MXPA99010548A - Process for making flurbiprofen lozenges - Google Patents

Abstract

A process producing a pharmaceutical lozenge formulation comprising the steps of:1) granulating a mixture of flurbiprofen and a bulking agent with a solution of a binding agent in a polar solvent to form granules;2) melting a lozenge-forming composition;3) mixing the granules with the molten lozenge-forming composition;4) forming the resulting mixture into lozenges each containing a therapeutically effective amount of flurbiprofen.

Description

PROCESS FOR ELABORATING FLURBIPROPHENE PILLS DESCRIPTION OF THE INVENTION The present invention relates to an improved process for the preparation of pharmaceutical compositions containing flurbiprofen, the formulation being in the form of a tablet. [2- (2-Fluoro-4-biphenylyl) propionic] flurbiprofen is a well-known non-steroidal anti-inflammatory drug that also has analgesic and antipyretic activity. The flurbiprofen molecule exists in two enantiomeric forms and the term "flurbiprofen" as used herein is proposed to encompass the individual enantiomers and mixtures thereof in any ratio includes a 1: 1 mixture which is referred to herein as flurbiprofen. racemic Flurbiprofen can exist in the form of pharmaceutically acceptable salts or in the form of derivatives such as esters and such salts or esters are encompassed by the term flurbiprofen as used herein. Flurbiprofen and its S (+) enantiomer have been proposed to treat medical conditions of the gums. REF .: 31929 EP 137668-A (Upjohn) describes the use of flurbiprofen to prevent or inhibit alveolar bone resorption. EP 486561-A (Sepracor) describes the use of S (+) - flurbiprofen to treat periodontal disease and to promote bone growth associated with the disease. Periodontal disease is established to include periodontitis, gingivitis and periodontosis. Both documents describe specifically the treatment of the gums and do not relate to any other part of the oral cavity. The pharmaceutical tablet formulations provided by the present invention are proposed to be used in the treatment of irritated throats by administration to a patient in need of such treatment of the composition of pharmaceutical tablets containing a therapeutically effective amount of flurbiprofen which releases flurbiprofen. in the oral cavity to supply flurbiprofen to the irritated throat surface. The solid dose form is a pill which is proposed to be sucked by the patient. The term "pill" as used herein is intended to encompass all dosage forms where the product is formed by cooling a sugar-based or alcohol-based melt (e.g., isomalt) containing the flurbiprofen. The therapeutically effective amount of flurbiprofen has been found to be 5% to 40% of the normal adult dose when taken for ingestion to achieve an anti-inflammatory and / or systemic analgesic effect. The flurbiprofen can therefore be present in the pharmaceutical composition in an amount of 2.5 to 20 mg, preferably 5 to 12.5 mg. When a pharmaceutically acceptable salt of flurbiprofen is used, the amount of salt used must be such to provide the desired amount of flurbiprofen. Suitable salts include the alkali metal salts for example the sodium salt or amino acid salts for example flurbiprofen salts of lysine, arginine or meglumine. It can be expected that flurbiprofen, in common with other anti-inflammatory agents without different steroids, causes an unpleasant burning sensation in the back of the mouth when it is retained in the mouth. This may be clearly unacceptable to the patient being treated. The present applicant has surprisingly found that the unacceptable burning sensation is not experienced when the pharmaceutical tablet formulations provided by the present invention are used to treat an irritated throat but that patients receive relief from irritated throat symptoms. According to the present invention there is provided a process for producing a pharmaceutical tablet formulation comprising the steps of: 1) granulate a mixture of flurbiprofen and an agent to increase the volume with a solution of a binder in a polar solvent to form granules; 2) melting a composition that forms a tablet; 3) mix the granules with the composition that forms the melted tablet; 4) forming the resulting mixture into tablets each containing a therapeutically effective amount of flurbiprofen. The agent for increasing the volume is calcium carbonate, tricalcium phosphate, lactose or microcrystalline cellulose (for example as sold under the trademark Avicel). The binder can be polyvinyl pyrrolidone and the polar solvent is an alcohol solvent such as industrial methylated spirit (IMS) or isopropanol (IPA). The amount of binder must be sufficient to ensure that the granule is strong enough not to be damaged during the storage and transportation of the granule. The granule can be dried before being mixed with the composition that forms the molten tablet to remove the polar solvent. The composition that forms the tablet may be a sugar-based or sugar-alcohol-based composition. If the composition forming the tablet is sugar-based, it may comprise a simple sugar (for example sucrose) or a mixture of sugars (for example a mixture of sucrose and glucose). If the composition forming the tablet is based on sugar alcohol it may comprise sorbitol, xylitol, maltitol, maltitol syrup, lactitol, mannitol or mixtures thereof which may be in the form of free sugar alcohols, derivatives thereof or mixtures thereof. A preferred composition forming the pellet comprises • an approximately equimolar mixture of alpha-D-gluco-pyranosyl-1,6-D-sorbitan and fa-D-glucosopyranosyl-1,1-D-mannitol (isomalt) optionally together with a hydrogenated glucose syrup such as lycasin. The composition forming the tablet is preferably heated to a temperature in the range of 110 to 170 ° C under vacuum to remove the water before they are added. the granulated components of the pharmaceutical pill formulation. The moisture content is preferably less than 2%, more preferably less than 1%. The molten mixture can be passed to individual molds in which each tablet is formed or can be extracted into a continuous cylindrical mass from which the individual pellets are formed. Then the tablets are cooled, subjected to visual check and packed in an adequate package. One suitable form of packaging is a blister pack made of waterproof plastic material (eg polyvinyl chloride) closed by a metal, for example aluminum foil. The patient removes the pellet by applying pressure to the vial to force the pellet to break and pass through the seal of the metal sheet. The pills will normally be sucked by the patient to release flurbiprofen. In addition to the components listed above, the pharmaceutical tablet formulations provided by the present invention may contain other ingredients such as acidity regulators, opacifiers, stabilizing agents, damping agents, flavors, sweeteners, coloring agents and preservatives. These additional ingredients can be dissolved in the composition that forms the molten tablet, either before or after the granule containing flurbiprofen has been added. In another embodiment of the invention, these additional ingredients can be incorporated into the granules. If required, one or more of the additional ingredients may be encapsulated to avoid interactions with other ingredients or one or more of the additional ingredients may be included in a coating applied to the cooled tablet. The pharmaceutical tablet formulations provided by the present invention are compositions that can be sucked by the patient and slowly release flurbiprofen. Flurbiprofen then passes over the mucous membrane of the throat where part is absorbed providing topical relief. The unabsorbed flurbiprofen is then ingested by the patient and absorbed into the bloodstream. The thus absorbed flurbiprofen can act systematically to provide analgesia, anti-inflammatory and antipyretic activity in addition to the relief that comes after the topical application of flurbiprofen to the mucous membrane of the throat. The invention will be illustrated by the following Examples which are given by way of example only.

