MXPA97006652A - Transparent compositions, quick release, non-steroid analgesics - Google Patents

Abstract

The present invention relates to the clear compositions for active substances of rapid release obtainable by extrusion of melts, containing non-steroidal analgesics, homopolymers of N-vinylpyrrolidone, saccharides or fatty alcohols and salts of sodium or potassium

Description

TRANSPARENT COMPOSITIONS, QUICK RELEASE, NON-STEROID ANALGESICS The present invention relates to the clear compositions, fast release, non-steroidal analgesics with antipyretic and anti-inflammatory action, obtainable by extrusion of a melt containing, in addition to one or more active substances, a) 50-100% by weight of homopoli eros of N-vinylpirrolidona with a value K Fikentscher 30, b) 0-30% by weight of water soluble saccharides or sugar alcohols or mixtures of these, and c) 0-20% by weight of one more sodium salts of physiologically acceptable potassium, wherein the amounts mentioned are based on the total of a), b) and e), and the subsequent formation. The invention also relates to a process for producing these compositions. Rapid release of the active substance is of crucial importance, particularly with analgesics to achieve a rapid level of pain-releasing action. In the case of active substances with low solubility in water, as represented, for example, by organic acids with analgesic activity, the rapid release of sufficient doses is often not easy to achieve. EP-A 607 467 proposes favoring the rapid release of ibuprofen by the addition of basic salts that are applied during the process of forming the granulate in the form of aqueous solutions of the active substance which has previously been mixed with an auxiliary substance. The granulate is then compressed to tablets in a conventional manner. However, this process is relatively elaborate and therefore rather economically unfavorable. It is also known that the forms of the medicaments can be produced in a very economical way by extruding molten polymeric masses containing active substances, with the subsequent continuous formation. EP-B 240 904 discloses this process for producing the solid dosage forms by extruding the polymer melts containing active substances, using the homo- or copolymers of N-vinylpyrrolidone as polymers. However, a fundamental problem, during the process of this type, is that the polymers that form the matrix on the one hand are sufficiently processable by melting, or become processable by the addition of a plasticizing substance, at the processing temperatures but, on the other hand, they give rise to forms of stable drugs under normal storage conditions, so cold flow does not occur. This problem is all the more difficult to solve when the intention is to produce forms of fast-release medications. Normally suitable for this purpose are, in particular, the relatively low molecular weight polymers that dissolve rapidly in the digestive juices. However, to a large extent, it is precisely these that show the phenomenon of the cold flow of the forms of finished drugs. The high molecular weight polymers generally do not show rapid release and can hardly be extruded without plasticizers since the glass transition temperature (DIN 52324) is considerably higher. An additional problem arises when the intention is to produce transparent drug forms by melt extrusion. The active substance is distributed in a completely uniform manner without compartmentalization only in transparent forms. This is indispensable for quick release. In addition, the use of transparent forms simplifies quality control and is pleasant for the patient. An object of the present invention is to find clear, fast release, non-steroidal analgesic compositions which can be produced in a simple manner by melt extrusion with subsequent formation and having good storage stability. We have found that this objective is achieved with the compositions defined at the beginning. The active substances suitable according to the invention are non-steroidal analgesics with antipyretic and anti-inflammatory effect., as well as those used for symptomatic antirheumatic therapy. Suitable active substances are therefore derivatives of salicylic acid, such as acetylsalicylic acid and derivatives of other organic acids and pyrazole derivatives. In this way, suitable active substances are derivatives of aryl acid such as diclofenac, tolmetin or somepirate, as well as derivatives of arylpropyl acid, such as ibuprofen, naproxen, fenoprofen, flurbiprofen or ketoprofen, or also the indole derivatives. and indenacetic, such as indomethacin or sulindac. Examples of suitable pyrazole derivatives are, for example, phenazone, aminophenazone, metamizole, propifenazone, phenylbutazone or oxyphenbutazone. The preferred active substances are ibuprofen, acetylsalicylic acid and ketoprofen, sulindac, indomethacin, flurbiprofen.

