MXPA98003206A - Employment of epinastin for the treatment of dolo - Google Patents

Abstract

The present invention relates to the use of epinastine as a medicament for the treatment of pain, in particular of migraine, Bing-Horton syndrome, tension headaches, muscle aches, inflammatory pain or neuralgia.

Description

EMPLOYMENT DK EPINASTINA FOR THE TREATMENT DK DOLORES DESCRIPTION OF THE INVENTION The invention relates to a new use of epinastine for the treatment and prophylaxis of pains, in particular of chronic pains or conditions caused by inflammations, as well as migraine in particular. Epinastine (3-amino-9, 13b-dihydro-1H-dibenz [c, f] imidazo [1, 5-a] -azepine hydrochloride) was described by Fügner et al. [Arzneimittelforschung 38_ (1988) 1446-1453]. This active substance can be used in the form of its racemate or in the form of the pure enantiomers or as a mixture based on different proportions of the two enantiomers. In therapy, epinastine is used in the form of hydrochloride; however, the present invention is not limited to the hydrochloride but concerns any salt by the addition of acids with a pharmacologically harmless acid as well as the use of the free base itself. The use of epinastine and its salts by the addition of acids for the treatment of asthma is known from the known state of the art. In the European patent specification EP-B-0 035 749 REF: 27047 it is disclosed that this active substance is also suitable for the therapeutic treatment of allergic diseases, such as allergic rhinitis, allergic conjunctivitis and allergic bronchitis. Headache is a symptom that occurs often. In most cases, the headache is of short duration and can be controlled well with weak analgesics, such as acetylsalicylic acid, paracetamol or ibuprofen. This headache is certainly considered annoying, but it does not lead to any essential harm. For him . contrary, chronic repetitive headaches, such; As a migraine, they can lead to such intense damage that a doctor should be visited. This severe form of headache can not often be treated adequately with a weak analgesic. On the other hand, there is no generally accepted classification system for headaches; Chronic repetitive headaches in the sense of the present invention relate predominantly to migraine and Bing-Horton syndrome. Migraine itself contains different secondary forms [J. Olesen and R.B.

Lipton, Neurology 4_4_ (1994) p. 6- p. 10 in relation to a classification]. Although migraine and tension headaches represent two different forms, they are considered by some scientists as a clinical continuum, with migraine at one end and tension headache at the other end of the spectrum [K.L. Kumar and T.G. Cooney: "Headaches" in "Medical Clinics of North America" Notebook 79 n ° 2 (1995) p. 261 to 286]. Therefore, it is assumed that many patients with tension headache also respond to a migraine therapy. Other different diseases that are accompanied by chronic pain, such as neuralgia, muscle pain and pain from inflammation (such as, for example, after a sunburn or in the case of osteoarthritis or also after sports injuries) present with repetitive pain chronic common mechanisms [Dray, A. Urban L. and Dickenson, A. Trends in Pharmacological Sciences 1994; 15: 190-197]. Current migraine therapy involves the use of rye alkaloids (for example ergotamine) and sumatriptan. Even though many patients use these medications, not all patients respond to them. In addition, numerous side effects are manifested - such as obtundation and vertigo -. Medications for the prophylaxis of migraine are carried out by metisergid, pizotifen, beta blockers (for example propanolol) and calcium channel blockers (for example flunarizine). The chronic application of these medications is accompanied by side effects that impair the quality of life of the patient; in this case, these medications can reduce, in general, only the periodicity of migraine attacks, but not avoid them altogether [H. C. Diener, Eur. Neurol. 3_4 (Suppl 2) (1994) 18-25]. It is therefore the object of the present invention to provide an active substance for the treatment of migraine that is both effective and also free of serious side effects. Another object of the present invention is to provide a medicine with a high degree of safety for certain groups of patients - such as children and patients with limited liver or kidney function or circulatory diseases of the heart.

