WO2001091733A2

WO2001091733A2 - Combination of active substances containing montirelin and a compound having an opioid effect

Info

Publication number: WO2001091733A2
Application number: PCT/EP2001/005345
Authority: WO
Inventors: Boris Chizh; Thomas Christoph; Babette-Yvonne Kögel; Achim SCHÜTTLER; Wolfgang Strassburger
Original assignee: Grünenthal GmbH
Priority date: 2000-05-26
Filing date: 2001-05-10
Publication date: 2001-12-06
Also published as: AR029096A1; AU2001274020A1; DE10025947A1; PE20011272A1; WO2001091733A3

Abstract

The invention relates to a combination of active substances containing montirelin and a compound having an opioid effect and/or respectively the physiologically compatible salts thereof; a medicament containing said combination of active substances; formulations for medicaments containing said combination of active substances; the use of said combination of active substances in the production of a medicament.

Description

Active ingredient combination containing montirelin and a compound with opioid activity

The present invention relates to a combination of active ingredients containing montirelin and a compound with opioid activity and / or in each case their physiologically tolerable salts, pharmaceutical compositions containing this combination of active ingredients, pharmaceutical formulations containing this combination of active ingredients and the use of this combination of active ingredients for the production of a pharmaceutical.

Pain is one of the basic symptoms in the clinic. There is a worldwide need for effective pain therapies. The urgent need for action for a patient-oriented and goal-oriented treatment of chronic and non-chronic pain conditions, whereby this means the successful and satisfactory pain treatment for the patient, is documented in the large number of scientific papers in the field of applied analgesics and basic research on the nociception have appeared recently.

Classic opioids, such as the morphine, are effective in the treatment of severe to very severe pain, but have undesirable side effects such as Respiratory depression, nausea, vomiting, addiction, sedation, constipation or tolerance development.

The object underlying the invention was therefore to provide analgesic drugs which are suitable for the treatment of severe to very severe pain. In addition, these drugs should have as few side effects of the known opioid analgesics as breathing depression, nausea, vomiting, dependency, sedation, constipation or tolerance development. According to the invention, this object is achieved by providing a new combination of active ingredients

a) Montirelin and / or at least one of its physiologically tolerable salts

and

b) a compound with opioid activity and / or at least one of its physiologically tolerable salts

contains.

This combination of active substances according to the invention surprisingly has a pronounced analgesic activity, the undesirable side effects which occur when opioids are administered alone no longer or only very weakly.

The preparation of montirelin of formula I below

and the preparation of its physiologically tolerable salts is disclosed in DE-PS-2449167. The compounds with opioid activity and their physiologically tolerable salts are also known from the literature, for example from E. Friderichs, T. Christoph, H. Buschmann, "Analgesics and Antipyretics", Ullmann ^'s Encyclopedia of Industrial Chemistry, Sixth Edition on CD- ROM, Wiley-VCH, Weinheim, 2000. The corresponding disclosures are hereby introduced as a reference.

The hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate can preferably be used as the physiologically compatible salt of montireline , Lactate, mesylate or a mixture of at least two of these salts.

As a compound with opioid activity, compounds with weak, strong or very strong opioid activity, i.e. appropriate analgesic effectiveness.

Codeine, dextropropoxyphene, dihydrocodeine, diphenoxylate, ethylmorphine, meptazinol, nalbuphin, pethidine (Mepeπ ^' din), tilidine, tramadol or viminol are preferably used as compounds with weak opioid activity, butorphanol, dextrinoramid, decocin are preferred as compounds with strong opioid activity Diacetylmorphine (heroin), hydrocodone, hydromorphone, ketobemidone, levomethadone, levomethadyl acetate, levorphanol, morphine, nalorphine, oxycodone, pentazocine or piritramide and as compounds with a very strong opioid activity, preferably alfentanil, buprenorphentanil, etuprofinilentinil, etupernorphentanil ,

The hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate can preferably be used as the physiologically tolerable salt of the compound with opioid activity. Stearate, butyrate, malonate, lactate, mesylate or a mixture of at least two of these salts can be used.

