BG64888B1 - Pharmaceutical combinations containing tramadol - Google Patents

Abstract

The invention relates to the use of pharmaceutical combinations containing as active ingredient tramadol or one of its enantiomers or one of its pharmaceutically acceptable salts and metoclopramide, domperidone or other substances having a prokinetic and antiemic 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

The present invention relates to the use of pharmaceutical combinations containing as an active ingredient tramadol or any of its enantiomers or its pharmaceutically acceptable salts and metoclopramide, domperidone or other prokinetic and antiemetic agents, or any of their pharmaceutically acceptable salts, for the treatment of migraine and migraine headache, as well as for the treatment of painful conditions that occur with nausea and / or vomiting (eg with chemotherapy) and / or delayed gastric emptying (e.g. doperativno, in diabetic gastroparesis).

BACKGROUND OF THE INVENTION

Migraine is a disease with recurrent headache attacks that lingers for 472 hours. Migraine attacks are overwhelmingly one-sided, beginning with dull pain, then with pulsating headaches of moderate to severe intensity. Typical accompanying symptoms of migraine are increased sensitivity to light and odors, paleness of the face, nausea and vomiting with or without neurological outbreaks such as the prodromal stage.

A migraine (ordinary) without aura is different from a (classic) migraine with an aura that always starts with a characteristic fluttering scotoma. Complicated migraines are present if visual disturbances persist for days or other neurological, focal symptoms with known specific forms of retinal, basilar, ophthalmoplegic, aphasic or hemiplegic migraine occur.

There are different ideas about the pathomechanism of migraines. The early hemodynamic notion that initial neurological attacks are triggered by regional extracranial dalatation with pain through the Nervus ophtalmicus and Nervus trigeminus clarifies the migraine processes only insufficiently.

Regional cerebral blood supply in migraine attacks with Aura okzipitalis is reduced, with the slow migration of cortical oligamy with interruption of the supply areas of individual arteries suggesting that not only vasomotor but also electrophysiological phenomena are involved, responding to so-called " spreading depression ”(Spierings ELH (1988); Recent advances in understanding migraine, Headache 28: 655-658).

Other findings suggest that accompanying headache is caused not only by extracranial vasodilation, but also by a central reduction of the pain threshold, which in the spinal cord and brain stem cells are activated after so-called excitation by the so-called rapidly inducing genes (IEG's immediate early genes) (Zimmermann M. (1995), Neurobiologie des Schmerzsystems. Neuroforum 1/95: 34-45).

Another theory - the model of neurogenic inflammation - offers the opportunity to clarify both changes in blood flow and increased sensitivity to vascular pain during migraine attacks. According to her, increased sensitivity to pain is triggered by enhanced sensitization of the sensory perivascular fibers of the trigeminal and vascular system. This increased sensitization causes pulsations of vessels that are not normally able to cause painful sensations, severe pain irritation and cause the throbbing persistent migraine pain. Neurogenic inflammation is caused by noxious stimulation of the perivascular nerve fibers of the meningeal blood vessels. From the nerve ends, which are probably nociceptors at the same time, neuropeptides such as substance P, neurokinin A and CGRP (related to the calcitonin gene peptide) are released which are capable of causing neurogenic inflammation. It can be shown that CGRP during the migraine attack also multiplies in the venous blood of the head.

By releasing neuropeptides, one circulus vitiosus is triggered: release of peptides - vasodilation and increase of capillary permeability - increased excitation of nociceptors - increased release of peptides. The active substances sumatriptan and the alkaloids of the turf inhibit the release of neuropeptides and thus interrupt the pain-causing circulation (Zimmermann M .: Chronische Schmerzen und ihre Ursachen, Deutsches Azrteblatt 93, Heft 43,1996: A-2749-2752).

Other findings have suggested primary neurogenic hypothalamic dysfunction, which confers a key role on vasoactive serotonin, which during the migraine attack is secreted in a reduced amount from the brain stem seam (Ferrari MD et al. (1989): Serotonin metabolosm in migraine, Neurology 39: 1239-1242; Pramod R. et al. (1989): 5-HT1-like receptor agonists and the pathophysiology of migraine, Trends in Pharmacological Sciences 10, 200-204).

Notwithstanding the many hypotheses and complex model ideas, the pathomechanism of migraine has not yet been understood. Migraines have a multifactorial genesis with genetic predisposition, external (like alcohol) and internal (like hormone) triggers. It is not a psychosomatic disorder, although psychiatric factors can cause an attack.