It is also possible to use mixtures of these active substances. The compositions according to the invention contain as component a) a homopolymer of N-vinylpyrrolidone with a K Fikentscher value of 30 (for the definition of the K value see -H Fikenstcher, Cellulose-Chemie ", 13, (1932), 58- 64 and 71-74) This homopolymer is readily soluble in water, where "soluble in water" means that at least 0.5, preferably at least 2 g of the polymer is dissolved in 100 g of water at 20 ° C, wherein it is suitable as a colloidal solution The preparation of the homopolymer is generally known Suitable as component b) are the water-soluble saccharides or sugar alcohols or mixtures thereof The suitable saccharides are, in particular, mono- or disaccharides such as galactose, fructose, dextrose, maastrose, maltose, isomaltulose (palatinose), lactose or sucrose Examples of suitable sugar alcohols are mannitol, xylitol, sorbitol, adonitol, dulcitol and in general the pentitols and hexitols. co components c) are the physiologically tolerated sodium and / or potassium salts, for example, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium chloride or potassium chloride, with sodium acetate being preferred. The ratios of the amounts of components a), b) and c) are chosen according to the invention so that the compositions contain: a) 50-100% by weight, preferably 60-90% by weight of component a) , b) 0-30% by weight, preferably 5-20% by weight of component b), and c) 0-20% by weight, preferably 5-20% by weight of component c). Where the established amounts are based on the total of a), b) and e). Preferred compositions contain 80-95% by weight of component a) and 5-20% by weight of component c), based on the total of a) and e). The total content of the active substance in the compositions may vary within wide limits depending on the dose required and the rate of release. In this way, the content of the active substance can be from 0.1 to 90, preferably from 0.5 to 60% by weight of the entire composition. The compositions according to the invention can additionally contain conventional pharmaceutical auxiliaries and in customary quantities.

The mixing of the active substance or the active substances with the polymeric binders and, where appropriate, the pharmaceutical additives can be carried out before or after the melting of the polymeric binder by processes customary in the art. The mixing is preferably carried out in an extruder, preferably a double-screw extruder or a single-screw extruder with mixing compartment. The melts are free of solvent. This means that no water or organic solvent is added. The production is carried out by extrusion at 50-180 ° C, preferably 60-150 ° C, and the subsequent formation of the still plastic extrudate, for example, by forming tablets, for example as described in EP-A 240 906 by passing the extrudate between two rollers that are driven in opposite directions and have mutually opposite depressions in the liner, the design of which determines the shape of the tablets. Cold cutting is also suitable. The hot cutting method is preferred. This requires that the extrudates be granulated immediately after leaving the array of nozzles in the extruder, for example, rotating blades or other suitable arrangement, quickly in the granulates whose length is close to the same diameter of the extrudate. These cut granules are cooled in the air or gas stream to a point where the surface is not tacky even before contact with other granules or a container wall, but, on the other hand, that the granulates are still sufficiently plastic that acquire a spherical shape through shocks, for example with the wall of a posterior cyclone. This results in a simple way in which the granules which are substantially spherical or lenticular in shape have diameters of 0.5 to 4, preferably 0.8 to 2 mm. The preferred smaller particles are mainly suitable for filling capsules. Solid forms of medicaments may also be provided with a conventional coating to improve appearance and / or taste (tablet coated with sugar). The compositions according to the invention of non-steroidal analgesics with antipyretic and anti-inflammatory action are transparent, stable during storage and show rapid release. "Rapid release" means that the release of the active substance measured with the palette method of USP XXII after 30 min. It is at least 70%. Surprisingly, despite the use of a relatively high molecular weight polymer, even drug forms with higher weights, such as 1,000 mg, showed rapid release. It is also advantageous that large tablets can be used as pills without having to swallow them, and the addition of sugar alcohols also means that there are no problems with taste. The swallowing of large tablets is often associated with difficulty, particularly for elderly patients or patients with dysphagia, so these rapid-release tablets have great advantages.

EXAMPLES The compositions indicated in each of the examples were pre-mixed and introduced into the feeding section of a double-screw extruder (Werner &Pfleiderer, ZSK 30). The extrusion of the melt was carried out with a product yield of 3-4 kg / h. The temperature in the individual zones ("sections") of the extruder and the temperature of the outlet of the heated nozzle are established for each of the tests. Bolus tablets weighing 1000 mg were produced from the extrudate by the calendering process described in EP-B 240 906. The release of the active substance was measured with the paddle method of USP XXIII. This in vi tro test method is used to determine the rate of dissolution of formed articles containing active substance, e.g., tablets.

