MXPA01006899A - MEDICINAL FORMULATIONS CONTAINING AN OPIOID AND AN&agr;-ANTAGONIST - Google Patents

Abstract

The invention relates to medicinal formulations containing an opioid, an&agr;-antagonist and/or their physiologically compatible salts, from which at least one medicinal active ingredient is released in a sustained manner.

Description

MEDICINAL FORMULATIONS CONTAINING AN OPIOID AND A-ANTAGO ISTA Description of the Invention The present invention relates to medicinal formulations containing an opioid, an a-antagonist and / or their physiologically acceptable salt, from which at least one medicinal active substance is progressively released. By virtue of its strong analgesic activity, opioids are applied to mitigate the acute semigraves and tortissima pains. A great disadvantage of the use of opioids is, however, in the serious side effects that go hand in hand with this. Thus, side effects frequently appear in the gastrointestinal tract, such as obstipation. Respiratory depression also ensues and, in the case of repeated administration, a dependency that can lead to abuse. Another disadvantage is the rapid development of tolerance. The administration of opioids and a-antagonists as mono-preparations by the application of various medicinal formulations is known. In addition to the known non-delayed systems, there are also opioid delay systems, as described in WO 95/14460 or EP-A-0 647 448, in which, among other things, butyrates, ketobemidones, codeins and the like are also used. . EP-B-0 271 193 discloses a delay system that exclusively employs hydromorphone. Delay systems with α-antagonists are disclosed in EP-A-0 805 677 or US 5,484,607. In both cases, clonidine is exclusively used as an antagonist. Accordingly, the present invention has for its object the task of providing a medicinal formulation suitable for the treatment of severe pain to tortissimos that does not have the typical side reactions of opioids, and which in particular retards a lot or completely prevents the development of a tolerance to opioids. According to the invention this problem is solved by providing medicinal formulations containing an opioid, an a-antagonist and / or respectively its physiologically acceptable salt, from which at least one medicinal active substance is progressively released. Preferably it is the opioid that is released progressively from the medicinal formulations according to the invention. the progressive release of the opioid occurs preferably during a time interval of 8 hours, more preferably 12 hours and most preferably 24 hours.

It is also preferable that both medicinal active substances are those that are released progressively from the formulation according to the invention. The medicinal formulation according to the invention preferably contains as an opioid morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphen, buprenorphine, levomethadone, fentanyl, sufentanil, etorphine, pentazocine, tilidine, tramadol, levorphanol, methadone, dihydromorphine, pethidine, piritramide and / or a physiologically acceptable salt of the mentioned opioids. Particularly preferably, the medicinal formulation according to the invention contains, as opioids, morphine, tramadol and / or a physiologically acceptable salt thereof. The medicinal formulation according to the invention preferably contains as a-antagonist clonidine, guanfacine, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, terizoline, ST-91, medetomidine, dexmedetomidine, agmatine, UK14,304, para-amino-clonidine, U-47,476A, DJ-741, ICI-106270, xylazine, talipexole (BHT-920), naphazoline, tizanidine and / or a physiologically acceptable salt of the a-antagonists mentioned. As an antagonist, the medicinal formulation according to the invention very preferably contains clonidine, guanfacine and / or a physiologically acceptable salt thereof. Very preferably, the medicinal formulation according to the invention contains as opioid morphine and / or tramadol, and as a-antagonist clonidine and / or in each case its physiologically acceptable salt. As physiologically acceptable salts of the active substances acetates, tartrates, sulphates, hydrochlorides, phosphates as well as further salicylates and acetylsalicylates are used for the group of opioids. The weight ratio of the opioid to the a-antagonist in the medicinal formulations according to the invention is 200 to 1 to 10 to 1. In a particularly preferred embodiment the weight ratio of the opioid to the a-antagonist is from 100 to 1 to 10 to 1. Preferably the medicinal formulation according to the invention is administered orally. Preferred oral medicinal formulations are tablets, dragees or capsules, more preferably tablets and very particularly preferably multilayer tablets. The medicinal formulation according to the invention can also exist in the form of multiple particles, such as, for example, in the form of micro-tablets, microcapsules, ion-exchange resinates, granules, crystals of active substance or agglomerates. The medicinal formulation according to the invention may also preferably exist as an agglomerated tablet, which very preferably disintegrates rapidly. The retardation of the respective active substances can be carried out by means of a retardant coating, the fixing to an ion exchange resin, integration in a delay matrix or a combination of these. Preferably the delay is obtained with the help of retardant coatings. Suitable retardant coatings comprise water-insoluble waxes or polymers, such as, for example, acrylic resins, preferably poly (meth) acrylates, or water-insoluble celluloses, preferably ethylcellulose. These materials are known from the state of the art, for example Bauer, Lehmann, Osterwald, Rothgang "Überzogene Arzneiformen", Wissenschaftliche Verlagsgesellschaft mbH Stuttgart, 1998, page 69 et seq. They are incorporated by this as a reference. In addition to the water-insoluble polymers, in order to adjust the rate of release of the active substance, the retardant coatings may optionally also contain non-retardant polymers, preferably water-soluble, in amounts of up to 30% by weight, such as polyvinylpyrrolidone, or celluloses. soluble in water, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose, and / or hydrophilic pore formers, such as sucrose, sodium chloride or mannitol and / or the known emollients. Another usual procedure for delay is the fixation of the active substances to the ion exchange resins. As an anionic ion exchange resin, cholestyramine is preferably used, as cationic ion exchange resins, polystyrene sulfonates are preferably used. For the delay the active substances can also be found in a retarder matrix, preferably uniformly distributed within it. As matrix materials it is possible to use physiologically acceptable hydrophilic materials known to the person skilled in the art. As the hydrophilic matrix materials, polymers are preferably used, particularly preferably cellulose ethers, cellulose esters and / or acrylic resins. Preferred matrix materials are ethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, poly (meth) acrylic acid and / or derivatives thereof, such as salts, amides or esters thereof.