For the treatment of migraine, many preparations are known that contain only one or several active substances in certain combinations. In general, anti-emetics such as metoclopramide or domperidone alone or in combination with non-opioid analgesics such as acetyl salicylic acid, paracetamol, ibuprofen or naproxen are recommended for the treatment of mild migraine attacks. In moderate to severe migraine attacks, the agents selected are anti-emetics in combination with lawn alkaloids such as ergotamine or dihydroergotamine or sumatriptan. Common side effects of ergotamine and dihydroergotamine are nausea, vomiting, vomiting, headache, muscle aches and general cold sensation, symptoms that may also lead to the re-intake of such medications when misused for a prolonged migraine attack. this to an overdose. Frequent use may result in persistent headache that contributes to the misuse of ergotamine. In severe side effects, blood supply disorders, coronary heart disease, arterial obstruction, hypertension, and pectanginous complications may occur. During pregnancy and menopause, as well as in children under the age of 12, lawn alkaloids should not be used.

Sumatriptan and its derivatives (almotriptan, eletriptan, naratriptan, risatriggan, solmitriptan) are very active antimigraine agents that, when administered orally, exceed the individual substances ergotamine, acetylsalicylic acid or metoclopramide. Sumatriptan is contraindicated in children, during pregnancy and menopause, in patients over 65 years of age and in patients with coronary heart disease. Adverse reactions may include pressure and warmth, a feeling of general weakness, tightness in the chest, hypertension, coronary heart disease, myocardial infarction, Angina pectoris.

Because migraine is obstructed or significantly delayed by migraine in the migraine, the stomach as a site of drug absorption, due to the relatively small absorption surface and significantly smaller vascularization than the small intestine, is of subordinate importance, in migraine attack only insufficient is achieved. or over time, delayed absorption of analgesics. Therefore, the emptying of the stomach plays a large role in the speed of the action of the anti-inflammatory agent.

By means of prokinetics such as metoclopramide and domperidone, gastric emptying and thus the absorption of the anti-inflammatory agent can be accelerated.

Metoclopramide and domperidone are justified in migraine therapy, however, not only because of their prokinetic action but also because of their action against symptoms such as nausea and vomiting, which are often present as accompanying symptoms.

Migraine medication is symptomatic in nature, it does not cure suffering. Mixed preparations of non-opioid analgesics and mixed preparations of turtle alkaloids are not recommended as they cause headache in the case of prolonged use, especially daily use. In addition, liver and kidney damage such as analgesic nephropathy is a possible consequence of long-term administration of combinations of analgesics.

Opioid analgesics are generally not suitable for migraine therapy because of their potential for abuse and dependence.

In the patent literature, the following combinations are known in particular for the treatment of migraine:

- paracetamol and metoclopramide (EP 011 489, EP 011 490, US 5 43 7 8 74, EP 695 546, EP 774 253)

- acetylsalicylic acid or L-lysinacetyl-salicylate thereof and metoclopramide (EP 606 031)

- analgesic (such as acetylsalicylic acid), antiemetic (such as metoclopramide) and antacid (CA20 20 018).

The above known combinations of analgesics known in the patent literature are generally suitable for the treatment of mild migraine attacks. They are not suitable for the treatment of moderate to severe migraines. In severe migraines, lawn alkaloids in combination with antiemetic or sumatriptan are generally indicated.

The disadvantage is that treatment with ergot alkaloids or sumatriptan can result in a number of partially severe cardiovascular side effects such as Angina pectoris, coronary heart disease, hypertension and myocardial infarction.

Therefore, there is a great need for an affordable, well-functioning, mild-to-severe migraine attack with little side effects.

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

SUMMARY OF THE INVENTION

The invention relates to the object claimed in the claims.

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

Tramadol belongs to the group of low-acting opioids. Compared to other opioids, it has a minimal development of tolerability in terms of analgesic activity, with a significant lack of opiate-typical side effects, and with very little potential for addiction.

The analgesic action of tramadol involves both opioid and non-opioid components, the latter by releasing serotonin (5-HT) and preventing the reuptake of serotonin and norepinephrine into the central nervous system.

The non-opioid active components make a significant contribution to the analgesic action of tramadol.

The reuptake of noradrenaline is mainly impeded by the (-) - enantiomer and the release of serotonin, and the inhibition of reuptake of serotonin by the synaptic cleft is triggered by the (+) - enantiomer. Both enantiomers contribute to human analgesic action.