Example 1 A pharmaceutical tablet formulation containing the following components expressed in milligrams per tablet is prepared.

Flurbiprofen Racemic 8.75 Calcium Carbonate 7.5 Polyvinylpyrrolidine 1.43 Colloidal Silicon Dioxide (Aerosil) 0.036 Magnesium Stearate 0.18 Solids from a 1: 1 mixture of sugar and liquid glucose at 2350 The flurbiprofen and calcium carbonate are mixed for two minutes and the mixture is granulated with a solution of the polyvinylpyrrolidine in isopropanol. The granules are dried and the colloidal silicon dioxide and magnesium stearate are added and the resulting mixture is mixed for five minutes. The mixture of sugar and liquid glucose is heated to 140 ° C and a vacuum is applied to reduce the water content of the melted sugar pellet base. The mixed granule mixture is then added to the molten sugar pellet base. The resulting mixture is cooled and formed into a continuous cylindrical mass from which the individual pellets are prepared. The granules produced by the above process are strong enough not to be damaged during transportation, show satisfactory flow properties in the process and do not stick to any of the exposed metal surfaces of the processing apparatus. By comparison with a similar process in which flurbiprofen and calcium carbonate are not granulated but are only mixed before being added to the molten sugar pellet base gives a mixture that has poor flow properties and thus gives origin to a non-acceptable variability in the content of flurbiprofen in the resulting pellets. A process in which flurbiprofen and calcium carbonate are granulated with water before being added to the molten sugar pellet base gives granules that are friable under the conditions in which they are used and which have a tendency to stick to the apparatus , of process. Therefore the present invention provides an improved process for the production of pharmaceutical tablet formulations containing flurbiprofen.