Also preferred are matrix materials consisting of hydrophobic materials, such as polymers, waxes, fats, oils, long-chain fatty acids, fatty alcohols or the corresponding hydrophobic esters or ethers or mixtures thereof. Hydrophobic materials which are very particularly preferably used are mono or diglycerides of fatty acids with 12-30 carbon atoms and / or fatty alcohols with 12-30 carbon atoms and / or waxes or mixtures thereof. It is also possible to use mixtures of the hydrophilic and hydrophobic materials mentioned as retarder matrix material. In another preferred embodiment, the delayed medicinal formulations can also contain both active substances in a delayed manner. The medicinal formulation according to the invention can also contain at least one of the active substances in the non-delayed form in addition to its delayed form. By means of the combination with the active substance released immediately, a high initial dose can be obtained for a rapid mitigation of pain. The progressive release of the delayed form thus prevents an extinction of the analgesic effect. Particularly preferably, the release of the active substances will be adjusted so that the delayed medicinal formulation only has to be administered at the most two, preferably only once a day. The skilled person knows by virtue of the effect of the analgesics on what proportion of mixture will have to be used to achieve the desired release of the active substances. In addition, the medicinal formulations according to the invention may comprise other coatings. As coatings there may also be those that dissolve depending on the pH. In this way it is possible to achieve that the subordinate units pass through the stomach tract without dissolving and not being released until the intestinal tract. It is also possible to use coatings that serve to improve the taste. The preparation of the medicinal formulations according to the invention can be carried out according to the various methods known to the person skilled in the art. Thus, tablets, for example, are prepared according to the usual manufacturing processes, such as, for example, extrusion, structuring processes, wet granulation, turbulent bed processes, dry mixtures or compression processes. As soon as the medicinal formulation according to the invention comprises coatings, these can be applied according to customary methods, such as, for example, dragee, spray deposition of solutions, dispersions or suspensions, by melting processes or by powder deposition processes. The amount of active substance to be administered depends on the active substances used as well as the route of application. For an oral application, clonidine, for example, is preferably applied in an amount between 1 μg and 500 μg, most preferably between 10 μg and 50 μg in each case referred to the base, and guanfacine preferably in an amount between 5 μg and 500 μg. μg and 900 μg, very preferably between 100 μg and 500 μg, in each case referred to the base. For an oral administration of the combination to be used, morphine is preferably applied in an amount between 0.1 mg and 20 mg, most preferably in an amount between 0.5 mg and 5 mg, in each case referred to the base, and tramadol preferably in an amount between 1 mg and 50 mg, most preferably in an amount between 1 mg and 20 mg, in each case referred to the base. The medicinal formulations according to the invention are preferably administered orally, parenterally or transdermally, especially preferably orally. Transdermal formulations can be prepared, for example, in the form of plasters with one or more matrices of active substance or one or more active substance reservoirs and a regulatory membrane.