Tramadol treatment may have side effects, sometimes nausea, vomiting, sweating, dry mouth, dizziness and numbness. Gastrointestinal complications or psychiatric side effects are rare.

Prokinetically acting compounds, whose main representatives are metoclopramide and domperidone, increase the tone of the lower esophagus sphincter and accelerate gastric emptying and passage through the small intestine. At the same time, these active substances are introduced as antiemetic agents, i. E. nausea suppression, vomiting and vomiting urges.

Metoclopramide and domperidone are indicated in gastroparesis, which may occur postoperatively and in some underlying diseases (eg, Diabetes mellitus, etc.). They are also given in functional dyspepsia (irritated stomach), as they are thought to be disorders of gastrointestinal motility.

They are also recommended for migraines and other painful conditions that occur with gastric emptying disorders.

Surprisingly, it has been found that the administration of tramadol in combination with prokinetically acting anti-emetics provides an improved treatment for, in particular, moderate to severe migraine attacks.

Opioids are generally not suitable for the treatment of migraines, as they are loaded with multiple side effects and can lead to mental and physical dependence.

In addition, opioids often act in a crippling manner, which increases the underlying migraine atony of the stomach and thus slows the absorption and action of the anti-inflammatory agent.

An exception to opioid analgesics is tramadol, which does not show those severe side effects that are typically observed with opioid administration.

It has also surprisingly been found that, by the combination of the invention of tramadol and in particular metoclopramide, migraine attacks can be actively suppressed and prevent the symptoms of nausea and vomiting.

This is all the more surprising since tramadol itself can cause nausea and vomiting to exacerbate these accompanying symptoms of migraine. Therefore, tramadol as a mono-drug for migraine treatment in the past was considered inappropriate.

By combination with metoclopramide, it is possible that the well-functioning anti-painkiller tramadol, which is moderately severe, is also available for the treatment of migraine.

Because migraine metoclopramide has its own analgesic effect, as confirmed by placebo-controlled studies, it is expected that synergistic analgesic effects will also occur when tramadol and metoclopramide are co-administered.

In addition, the combination can improve the tolerability of tramadol, accelerate the absorption of tramadol in the gastrointestinal tract, and prevent the onset of migraine accompanying symptoms of nausea and vomiting. Also with respect to their pharmacodynamic and pharmacokinetic properties, the substances tramadol and metoclopramide, respectively. domperidone are suitable as partners for combination in a particular pharmaceutical formulation. The analgesic action of tramadol lasts for about 4-7 hours at a terminal elimination half-life of about 5-6 hours. The duration of the prokinetic action of metoclopramide and domperidone is about 1-2 hours, antiemetic about 3-5 hours. The half-life is 4-6 hours.

In another embodiment of the present invention, the combinations may further comprise non-steroidal anti-inflammatory agents such as acetylsalicylic acid, ibuprofen, naproxen or also paracetamol. It is thus achieved that, on the one hand, various analgesic mechanisms (centrality of tramadol and peripheral and central analgesic and inflammatory action of non-steroidal anti-inflammatory drugs) can be used for the treatment of moderate to severe migraine attacks, which is important for resistant of therapy forms of migraine. On the other hand, the total dose of tramadol, resp. the additional analgesic partner in the combination with the same or improved pain relief and adverse effects (eg gastrointestinal complications with non-steroidal anti-inflammatory drugs) are reduced, respectively. avoided by appropriate composition of partners in the combination.

These combinations are particularly suitable for the treatment of moderate to severe migraine pain or migraine headache.

In addition, these combinations are suitable for:

- moderate to severe acute and chronic pain that occurs with nausea and / or vomiting (eg, vomiting caused by chemotherapy);

- moderate to severe acute and chronic pain with concomitant gastric emptying disorders (eg postoperatively or with diabetic gastroparesis, etc.), and

- nausea or vomiting with tramadol therapy.

Based on clinical studies, the activity of the claimed migraine treatment combinations will be further elucidated with an example of a combination of tramadol and metoclopramide.

Eight patients with moderate to severe migraine headache who are no longer amenable to treatment with low-acting analgesics (eg acetylsalicylic acid, ibuprofen or paracetamol) are included in the monitoring of administration.

The severity of migraine headache and the accompanying symptoms before the start of treatment is documented and the evaluation of the action in the later course of treatment is undertaken by patients. Pain intensity before and after drug administration was measured with a 100 mm long VAS scale at time points 0.30 min, 1 h, 2 h, 4 h, 6 h and 12 h. The severity of migraine-related phenomena and their changes after drug administration are documented on a multilevel verbal assessment scale. The patient later gives a general assessment of the action and tolerability.

