SK284937B6 - Use of prokinetically active antiemetic and tramadol for the manufacture of a medicament for the treatment of migraine - Google Patents

Abstract

The invention relates to the use of pharmaceutical combinations of at least one prokinetically active antiemetic like metoclopramide and domperidone, or pharmaceutically acceptable salts thereof, and tramadol, its enantiomers or pharmaceutically acceptable salts in the weight ratio of 1 : 4 to 1 : 10 for the manufacture of a medicament for the treatment of migraine or migrainoid headaches.

Description

Technical field

The invention relates to the use of pharmaceutical combinations which contain tramadol or its enantiomers or pharmaceutically acceptable salts thereof as an active ingredient for the treatment of migraine and migraine headache.

BACKGROUND OF THE INVENTION

Migraine is a disease with recurrent seizure headaches lasting 4 to 72 hours. Migraine attacks are predominantly one-sided, subdued, then throbbing headaches of moderate to severe intensity. Typical accompanying features of migraine are hypersensitivity to light and noise, pallor of the kidney, nausea and vomiting with or without neurological blackouts of the lesions as a prodromal stage.

A simple migraine without aura differs from (classical) migraine with aura, which begins with a characteristic flashing scotoma. Complicated migraine is when visual disturbances persist for several days or when other neurological focal symptoms occur with known special forms of retinal, basilar, ophthalmoplegic, aphasia or hemiplegic migraine.

There are different ideas about the pathomechanism of migraine. The previous haemodynamic notion that initial neurological outages were induced by regional intracranial vasoconstriction and the subsequent pulsating headache by extracranial vasodilatation with the guidance of pain through the ophthalmic nerve and the trigeminus nerve, explain inadequately the migraine processes.

Regional cerebral blood flow is occipitally reduced in a migraine attack with an aura, and the slow wandering of cortical oligamia overflowing the arterial supply area suggests that not only vasomotor but also electrophysiological phenomena are involved in so-called "spreading depression" (Spierings ELH (1988); Recent advances in the understanding of migraine (Headache 28: 655 -658).

Other findings suggest that concomitant headaches are caused not only by extracranial dilatation but also by a central reduction in the pain threshold, so-called IEG's immediate early genes (Zimmermann, M.) are activated in spinal cord and brainstem cells after noxic irritation. 1995); Neurobiology des Schmerzsystems, Neuroforum 1/95: 34-45).

Another theory - the neurogenic stimulus model - offers the possibility of clarification by altering the blood flow to the pain of increased tissue sensitivity during a migraine attack. Accordingly, increased pain sensitivity is induced by increased sensitization of the sensory perivascular vessels of the trigeminovascular system. This increased sensitization is vascular pulsations that are not normally in a state of causing pain, potent pain irritants and condition pulsating drumming migraine pain. The neurogenic stimulus is induced by the noxic stimulation of the perivascular nerve fibers of the meningeal blood vessels.

Neuropeptides such as substances P, neurokinin A and calcitoningene related peptide (CGRP), which are capable of eliciting a neurogenic stimulus, are released from the nerve endings, which are simultaneously nocireceptors. CGPR can also be detected during a migraine attack with increased head vein blood. The release of neuropeptides triggers circulus vitiosus: peptide release - vasodilation and capillary increase in permeability - increased induction of nociceptors - increased release of peptides. The active ingredients sumatriptan and ergotalkaloids inhibit neuropeptide release and thus interrupt the pain-inducing cycle (Zimmermann, M: Chronische Schmerzen und ihre Ursachen, Deutsches Arteblatt 93, Heft43, 1996: A-2749-2752).

Other findings suggest primary neurogenic hypothalamic dyslexia, with vasoactive serotonin that is diminished from RAPHE nuclei of the brainstem, a key role (Fcrrari MD et al (1989): Serotonin metabolism in migraine. Neurology 39: 1239-1242; et al (1989): 5-HT1-like receptor agonists and the pathophysiology of migraine, Trends in Pharmacological Sciences 10,200-204).

Despite many hypotheses and complicated model ideas, the pathomechanism of migraine is still misunderstood. Migraine has a multifactorial genesis with genetic predisposition, an external (like alcohol) and an internal (like hormone) trigger mechanism. It is not a psychosomatic disease, although psychological factors can trigger the seizure.

For the treatment of migraine, many preparations are known which contain single active substances or more active substances in a fixed combination.