Surprisingly, it has now been found that the active substance epinastine fulfills these missions in an extraordinary manner. This is confirmed by the following test results: In test animals, an inflammation reaction in the dura can be triggered by electrical excitation of the trigeminal ganglion, conditioned by the release of neuropeptides, such as substance P, from sensory nerve endings. . Plasma extravasation can be measured with the help of the Evans blue marker. This model with animals is used in general to find substances that are suitable for the treatment of migraine. Surprisingly enough, epinastine was extraordinarily well effective in this model. A model with animals often used for pain caused by inflammation was first described by Randall and Selitto [L.O. Randall and J.J. Selitto, Arch. Int. Pharmacodyn 111, (1957) 409-419]. By intraplantar injection of cells. of yeast a reaction of inflammation is induced in the leg of the rat; Next, hyperalgesia conditioned by inflammation is measured.

Epinastine was also surprisingly effective in this model. From the known state of the art, epinastine is known as an antihistamine. The interaction between a ligand (for example an active substance) and a receptor can be quantified by an affinity constant (Ki). The lower the value of the affinity constant, the firmer the union between the active substance and the receptor. Particular consideration is given to the junctions that have a Ki value that is smaller or has the same order of magnitude of the expected concentration of the active substance in the target tissue (eg plasma). The 5HT7 receptor is a particular type of receptor that binds 5-hydroxytryptamine (for a classification, see: "Trends in Pharmacological Sciences 1994 Receptor &Ion Channel Nomenclature Supplement"). Surprisingly, a good binding of epinastine to the 5HT7 receptor is found. Ki values for epinastine and two comparative antihistamines are listed in Table 1. The invention described is now explained by the following examples. Other different executions will be evident to the expert in the matter from the following description. However, attention is expressly called to the fact that the examples and the description are intended solely for the purpose of explanation and are not to be construed as limiting the invention.

Examples: Investigation of apinastine binding to 5HT7 racaptor Binding of 2 nM 3H-LSD to a rat 5HT7 receptor was expressed in CHO cells, measured for 60 minutes at 37 ° C in 50 nM Tris-HCl buffer, pH 7.4, which in addition, it contained 10 mM MgCl 2 and 0.5 mM EDTA. The reaction ended with a rapid vacuum filtration through fiberglass filters that had previously been treated with 0.1% polyethylene glycol. The binding examinations were carried out in the absence and in the presence of 6 to 8 concentrations of epinastine that were between 3 nM and 10 μM, in each case as double determinations. For each concentration the radioactivity deposited on the filter was determined and compared with the control value in order to determine the interaction of the d substance with the cloned 5HT7 receptor. The non-specific binding was determined in the presence of 5-carboxyamidotriptamine (5-CT). The IC50 for the ejection of the radioactive ligand was determined by graphical extrapolation and the Ki values were calculated after a correction for the displacement of the radioligand occupation according to the formula of Cheng and Prusoff [Biochem. Pharmacol 2_2 (1973) 3099-3108]. Three experiments were carried out. In each of the assays, epinastine showed a surprisingly good binding to the 5HT7 receptor. For epinastine, the mean Ki value was 33 nM, for the (+) enantiomer at 28 nM and for the (-) enantiomer at 189 nM. The individual Kx values for epinastine and its enantiomers, which were found in the three trials, are listed in Table 1 together with the Ki values of two known antihistamines: Table 1: Apinastine binding (racamate and enantiomer) and two comparative antihistamines (Ketotifen and Mepyramin) to the 5HT receptor Investigation of epinastine activity on plasma extravasation induced by electrical stimulation of the trigeminal ganglion in the dura mater of rats Male Wistar rats weighing 175-190 g were anesthetized i.p. with nembutal 50 mg / kg. The jugular vein was cannulated for intravenous injection of the substances. Afterwards, the animals were placed in a stereotactic frame. Symmetrical drills were made, 3.0 mm lateral and 3.2 mm posterior of the bregma, through which the electrodes were introduced to a depth of 9.5 mm. 10 minutes before the start of electrical stimulation of the right trigeminal ganglion (5 minutes, 2 mA, 5 Hz, ms) the test substances (epinastine or the solvent control) were administered intravenously. As a marker for extravasation of plasma proteins, Evans blue (30 mg / kg) was also administered intravenously 5 minutes before electrical stimulation. 15 minutes after the end of the electrical stimulation, the animals were perfused with 50 ml of physiological sodium chloride solution through the left ventricle of the heart, in order to wash Evans intravascular blue out. The dura was removed, blistered dry and weighed. Evans blue was extracted from the tissue with 0.3 ml of formamide at 50 ° C for 2.4 h. The dye content was determined photomatically at a wavelength of 620 nm, interpolated by a standard curve and then expressed as ng of Evans blue content per mg of tissue.