In a particularly preferred embodiment of the present invention, the active compound combination according to the invention contains morphine or fentanyl and / or at least one corresponding physiologically tolerated salt as a compound with opioid activity.

If the active ingredient combination according to the invention contains a component with weakly opioid activity as component b), this should be the case

Weight ratio of components a): b) are preferably in the range from 1:10 to 1: 2000, particularly preferably in the range from 1:50 to 1: 1500 and very particularly preferably in the range from 1: 100 to 1: 1000. If component b) is a compound with strong opioid activity, the weight ratio of components a): b) should preferably be in

Range from 1: 1 to 1: 200, particularly preferably in the range from 1: 5 to 1: 150 and very particularly preferably in the range from 1:10 to 1: 100.

For compounds with very strong opioid activity as component b), the weight ratio of components a): b) in the active ingredient combination should preferably be in the range from 1: 0.1 to 1:20, particularly preferably in the range from 1: 0.5 to 1 : 15, most preferably in the range from 1: 1 to 1:10.

The invention further also relates to medicaments containing the active compound combination according to the invention and, if appropriate, further active compounds and / or auxiliaries. These medicaments according to the invention are preferably used to combat pain, in particular to combat chronic and / or acute pain. The invention also relates to pharmaceutical formulations in various dosage forms which contain the active compound combination according to the invention and, if appropriate, further active compounds and / or auxiliaries.

Preferred pharmaceutical formulations are tablets, chewable tablets, chewing gums, dragées, capsules, drops, juices, syrups, suppositories, transmucal therapeutic systems, transdermal therapeutic systems, easily reconstitutable dry preparations, solutions, emulsions, suspensions, powders or sprays. Pharmaceutical formulations in the form of tablets, capsules, drops or solutions are particularly preferred.

In another preferred embodiment, the pharmaceutical formulations according to the invention are in multiparticulate form, particularly preferably as microtablets, microcapsules, microspheroids, ion exchange resinates, granules, active ingredient crystals or pellets, very particularly preferably as microtablets, granules or pellets. Pellets in the sense of the present invention also include pellets or build-up pellets produced by extrusion and / or spheronization.

The pharmaceutical formulations according to the invention are preferably suitable for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, pulmonary, rectal, transdermal, nasal or intracerebroventricular administration, pharmaceutical formulations for oral or intravenous administration being particularly preferred.

Preparations in the form of tablets, chewable tablets, chewing gums, dragees, capsules, granules, are preferably suitable for oral administration.

Drops, juices, and syrups. A transmucal therapeutic system is preferably suitable for buccal application. Solutions are preferably suitable for parenteral, topical and inhalation administration,

Suspensions, emulsions, easily reconstitutable Dry preparations, microspheroids, sprays, suppositories or plasters (eg transdermal therapeutic systems). Suppositories or solutions are particularly preferred for parenteral administration, transdermal therapeutic systems for topical administration and powders or solutions for inhalation administration.

In addition to an active ingredient combination according to the invention, carrier materials, fillers, solvents,

Diluents, colorants, flavorings, binders or mixtures of at least two of these materials can be used. The selection of these auxiliaries and their amounts depend on the manner in which the medicament is to be applied. The person skilled in the art is aware of the auxiliaries suitable for the particular form of application and their amounts. The pharmaceutical formulations according to the invention can be prepared by the customary methods known to those skilled in the art.

The pharmaceutical formulations according to the invention can also contain at least one active ingredient component a) or b) in retarded form.

The respective active substance is preferably retarded by a retarding coating, by fixation to an ion exchange resin, by embedding in a retarding matrix or by a combination of these retardations.