In general, anti-emetics such as metoclopramide or domperidone, alone or in combination with non-opioid analgesics such as acetylsalicylic acid, paracetamol, ibuprofen or naproxen, are recommended for the treatment of migraine attacks. In moderate to severe migraine attacks, antiemetics are selected in combination with themed alkaloids such as ergotamine or dihydroergotamine, or sumatriptan.

Common side effects of ergotamine and dihydroergotamine are nausea, vomiting, nausea, headache, muscle aches and a general feeling of cold, symptoms that may lead to repeated use of such agents and thus overdose if incorrectly assumed continued migraine attacks. Frequent use may result in permanent headaches that contribute to the overuse of ergotamine. Serious side effects may include bleeding disorders, coronary heart disease (HCV), arterial disease (AVK), hypertonia and pectanginous complaints. Ergothalkaloids must not be used during pregnancy and breast-feeding as well as in children under 12 years of age.

Sumatriptan and its derivatives (almotriptan, eletriptan, naratriptan, rizatriptan, zolmitriptan) are very effective drugs for migraine which, when administered orally, are preferable to ergotamine, acetylsalicylic acid or metoclopramide. Sumatriptan is contraindicated in children, pregnancy and breast-feeding, in patients over 65 years and in patients with coronary heart disease. Feelings of pressure and heat, general feeling of weakness, shortness of breath, hypertonia, coronary heart disease (KHK), myocardial infarction, angina pectoris may occur as adverse reactions.

Since gastric emptying is significantly slowed in migraine and is significantly slowed down and the stomach as a resorption site of farmers due to the relatively small resorption area and is of minor importance compared to the small intestine with significantly less vascularization, the migraine attack suffers from insufficient or delayed absorption of the analgesic. Thus, the time of gastric emptying plays a major role in the rate of onset of painkiller effect.

By using prokinetics such as metoclopramide and domperidone, gastric emptying and thus drug resorption can be accelerated.

Metoclopramide and domperidone have their merit in the treatment of migraine, but not only because of their prokinetic effects, but also because of their effect against symptoms such as nausea and vomiting, which often occur as accompanying symptoms in migraine.

The medical treatment of migraine is symptomatic in nature, not treating the disease. Mixed formulations of non-opioid analgesics and mixed formulations of secular alkaloids are discarded as they cause headaches alone when taken for a long time, especially daily use. Furthermore, as a consequence of long-term use of combinations of analgesics, liver and kidney damage such as so-called nephropathy by analgesics are possible.

Opioid analgesics are generally inappropriate due to their potential abuse and the development of addiction to migraine therapy.

In particular, 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 L-lysine salicylate and metoclopramide (EP 606 031),

- an analgesic (such as acetylsalicylic acid), an antiemetic (such as metoclopramide) and an antacid (CA 20 20 018).

The analgesic combinations disclosed in the patent literature are generally suitable for the treatment of mild migraine attacks, and are not suitable for the treatment of moderate to severe migraine attacks. In severe migraines, ergotalkaloids are generally indicated in combination with an antiemetic or sumatriptan.

A disadvantage is that a number of severe cardiovascular side effects such as angina, coronary heart disease (KHK), hypertonia and myocardial infarction may occur with ergotalkaloid or sumatriptan therapy.

Therefore, there is still a great need for a reliable, moderate to severe migraine seizure with a well-acting painkiller with minor side effects.

It is therefore an object of the present invention to provide an improved therapeutic for the treatment of moderate to severe migraine attacks.

SUMMARY OF THE INVENTION

The invention thus relates to the subject matter claimed in the claims.

Tramadol (1RS; RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol is an analgesic that is effective in moderate to severe pain.

Tramadol belongs to a group of poorly active opioids. Tramadol, in comparison with other opioids, is characterized by minimal tolerance development in terms of analgesic effect, absence of typical opioid side effects, as well as very low potential addictiveness.

The analgesic effect of tramadol includes both opioid and non-opioid components, the latter by releasing serotonin (5HT) and inhibiting the recuperation of serotonin and noradrenaline into the central nervous system (CNS).

Non-opioid active components make a substantial contribution to the analgesic effect of tramadol. Norepinephrine reuptake is predominantly prevented by the (-) enantiomer and serotonin release as well as preventing serotonin reuptake from the synaptic graft are elicited by the (+) enantiomer. Both enantiomers contribute to an analgesic effect in humans.

Side effects such as nausea, vomiting, sweating, dry mouth, dizziness and dizziness may occasionally occur with tramadol treatment. Gastrointestinal problems or psychological side effects of various kinds are rarely observed.