Data evaluation: The extravasation was expressed as the quotient of the Evans blue content of the stimulated side and the Evans blue content of the unstimulated side. The results are indicated as average value. The results are shown in Table 2.

Table 2 Effect of epinastint in a model of migraine with animals Control group treated with 1 ml / kg of 0.9% sodium chloride solution EB - Evans blue Valo r medium 1.25 Group treated with apinastine 10 μg / kg i.v. in 1 ml / kg of 0.9% sodium chloride solution Average value 0.98 Table 2 shows that in the model with animals for migraine, treatment with epinastine significantly inhibited extravasation of Evans blue induced by electrical stimulation of the trigeminal ganglion.

Investigation of epinastine in terms of hiparalgasia induced by washing the leg of rats The method according to Randall and Selitto was modified by the use of an analgesiometer (Basile, Milan). To groups of 10 fasting rats of the race Chbb: THOM (weight 110-140 g, 5 males, 5 females) were orally administered Natrosol 250 HX 1% (1 ml / 100 g of body weight) containing 0, 0.3, 1.0, 3.0 or 10 mg / kg of epinastine (racemate). One hour later, the animals received a subplantar injection of a suspension of yeast cells in a volume of 0.1 ml in the right hind paw. 3 hours after the injection of the yeast suspension the pain threshold was determined, increasing the pressure on the inflamed leg until an externalization of the pain occurred. From the threshold of pain, measured at different doses of epinastine, an ED50 was determined by regression analysis. As shown in Table 3, epinastine increases the pain threshold. The dose of epinastine that increased pain threshold by 50% amounted to 1.1 mg / kg.

Table 3: Effect of epinastine on the pain sensation of the inflamed rats leg Assay on the analgesic effect by Randall-Selitto Type of animal: male / female rats Weight: 110 to 140 g Feeding: fasting Application: 1.0 ml / 100 g p.o. Vehicle: Natrosol at 1% Value for 90 minutes Epinastine or its enantiomers can be used for the treatment of pain in the form of an aqueous solution for injection (for example for intravenous application, intramuscular or subcutaneous), in the form of a tablet, as a suppository, as an ointment, as a plaster for transdermal application, as an aerosol for application by inhalation through the lungs or as a nasal spray. The active substance content of a tablet or a suppository is between 5 and 200 mg, preferably between 10 and 50 mg. In the case of inhalation, the individual dose ranges between 0.05 and 20 mg, preferably between 0.2 and 5 mg. If of a parenteral injection, the individual dose is between 0.1 and 50 mg, preferably between 0.5 and 20 mg. The mentioned doses can be administered, if necessary, several times a day. Particularly advantageous could be the combination with other therapeutic principles, for example with acetyl-silicosic acid or paracetamol, or NSAID's, such as ibuprofen, meloxicam, indomethacin or naproxen, 5HT1D agonists, such as sumatriptan, MK-462, naratriptan or 311C; CP-122,288; UK 116,044; D2 dopamine receptor antagonists, such as metoclopramide; rye alkaloids, such as ergotamine, dihydroergotamine or metergoline; clonidine; metisergid; dotarizin; lisurid; pizotifen, valproat, aminotriptiline, beta-blockers (for example propanolol, metoprolol); calcium channel blockers (for example flunarizine or lomerizine) or neurokinin antagonists. In the following some examples are given for pharmaceutical preparations with the active substance: Tablets: Epinastine 20 mg Magnesium stearate 1 mg Corn starch 62 mg Lactose 83 mg Polyvinyl pyrrolidone 1.6 mg Solution for injection Epinastine 0.3 g Sodium chloride 0.9 g Water for injection up to 100 ml The solution can be sterilized using standard processes.

