MXPA96003140A - Rapid desintegration medicine based on detramadol or a trama salt - Google Patents

Abstract

The present invention relates to tablets of tramadol or a tramadol salt free of binders, for oral application, containing microcrystalline cellulose and tramadol or a tramadol salt in a weight ratio of at least 2.

Description

MEDICATION OF QUICK TRIMADOL-BASED DESINTEGRATION OR A TRAMADOL SALT DESCRIPTION OF THE INVENTION The invention relates to Trabletas free of tramadol binding agent or a Tramadol salt for oral application. In order to obtain the release of the active substance as rapidly and as definitely as possible in the case of solid drugs as tablets, a very rapid disintegration of the drug in the release medium must be achieved. Disintegration, that is the separation of tablets into individual granulated particles, depends on multiple factors; thus the rate of disintegration can be limited strongly due to the binders [granulators], lubricants, fillers and in the case of fillers especially due to their solubility. In addition, the size and shape of the particle as well as the hardness of the tablet, which largely depends on the pressure force used during the preparation, exert a great influence on the rate of disintegration. In many cases, the disintegration time increases from a determined hardness of the tablet. The rate of disintegration of the tablets can be increased by the addition of explosive agents. Explosive agents are substances that can accelerate the disintegration of tablets in contact with water, buffer solutions or gastric juices. Examples of known detonating agents are starches, slightly substituted sodium carboxymethyl celluloses, ligands substituted hydroxypropyl celluloses, calcium caarboxymethyl celluloses, alginic acid, cross-linked cross-linked carboxymethyl celluloses and cross-linked cross-linked polyvinylpyrrolidones. From this it is known that the effect of the detonating agents as well as the decomposition of the tablets can be greatly influenced with auxiliary and / or active substances slightly soluble in water, since by means of the reduction of the volume during the dissolution of the Additional substances are prevented from disintegrating the tablets. To this it is necessary to add that the substances soluble in water in certain media possess binder properties and the capillaries in the tablet are closed due to a rapid formation of a highly concentrated diffusion limiting layer. For tablets with active substances which are very difficult to dissolve in water, it is proposed in WO 87/019369 to melt water-soluble mannitol together with a detonating agent and finally grind them. The coarse particles that are formed with a preferred grain size of between 0.1 and 0.6 mm have a solubility in water less than untreated mannitol. Tablets with a water-soluble active substance, which were pressed with molten and ground mannitol, disintegrate in very fast water. European Patent Application EP 124 027 also discloses readily dissolvable tablets for active substances which are difficult to dissolve in water. They contain the active substance in a given grain size distribution in combination with cellulose and microcrystalline starches. In order to achieve a good detonating agent effect, according to the patent application DE 16 17 343, the detonating agent, the binder and the auxiliary substances can be suspended and finally dried by means of spraying. The spray-dried auxiliary substance mixture obtained allows a rapid disintegration of the tablets. In addition, European patent application EP 130 683 spray-dried tablets containing N-acetyl-p-aminophenol as well as partially gelatinized starches, optionally in combination with microcrystalline celluloses as an additional disintegrating agent, are known. The disintegration time of these spray-dried tablets with pharmaceutically acceptable hardness is 3 to 5 minutes, however it is considered moderate. It is known from the US patent brief. 3, 181,998, that the delay of the disintegration caused by the binder can be counteracted by the presses, when enzymes are added in the dry state in the drug formulation. The enzymes are activated by the contract with water or gastric juices and accelerate the disintegration of the tablets by means of the dissociation of the starches, cellulose derivatives or gelatins used as binders. Another factor that influences the rate of disintegration of the tablets, is the hardness of the tablet. High pressure forces during tabletting produce high hardness in the tablets, this is high adhesion forces in the presser that hinder disintegration upon contact with aqueous medium. In the U.S. patent brief. 5,254,355 attempts to solve this problem by pressing dry mixtures to form tablets, with low strengths less than 35 N and then the hardness is increased by at least about 10 N by means of the glazing of the surface of the tablets. This achieves that in the interior of the tablets the binding forces are reduced and good disintegration is possible. In the effervescent tablets known from the patent application DE 39 09 520 the rapid disintegration of the tablets is promoted by means of auxiliary substances, which on contact with water produce C02. Tramadol hydrochloride, this is (1RS, 2RS) -2- [(dimethylamino) methyl] -1- (3-methoxyphenyl) -cyclohexanol hydrochloride, is an effective analgesic in severe to moderate pain. The excellent water solubility of this substance has so far prevented the successful development of tablets that rapidly disintegrate in water. If, for example, Tramadol is mixed and granulated with an insoluble auxiliary substance such as calcium dihydrophosphate and a detonating agent such as Kollidon ™ CL, the tablets obtained with a hardness of 80 N require a total disintegration of 5 minutes. Even when the content of the detonating agent increases, the disintegration can not be accelerated. A disintegration rate of 5 minutes is not acceptable for a tablet that must rapidly disintegrate in water and rapidly release the active substance. The invention therefore proposed the task of developing a tablet containing Tramadol or Tramadol salt, which rapidly disintegrates in water and rapidly releases the active substance, so as to form a suspension