Prokinetically active compounds, the main representatives of which are metoclopramide and domperidone, increase the tone of the lower esophageal sphincter and accelerate gastric emptying and passage through the small intestine.

At the same time, these active substances are used as antiemetics, i.e. to suppress nausea, nausea and vomiting.

Metoclopramide and domperidone are indicated in gastroparesis, which may occur postoperatively and in some underlying diseases (for example, diabetes mellitus and others). They are also given for functional dispepsia (gastric irritation), as well as where the cause of gastrointestinal motility disorders is suspected.

They are also indicated for migraine and other painful diseases that result from gastric emptying disorders.

Surprisingly, it has been found that the administration of tramadol in combination with prokinetically active antiemetics provides an improved formulation especially for the treatment of moderate to severe migraine attacks.

Opioids are generally not suitable for the treatment of migraine because they are burdened with a number of side effects and can lead to psychological and physical dependence.

In addition, opioids often cause constipation, thereby enhancing the migraine-induced gastric atonia, thereby delaying the resorption and onset of the painkiller effect. Exception among opioid analgesics is tramadol, which does not have these serious side effects, which are typically seen with opioids.

Surprisingly, it has also been found that, according to the invention, the combination of tramadol, and in particular metoclopramide, effectively reduces migraine attacks and can prevent the occurrence of nausea and vomiting symptoms.

This was all the more surprising in that tramadol itself could induce as nausea as vomiting, or it could intensify these accompanying migraine symptoms.

Therefore, tramadol has been previously viewed as a monopreparation for treating migraine as inappropriate.

In combination with metoclopramide, it is possible that, in moderate and severe pain, a well-effective painkiller tramadol can also be made available.

Because metoclopramide alone has an analgesic effect in migraine, as evidenced by the placebo control studies, a synergistic analgesic effect can be expected when tramadol and metoclopramide are co-administered.

In addition, the tolerability of tramadol can be improved by a fixed combination, the absorption of tramadol in the stomach and intestinal tract is accelerated and the accompanying symptoms of migraine nausea and vomiting are prevented. Also with respect to pharmacodynamic and pharmacokinetic properties, the substances tramadol and metoclopramide and domperidone, respectively, are suitable as combination partners in a fixed pharmaceutical formulation. The analgesic effect time of tramadol is about 4 to 7 hours, at the terminal elimination half-life about 5 to 6 hours. The prokinetic action time of metoclopramide and domperidone is about 1 to 2 hours and the antiemetic time is about 3 to 5 hours. Half-life breaks down 4 to 6 hours.

Based on clinical trials, the efficacy of the claimed combinations for the treatment of migraine should be further elucidated by way of example of the combination of tramadol and metoclopramide.

8 patients with moderate to severe migraine headaches who could not be adequately controlled with poorly effective analgesics (eg acetylsalicylic acid, ibuprofen or paracetamol) were included in the use observations.

The existing strength of migraine headaches and the expression of accompanying symptoms was documented and the effect was assessed by patients in the course of treatment.

Pain intensity before and after drug intake was measured on a 100 mm long VAS-scale at 0.30 min, 1 h, 2 h, 4 h, 6 h and 12 h. The formation of accompanying migraine phenomena and their changes after drug intake were documented on a multi-stage verbal rating scale. The patient could further pass a global assessment on the effect and tolerability.

Of the 8 patients treated, seven were women and one was male. Patients' age averaged 44.7 years (35 to 63). Body height and body weight were on average 169.3 cm (159-186) and 70.4 kg (55-103 kg), respectively.

All patients met the IHS Action Criteria for Migraine Diagnosis and had at least 5 migraine attacks lasting 4 to 72 hours. Localization of the headache was strictly one-sided, the intensity of headache was intensified by physical activity.

All patients suffered from headaches, nausea and hypersensitivity during the seizure, 28% of patients additionally vomited and 43% were light sensitive. Migraine was on average 15.3 years (2 to 38 years); the average seizure frequency was 4.1 days per month (2 to 8 days / month).

At the time of the study, 11 acute migraine attacks were treated and treated with a free combination of tramadol and metoclopramide.

Table 1

All patients were taking the drug simultaneously in an oral single dose of 100 mg tramadol (2 tramadol AWD capsules and 50 mg tramadol / HCl) and 10 mg metoclopramide solution (30 drops metoclopramide 5 mg Temmler solution).

Prior to documented treatment, migraine pain reported by patients was severe to very severe. On average, the initial pain on the VAS scale was 75 ± 7 mm (62-83 mm).