Aqueous solution for nasal application or inhalation Epinastine 0.3 g Sodium chloride 0.9 g Benzalkonium chloride 0.01 mg Purified water up to 100 ml The above solution is suitable for nasal application in an atomizer or in combination with an apparatus that produces an aerosol with particle size preferably between 2 and 6 μM, for application through the lung.

Capsules for inhalation Epinastine is packaged in hard gelatine capsules in micronized form (particle size essentially between 2 and 6 μM), possibly with addition of micronized support substances, for example lactose. For the inhalation, usual apparatuses for the inhalation of powders are used. In each capsule, for example between 0.2 and 20 mg of epinastine and 0 to 40 mg of lactose are introduced.

Spray for inhalation Epinastine 1 part Soybean lecithin 0.2 parts Propellant gas mixture up to 100 parts The preparation is preferably introduced into an aerosol container loaded with a metering valve and the individual stroke is dimensioned so that a dose of 0.5 mg is delivered. For the other dosages of the indicated range, preparations with a greater or lesser portion of active substance are conveniently used.

Ointment Composition g / 100 g of ointment Epinastine 2 Fumed hydrochloric acid 0.011 Sodium pyrosulfite 0.05 Mixture based on equal parts of cetyl alcohol and stearyl alcohol 20 White vaseline 5 Synthetic bergamot oil 0.075 Distilled water up to 100 The components are prepared in the usual way to give an ointment.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers. Having described the invention as above, property is claimed as contained in the following:

Claims (13)

1. Use of epinastine in the form of its enantiomers, its mixtures or the racemate as a medicament for the treatment of pain.

2. Use of epinastine according to claim 1 as a medicament for the treatment of migraine, Bing-Horton syndrome, tension headaches, muscle pain, inflammatory pain or neuralgia.

3. Use of epinastine as a racemate or in the form of its enantiomers which is presented as a free base or as a salt by the addition of acids with a pharmacologically harmless acid for the preparation of a medicament for the therapeutic treatment of pains.

4. Use of epinastine according to claim 3 as a racemate or in the form of its enantiomers present in free base form or as an acid addition salt with a pharmacologically harmless acid for the preparation of a medicament for the therapeutic treatment of migraine, Bing-Horton syndrome, tension headaches, inflammatory muscle pain or neuralgia.

5. Use of epinastine in the form of racemate or its enantiomers according to claim 1 or 2, in combination with another analgesic.

6. Use of epinastine in the form of racemate or its enantiomers according to claim 5, characterized in that the analgesic used in combination with NSAID, a 5HTα antagonist, a dopa ina D2 receptor antagonist, a rye alkaloid, a beta blocker , a calcium channel blocker or a neurokinin antagonist.

7. Use according to claim 6, characterized in that the NSAID is ibuprofen, meloxicam, indomethacin or naproxen.

8. Use according to claim 6, characterized in that the 5HT? D agonist is sumatriptan, MK-462, naratriptan or 311C.

9. Use according to claim 6, characterized in that the dopamine D2 receptor antagonist is metoclopramid.

10. Use according to claim 6, characterized in that the rye alkaloid is ergotamine, dihydroergotamine or metergoline.

11. Use according to claim 6, characterized in that the beta-blocker is propranolol or metoprolol.

12. Use according to claim 6, characterized in that the blocker of calcium channels is flunarizine or lomerizine.

13. Use according to claim 6, characterized in that the analgesic to be used in combination is acetylsalicylic acid, paracetamol, clonidine, metisergid, dotarizine, lisurid, pizotifen, valproat, aminotriptilin, CP-122,288 or UK 116,044.