Suitable retarding coatings include water-insoluble waxes or polymers such as acrylic resins, preferably poly (meth) acrylates, or water-insoluble celluloses, preferably ethyl cellulose. These materials are from the prior art, for example Bauer, Lehmann, Osterwald, Rothgang "coated drug forms", scientific Verlagsgesellschaft mbH Stuttgart, 1988, page 69 ff. They are hereby introduced as a reference and are therefore considered part of the disclosure.

In addition to the water-insoluble polymers, the retarding coatings can optionally also be non-retarding, preferably water-soluble polymers in amounts of up to 30 wt , Sodium chloride or mannitol and / or the known plasticizers.

In addition, the active ingredient combination according to the invention can have further coatings. Coatings that dissolve depending on the pH can also be present as coatings. It can thus be achieved that the pharmaceutical formulation passes through the gastrointestinal tract undissolved and the active substance combination according to the invention is only released in the intestinal tract. Coatings can also be used to improve the taste.

Another common method of retardation is the fixation of the active ingredients to ion exchange resins. Cation exchange resins, preferably polystyrene sulfonates, can be used to retard both component a) and component b).

For retardation, the active ingredient combination according to the invention can also be present in a retarding matrix, preferably evenly distributed. Physiologically compatible, hydrophilic materials which are known to the person skilled in the art can be used as matrix materials. Polymers, particularly preferably cellulose ethers, cellulose esters and / or acrylic resins, are preferably used as the hydrophilic matrix materials. Matrix materials are very particularly preferred

Ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Hydroxymethyl cellulose, poly (meth) acrylic acid and / or their derivatives, such as their salts, amides or esters.

Matrix materials made of hydrophobic materials, such as hydrophobic polymers, waxes, fats, long-chain fatty acids, are also preferred.

Fatty alcohols or corresponding esters or ethers or their mixtures. Mono- or diglycerides of C ₂ -C ₃ -fatty acids and / or C ₂ -C ₃ o-fatty alcohols and / or waxes or mixtures thereof are particularly preferably used as hydrophobic materials.

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

In a further preferred embodiment, the pharmaceutical formulation according to the invention contains at least one of the active ingredient components a) or b) in addition to its retarded form and also in its unretarded form. Combined with the immediately released active ingredient, a high initial dose can be achieved for quick pain relief. The slow release from the retarded form then prevents the analgesic effect from subsiding.

The amount of the active compound combination according to the invention to be administered to the patient varies, for example, depending on the weight of the patient, the type of application, the indication and the severity of the disease. The amount to be administered and the release of the active compound combination according to the invention are preferably adjusted so that they have to be applied at most twice, preferably only once a day. In the case of a single application per day, the active compound combinations according to the invention preferably contain 0.1 to 50 mg, particularly preferably 1 to 5 mg montirelin and 0.1 to 2000 mg, preferably 0.5 mg to 1000 mg of a compound with opioid activity.

When administered twice a day, the active compound combinations according to the invention preferably contain 0.05 to 25 mg, preferably 0.5 to 2.5 mg montirelin and 0.05 to 1000 mg, preferably 0.25 to 500 mg of a compound with opioid activity.

Another object of the invention is the use of an active ingredient combination according to the invention for the manufacture of a medicament, preferably for the manufacture of a medicament for combating pain, particularly preferably for combating chronic and / or acute pain, since the active substance combinations according to the invention have a very good action in combating from severe to very severe pain, especially when fighting chronic and / or acute pain.

The active ingredient combination according to the invention surprisingly shows an improved analgesic activity compared to the opioid active ingredient alone. In addition, there are fewer undesirable side effects.

The increased antinociceptive effect has the advantage that the dose of the compound with opioid activity required for effective pain control can be reduced compared to the sole administration of this compound. This means that the undesirable side effects that are usually associated with the application of a compound with opioid activity, such as, for example, respiratory depression, vomiting, dependence, sedation, constipation or development of tolerance, no longer occur or only very weakly. Pharmacological examinations:

Focal jet test on the rat:

The analgesic effectiveness of the invention

Active ingredient combinations and the comparative solutions were tested in the tail-flick test on the rat according to D'Amour and Smith, J. Pharm. Exp. Ther. Volume 72, pages 74-79, 1941 examined. Female Sprague Dawley rats (Janvier, France) weighing between 120 and 150 g were used for this.