Two patients who each treated two migraine attacks did not feel any improvement during treatment and were declared unresponsive and excluded from the analysis.

Six patients remained to treat 7 migraine attacks. A 100 mm long VAS scale was used in this study to quantify headache, which is also commonly used in other pain studies.

Headaches were evaluated approximately according to the following breakdown:

mm (no headache, grade 0), up to 30 mm (light headache, grade 1), up to 60 mm (moderate headache, grade 2), 61 to 100 mm (severe headache, grade 3).

In the study of migraine, the percentage of patients whose Grade 3 or 2 headache intensity has improved to Grade 1 or 0 over a defined period of time (usually 2 or 4 hours) is generally taken as a criterion for success.

Tramadol Metaclopramide Response: Headache Intensity vs. Initial Pain Difference in mm VAS (values in brackets reproduce the percentage change in pain intensity)

patient 0 h nm Q í »h 1 h and mm 2 h 1 4 m h and 6 mm h % have got 12 h % 1 62 -2 -X 2) -14 (-22.6) -24 (-38.7) -27 (-43.6) -28 -45.2) -62 (100) 2 83 -19 -22.9) -42 {-50.61 -to (-72.3) -61 (-73.5) -45 -54.2) -43 (-51.8) 3 81 12, S) -9 (-11.1) -21 (-25.9) -37 (-45.7) -81 -100) -81 (100) 4 70 -37 -52.9) -37 {-52.9) -38 (-54.3) -30 {42,91 * -30 -42.9) -29 s-41.4) 5 72 -6 -8.3) -32 t-44.4) -67 (- 93.1) -70 t-97.2) -72 -100) -72 (100) 6 80 -70 -87.5) -65 (-91.3) -59 (-73.9) -45 (-56.3) -80 -100) -80 (-1001 7 77 2 (2.61 (1,3) ♦ -77 (100) -77 -100) -77 (-1001 average 75 -18, S. (-24.25) -28.29 (-37.36) -38.43 (-51.15) -49.57 (65.58) -59 -77.46) -63.43 (-84.75) Std. 7 26.66 (34.04) 22.58 (28,271 24.81 (31.97) 29.88 (25.94) 23, 86 (28.32) 20.19 (26,22) Outgoing.

Hodnota Missing value

On the other hand, given the conventions for assessing the success or efficacy of migraine agents in Table 2, we also reported the resulting treatment as a percentage of patients who had reduced their headache from grade 3 or 2 to grade 1 or 0 (including non-responders) .

Table 2

Improving the intensity of headache from grade 3 or 2 to grade 1 or 0 depending on the time of oral administration of 100 mg tramadol capsules and 10 mg metoclopramide solution

Time Number of patients (N = 8) Grade improvement 3-2 to 1-0 (% of patients) 0.5 h 2 25 1 h 5 62 2 h 6 75 4 h 6 75 6 h 6 75 12 h 6 75

On average, headaches improved by 24.3% in the group of respondents after receiving a free combination of tramadol and metoclopramide in the group of respondents within 30 minutes and 51.1 after 2 hours due to the initial pain. After 4 and 6 hours, the pain intensity reduction was on average 65.6% and 77.5%, respectively (see Table 1).

For the overall group of patients treated (responder inclusive unresponsive), efficacy (improving headache from severe or moderate to light or painless) resulted in 25% at 30 minutes and 75% at two hours (see Table 2).

In summary, it can also be inferred from the present data that the combination of tramadol and metoclopramide in an enriched dosage is a promising alternative to the currently available migraine medications that can be used therapeutically in moderate to severe acute migraine headaches.

These combinations may be formulated as tablets, effervescent tablets, capsules, granules, retarded tablets, retarded capsules (single or multiple unit formulations), ampoules for intravenous and intramuscular injection, and in the form of infusion solutions, suspensions, suppositories or other suitable dosage forms. .

Retarded forms may contain the active compounds in total or partial retard form with or without an initial dose.

The active substances may exist together or in partially or totally separate formulations from one another, so that separate or time-delayed release is also possible.

Where such completely separate formulations exist, they are coordinated with each other and contain, in each case, the active ingredients in a dosage unit in the same amounts and corresponding weight ratios in which they may be present in the combined mixture.

In these pharmaceutical compositions, the active ingredients may also be in the form of their pharmaceutically usable salts.

Preferably, orally administered pharmaceutical compositions in which the shown combinations are contained.

For the preparation of pharmaceutical compositions comprising these combinations, the active compounds are desirably formulated in the indicated amounts with a physiologically tolerable carrier and / or diluent and / or excipients.

