MXPA00000605A - Medicinal formulations containing an opioid and an alpha antagonist - Google Patents

Abstract

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

Description

DELAYED MEDICINAL FORMULATIONS CONTAINING A COMBINATION OF AN OPIOID AND AN AGONIST Description of the Invention The present invention relates to delayed medicinal formulations containing a combination of an opioid or one of its physiologically acceptable salts and an a-agonist or an its physiologically acceptable salts, and with its use as analgesics. By virtue of its strong analgetic activity, opioids are applied to mitigate acute and semi-severe acute pain. 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. In addition, depression occurs 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-agonists as monopreparated by the application of various medicinal formulations is known. In addition to the known non-retarding systems there are also delayed systems with opioids, 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 delayed system that exclusively employs hydromorphone. Systems delayed with a-agonists are disclosed in EP-A-0 805 677 or US 5,484,607. In both cases, clonidine is exclusively used as a-agonist. The object of the present invention is to develop delayed medicinal formulations containing a combination of an opioid, an a-agonist and lactose or sodium hydrophosphate and administered in low doses, so that the above-mentioned disadvantages of opioids do not appear. . It was found that delayed medicinal formulations containing a combination of an opioid, an α-agonist or the physiologically acceptable salts of the active substance employed and lactose or sodium hydrophosphate fulfill the imposed task. Accordingly, a delayed medicinal formulation containing a combination of an opioid or a physiologically acceptable salt thereof, an a-agonist or a physiologically acceptable salt thereof, and lactose or sodium hydrophosphate, with or without other substances are subject of the invention. pharmaceutical auxiliaries, and their use in the case of states of algesia.

A delayed medicinal formulation according to the invention comprises an opioid from the group of morphine, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphen, buprenorphine, levomethadone, fentanyl, sufentanil, etorphine, pentazocine, tilidine, tramadol, levorphanol, methadone, dihydromorphine, pethidine. , piritramide or a physiologically acceptable salt of the mentioned opioids. As opioids, morphine, tramadol, or a physiologically acceptable salt thereof are preferred. In a delayed medicinal formulation according to the invention, an a-agonist of the group comprised of clonidine, guanfacine, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, terizoline, ST-91, medetomidine, dexmedetomidine, is used. agmatine, UK14,304, para-amino-clonidine, U-47,476A, DJ-741, ICI-106270, xylazine, talipexole (BHT-920), naphazoline, tizanidine or a physiologically acceptable salt of the a-agonists mentioned. As a-agonists, clonidine, guanfacine or a physiologically acceptable salt thereof are preferably used. Among the physiologically acceptable salts which can be used for both groups of active substances are acetates, sulfates, hydrochlorides, phosphates as well as, in addition, salicylates and acetylsalicylates for the group of opioids. The weight ratio of the opioid to the a-agonist in the formulations Delayed medicinal preparations according to the invention is 200 to 1 to 10 to 1. In a particular embodiment, the weight ratio of the opioid to the a-agonist is 100 to 1 to 10 to 1. The opioid and the -agonist are applied together in particular in a dosage form that is intended for oral administration. The amount of active substance to be administered is a function of the active substances to be used as well as of 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 in an amount between 5 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 typically applied in an amount between 0.1 mg and 20 mg, preferably in an amount between 0.5 mg and 5 mg in each case referred to the base, and tramadol in particular in an amount between 1 mg and 50 mg, preferably in an amount between 1 mg and 20 mg, in each case referred to the base. The retardation of the active substances is adjusted in such a way that on the one hand the same intensity of delay is allowed as expressed as a percentage application of active substance per unit of time referred to the respective dose, and on the other hand delays of a different type are carried out. intensity to compensate for the different half-lives of the active substances. The delayed medicinal formulations according to the invention show a release of the active substance over a period of time from 6 to 12 hours. By the combination according to the invention, it is possible to reduce notably the amount of opioid necessary for the suppression of the pains, and surprisingly a reduction of the frequency of the medication takes is achieved. These delayed medicinal formulations according to the invention are applied for the treatment of states of acute or chronic semigrave to severe algesia. In the medicinal formulations delayed according to the invention or both active substances are found in delayed form or only one of the two. In a particular embodiment in which only one active substance is present in a delayed form, the opioid is preferred as a delayed active substance. In another embodiment, oral formulations comprising both delayed active substances and pharmaceutical carriers are preferred. In addition to the combination of an opioid or a physiologically acceptable salt, an α-agonist or a physiologically acceptable salt thereof, lactose or sodium hydrophosphate, the delayed medicinal formulations according to the invention may comprise further pharmaceutical auxiliaries. This is pharmaceutical auxiliaries from the group of binders, fillers, lubricants, vehicles, decomposition promoters, solvents, thinners, dyes, retarding substances and / or their mixtures. Both the choice of the auxiliary substances and also of the amounts to be used are a function of the form of application that can be given to the delayed medicinal formulations according to the invention, oral, parenteral or transdermal. In a particular delayed embodiment of the present invention it is possible to employ in a delayed parenteral or transdermal medicinal formulation a combination of the active substances which achieve sufficient effects at low dosages, such as for example the opioids buprenorphine, fentanyl or physiologically acceptable salts of the themselves in combination with the α-agonist clonidine or a physiologically acceptable salt thereof. A parenterally delayed medicinal formulation with the aforementioned opioids in combination with an a-agonist, for example clonidine, can be made by the use of polylactic acid, polyglycolic acid or mixtures of these acids. Delayed transdermal formulations can be made in the form of patches with one or more matrices of active substance or one or more active substance reservoirs, and a controlling membrane. The delayed medicinal formulation according to the invention can exist in the form of solid oral medicinal forms such as capsules and even microcapsules, tablets, dragees, pellets or pellets. Thus, the tablets are manufactured according to the usual pharmaceutical manufacturing processes, such as extrusion, structuring process, wet granulation, turbulent bed process, dry mixing or pressing processes, and then a coating of retarding substances is provided. auxiliary The delay can be carried out both by means of a delaying matrix and also by a delaying coating. Likewise, combinations of both delay methods are possible. Among the pharmaceutical auxiliaries are, as already explained above, binders, fillers, lubricants, vehicles, decomposition promoters, solvents, diluents, dyes, retarding auxiliaries and / or mixtures thereof. The term "fillers" includes among others starch, microcrystalline cellulose, dextrose, mannitol or mixtures thereof. As binders, hydroxypropylmethylcelluloses, polyvinylpyrrolidones, hydroxypropylcelluloses, starch pastes or mixtures of these can be used. The group of the decomposition promoters belong within the framework of the present invention substituted lower hydroxypropylcelluloses, cross povidones, cross caramels, starch pastes or mixtures thereof. From the group of lubricants used, magnesium stearate, stearic acid, calcium stearate, fatty alcohols or mixtures of these can be exemplified. In the context of the present invention, hydroxyethyl cellulose, ethyl cellulose, alginates, polyacrylates (Eudragit RE 30 D, Eudragit R RS), fats, castor oil hydrate or mixtures of these.

