SE447450B - PHARMACEUTICAL COMPOSITIONS WITH CONTINUOUS TABLE PREPARATION AND WAY TO PREPARE THESE - Google Patents

Description

447 450 the pesticide, a release control agent and an erosion promoting agent.

The present invention relates to a sustained release tablet pharmaceutical composition comprising (a) an orally active therapeutic agent, (b) 0.8 to 1.6% by weight, based on the total weight of the tablet, of a release control agent selected from cellulose acetate phthalate, cellulose acetate derivatives , shellac, zein, acrylic resins, ethylcellulose, hydroxypropylmethylcellulose phthalate, sandarac or modified shellac, and (c) 1.0 to 7.5% by weight, based on the total weight of the tablet, of an erosion promoting agent selected from maize starch, rice starch , potato starch or other vegetable starch species, modified starch, starch derivatives, cellulose, cellulose derivatives, modified cellulose, modified cellulose derivatives, alginic acid, alginates, bentonite, aluminum magnesium silicate, crosslinked polyvinylpyraranths or a critical factor is calculated according to equation I CF = cA I i / (cs) where CF is the critical factor, CA is the amount of therapeutic agent per tablet in mg divided by the amount of release control agent per tablet in mg and CS is the amount of erosion-promoting agent per tablet in mg mg divided by the amount of release control agent per tablet in mg and is in the order of 20 to 450.

All percentages are given as a percentage by weight of the total weight of the tablet. The preferred amount of release control agent is in the order of 1.55 - 1.6% by weight and the preferred range of erosion promoting agents is in the order of 2 - 5% by weight. I than 447 450 but the critical factor is suitably above 50 and is preferably in the order of 80-330 and preferably in the order of 210-330.

The preferred release control agent is cellulose acetate phthalate.

The preferred erosion promoting agent is corn starch.

ASA tablets suitably contain 650-800 mg of ASA per tablet, about 5.0 to about 1.3.6 mg per tablet of release control agent and about 13.4 to about 63.8 mg of erosion promoting agent per tablet.

Other anti-inflammatory therapeutic agents may be used in the pharmaceutical compositions of the present invention.

For example, tablets may be prepared containing 400 to 600 mg of ibuprofen per tablet or 100 to 300 mg of flurbiprofen per tablet.

The pharmaceutical compositions of the present invention may also contain inert fillers or diluents, flow aids or tableting aids.

The tablets of the present invention preferably have - 18 Kp. However, it has been found that a satisfactory release characteristic of a hardness on the Schleuniger scale of 6.5 ka can be obtained with tablets of varying hardness. This facilitates the large-scale production of the tablets because any variations in hardness caused by the tableting machinery do not cause a significant change in the release characteristics.

The pharmaceutical composition is prepared by granulating a mixture of an orally active therapeutic agent and an erosion promoting agent selected from corn starch rice starch, potato starch and other vegetable starches, modified starch, starch derivatives, modified cellulose, cellulose-modified cellulose, derivatives, alginic acid, alginates, bentonite, aluminum-magnesium silicate, crosslinked polyvinylpyrrolidone, ion exchange resins or adhesives, with a solution of a release-controlling agent selected from cellulose acetate phthalate, cellulose acetate derivative, shellac, zein, acrylic cellulose, cellulose, in an organic solvent and then pressing the granules so prepared into tablets, the final tablet containing 0.8 to 1.6% by weight, based on the total weight of the tablet, of the release controlling agent. and 1.0 to 7.5% by weight, calculated on the total weight of the tablet, of the erosion promoting agent and that the relative amounts of the components are such that a critical factor is calculated according to the equation I - cA CF "7 * Tws I wherein CF is the critical factor, CA is the amount of therapeutic agent per tablet in mg divided by the amount of release control agent per tablet in mg and CS is the amount of erosion-promoting agent per tablet in mg divided by the amount of release control agent per tablet in mg, and is in the range of 20 to 450.

The compositions of the present invention may be prepared by dissolving the release control agent in a suitable organic solvent such as lower aliphatic alcohols such as methanol, isopropanol or n-propanol, acetone or lower aliphatic ketones such as methyl ethyl ketone, chloroform, carbon tetrachloride, ethyl acetate and non-chlorate hydrocarbons or in a solvent mixture such as methylene chloride and denatured alcohol [1: 1 (v / v)].