Examples of carriers and excipients are gelatin, natural sugar such as raw sugar, milk sugar, lecithin, pectin, starches (e.g., corn starch or amylose), cyclodextrin and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate, gum arabic, alginic acid, talc, lycopodium, silicic acid, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methyloxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, methyloxypropylmethylcellulose phthalate, C 12 -C 22 fatty acids, emulsifiers, oils and fats, in particular also polyglycine esters of glycine esters polyhydric alcohols and polyglycols such as polyethylene glycols, esters of C 2 -C 22 aliphatic saturated or unsaturated fatty acids, C 1 -C 20 monohydric alcohols or polyhydric alcohols such as glycols, glycerol, diethylene glycol, 1,2-p ropenylene glycol, sorbitol, mannitol.

Other excipients which may be considered are disintegrating agents (so-called disintegrants), cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, sodium carboxymethylcellulose, microcrystalline cellulose.

Known coating agents may also be used. Polymerizates and copolymers of acrylic and / or methacrylic acid and / or esters thereof, zein, ethylcellulose, ethylcellulose succinate, shellac.

Suitable plasticizers for the coating substances are: citric acid and tartaric acid esters, glycerol and glycerol ester, polyethylene glycol of different chain lengths. Water or physiologically tolerated organic solvents such as alcohols or fatty alcohols are suitable for the preparation of solutions or suspensions.

For liquid preparations, it may be desirable to use preservatives such as potassium sorbate, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, antioxidants such as ascorbic acid, and, for example, peppermint oil to improve the taste.

Known and conventional dissolving agents and emulsifiers, such as polyvinylpyrrolidone and Polysorbate 80, can be used in the preparation of the preparations.

For further examples of carriers and excipients, see also, e.g. H. P. Fiedler 'Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und Angrenzende Gebiete'.

In pharmaceutical preparations containing combinations of a prokinetically active antiemetic and tramadol, their weight ratio should be 1: 4 to 1: 10. These pharmaceutical preparations usually contain, as a single dose, 5 to 80 mg of the antiemetic or salt thereof and 50 to 400 mg of tramadol. or a salt thereof. The daily dose should preferably contain 20 to 80 mg of an antiemetic and 200 to 400 mg of tramadol.

Said daily doses may be used, depending on the therapeutic indication, either in the form of a single administration of the total amount or in the form of 2-4 subdoses per day. In general, administration of 2 to 2 is preferred

4 times.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 shows an in vitro release curve of tramadol hydrochloride from retarded pellets containing 3.5 wt. ethylcellulose and 2.3% shellac.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are intended to further illustrate the invention but do not constitute a definitive list.

Example 1 - Preparation of Metoclopramide Solution

802.4 g of purified water are placed in a suitable container and 4.7 g of metoclopramide hydrochloride-1H ₂ O, 0.1 g of ascorbic acid, 170.1 g of sorbitol, 2.8 g of potassium sorbate and a solution of 18.9 g are added under stirring. g of ethanol 96% (v / v), 0.7 g of methyl 4-hydroxybenzoate and 0.3 g of propyl 4-hydroxybenzoate and stirred until all components have dissolved. Filter the solution through a suitable filter.

formula Mass fraction (¾) Hetoklcipraraidhydrochlorid. 1 Η ₂ Ο 0.47 Ascorbic acid 0.01 sorbitol 17.01 Ká1unsorbá t 0.26 Ethanol 96% (v / v) 1.89 N-ethyl-4-hydroxybenzoate 0.07 Propyl 4-hydroxybenzoate 0.03 Purified water 80,24

Filling the solution

The solution is filled on a suitable filling device into suitable drip-vials.

Example 2

Preparation of tramadol solution

484.2 g of purified water are placed in a suitable container and 100.0 g of tramadol hydrochloride, 1.5 g of potassium sorbate, 161.8 g of ethanol 96% (v / v), 124.5 g of 1,2-propylene glycol are added under stirring. , 200.0 g of crystal sugar, 1.0 g of Polysorbate 80, and 1.0 g of peppermint oil and mixed until all components were dissolved. Filter the solution through a suitable filter.

formula Mass fraction (%) tramadol 9, 3 potassium sorbate 0.1 Ethanol 56% (v / v) 15.1 Propylene glycol 1,2 11.6 Crystal Sugar 18.6 Polysorbate 80 0.1 Matt oil 0.1 Purified water 45.1

Filling the solution

The solution is filled on a suitable filling device into suitable drip-vials.