Of the 8 patients treated, seven were women and one was a man. Patients' ages are on average 44.7 years (35-63 years). Body sizes and body weights averaged 169.3 cm (159-186 cm), respectively, 70.4 kg (65-103 kg). All patients met the IHS operative diagnostic criteria for a migraine diagnosis and had already had at least 5 migraine attacks that showed a duration of 4-72 hours. The localization of pain in the head is strictly one-sided, the intensity of headache increases with the activity of the body. All patients complained of headache attacks simultaneously with nausea and noise sensitivity, 28% of patients further vomiting, and 43% of light sensitivity. Migraines occurred on average from 15.3 years (2-38 years); the average incidence of seizures is 4.1 days per month (28 days per month).

During the study period, patients received 11 acute migraine attacks treated with free combinations of tramadol and metoclopramide.

All patients took the drug at the same time as a single oral dose of 100 mg tramadol (2 tramadol AWD) capsules 50 mg tramadol hydrochloride) and 10 mg metoclopramide solution (30 drops metoclopramide Temmler 5 mg solution). Before documenting treatment, migraine pain is evaluated by patients as severe to too severe. The baseline pain was a mean on the VAS scale of 75 + 7 mm (62-83 mm).

Two patients who each treated for two migraine attacks did not experience any improvement in pain during treatment and were declared inappropriate and excluded from the analysis. There are 6 patients left who are treating 7 migraine attacks. To quantify head pain, a 100 mm long VAS scale was introduced, which is commonly used in other pain studies.

Head pain is rated roughly on the basis of the following distribution:

mm (no headache, grade 0) 1-30 mm (mild headache, grade 1) 31-60 mm (moderate severe headache, grade 2)

61-100 mm (severe to very severe headache, grade 3).

In the migraine study, the most commonly considered outcome measure is the percentage of patients who experience grade 3 headache intensity within a certain period of time (usually after 2 or 4 hours). or 2 to 1 or 0.

ι ца 1 1 ramadol-metoclopramide respondents: Difference in headache intensity versus baseline pain in mm VAS (values in parentheses reproduce the percentage change in pain intensity)

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On the other hand, based on the aforementioned conditionality of the evaluation of the results, respectively the action of the migraine agents in Table 2, the treatment result is given in addition as a percentage of patients who have experienced an improvement in the severity of the headache of grade 3 or 2 to 1 or 0 (ultimately non-respondents).

Table 2. Improvement of grade 3 or 2 headache intensity of grade 1 or 0 as a function of time after oral administration of 100 mg tramadol capsules and 10 mg metoclopramide solution.

Time Number of patients (n = 8) Grade 3-2 improvement 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

The average headache after taking a free combination of tramadol and metoclopramide in the respondent group within about 30 minutes was about 24.3% and after about 2 hours about 51.1% improved from the initial headache. After 4 and 6 hours, the reduction in pain intensity averaged 65.6%, respectively. 77.5% (see Table 1).

Activity (improvement of headache from severe or moderate to mild or lacking headache) was shown in the whole group of treated patients (including non-respondents) 25% after 30 min and 75% after 2 h. (see Table 2).

In summary, it can be concluded from the available data that the combination of tramadol and metoclopramide in the dosage taken may be a promising alternative to the antimigraine medications available so far, which are used therapeutically for moderate to severe acute migraine headaches.

These combinations can be taken in the form of tablets, effervescent tablets, capsules, granules, powders, depotablets, depocapsules (single and multiple unit dosage forms), ampoules for intravenous and intramuscular injection, and in the form of infusion solutions, suspensions, suppositories or other suitable dosage forms.

Depot dosage forms may contain the active ingredient in complete or partially delayed release form, with or without a partial starting dose.

The active ingredients may be present together or partially or completely separated from each other, so that it may also be separate or stepwise in time of administration.

In the case of such completely separate preparation, they are separated from each other and contain each active ingredient in unit dosage in the same amount and corresponding weight ratio as they are in the combined mixture.

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

Preferably the orally administered pharmaceutical compositions containing said combination.

For the preparation of pharmaceutical preparations containing these combinations, the active ingredients in a given amount are treated with physiologically acceptable carriers and / or diluents and / or excipients in the usual manner.