The therapeutic agent in powder form is intimately mixed with the erosion promoting agent, preferably corn starch, and the solution of the release control agent, preferably of cellulose acetate phthalate, is added to the mixing powders in a steady stream. The mixing continues to form a wet granular mass. The wet mass is dried to remove residual organic solvent, leaving the release control agent in intimate contact with the particles from the therapeutic agent and the erosion promoting agent. The granular mass is reduced to a suitable granular size by forcing the material through a sieve and mixing the dried granules to ensure homogeneity before being pressed into tablets using a conventional rotary or single station tablet press. The tablets can then be printed directly using conventional tablet printing devices and product identification materials. Tablet identification can also be done by embossing the final product during compression.

The invention is illustrated by the following examples.

The examples refer to the accompanying drawings in which: Figure 1 is a graphical illustration of the results of the tests described in Example 7 and shows the mean room levels of ASA during the first eight hours of a 24 hour study on one and each of two subjects, which receives two 650 mg tablets as a single dose of 1300 mg of ASA, the tablets being in accordance with the present invention (solid and broken lines), compared to a single 650 mg tablet also according to the present invention (alternating dotted and dashed lines) .

Figure 2 is a graphical illustration of the results of the tests described in Example 8 and shows the mean room levels of salicylic acid over a 120 hour period including oral multiple doses (nine doses of 2 x 650 mg each - 12 hour intervals over a 96 hour period). of the ASA tablets of the present invention on eight subjects with blood samples taken at the 447,450 hours indicated.

Figure 3 is a graphical illustration of the results of the tests of Example 8 and with the description of Figure 2 showing the serum levels of ASA. Figure 4 is a graphical representation of the two departmental models used to provide the simulated zero-order absorption curves shown in Figures 5 and 6.

Figure 5 is a graphical illustration of the results of a comparison between a simulated data curve for absorption of the zero order of ASA (solid line) and the actual values from blood samples taken on day 1 for the treatment of subject l (dashed line) from Example 8 and Figure 6 are a graphical illustration of the results of a comparison between the theoretical values for absorption of the zero order of ASA (solid line) in a second subject and the actual values of blood samples taken on day 1 of the treatment of subject 2 (dashed line) from Example 8.

Example 1 Cellulose acetate phthalate (67.3 grams) was slowly added to the vortex of a mixture of ethanol (denatured, 625 ml) and methylene chloride (175 ml) prepared from a high speed stirrer. Stirring was continued until solution was reached.

ASA (4.375 kg, 425 Å crystals USP) and corn starch (0.2255 kg, USP) were deaggregated through a 425 μm sieve to a bowl of a Hobart mixer. The dry powders were mixed for five minutes at rate 1. The cellulose acetate phthalate solution was added to the mixing powders over a thirty second period of mixing at rate 1. Additional mixing for four minutes at rate 2 was performed to promote granulation.

The wet granular mass was discharged on stainless steel trays and air dried until it could be forced through an 850 micron sieve. The sieved granules were further air dried to remove residual solvent. The granules were weighed, tumbled and compressed on a conventional rotary tablet press using half-inch flat tools with beveled corners to make tablets containing 650 mg of ASA with a hardness of 8-10 Kp (Schleuniger).

Example 2 Cellulose acetate phthalate (750 grams) was slowly added to the vortex of a mixture of methylene chloride (3.75O ml) and ethanol (3.75O ml).

Stirring was continued until a solution was obtained.

ASA (60 kg, 120 / mn powder USP) and corn starch (3.0 kg, USP) were placed in the bowl of a Littleford MGT 400 mixer. The dry powders were mixed using the propulsion device at speed 1 for two minutes. The cellulose acetate phthalate solution is poured in a steady stream on the powders mixed at the propulsion speed 1 and the chopper speed 1.

After addition of the solution, the mixing was continued at the propulsion and decomposition rate 2 until a suitable granular mass was obtained. The wet granular mass was spread on stainless steel trays and dried in a forced draft oven at a temperature not exceeding 49 ° C. The dry granular mass was processed by a Jackson Crockatt granulator equipped with a 1,188 stainless steel screen. The dried sized granules were mixed in a drum mixer for five minutes and compressed on a conventional rotary tablet press using capsule-shaped tools which gave tablets containing 800 mg of ASA with a hardness of 8 - 11 Kp (Schleuniger).