The rats were placed individually in a test cage and the tail base was exposed to the focused heat radiation from an electric lamp (tail-flick type 50/08 / 1.bc, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from switching on the lamp until the tail suddenly jerked away (pain latency) was 3 to 5 seconds in untreated rats. Before the solutions of the active compound combinations according to the invention and the comparison solutions were applied, the rats were pretested twice within five minutes and the mean value of these measurements was calculated as the pretest mean. The solution of the active compound combinations according to the invention and the comparison solutions were then administered intravenously. The pain measurement was carried out 10, 20, 40 and 60 minutes after the intravenous application. The analgesic effect was determined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula:

[(Tι-T ₀ ) / (T ₂ -To)] x 100

Here, the time To is the latency before application, the time Ti is the latency after application of the active ingredient combination and the time T _{2 is} the maximum exposure time (12 seconds). The following example serves to explain the invention, but does not restrict the general idea of the invention.

Example:

To investigate the antinociceptive effect of the active ingredient combination of montirelin and morphine, a group of 10 rats were each administered 0.9% saline solution containing 1.46 mg morphine per kg body weight of the rat and 0.1 mg montirelin per kg body weight of the rat ,

Comparative Example:

For comparison, a 0.9% saline solution containing only 1.46 mg morphine per kg body weight of the rat was administered intravenously to a second group of 10 rats.

The results of these investigations are shown in FIG. 1.

FIG. 1 shows that the comparison solution, which contains the morphine alone, already has good analgesic activity. As can be seen from FIG. 1, the application of the solution containing the active ingredient combination of montirelin and morphine has a very much improved analgesic effect compared to the sole application of morphine.

Claims

claims:

1. Containing active ingredient combination

a) Montirelin and / or at least one of its physiologically tolerable salts

and

b) a compound with opioid activity and / or at least one of its physiologically tolerable salts.

2. Active ingredient combination according to claim 1, characterized in that there is a compound with weak, strong or very strong opioid activity as component b).

3. Active ingredient combination according to claim 2, characterized in that as a compound with weak opioid activity codeine, dextropropoxyphene, dihydrocodeine, diphenoxylate, ethyl morphine, meptazinol, nalbuphine, pethidine (meperidine), tilidine, tramadol or

Viminol is present.

4. Active ingredient combination according to claim 3, characterized in that the weight ratio of component a) to component b) in the range from 1:10 to 1: 2000, preferably in the range from 1:50 to 1: 1500, particularly preferably in the range from 1 : 100 to 1: 1000 lies.

5. active ingredient combination according to claim 2, characterized in that as a compound with strong opioid activity butorphanol,

Dextromoramide, decocin, diacetylmorphine (heroin), hydrocodone,

Hydromorphone, ketobemidone, levomethadone, levomethadyl acetate,

Levorphanol, morphine, nalorphine, oxycodone, pentazocine or

Piritramide, preferably morphine, is present.

6. Active ingredient combination according to claim 5, characterized in that the weight ratio of component a) to component b) in the range from 1: 1 to 1: 200, preferably in the range from 1: 5 to 1: 150, particularly preferably in the range from 1 : 10 to 1: 100.

7. Active ingredient combination according to claim 2, characterized in that alfentanil, buprenorphine, etorphine, fentanyl, remifentanil or sufentanil, preferably fentanyl, is present as a compound with a very strong opioid activity.

8. Active ingredient combination according to claim 7, characterized in that the weight ratio of component a) to component b) in the range from 1: 0.1 to 1:20, preferably in the range from 1: 0.5 to 1:15, particularly preferably is in the range of 1: 1 to 1:10.

