Abstract:
The invention relates to a sustained release tablet containing diclofenac-Na as active material and methylhydroxypropylcellulose as sustained release agent.

Description:
BACKGROUND OF THE INVENTION 
     1) Field of the Invention 
     The object of the present invention is to provide a tablet containing diclofenac-Na which provides sustained release of the active material. 
     2) Background Art 
     Tablets containing diclofenac-Na as the active material and hydroxypropylmethylcellulose as carrier and additive are known from WO-A-9 501 781. However, it is desirable to provide sustained release tablets which provide sustained release of the active material, so that an effective plasma concentration of diclofenac-Na is ensured even after a long interval of time (&gt;12 hours). 
     SUMMARY OF THE INVENTION 
     This object is met according to the invention by a sustained release tablet containing diclofenac-Na as active material and methylhydroxypropylcellulose as sustained release agent, as well as customary additives, in which the ratio of methylhydroxypropylcellulose to diclofenac-Na amounts to ≧0.3. 
     It has been shown in in vitro experiments that tablets with a total content of 150.0 mg diclofenac-Na and 35.0 mg methylhydroxypropylcellulose per tablet release up to 100% sustained over approximately eight hours (Method: USP XXII, Paddle apparatus). However, it has unexpectedly been found that this sustained release effect is not present in vivo; rather a delay of only approximately 1 hour can be attained. Accordingly it was not to be expected that an alteration in the ratio of methylhydroxypropylcellulose to diclofenac-Na would allow a satisfactory sustained release in vivo to be obtained. Thus for example, with a two-layer sustained release tablet according to the invention with a total content of diclofenac-Na of 150.0 mg diclofenac-Na per tablet and a ratio of methylhydroxypropylcellulose to diclofenac-Na in the sustained release part of 122.5:125.0 and a ratio of methylhydroxypropylcellulose to diclofenac-Na in the initial part of 0:25 allowed a sustained release of approximately 15 hours to be attained in vivo. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     According to a particular embodiment a sustained release tablet according to the invention comprises 
     (a) a tablet portion containing diclofenac-Na and methylhydroxypropylcellulose with a ratio of methylhydroxypropylcellulose to diclofenac-Na≧0.3 and 
     (b) an additional tablet portion containing diclofenac-Na and methylhydroxypropylcellulose with a ratio of methylhydroxypropylcellulose to diclofenac-Na&lt;0.3 or without methylhydroxypropylcellulose, 
     as well as customary additives in each, wherein the sustained release tablet is obtainable in that the tablet portions (a) and (b) are made separately from one another and then brought together and the finished sustained release tablet obtained. 
     The portions (a) and (b) can be pressed together, especially to form a multi-layer tablet. 
    
    
     The invention will now be explained in more detail with reference to examples and figures, in which: 
     FIG. 1 shows release of diclofenac-Na in vitro from tablets according to example 2, example 3 or comparative example 1; 
     FIG. 2 shows release of diclofenac-Na in vivo of a tablet according to example 1 and a standard tablet in the trade; and 
     FIG. 3 shows the plasma level of a tablet according to example 2 and standard tablet in the trade; 
     FIG. 4 shows the plasma level (with standard deviation) of a tablet according to example 3 after as single oral administration. 
    
    
     EXAMPLES 1 AND 2 
     sustained release tablets without initial portion 
     
         ______________________________________               1    2Example                mg per tablet!______________________________________1 diclofenac-sodium   125.0  100.02 lactose.1H.sub.2 O  70.4   50.03 methylhydroxypropylcellulose                 122.5  50.04 colouring           0.1    0.05 water for granulation6 magnesium stearate  3.5    2.07 highly dispersed silicon dioxide                 3.5    0.0                 325.0  202.0______________________________________ 
    
     The colouring (4) was stirred into the water (5). Diclofenac-Na (1), lactose (2) and methylhydroxypropylcellulose (3) were added in a fluidised bed granulator and granulated with the aqueous colouring solution. The resultant granulate as well as magnesium stearate (6) and highly dispersed silicon dioxide (7) were passed through a forced sieve (1.25 mm) and homogenised in a container mixer. The resultant mixture was pressed into tablets on a rotating table tablet machine. 
     The release of diclofenac-Na according to USP XXII of a tablet according to example 2 can be seen from FIG. 1. 
     EXAMPLE 3 
     Tablet with initial and sustained release portions (two-layer tablet). 
     