Examples 3 to 6 Four batches of tablets having the compositions of Table I were prepared as described in Example 1. The decay time in a buffer at pH 7.5 was determined according to the procedure described in the United States Pharmacopoeia XX p. 958 but excluding the discs and release properties was determined in a buffer at p fl 7.5 according to the procedure described in th fl United States Pharmacopoeia XX p. 959 but using a modified 447 450 version of the apparatus described as apparatus 1 in which a propeller is mounted on the shaft above the basket. The results of these tests are set forth in Table 1 which also shows the results obtained using conventional ASA tablets (Examples A) and tablets (Examples E and C) in which the critical factor is greater than required by the present invention. Dissolution data for Examples 4 and 6 were obtained using an additional batch of tablets prepared in the same manner as those indicated for the decomposition experiments. 447 450 .fifl muuwmv lamm Onufš fl w mad> m .mc fl ømcw fl ow wmHwxHmnm .Lä äwš .äušn fl s m v mmm f som <2. u mn fi nmm fi uu O _. go wwcm flfl wn fl om wm fl w fi n fi m nä fl xumu fififi uo umuøc fl e om own oow fl mä fi ø fi Twxu fl fifi mâ mo wwüvšwpm mumn fi wuwåo Hw fi c fl xmm Owv fl mco fi ucw. 4 m.mm mms .oom ow m w. dß mmm om _. cmmc fl n m .mm mmamxnmßm _ r .om SN om | wä | w fifi oa äšøn fl a om X w vw omw. <2 m. M.> M man oom or mdo m. vu: Nm om r øwmc fl: od mm fi wvmn fl m w .mm mmm om lwnoumu flfi oc. umvß flflfl O .NA omm oom - N. O? Bm as if N .Nm if: if v cwm fi a ä. M _. wm fl w fifi w m. .E åw oo àäï fi ïo: »mpšüa 32 mä emo _ m. mm oaw uncle O _. mad w. «ß www conv cmma fi c d.m ~ ww fl mæm fi m. r. mm mmw oo nwuonwu fifl o: umvwš fi ë om X ßw omm W ma ^ .c fl ao w fl p E. m wo »wmmH> w fl> mm fl nnm fi hm | mwmMmMmM» m | w fi Hmmwwø = @ m Amowmww fl mw .mwmwmmmmwm Hwmawxm mmm wmcmz H QAWQQB 4477450 10

Test time Acetylsalicylic acid, dissolved (hours) (%) 0.5 23.8 1 34.8 2 61.3 3 82.4 These results, when stated as a function of time against dissolved percent acetylsalicylic acid, gave a straight line indicative of the release of zeroed the scheme. Linear regression analysis of data gives a correlation coefficient of 0.999, compared to a straight line value of 1.0.

The solution of the tablets according to Example 3 and an additional batch prepared according to Example 6 were evaluated according to a method comprising pH change. The method was in accordance with the United States Pharmacopoeia XX p. 959 using the modification described above. The results are shown in Table 2.

TABLE 2 Time Initial mg ASA released Cumulative «Percentage of theo- (hours) pH at the end of the amount of free-retired amount of time made ASA mg free9j0rd ASA example.6 example.3 example.6 example.3 example.6 example.3 O -1/2 1.2 50 46 50 46 7.7 7.1 0-1 1.2 72 60 72 60 ll, l 9.2 1-3 4.4 125 96 197 156 30.3 24.0 3 -6.5 7.5 410 425 607 581 93.4 89.4 The level of chemical degradation that occurs during storage of the tablets of the present invention is less than that which occurs with conventional ASA preparations. Acetylsalicylic acid decomposes to 447,450 ll salicylic acid and this reaction is promoted by elevated temperature. The reaction is easy and has led to the United States Pharmacopoeia adopting an upper limit for the level of free salicylic acid (FSA) in ASA tablets of 0.3 percent.

Tablets prepared according to Examples 1 and 5 were evaluated for free salicylic acid (FSA) after storage under extreme conditions. The results are shown in Table 3.