This was done by balancing 900 ml of a phosphate buffer solution with a pH of 6.8, with the addition of 0.1% sodium lauryl sulfate, in a 1 L round base vessel at 37 ° C. An appropriate amount of the drug form was weighed. The release of the active substance from the boluses was determined in this test without changing the USP XXI at a palette speed of 100 rp after 30 minutes in each case, by UV spectroscopy. Example 1 Temperatures of the extruder zones (sections 1-5) 20, 80, 140, 130, 130 ° C. Temperatures of the extruder head 130 ° C, nozzle outlet temperature 130 ° C. Active substance Component to ibuprofen 20% by weight polyvinylpyrrolidone with K value of 30, 80% by weight Release after 30 min .: 82% Example 2 Temperatures of the extruder zones (sections 1-5) 60, 120, 120, 110, 120 ° C. Temperatures of the extruder head 130 ° C, nozzle outlet temperature 120 ° C. Active substance Component a Component b ibuprofen 20% by polyvinyl pyrrolidone D-mannitol 10% by weight with K value by weight 30, 70% by weight Release after 30 min. : 72% Example 3 Temperatures of the extruder zones (sections 1-5) 60, 120, 120, 120, 130 ° C. Temperatures of the extruder head 130 ° C, nozzle outlet temperature 160 ° C. Active substance Component a Component b ibuprofen 20% by polyvinylpyrrolidone D-mannitol at 20% weight with K value of 30, by weight 60% by weight Release after 30 min. : 70% Example 4 Temperatures of the extruder zones (sections 1-5) 70, 130, 130, 140, 130 ° C. Temperatures of the extruder head 130 ° C, nozzle outlet temperature 160 ° C. Active substance Component a Component b ibuprofen 20% by polyvinylpyrroli Na acetate at 13.5 weight donates with K value by weight of 30, 66.5% by weight Release after 30 min. : 95% Example 5 Temperatures of the extruder zones (sections 1-5) 70, 130, 130, 140, 130 ° C. Temperatures of the extruder head 130 ° C, nozzle outlet temperature 160 ° C. Active substance Component a Component b ibuprofen 20% by polyvinylpyrrolidone Na Acetate at 5 weight a with K value of% by weight 30, 75% by weight Release after 30 min .: 95% Example € Temperatures of the extruder zones (sections 1-5) 60, 120, 120, 120, 130 ° C. Temperatures of the extruder head 130 ° C, nozzle outlet temperature 160 ° C. Active substance Component a Component b component c ibuprofen 20% polyvinylpyrroli D-mannitol 5 Acetate by weight donates with K value by weight Na at 5% of 30, 70% by weight weight Release after 30 min. : 80%

Claims (5)

1. A composition, transparent and fast release, of a non-steroidal analgesic with antipyretic and anti-inflammatory action, obtainable by extrusion of a melt containing, in addition to one or more active substances, a) 50-100% by weight of N-homopolymers -vinylpyrrolidone with a K value Fikentscher 30, b) 0-30% by weight of water soluble saccharides or sugar alcohols or mixtures thereof, and c) 0-20% by weight of one more physiologically acceptable potassium sodium salts, wherein the amounts mentioned are based on the total of a), b) and e), and the subsequent training.

2. The composition, according to claim 1, comprises 5-20% by weight of component c).

3. The composition, according to claim 1 or 2, has ibuprofen as the active substance.

4. The composition, according to any of claims 1 to 3, contains sodium acetate as component c).

5. A process for producing clear, fast release compositions according to any of claims 1 to 4, which comprises the extrusion of a melt containing, in addition to one or more active substances, a) 50-100% by weight of homopolymers of N-vinylpyrrolidone with a Fikentscher K 30 value, b) 0-30% by weight of water soluble saccharides or sugar alcohols or mixtures thereof, and c) 0-20% by weight of one more sodium salts of physiologically acceptable potassium, wherein the amounts mentioned are based on the total of a), b) and e), and the subsequent formation.