Examples of carriers and excipients are gelatin, natural sugar such as cane sugar or milk sugar, lecithin, pectin, starches (e.g., corn starch or amylose), cyclodextrins and cyclodextrin derivatives, dextran, polyvinylpyrrolidone, polyvinyl acetate, arabic acid, arginic gum , talc, lycopodium, silicic acids, calcium hydrogen phosphate, cellulose, cellulose derivatives such as methyloxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, fatty acids with 12-acyl acid , emulsifiers, oils and fats, in particular also vegetable glycerol esters and polyglycerol esters of saturated fatty acids, mono- or polyvalent alcohols and polyglycols such as polyethylene glycol, esters of aliphatic saturated or unsaturated fatty acids with 2 to 22 C atoms with monovalent aliphatic with 1 to 20 C atoms or polyvalent alcohols such as glycols, glycerol, diethylene glycol, propylene glycol 1,2, sorbitol, mannitol.

Other excipients include disintegrants (so-called disintegrants), cross-linked polyvinylpyrrolidone, sodium carboxymethylstarch, sodium carboxymethylcellulose, microcrystalline cellulose. Also known wrapping agents may be employed. Polymers such as copolymers of acrylic acid and / or methacrylic acid and / or their esters, Zein, ethylcellulose, ethylcellulose succinate, shellac.

The plasticizers for coating agents may include: citric and tartaric acid esters, glycerin and glycerol esters, polyethylene glycol of different chain lengths. For the preparation of solutions or suspensions, for example, water or physiologically acceptable organic solvents such as alcohols and fatty alcohols are considered.

Liquid preparations may require the use of preservatives such as potassium sorbate, methyl 4-hydroxybenzoate or propyl 4-hydroxybenzoate, antioxidants such as ascorbic acid and taste-enhancing substances such as peppermint oil.

In the preparation of preparations, known and common dissolution agents, respectively emulsifiers, such as polyvinylpyrrolidone and polysorbate 80 may be used.

For more examples of suitable carriers and excipients, see also Dr. Η. R. Fiedler “Lexicon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete”

In pharmaceutical preparations containing combinations of prokinetically acting antiemetic agents and tramadol, the ratio should be 1: 4 to 1:10. These pharmaceutical compositions generally contain 580 mg of anti-emetic or any salt thereof and 50,400 mg of tramadol or any salt thereof in a single dose. The daily dose should preferably contain 20-80 mg antiemetic and 200-400 mg tramadol.

Said daily doses may be administered depending on the therapeutic indication, either in the form of a single total dose or in the form of 2 to 4 partial doses per day. It is generally preferred to take 2 to 4 times a day.

Examples of carrying out the invention

The following examples further illustrate the invention and do not constitute any limiting enumeration.

Example 1.

Preparation of metoclopramide solution In an appropriate vessel, 802.4 g of purified water is pre-filled and 4.7 g of metoclopramid hydrochloride-water, 0.1 g of ascorbic acid, 170.1 g of sorbitol, 2.8 g of potassium sorbate are added with stirring. pre-prepared solution of 18.9% ethanol 96% (v / v), 0.7 g methyl-4-hydroxybenzoate and 0.3 g propyl 4-hydroxybenzoate and stirred until all the ingredients were dissolved. The solution is filtered through a suitable filter.

Recipe Weight parts (%) Metoclopramidhydrochloride-1-water 0.47 Ascorbic acid 0.01 Sorbitol 17.01 Potassium sorbate 0.28 Ethanol 96% (v / v) 1.89 Methyl 4-hydroxybenzoate 0.07 Propyl 4-hydroxybenzoate 0.03 Purified water 80.24

Filling the solution:

The solution is filled with a suitable filling machine into suitable dropper glasses.

Example 2.

Preparation of tramadol solution

484.2 g of purified water is pre-filled in a suitable vessel and 100.0 g of tramadol hydrochloride, 1.5 g of potassium sorbate, 161.8% ethanol 96% (v / v), 124.5 g of propylene glycol are added with stirring 25. 1.2, 200.0 g of crystalline sugar, 1.0 g, polysorbate 80 and 1.0 g of peppermint oil and stirred until all ingredients are dissolved. The solution is filtered through a suitable filter.

Recipe Weight parts (%) Tramadol hydrochloride 9.3 Potassium sorbate 0.1 Ethanol 96% (v / v) 15.1 Propylene glycol 1,2 11.6 Crystal sugar 18.6 Polysorbate 80 0.1 Mint oil 0.1 Purified water 45,1

Filling the solution:

The solution is filled with a suitable filling machine in suitable dropper glasses.

Example 3.