TABLE 3 Example Time Storage FSA level percent l 0 _ 0, 04 3 months 40oC 0.12 5 O - 0.06 6 months 4030 0.14 37 C / 75% 0.22 relative humidity It is generally known that during similar storage conditions the limiting amount of FSA, ie. 0.3 percent, would be exceeded by conventional ASA preparations. Tablets prepared according to Examples 4, 5 and 6 were subjected to a drop test in a Roche "friabilator". After 100 drops, a weight loss between 0.12 and 0.46% by weight was observed.When the test was extended to give 750 drops The edges of the tablets were worn but the tablets did not break in. A commercially available aspirin tablet with sustained release showed a weight of 0.85 percent after 100 drops and severe abrasion after 750 drops.

Example 7. Serum levels after a single oral dose Tablets containing 650 mg of ASA were prepared according to the method of Example 1. A volunteer subject was given a single oral dose of 650 mg while two other subjects received a single dose of 1300 mg (two 650 mg tablets ). Blood samples were taken from each catheter inserted through a catheter inserted into a vein in the forearm. The samples were collected in a refrigerated vacutainer tube at the following times: before dosing and at 15, 30, 45 and 60 minutes; 1.5, 2.0, 2.5, 3.0, 4.0, 8.0, 22.0, 16.0 and 24 hours after dosing. The blood samples were analyzed for plasma salicylic acid and acetylsalicylic acid using high pressure liquid chromatography. Table 4 and Figure 1 show the results of these measurements. Figure 1 shows the results for subject 1 as a year-round line, those for subject 2 as an alternatively dotted and dashed line and these for subject 3 as a broken line. X axis represents the time in hours and the surface axis the plasma concentration of ASA in micrograms / ml.

TABLE 4 Plasma acetylsalicylic acid and salicylic acid values over a 24-hour period 1 0 2 '5 Subject no 1300 mg 650 mg 1500 mg ä0S mkg / ml mkg / ml mkg / ml I fl kttagelsetid ASA SA ASA SA ASA SA (hours) 0, 1 0.1. 0.1 0.1 _.0.1 0.1. -å: 0.1 -0.38 0.1 0.1 5 0.1 "0.2 'å 0.1 0.93 0.1 0.1 0.46 0.99 å 0.43 1.58 0.1 0.28 0.49 1.81 1 0.41 2.18 0.19 0.67 0.53 2.26 1.5 .0.37 5.19 0.55 1.55 0.71 5.24 2.0 0.59 4.30 0.30 2.45 0.61 4.07 2.5 0.61 5.55 0.25 3.08 0.51 4.99 3.0 _o.4s 5.70 0.35 5.29 0.89 6.01 4.0 0.68 8.89 0.38 4.27 0.97 10.70 8.0 0.39 17.00 0.18 5.47 0.20 11.50 12.0 0.1 17.90 0.1 3.72 O.2619.30 16.0 0.1 8.87 0.1 5.83 0.20 14.00 24.0 0.1 0.36 0.1 2.96 0.17 9.24 447 450 Serum levels of acetylsalicylic acid peaked for all three subjects four hours after drug intake, levels did not return to 0.1 micrograms / milliliter until after eight hours, compared with the established half-life. the ring time (t = 1/2) of 20 minutes for serum acetylsalicylic acid after administration of a standard 650 mg tablet.

Example 8. Serum levels after multiple oral doses ASA tablets prepared according to the method of Example 1 were orally administered to eight healthy volunteers at doses of 1300 mg (two 650 mg tablets) twice daily at 8 and 20 at nine consecutive doses. wherein the last dose was given in the 96th hour to determine the pharmacodynamic steady state of the ASA tablet formulation of the invention. Blood samples were taken from the subjects for predetermination of time intervals during the study process. The blood samples were analyzed by high performance liquid chromatography for salicylic acid and acetylsalicylic acid levels. Individual blood levels of salicylic acid and acetylsalicylic acid found on day five of the study are shown in Tables 5 and 6. Graphic representation of the mean blood levels of salicylic acid and acetylsalicylic acid for the whole experiment is shown in Figure 2 and 2, respectively. In these figures, the numbers on the axis represent the time in hours and the numbers on the y axis represent the SA and ASA levels in the blood in micrograms / ml.

Example 9. Comparison between ASA absorption with a theoretical zero scale curve.