In addition to an opioid, an a-antagonist and / or respectively a physiologically acceptable salt thereof, the medicinal formulations according to the invention may comprise other active and / or auxiliary pharmaceutical substances. In the case of pharmaceutical adjuvants, these are preferably binders, fillers, lubricants, vehicles, disintegration promoters, solvents, diluents, dyes, retardation aids and / or their mixtures. Both the choice of the auxiliary substances and also of the amounts to be used will depend on the form of application, whether oral, parenteral or transdermal, of the delayed medicinal formulations according to the invention. The term "filler substances" refers, inter alia, to starch, microcrystalline cellulose, dextrose, mannitol or mixtures thereof. Preferred binders are hydroxypropylmethylcelluloses, polyvinyl-iridolines, hydroxypropylcelluloses, starch pastes or mixtures thereof. As promoters of the disintegration, preferably internally substituted hydroxypropylcelluloses, crosspovidones, cross-caramel, starches, pectins, alginates, surfactants or mixtures thereof are used. From the group of lubricants used, magnesium stearate, stearic acid, calcium stearate, fatty alcohols or mixtures of these can be exemplified. Another object of the present invention is the use of the medicinal formulations according to the invention for combating semigraves to very serious algesias. Compared with the use of the opioid as the sole active substance, the medicinal formulations according to the invention show a remarkable strengthening of the analgesic effect. This means that with the same analgesic effect, it is possible to significantly reduce the amount of opioid that is used. In addition, the potential for dependence caused by opioids and the effect of obstipation in comparison with the application of the opioid as a single active substance is markedly reduced. This reduction in side effects is further improved by virtue of the fact that due to the progressive release only a relatively small amount of the active substances is released. A particular advantage of the delayed medicinal formulations according to the invention is that the development of a tolerance against the opioid is greatly retarded and even completely avoided.

The following examples serve to explain the invention, but do not limit the general idea of the invention. E ploses The granulation was carried out in a fast mixer "Lódiger FM 5", and the preparation of the tablets with an eccentric press "Fette". The term "PVP" refers within the scope of the invention to polyvinyl pyrrolidones. The term "Morphine HCl" means morphine hydrochloride trihydrate within the scope of the present invention. The term "Tramadol HCl" means tramadol hydrochloride trihydrate within the framework of the present invention. The term "min." it means minute. The term "rpm" means revolutions per minute.

Example 1 Preparation of a two-layer tablet with delayed opioid and non-delayed a-antagonist.

The two-layer tablets produced were constituted by a delayed layer containing the active substance morphine HCl and a non-retarded layer containing the active substance clonidine. For the delayed granulation, morphine HCl, a part of the lactose, hydroxyethylcellulose and ketoestearylalcohol are processed in a suitable mixer. The mixture was heated to 80 ° C and granulated. The granulate was sieved after cooling, and was mixed with magnesium stearate and talc. For the non-retarded granulate the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were intermixed to the dry granulate. Both granulates were compressed to two-layer tablets.

The investigation of the in vitro release was carried out in a paddle stirrer apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. Examination of the two-layer tablet yielded the following release profile over a time interval of 480 minutes (mean value n = 6) Release of morphine HCl Release of clonidine HCl Example 2 Preparation of a two-layer tablet with delayed opioid and non-delayed a-antagonist The two-layer tablets produced were constituted by a delayed layer containing the active substance morphine HCl and a non-retarded layer containing the active substance clonidine. For the delayed granulation, morphine HCl, a part of the lactose, hydroxyethylcellulose and ketoestearylalcohol are processed in a suitable mixer. The mixture was heated to 80 ° C and granulated. The granulate was sieved after cooling, and mixed with magnesium stearate and talc. For the non-retarded granulate, the remaining lactose and corn starch were granulated with a solution of clonidine HCl, PVP 30 and purified water in a suitable mixer. Magnesium stearate and PVP Cl were added to the dry granulate. Both granulates were compressed to two-layer tablets. Investigation of the in vitro release was carried out in a leaf agitator apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. Examination of the two-layer tablet yielded the following release profile over a time interval of 480 minutes (mean value n = 6) Release of morphine HCl Release of clonidine HCl Example 3 Preparation of a two-layer tablet with delayed opioid and delayed a-antagonist. The two-layer tablets produced consisted of a retarded layer containing the active substance tramadol HCl and another delayed layer containing the active substance clonidine HCl.

Preparation of the first layer with HCl screening The tramadol HCl was mixed with the microcrystalline cellulose, the methylhydroxypropylcellulose, a part of the highly dispersed silicon dioxide and the magnesium stearate, and was precompressed to tablets. Next, the tablets that were sifted were mixed with the remaining magnesium stearate and silicon dioxide.