containing the active substance and capable of drink immediately It was found that to meet the requirements imposed on the drug to be developed of being a tablet free of binders, they contain Tramadol or a Tramadol salt in combination with microcrystalline cellulose in a certain weight ratio. Therefore objects of the invention are talablets free of binders for oral application, containing microcrystalline cellulose and Tramadol or a Tramadol salt in a weight ratio in a weight ratio of at least 2: 1. Binder-free tablets are preferred, in which the weight ratio of the microcrystalline cellulose to Tramadol or a Tramadol salt is at least 3: 1 and especially at least 4: 1. The tablets according to the invention disintegrate in water very quickly and release Tramadol or the Tramadol salt very quickly. Thus immediately after the tablet is contacted with water, a drinkable suspension containing the active substance is formed. With the tablets according to the invention the positive properties of a solid medicament are obtained as an exact dosage, good durability, possibility of hygienic packing and avoiding preservatives and when ingested the positive properties of a liquid medicament are obtained, for example they can be easily swallowed and the active substance dispersed rapidly in the blood. Especially preferred are tablets according to the invention, which contain the starch especially in a weight ratio of starch to Tramadol or Tramadol salt 1: 1. In these tablets, the influence of the hardness of the tablet on the rate of disintegration is clearly reduced. If the hardness of the tablets according to the invention that do not contain starch [example 1], increases from 80 N to 100 N, increases the disintegration time from 30 seconds to 120 seconds. On the contrary, the disintegration time of a tablet according to the invention contag starch [example 2] increases with an increase in hardness from 80 N to 100 N from 30 seconds to 55 seconds. The tablets according to the invention contag starch thus show a release of the accelerated active substance. In the tablets according to the invention, the weight ratio of microcrystalline cellulose to Tramadol sal tramadol to starch is at least 2: 1: 1. If the weight ratio of microcrystalline cellulose is lower compared to tramadol and Tramadol salt and starch, then the rate of disintegration of the tablets is greatly reduced. Also, the substitution of microcrystalline cellulose by lactose solute in water or water-insoluble calcium hydrophosphate causes a clear reduction in the rate of disintegration. The tablets according to the invention contain per tablet of 5 to 100 mg, preferably 10 to 200 mg of Tramadol and / or a salt of Tramadol, especially Tramadol hydrochloride. As optional constituent parts, the tablets according to the invention may contain at least 0.5 to 10 weight percent of a detonating agent, for example cross-linked polyvinylpyrrolidone [PVP-CL], cross-linked carboxymethylcellulose and / or sodium carboxymethyl starch, and up to 20 weight percent flavor enhancing substances, such as sweeteners, for example sodium saccharin, sodium cyclamate and / or aspartame, as well as flavorings, for example fruit and / or flavor aromas. The preparation of the tablets according to the invention is preferably carried out by mixing the constituent parts and subsequently pressing. Examples The hardness of the tablets was determined with a Heberlein hardness measuring instrument [Model 2E / 205]. Example 1 For the preparation of 200,000 tablets, 10,000 g of Tramadol hydrochloride 44,400 g of microcrystalline cellulose were mixed 2,000 g of sodium saccharin 1,000 g of peppermint flavor 2,000 g of anise aroma 400 g of highly dispersed silicon dioxide 200 g of Magnesium stearate in a mixer. The mixture was then passed through a 0.6 mm screen and mixed again in a mixer. Subsequent tablet formation was performed in a press for Fette P 2,000 tablets. The tablets obtained with a diameter of 10 mm and an average height of 3.2 mm had an average weight of 300 mg and a hardness between 60 and 80 N. Example 2 200,000 tablets were prepared under the conditions given in Example 1 consisting of 10,000 g of tramadol hydrochloride 48,400 g of microcrystalline cellulose 10,000 g of corn starch 2,000 g of sodium saccharin 1,000 g of peppermint flavor 2,000 g of anise aroma 400 g of highly dispersed silicon dioxide 200 g of magnesium stearate The tablets obtained with a diameter of 10 mm and an average height of 3.9 mm they had an average weight of 370 mg and a hardness of 60 and 80 N. EXAMPLE 3 Under the conditions given in Example 1, 200,000 tablets consisting of 10,000 g of hydrochloride were prepared. Tramadol 29,400 g of microcrystalline cellulose 10,000 g of corn starch 2,000 g of sodium saccharin 1,000 g of peppermint flavor 2,000 g of anise aroma 400 g of highly dispersed silicon dioxide 200 g of magnesium stearate The tablets obtained with a diameter of 10 mm and an average height of 3.9 mm had an average weight of 275 mg and a hardness between 60 and 80 N. EXAMPLE 4 Under the conditions given in example 1 were prepared 200,000 tablets consisting of 10,000 g of Tramadol hydrochloride 20,400 g of microcrystalline cellulose 10,000 g of corn starch 2,000 g of sodium saccharin 1,000 g of peppermint flavor 2,000 g of anise flavor 400 g of highly dispersed silicon dioxide 200 g of magnesium stearate The tablets obtained with a diameter of 10 mm and an average height of 3.9 mm had an average weight of 230 mg at a hardness between 60 and 80 N. EXAMPLE 5 Under the conditions given in Example 1, 200000 tablets were prepared. from 10, 000 g of Tramadol hydrochloride 20,140 g of microcrystalline cellulose 10,000 g of corn starch 2,000 g of sodium saccharin 260 g of PVP-CL 1,000 g of peppermint flavor 2,000 g of anise aroma 400 g of highly dispersed silicon dioxide 200 g of magnesium stearate The tablets obtained with a diameter of 10 mm and an average height of 3.9 mm had an average weight of 230 mg at a hardness between 60 and 80 N. Example 6 fComparative! Under the conditions given in Example 1, 200,000 tablets were prepared with the composition given in Example 2, instead of water-soluble lactose microcrystalline cellulose being used instead.