To demonstrate that the in vivo absorption characteristics of aspirin tablets prepared according to the present invention are generally of the zero order, results from subjects 1 and 2 of Example 8 were compared with the predicted results calculated by a computer. The computer calculations were based on two departmental models with first-order metabolism.

This model is shown diagrammatically in Figure 4. The model estimates that the total dose D is absorbed at a constant rate cow during a period of time T. By the end of time T, all doses will have been absorbed. The model also assumes that 60 percent 447 450 14 of ASA passes the liver 2 in an unhydrolyzed state before passing into a central compartment 3 which has a visible distribution volume of 6.3 liters. The acetylsalicylic acid can reversibly pass from the central compartment 3 to the body tissue (shown as 4) or can be irreversibly removed as metabolites (shown diagrammatically as 5). The rate constants used in the model and shown in Figure 4 are taken from Rowland and Riegelman J. Pharm. Sci. volume 57 p. 1313 (1968).

The time T required for the full dose to be absorbed limits the degree to which the multiple doses overlap. In Figure 5, the results obtained from subject No. 1 in Example 8 (dotted line) are compared with the data generated curve (solid line) obtained when T was given the value for 16 hours. The results obtained from subject No. 2 according to Example 8 (dotted line) are shown in Figure 6 and compared with the data generated curve (solid line) generated when T was given the value for six hours. In Figures 5 and 6, the numbers on the x-axis represent the time in hours and the figures on the y-axis represent the ASA levels in the blood in micrograms / ml.

There is a reasonable agreement between the experimental curves and the theoretical curves which shows that in vivo there is a close approximation to zero order absorption with ASA tablets prepared according to the present invention. 447 450 15 Ho.m mm.> Ss @ _w o> _w om_m «> .oH mo.oH« @ .oH «m.oH oH.oH m« ~ oH: www Hm.HH mo. @ N ~ w_o « om_H «Hm.« «~ om« «m. ~« w ~. ~ «ow_mm> w.wm m> _wm Hwwwz @mm wß_mH wm.mH m @ _mH ~ m_mH Ho.« ~ Hw_wH> m.wH4 wm. mH «o. ~ H mm_oH wo« .o mm.oH> o. «m>«. mm mH.mm ~ «. ~ m ß«. «~ om.o ~ m @ .mH mm.« H wm. HH> o>. ~ @ M.mH mm_ @ m «m.om Hm_m ~ N ~ .om mø.w ~ ow.w ~ w ~ .m ~ Hw.« ~ Mw_- w wH. ~ H> m. Hm @H_mm ~ «.« M Hm.mm> ~ _ «m mm.w ~ w> .om ~« _Hm @ m_ ~ m> m.wm m> w_wH mH.o «mw_Nm HH. @« «O_o @ w «.> wm«.> wm @. ~ @ m @. ~ w æ> _w @ w «. ~> 4 Hm.m mw.> m« w. «w> ~.«>> w_mm> «_ «M ~ w_> w Hm.om H« _mw> m.wß m.ow m ~ mm «« om>> o_mm -.mß mm_m> @ m.mw mo. ~> ~ H_> ß wm_m> m ~. w @ mm_mw N wm.H Hm.w H «_oH m> _ ~ H mo_mH m ~ .wH wm.mH m @ _oH mo ~ oH æ @ _m> H_m H« ~ wH NH oH ww 4 NH m_o o nu wow nwumw. ~ Ho zmw fl oH_o @Ho mN_o Hm.o ~ m_o m «_o« mo> wo Hæ.o> @_ o wm \ o Hwwwz mo.o wH.o mH_o @H_o mm_o m «.o¶ ~ w_o ow_o ww_o mw. o mw_o w mo.o wo_o mH_o> mo om.o @ ~ .om> .o «mo om.o H« _o mH.o ß mo.o wH.ow ~ .o @ «. om« .o Hm.o mm_o mw.o ~ w_o om. om ~ _o w wH_o m ~ .o mN.o «~ .om« _o mw.o ~ mo mm.om «.o mm.o«> .om mo_o w ~ .om «_o @ ~ _o m« ~ om @_o mm.o mw.o ww_o mw_o @oH Q oH.o mo.o mo.o mo_o ¶mo.ow ~ .oo «~ ow @ .om> _o w> .ø m> _o M mo ~ o wH .om ~ _o> «~ ow ~ .o -_o>« _ o @>. o> @_ H> o_H Hw.o N @o_o wH_o N ~ .ow «.o« mo Hm_o m «_o>«. _o mm.o mH.o H vw, @ fi NH o fl mw «NH mo o Ma men umumw Anmas fi u. ø fl a _ gsm HE \ EmHm0Hx fl E .Emm mmm nww> fl: mu> mH> o «HmmH» umu @ H> H fl wnmä 447 450 Exemgel 10.