         ______________________________________              mg per tablet!______________________________________ 1-7 as example 1   325.0 8 diclofenac-sodium               25.0 9 lactose. 1H.sub.2 O               15.010 CaHPO.sub.4. 2H.sub.2 O               20.011 microcrsyt. cellulose               24.512 maize starch     10.013 Na-carboxymethyl starch               4.014 magnesium stearate               1.015 highly dispersed silicon dioxide               0.5               425.0______________________________________ 
    
     Example 1 was repeated. The above components (8) to (15) were passed though a forced sieve (0.8 mm) and homogenised in a container mixer. The resulting mass was pressed on to the sustained release portion according to example 1 as an initial portion or second layer, to form a two-layer tablet. 
     The release of diclofenac-Na according to USP XXII can be seen in FIG. 1. 
     Comparative Example 1 
     Two-layer tablet. 
     
         ______________________________________              mg per tablet!______________________________________ 1 diclofenac-sodium               125.0 2 lactose. 1H.sub.2 O               87.5 3 methylhydroxypropylcellulose               35.0 4 colouring        0.0 5 water for granulation 6 magnesium stearate               2.5 7 highly dispersed silicon dioxide               0.0 8 diclofenac-sodium               25.0 9 lactose. 1H.sub.2 O               15.010 CaHPO.sub.4. 2H.sub.2 O               20.011 microcrsyt. cellulose               24.512 maize starch     10.013 Na-carboxymethyl starch               4.014 magnesium stearate               1.015 highly dispersed silicon dioxide               0.5               350.0______________________________________ 
    
     A two-layer tablet was made with the above components as in example 3. 
     The release of diclofenac-Na according to USP XXII as a function of time can be seen in FIG. 1. 
     Example of use 1 
     The mean diclofenac-Na plasma concentration was determined as follows with eight test subjects. Thus the concentration was followed up for four days beginning with the fourth day after repeated oral administration of one tablet according to example 3 per day (150 mg diclofenac-Na per day), each tablet being given at 8.00 hours. The graph of the plasma concentration is shown in FIG. 2 by white squares. 
     Example of use 2 
     The mean diclofenac-Na plasma level with a tablet according to example 2 was determined with 12 test subjects, the graph being shown in FIG. 3 by a continuous line. 
     Comparative example of use 1 
     Example of use 1 was repeated with the following exceptions. Thus the mean diclofenac-Na concentration was determined beginning with the fourth day after repeated oral administration of diclofenac-Na standard tablets in the trade (50 mg diclofenac-Na per tablet), these being taken at 8.00, 16.00 and 0.00 hours. The graph of the plasma concentration is shown in FIG. 2 by stars. 
     Both in example of use 1 and in the comparative example of use 1 150 mg diclofenac-Na per day was administered. A comparison of the plasma concentration now shows that even 15 hours after administration of a tablet according to the invention, an appreciable plasma concentration could be observed, while with the comparison tablets the plasma concentration had already fallen to a comparable value after approximately 6 hours. 
     Comparative example of use 2 
     In this comparative example of use the plasma level (average over 12 subjects) of a standard diclofenac-Na tablet in the trade (100 mg per tablet) was measured as in example of use 2. The graph of the plasma level is shown in FIG. 3 by a broken line. 
     Example of use 3 
     The mean diclofenac-Na plasma level with a tablet according to example 3 (125.0 mg initial portion and 25.0 mg sustained release portion diclofenac-sodium) was followed over 24 hours with 12 test subjects, the graph being reproduced in FIG. 4 by white squares. The standard deviation is represented by vertical bars.