists. Use according to claim 1, characterized in that the pharmaceutical combinations contain 5-80 mg of an antiemetic or one of its salts, and 50-400 mg of tramadol or one of its salts. Use according to claim 1, characterized in that the pharmaceutical combinations are preferably administered orally.