Cellulose acetate phthalate (50 g) was added slowly to a rapidly stirred mixture of ethanol (620 ml) and methylene chloride. Stirring was continued until a solution was obtained. This solution was added to a mixture of ibuprofen, 2- (4-isobutylphenyl) -propionic acid (2.5 kg), dicalcium phosphate dihydrate sold under the trade name Emcompress (0,75 kg) and maize starch (0,55 kg), which was thoroughly mixed. The wet granular mass was air dried on stainless steel trays and passed through a 1.40 mm sieve and further dried to remove any solvent.

An amount of dried granules corresponding to approximately 0.05 kg was removed from the main mass and mixed with a colloidal silicon dioxide sold under the trade name Aerosil 200 (0.5% based on the total weight of the granules). This premix was then mixed with the granule mass for 10 minutes.

The mixed granules were obtained in a yield of 98.4%.

The flow properties of the granules judged by the method of Carr (Brit. Chem. Eng. 15, 1541-1549, 1970) were found to be satisfactory to passable.

The granules were compressed on a conventional rotary tablet press using half inch flat beveled edge tools to give tablets containing 400 mg of ibuprofen with a hardness of 8 to 12 kp (Schleuniger).

The CF for this example is 155 and the weight percent of release control and erosion promoting agents is 1.44 and 4.46, respectively.

Tablets prepared from granules prepared in the above-mentioned manner were compressed to different hardness and the obtained tablets were subjected to decomposition test (United States Pharmacopoeia XX, p. 959) in a buffer at pH 7.5 at 37 ° C. 447 450 18 Hårahét Meaeisönaerfailtia kp _ _. 4 (minutes) 4.14> zss 8.54> 27s 1o, as _ _> 24o A conventional ibuprofen tablet disintegrated in less than a minute and a sugar-coated tablet disintegrated within 5 to 10 minutes.

The in vitro dissolution test (United States Pharmacopoeia XX, p. 959) shows that the tablets of Example 10 (hardness 10.86 kp) gave a sustained release of ibuprofen compared to conventional ibuprofen tablets. Each attempt was repeated six times.

Amount of dissolved ibuprofen (mg) Time / _ Conventional tablet minutes Example 10 (pH 7.5) (pH 6.8) initial after 3 months initial after 3 months storage at 40 ° C storage at 40 ° C 10 - - 277 62 20 - - 318 110 30 68 63 365 163 60 100 99 383 248 120 169 163 180 219 217 240 265 274 toe 155 153 8.4 41.3 In the above results, the time it took for 50% of ibuprofen to dissolve. The results after 3 months of storage show that the tablets of the present example have good storage stability. 447 450 19 The results for the tablets of Example 10, which were not stored, gave a straight line when the amount of ibuprofen dissolved was indicated against time. Linear regression analysis of the results gave a correlation coefficient of 0.996, thus indicating in vitro resolution of the zero order.

Examples 11 and 12.

Tablets containing flurbiprofen, (2- (2-fluoro-4-biphenylyl) -propionic acid), were prepared by adding a solution of cellulose acetate phthalate to a mixture of the active ingredient dicalcium phosphate dihydrate (sold under the tradename Emcompress) and corn starch. The wet mass was air dried, sieved and further dried to remove organic solvents. Magnesium stearate (0.5% of the total weight of the granules) was added and the granules were tableted.

The compositions of Examples 11 and 12 are given below.