Example 7 Comparative1 Under the conditions given in Example 1, 200,000 tablets were prepared with the composition given in Example 2, using insoluble calcium hydrophosphate instead of microcrystalline cellulose. Determination of the disintegration time and the release time of tablets containing Tramadol. The release times were determined spectrophotometrically according to Ph.Eur./DAB in a leaf agitator apparatus in 600 ml of gastric juice with a pH value of 1.2. The temperature of the release medium was 37 ° C ± 0.5 ° C and a stirring speed of 75 Upm. The decay times were determined with an Erwe disintegration tester a [Z T6-1-D]. The results are shown in the following table: TABLE: < UO 1) s means seconds, min means minutes

Claims (5)

1. CLAIMS 1. - Tramadol or tramadol salt tablets free of binders, for oral application, containing microcrystalline cellulose and Tramadol or a Tramadol salt in a weight ratio of at least 2: 1.
2. 2. Tablets according to claim 1, characterized in that the weight ratio of microcrystalline cellulose to Tramadol or a Tramadol salt is at least 3: 1, preferably at least 4: 1.
3. 3. Tablets according to one or both of claims 1 and 2, characterized in that the tablets contain starch.
4. 4. Tablets according to claim 3, characterized in that the proportion by weight of starch to Tramadol or a salt of Tramadol is 1: 1.
5. 5. Tablets according to one or more of claims 1 to 4, characterized in that the tablets contain 0.5 to 10 weight percent of at least one detonating agent as an optional constituent.