Example 3

Retarded tablets containing tramadol and metoclopramide Preparation of cores containing active substances

Approximately 2200 g of a 15% ethylcellulose / shellac (6: 4) solution in an ethanol-water mixture of about 96% are fed into the auction boiler per 1000 g of neutral sized pellets (eg between 0.5 and 0.6 mm in diameter) [ I / O] 4824 g of tramadol hydrochloride-metoclopramide hydrochloride. 1H ₂ 0-Aerosil® 200 g mixture. The cores obtained are finally dried and sieved (0.8 to 1.4).

Application of membrane

A membrane was applied to 6.15 kg of the active ingredient-containing cores thus obtained by administering 470 g of a 15% solution of 4-cellulose / cellulose / shellac (6: 4) in an ethanol-water mixture of about 96% [V / V]. 700 g talc is added as a separating agent.

formula Mass fraction (%) tramadol 57.8 Metoklopramldhydrochlorid. H /> 11Λ Neutral pellets 14.4 Ethyl cellulose 3.5 shellac 2.3 Aerosol 200 0.3 talc 10.1 Ethanol / water mixture approx. 96 i / v) qs

Release of the active substance

The release of in vitro tramadol hydrochloride from the retarded pellets of Example 3 was determined according to USP 23 / NF 18 in instrument 3. The temperature of the released medium was 37 ° C, the number of strokes of the tubes was 20 strokes per minute and the amount of test solution for 175 ml.

The study was started with the test solution pH 1.5, after the first hour the sample tubes were replaced in 175 ml of the test solution pH 4.5, after 2 hours in the test solution pH 6.9 after 4 hours in the test solution pH 6 9 after 6 hours to pH test solution

7.2 and after 8 hours to the test solution pH 7.5. The amount of active substance released in the dissolution medium at given times was determined spectrophotometrically. The following release values for tramadol hydrochloride were obtained:

Time in hours %. 39 2 57 4 70 6 78 84 12 93

The in vitro release curve of the retard tablets is shown in Figure 1.

Example 4

Capsules containing tramadol and metoclopramide

Preparation of filler for capsules

323 g of tramal hydrochloride, 6.5 metoclopramide hydrochloride, 1H ₂ O, 597 g of calcium hydrogen phosphate, 0.5 Aerosil® 200 and 1.0 g of magnesium stearate are sieved and mixed in a suitable mixer.

formula Mass fraction (%) tramadol 32.3 Metoklopramidhydrochlorid. IHjO 6.5 Ka1ciumhydrogenfosfát 59.7 Aerosil® 230 0.5 Magnesium 1.0

Capsule preparation:

The filler mass is filled with a desired weight of 155 mg on a suitable filler into hard gelatin capsules of appropriate size.

Example 5

Beverage tablets containing tramadol and metoclopramide

Preparation of the powder mixture

Tramalhydrochloridu 251 g, 25 g metoklopramidhydrochloridu.lH ₂ O, 597 g, 4 g of Aerosil Aspartamu® 200,50, 100 g of crospovidone, 700 g of microcrystalline cellulose, 819.5 g of lactose monohydrate, 37.5 g aromatic flavoring (e.g., strawberry 10 g of sodium dodecyl sulfate and 3 g of magnesium stearate are sieved and mixed in a suitable mixer.

formula Mass fraction 1%) tramadol 12.55 Metoklopramidhydrochlorid. 1 H? O 1.25 Aerosol® 20 (J 0.20 Aspartam® 2.50 crospovidone 5.00 Microcrystalline cellulose 35, 0C lactose 40, 98 aroma 1.88 sodium dodecyl sulfate 0, 50 Ma gné z. i uras tea rat 0.15

Preparation of tablets

The powder mixture is compressed into tablets (400 mg nominal) using a suitable tablet press.

Claims (4)

PATENT CLAIMS Use of pharmaceutical combinations of at least one prokinetically active antiemetic or pharmaceutically acceptable salts thereof and tramadol, its enantiomers or pharmaceutically acceptable salts thereof in a weight ratio of 1: 4 to 1: 10 to each other for the preparation of medicaments for the treatment of migraine or migraine headache. Use according to claim 1, characterized in that the pharmaceutical combinations comprise as an anti-emetic an metoclopramide, domperidone or 5-HT ₃ -antagonists. Use according to claim 1, characterized in that the pharmaceutical combinations comprise 5 mg to 80 mg of an antiemetic or a salt thereof and 50 mg to 400 mg of tramadol or a salt thereof. Use according to claim 1, characterized in that the medicament is for oral administration.