9. Active ingredient combination according to one of claims 1 to 8, characterized in that a hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, tartrate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate as the physiologically compatible salt of the compound with opioid activity , Glutamate, embonate, fumarate,

Aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate or a mixture of at least two of these salts is present.

10. Active ingredient combination according to one of claims 1 to 9, characterized in that the physiologically acceptable salt of

Montirelins a hydrochloride, hydrobromide, sulfate, sulfonate, phosphate, tartrate, embonate, formate, acetate, propionate, benzoate, oxalate, succinate, citrate, glutamate, fumarate, aspartate, glutarate, stearate, butyrate, malonate, lactate, mesylate or a mixture from at least two of these salts.

11. Medicaments containing an active ingredient combination according to one of the

Claims 1 to 10 and optionally further active ingredients and / or

Excipients.

12. Medicament according to claim 11 for combating pain.

13. Medicament according to claim 12 for combating chronic pain.

14. Medicament according to claim 12 for combating acute pain.

15. Medicament formulation containing an active ingredient combination according to one of claims 1 to 10 and optionally further active ingredients and / or

Excipients.

16. Pharmaceutical formulation according to claim 15, characterized in that it is in the form of tablets, chewable tablets, chewing gums, dragees, transdermal therapeutic systems, transmucosal therapeutic systems, capsules, suppositories, drops or as juice, syrup, solution, emulsion, suspension, easily reconstitutable Dry preparation, powder or as a spray, preferably in the form of tablets, capsules, drops or as a solution.

17. Pharmaceutical formulation according to claim 15, characterized in that it is in multiparticulate form, preferably in the form of microtablets, microcapsules, microspheroids, ion exchange resinates, granules, active substance crystals or

Pellets, particularly preferably in the form of microtablets, granules or pellets.

18. Pharmaceutical formulation according to one of claims 15 to 17 for oral, intravenous, intramuscular, subcutaneous, intrathecal, epidural, buccal, sublingual, rectal, pulmonary, transdermal, nasal or intracerebroventricular, preferably for oral or intravenous administration.

19. Pharmaceutical formulation according to one of claims 15 to 18, characterized in that at least one of the active ingredient components a) or b) is in retarded form.

20. Medicament formulation according to claim 19, characterized in that the retardation is carried out by a retarding coating, fixation to a cation exchange resin, embedding in a retarding matrix or a combination thereof.

21. Medicament formulation according to claim 20, characterized in that the coating is based on a water-insoluble polymer or wax.

22. Pharmaceutical formulation according to claim 21, characterized in that as a water-insoluble polymer

(Poly) acrylic resin or cellulose derivative, preferably alkyl cellulose, is used.

23. Pharmaceutical formulation according to claim 22, characterized in that ethyl cellulose and / or a poly (meth) acrylate as

Polymer is used.

24. Medicament formulation according to claim 20, characterized in that the matrix is hydrophilic matrix material, preferably polymers, particularly preferably cellulose ether,

Cellulose esters and / or acrylic resins, very particularly preferably ethyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, poly (meth) acrylic acid and / or their salts, amides and / or esters.

25. Pharmaceutical formulation according to claim 20 or 24, characterized in that the matrix is hydrophobic matrix material, preferably polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers or their

Mixtures, particularly preferably mono- or diglycerides of C ₂ -C ₃ o-fatty acids and / or C ₂ -C ₃ o-fatty alcohols and / or waxes or mixtures thereof.

26. Pharmaceutical formulation according to claim 20, characterized in that polystyrene sulfonates are used as the cation exchange resin.

27. Pharmaceutical formulation according to one or more of claims 19 to 26, characterized in that at least one of the

Active ingredient components a) or b) are also present in the unretarded form in addition to the retarded form.

28. Use of an active ingredient combination according to one of claims 1 to 10 for the manufacture of a medicament.

29. Use according to claim 28 for the manufacture of a medicament for combating pain.

30. Use according to claim 29 for the manufacture of a medicament for combating chronic pain.

31. Use according to claim 29 for the manufacture of a medicament for combating acute pain.