Preparation of the second layer with clonidine HCl Lactose and hydroxyethylcellulose were prepared and mixed in a suitable mixer. The mixture was moistened with a solution of clonidine HCl in water. After drying, it was mixed with keto stearyl alcohol, it was heated to 80 ° C and then granulated. The cooled granulate was sieved and mixed with talc and magnesium stearate, and both granulates were compressed into two-layer tablets. The investigation of the in vitro release was carried out in a leaf agitator apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. Examination of the two-layer tablet yielded the following release profile over a 600 minute time interval (mean value n = 6) Release of tramadol HCl Release of clonidine HCl Example 4 Preparation of a two-layer tablet with delayed opioid and a-antagonist. The two-layer tablets produced consisted of a retarded layer containing the active substance tramadol HCl and another delayed layer containing the active substance clonidine HCl.

Preparation of the first layer with HCl screening The tramadol HCl was mixed with the microcrystalline cellulose, the methylhydroxypropylcellulose, a part of the highly dispersed silicon dioxide and the magnesium stearate, and was precompressed to tablets. Next, the tablets that were sifted were mixed with the remaining magnesium stearate and silicon dioxide.

Preparation of the second layer with clonidine HCl Lactose and hydroxyethylcellulose were prepared and mixed in a suitable mixer. The mixture was moistened with an aqueous solution of clonidine HCl. After drying, it was mixed with keto stearyl alcohol, heated to 80 ° C and then granulated. The cooled granulate was sieved and mixed with talc and magnesium stearate, and both granulates were compressed into two-layer tablets. The investigation of the in vitro release was carried out in a leaf agitator apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. Examination of the two-layer tablet yielded the following release profile over a 600 minute time interval (mean value n = 6) Release of tramadol HCl Release of clonidine HCl Example 5 Preparation of various medicinal formulations in the form of agglomerates (pellets). 5.1 Active rapid release substance that adheres to a delayed pellet. On delayed morphine pellets, the active substance clonidine was applied as an antagonist with the aid of a suitable coating installation. The processed pellets were filled into capsules or compressed into tablets.

The components of the delayed pellets contained: Component Quantity per capsule in mg The neutral initiator cores are introduced in a coating installation and moistened with an ethanolic solution of polyethylene glycol 4000. A mixture of morphine sulphate and lactose was applied several times to the wet cores, and the cores were dried. This process was repeated until the entire mixture of morphine sulfate / lactose had been applied. A suspension of clonidine HCl, hydroxypropylmethylcellulose, polyethyleneglycol 4000 and propylene glycol was applied to the morphine pellets produced in this way in a coating installation. The application had the following composition: The total amount per capsule was 31.98 mg. The investigation of the in vitro release was carried out in a rotating basket apparatus with a volume of 600 ml of diluted hydrochloric acid, a pH of 1.2 and a speed of 100 rpm. Examination of the two-layer formulation yielded the following release profile over the time interval (mean value n = 6) Release of morphine sulfate . 2 Mixed pellets in capsules Production of tramadol pellets Tramadol hydrochloride, microcrystalline cellulose, sodium hydrophosphate and substituted hydroxypropylcellulose were wetted with an aqueous solution of hydroxypropylmethylcellulose and extruded through a 0.5 mm perforated disk in a Pharmatex 35 T extruder. The extrudate was a Spheromat was dried on a turbulent bed, and then this was coated in a delayed manner with an aqueous dispersion of ethylcellulose and dibutylsebasate. Preparation of clonidine pellets The microcrystalline cellulose and the substituted lower hydroxypropylcellulose were wetted with an aqueous solution of hydroxypropylmethylcellulose and clonidine HCl. The mixture was extruded through a 0.5 mm perforated disk with a Pharmatex 35 T extruder, rounded in a Spheromat and dried on a turbulent bed. The pellets coated with tramadol and clonidine were filled into capsules and compressed into tablets. The investigation of the in vitro release was carried out in a rotating basket apparatus with a volume of 600 ml of diluted hydrochloric acid, a pH of 1.2 and a speed of 100 rpm. Examination of the capsules yielded the following release profile over the time interval (mean value n = 6) Release of tramadol HCl Release of clonidine HCl Example 6 The matrix tablet contained the following composition: Morphine HCl, lactose, hydroxyethylcellulose or etho-setosyl alcohol were mixed. The mixture was wetted with aqueous clonidine HCl. The resulting mixture was dried, then heated to 80 ° C and granulated. After cooling the granulate was sieved, mixed with magnesium stearate and tabletted. The investigation of the in vitro release was carried out in a leaf agitator apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. Examination of the matrix tablet yielded the following release profile over a time interval of 480 minutes (mean value n = 6) Release of morphine HCl Release of clonidine HCl Preparation of a matrix tablet with the following composition: The total amount of the starting substances was 200 g. The components were sieved (0.63 mm), then mixed for 10 minutes in a small Kubus mixer, and compressed into tablets of 10 mm in diameter and a radius of bulging of 8.5 mm and an average weight of 300 mg in a press eccentric Korsch EK 0. The investigation of the in vitro release was carried out in a leaf agitator apparatus with a volume of 600 ml of dilute hydrochloric acid, a pH of 1.2 and a speed of 75 rpm. Examination of the matrix tablet yielded the following release profile over a time interval of 480 minutes (mean value n = 6) Release of tramadol HCl Release of clonidine HCl