Examples The granulation was carried out in a fast mixer "Lddiger FM 5", and the preparation of the tablets with an eccentric press "Fette". Under the term "PVP", polyvinyl pyrrolidones are understood within the scope of the invention. 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 expression "min." it means minute. The expression "UpM" means revolutions per minute.

Example 1 Preparation of a bilayer tablet with delayed opioid and non-delayed a-agonist.

The two-layer tablets produced consisted of 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. The magnesium stearate and PVP Cl were made to the dry granulate. Both granulates were compressed into 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 2 Preparation of a two-layer tablet with delayed opioid and non-delayed a-agonist 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. Morphine is processed for the delayed granulation HCl, a part of the lactose, hydroxyethylcellulose and ketoestearylalcohol 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. The magnesium stearate and PVP Cl were made to the dry granulate. Both granulates were compressed into 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-agonist.

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 time interval of 600 minutes (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-agonist. 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 time interval of 600 minutes (mean value n = 6) Release of tramadol HCl Release of clonidine HCl Example 5 Preparation of various medicinal formulations in the form of pellets 5.1 Active substance with rapid release applied on a delayed pellet On delayed morphine pellets, the active substance clonidine was applied as a-agonist with the aid of a suitable coating installation. The processed pellets were filled into capsules or compressed into tablets. The coents of the delayed pellets contained: The neutral initiator cores are introduced into 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 coition: 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 Release of clonidine HCl 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, matrix intact 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. 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 morphine HCl Release of clonidine HCl

Claims (14)

1. CLAIMS 1. Delayed drug formulation comprising a combination of an opioid or a physiologically acceptable salt thereof, an a-agonist or a physiologically acceptable salt thereof, and lactose or calcium hydrofosphate with or without other pharmaceutical auxiliaries. Delayed drug formulation according to claim 1, characterized in that opioids of the morphine group, hydromorphone, codeine, oxycodone, dihydrocodeine, dextropropoxyphen, buprenorphine, levomethadone, fentanyl, sulfentanil, etorpina, pentazocine, tilidine, tramadol, levorphanol are employed. , methadone, dihydromorphine, pethidine, piritramide, or a physiologically acceptable salt thereof. 3. Delayed drug formulation according to claim 1 and 2, characterized in that morphine, tramadol or a physiologically acceptable salt thereof are used as opioids. 4. Formulation of delayed medication according to claims 1 to 3, characterized in that a-agonists of the group of clonidine, guanfacine, guanabenz, lofexidine, adrenaline, methyldopa, noradrenaline, methoxamine, oxymetazoline, xylometazoline, terizoline, ST-91 are employed. , medetomidine, dexmedetomidine, agmatine, UK14,304, para-amino-clonidine, U-47, 476A, DJ-741, ICI-106270, xylazine, talipexole (BHT-920), naphazoline, tizanidine or a physiologically acceptable salt of the same. 5. Delayed drug formulation according to one of claims 1 to 4, characterized in that clonidine, guanfacine or a physiologically acceptable salt thereof are used as a-agonists. 6. Delayed drug formulation according to one of claims 1 to 5, characterized in that the formulation is administered orally, parenterally or transdermally. 7. Delayed drug formulation according to one of claims 1 to 6, characterized in that the formulation is administered orally. 8. Delayed drug formulation according to one of claims 1 to 7, characterized in that one of the two active substances exists in a delayed form. 9. Delayed drug formulation according to one of claims 1 to 8, characterized in that the opioid exists in a delayed form. 10. Delayed drug formulation according to one of claims 1 to 7, characterized in that both active substances exist in delayed form. 11. Delayed drug formulation according to one of claims 1 to 10, characterized in that the weight ratio of opioid to a-agonist is 200 to 1 to 10 to 1. 12. Delayed drug formulation in accordance with one of claims 1 to 11, characterized in that the weight ratio of the opioid to the a-agonist is 100 to 1 to 10 to 1. 13. Delayed drug formulation according to one of claims 1 to 12, characterized because pharmaceutical auxiliaries of the group of binders, vehicles, fillers, disintegration promoters, lubricants, diluents, colorants and / or mixtures thereof are used. 14. Use of the delayed drug formulation according to one of claims 1 to 13, for application in the case of states of acute or chronic mild to severe algesia.