Delayed release tramadol-metoclopramide pellets

Preparation of cores containing the active substance.

Approximately 2200 g of a 15% ethylcellulose / shellac solution (6: 4) in an ethanol-water mixture of about 96% (1000 g) are added to 1000 g of neutral size pellets of suitable size (eg with a diameter between 0.5 and 0.6 mm). v / v) 4824 g of tramadolhydrochloride-metoclopramidhydrochloride-1-water-Aerosil® 200 in a dye pot The resulting kernels were finally dried and sieved (0.8-1.4 mm).

Applying the sheath

A shell was added to 6.15 kg of the active substance-containing cores, to which was added 470 g of a 15% solution of ethylcellulose / shellac (6: 4) in an ethanol water mixture of about 96% (v / v). Powder with 700 g of talc as a separating agent.

Recipe Weight parts (%) Tramadol hydrochloride 57,8 Metoclopramidhydrochloride-1-water 11.6 Neutral pellets 14,4 Ethyl cellulose 3.5 Shellack 2.3 Aerosil 200 0.3 Talc 10,1 Ethanol-water mixture about 96% (v / v) q.s.

Release of the active substance

The in vitro release of tramadol hydrochloride from delayed release pellets according to Example 3 was determined according to USP 23 / NF 18 in apparatus 3. The release temperature was 37 ° C, the number of tube runs with samples 20 strokes / min and the amount of tests test interval solution 175 ml.

The test is started with a pH 1.5 test solution, after the first hour, replace the sample tubes in 175 ml test solution at pH 4.5, after 2 h in pH 6.9 test solution, after 4 h. in a new pH 6.9 test solution, after 6 h in a pH 7.2 test solution and after 8 h in a pH 7.5 test solution. The amount of free active substance present in the middle of the solvent prior to the aforementioned periods is determined spectrophotometrically. The following release values for tramadol hydrochloride were obtained.

Time in hours Released part by weight. % 1 39 2 57 4 70 6 78 8 84 12 93

The in vitro release curve of the sustained release pellets is presented in Figure 1.

Example 4.

Tramadol-metoclopramide capsules

Preparation of a capsule filling table

323 g of tramadol hydrochloride are screened,

6.5 g metoclopramidhydrochloride-1-water, 597 g calcium hydrogen phosphate, 0.5 g Aerosil® 200 and

1.0 g of magnesium stearate and mixed in a suitable mixer.

Formulation: Weight parts (%) Tramadol hydrochloride 32.3 Metoclopramidhydrochloride-1 - water 6.5 Calcium hydrogen phosphate 59,7 Aerosil * 200 0.5 Magnesium stearate 1.0

Preparation of capsules

The capsule filling mass is filled with the weight of 155 mg sol filled with a suitable capsule filling machine, in solid desires - 25 new capsules of suitable size.

Example 5.

Tramadol + metoclopramide drinking tablets Preparation of the powder mixture

Sift and mix in a suitable mixer 251 g of tramadol hydrochloride, 25 g of metoclopramide 1H ₂ O, 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 aroma (eg strawberries), 10 g of sodium dodecyl sulfate and 3 g of magnesium stearate.

Recipe Weight parts (%) Tramadol hydrochloride 12.55 Metoclopramidhydrochloride-1-water 1,25 Aerosil * 200 0.20 Aspartam® 2.50 Crospovidone 5,00 Microcrystalline cellulose 35,00 Lactose 40.98 Aroma 1.88 Sodium dodecyl sulfate 0.50 Magnesium stearate 0.15

tt ______________ _ _ / r

Preparation of tablets:

The powder mixture is tableted with a suitable tablet machine in 400 mg tablets.

Claims (4)

Claims Use of pharmaceutical combinations of at least one prokinetically acting antiemetic or a pharmaceutically acceptable salt and tramadol, enantiomers or pharmaceutically acceptable salts thereof for the preparation of a medicament for the treatment of migraine or migraine headache. Use according to claim 1, characterized in that the pharmaceutical combinations contain, as antiemetic, metoclopramide, domperidone or 5-HT _3- antagonists. Use according to claim 1, characterized in that the pharmaceutical combinations contain from 5 to 80 mg of anti-emetic or any salt thereof and from 50 to 400 mg of tramadol or any salt thereof. Use according to claim 1, characterized in that the pharmaceutical combinations are preferably administered orally. Attachment: 1 figure Publication of the Patent Office of the Republic of Bulgaria 1797 Sofia, 52-B Dr. GM Dimitrov Blvd.