Claims (21)

1. CLAIMS 1. Medicinal formulation containing an opioid, an a-antagonist and / or respectively its physiologically acceptable salt, from which at least one medicinal active substance is progressively released.
2. 2. The medicinal formulation according to claim 1, characterized in that the opioid is released progressively.
3. 3. The medicinal formulation according to claim 1 or 2, characterized in that the opioid is progressively released during a time interval of 8 hours, preferably 12 hours, most preferably 24 hours.
4. Medicament formulation according to one of claims 1 to 3, characterized in that both active substances are progressively released.
5. 5. Medicinal formulation according to one of claims 1 to 4, characterized in that morphine, hydromorphone, codeine, oxycodone, dihydrocodeine exist as an opioid. , dextropropoxyphen, buprenorphine, levo-methadone, fentanyl, sulfentanil, etorphine, pentazocine, tilidine, tramadol, levorphanol, methadone, dihydromorphine, pethidine, piritramide and / or a physiologically acceptable salt thereof.
6. 6. Medicinal formulation according to claim 1, characterized in that morphine, tramadol and / or a physiologically acceptable salt thereof exist as opioid.
7. The medicinal formulation according to one of claims 1 to 6, characterized in that clonidine, guanfacine, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, terizoline, ST-91, medetomidine, dexmedetomidine, are present as a-antagonist. agmatine, UK14,304, para-amino-clonidine, U-47, 476A, DJ-741, ICI-106270, xylazine, talipexole (BHT-920), naphazoline, tizanidine and / or a physiologically acceptable salt thereof.
8. 8. The medicinal formulation according to claim 7, characterized in that clonidine, guanfacine and / or a physiologically acceptable salt thereof exist as a-antagonists.
9. The medicinal formulation according to one of claims 1 to 8, characterized in that the weight ratio of the opioid to the a-antagonist is from 200 to 1 to 10 to 1, preferably from 100 to 1 to 10 to 1.
10. 10. Formulation medicinal composition according to one of claims 1 to 9, characterized in that it exists as a tablet, capsule or lozenge, preferably as a multilayer tablet.
11. 11. The medicinal formulation according to one of claims 1 to 9, characterized in that it exists in the form of multiple particles, preferably in the form of micro-tablets, micro-capsules, ion exchange resinates, granules, active ingredient crystals or agglomerates.
12. The medicinal formulation according to one of claims 1 to 11, characterized in that the delay was carried out by means of a retardant coating, the attachment to an ion exchange resin, the integration in a delay matrix or by a combination of these.
13. 13. The medicinal formulation according to claim 12, characterized in that the coating is based on a polymer or wax insoluble in water.
14. 14. The medicinal formulation according to claim 13, characterized in that a polyacrylic resin or a cellulose derivative, preferably alkylcellulose, is used as the water-insoluble polymer.
15. 15. The medicinal formulation according to claim 14, characterized in that ethylcellulose and / or a poly (meth) acrylate are used as the polymer.
16. 16. The medicinal formulation according to claim 12, characterized in that the matrix comprises at least one polymer, a wax, a fat, a fatty acid, a fatty alcohol or a corresponding ester or ether.
17. 17. Medical formulation according to claim 16, characterized in that cellulose ethers, cellulose esters and / or acrylic resins are used as polymers.
18. 18. The medicinal formulation according to claim 12, characterized in that ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, mono- and diglycerides of fatty acids with 12 to 30 carbon atoms and / or fatty alcohols with 12 to 30 atoms are used as matrix material. carbon, or mixtures of these. The medicinal formulation according to one of claims 1 to 18, characterized in that at least one of the medicinal active substances exists in a delayed and non-delayed form. The medicinal formulation according to one of claims 1 to 19, characterized in that the formulation is administered orally, parenterally or transdermally, preferably orally. The medicinal formulation according to one of claims 1 to 20 for the treatment of states of acute or chronic algesia, semigrave to severe.