Example 2 The granules which additionally contain a powder flavoring agent are prepared in a manner similar to that described in Example 1. Satisfactory tablets are produced in which the flavoring agent is not degraded and does not react with flurbiprofen.

Example 3 A pharmaceutical tablet formulation is prepared which contains the following components expressed in milligrams per tablet.

Flurbiprofen Racemic 8.75 Calcium Carbonate 7.5 Polyvinylpyrrolidine 1.43 Colloidal Silicon Dioxide (Aerosil) 0.036 Magnesium Stearate 0.18 Iso alt 1885 Lycasin 440 Flavoring Agents See below The flurbiprofen and the calcium carbonate are mixed for two minutes and the mixture is granulated with a solution of the polyvinyl pyrrolidine in isopropanol. The granules are dried and the colloidal silicon dioxide and magnesium stearate are added and the resulting mixture is mixed for five minutes. A molten pest base is prepared by dissolving the isomalt in the minimum amount of water. The lycasin is added and the mixture is heated to 110-120 ° C. The mixture is then heated at 145 ° C under vacuum to remove the water to give the molten tablet base. The mixed granule and the flavoring agents, which are a mixture of grapefruit (3.75 mg), orange (1.65 mg) and anise (0.348 mg), where the amounts in parentheses are the amount of each flavor component present in each tablet, are added then to the base of melted tablet. The resulting mixture is cooled and formed into a continuous cylindrical mass from which the individual pellets are prepared.

The granules produced by the above process are strong enough not to be damaged during transportation, show satisfactory flow properties in the process and do not stick to any of the exposed metal surfaces of the processing apparatus. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

RE IVIND ICATIONS Having described the invention as above, the content of the following claims is claimed as property:

1. A process for producing a pharmaceutical pellet formulation, characterized in that it comprises the steps of: i) granulating a mixture of flurbiprofen and an agent to increase the selected volume of calcium carbonate, tricalcium phosphate or microcrystalline cellulose with a solution of a binder in industrial methylated alcohol or isopropanol to form granules; ii) melting a composition that forms the tablet; iii) mixing the granules with the composition that forms the molten tablet; iv) forming the resulting mixture into tablets each containing a therapeutically effective amount of flurbiprofen.

2. A process according to claim 1, characterized in that the agent for increasing the volume is calcium carbonate.

3. A process according to any of the preceding claims, characterized in that the binder is polyvinylpyrrolidine.

4. A process according to any of the preceding claims, characterized in that the polar solvent is industrial methylated alcohol or isopropanol.

5. A process according to claim 4, characterized in that the compositions forming the tablet comprise one or more sugars.

6. A process according to claim 5, characterized in that the compositions forming the tablet comprise a mixture of sucrose and glucose.

7. A process according to any of claims 1 to 4, characterized in that the composition forming the tablet comprises one more of sorbitol, xylitol, maltitol, maltitol syrup, lactitol, mannitol or derivatives thereof.

8. A process according to claim 7, characterized in that the composition forming the pellet comprises an approximately equimolar mixture of alpha-D-glucopyranosyl-1,6-D-sorbitol and alpha-D-glucopyranosyl-1,1-D-mannitol. .

9. A process according to claim 8, characterized in that the composition forming the tablet also comprises a hydrogenated glucose syrup.