CAP solution Example 11 Example 12 Cellulose acetate phthalate 9 g 8.33 g Denatured ethanol 60 ml 55 ml Methylene chloride 60 ml 55 ml Modify components Flurbiprofen 300 g 100 g Emcompress 240 g 400 g Maize starch 18.6 g 17.2 g Weight flurbiprofen per tablet 300 mg 100 mg Tablet hardness (bp) 8.7 in 1.2 7.14 in 0.54 CF 25 25 release control agent 1.58 1.58% erosion promoting agent 3.27 3.27 The average decay time of the tablets according to examples ll and 12 in a buffer at pH 7.5 was determined according to the method described on p. 958 in United States Pharmacopoeia XX.

The results obtained are shown below. 447 450 zo Example 11 Example 12 Mean decay time (minutes)> 300> 36O residue (%) 3.7 4.9 The dissolution of flurbiprofen over a period of time for the tablets of Examples 11 and 12 was determined using the apparatus described on p. 959 in United States Pharmacopoeia XX. Phosphate buffer at pH 6.8 was used. The experiments were repeated six times and the mean value of the amount of actively released material is given below. % dissolved flurbiprofen Example ll 7Example 12 Time (hours) 1 9.6 10.6 2 22.5 17.1 3 29.3 _ 24.7 4 34.8 28.8 5 44.8 35.1 7 56, 9 47.7 lo 74.0 68.5 A curve plotted for the percentage of dissolved flurbiprofen against the time of each of these result sets gave a straight line, which showed that a zero-order mechanism works in this case. The use of regression analysis on the data shows a correlation coefficient of 0.993 for Example 11 and 0.999 for Example 12.

By comparison with a conventional flurbiprofen tablet containing 100 mg of flurbiprofen in the same test, complete dissolution was shown within approximately one hour.

The tablet of Example 12 was used in an experiment in which the plasma level of flurbiprofen in four volunteers was measured after a single dose and the results are shown in the column marked A with Table VII. The results obtained with a conventional 10 mg mg flurbiprofen tablet using a similar experiment with the same volunteers 447 450 21 subjects are shown in the column marked B with Table VII. N.D. shows that no flurbiprofen could be detected.

Table VII Flurbíprofen concentrations in plasma, micrograms / ml Time Trial Trial ~ Trial Trial (hourly person 1 person 2 person 3 person 4 Mar) ABABABAB 0.5 ND 1.0 ND 6.0 5.6 10.9 0 .4 7.8 1 ND 8.7 0.5 11.9 12.1 15.8 0.7 14.0 2 0.9 10.9 1.7 12.1 15.8 11.2 1.4 10.9 3 3.5 9.2 5.6 8.9 11.1 8.0 5.8 7.2 4 4.8 6.4 10.3 6.5 7.7 6.0 5.3 5.5 5 4.1 4.6 7.3 4.7 5.7 4.8 4.5 3.7 6 3.4 3.7 5.6 4.0 4.6 3.7 3.6 3.1 9 3.8 1.9 2.7 2.1 2.6 2.0 2.7 1.5 12 2.5 1.2 l, 6 1.3 1.6 1.4 2.8 1.0 24 0.5 0.2 0.2 0.2 0.3 0.3 0.3 0.4 ND 30 ND ND ND ND 0.2 ND 0.2 ND Although the above examples show that the present invention can be used for various orally active therapeutic agents or drugs for administering controlled release tablets, the invention is not limited to tabletting the specific drugs according to the examples. The invention can be greatly varied in this regard and can be used for tableting controlled release tablets containing all orally active drugs, although the invention is preferably used for tableting drugs of an acidic nature, especially aspirin and non-steroidal anti-inflammatory arylalkanoic acid agents comprising their salts , esters, anhydrides and other derivatives listed above. These compounds are antipyretics, analgesics and anti-inflammatory drugs. Other representative types of orally active drugs that can be incorporated into sustained release tablets of the invention include sedatives, simulants, antibiotics, antispasmolytic agents, nutrients, hematins, anthelmintics, expectorants, hormones of various kinds including adrenocorticosteroids, androgenic steroids. , estrogenic steroids, progestational steroids and anabolic steroids, non-steroidal equivalents of the foregoing, psycho-energetic and antiviral agents.

Claims (9)

23 447 450 PATENT REQUIREMENTS A sustained release pharmaceutical composition in tablet form comprising (a) an orally active therapeutic agent, (b) 0.8 to 1.6% by weight, based on the total weight of the tablet, of a release control agent selected from cellulose acetate phthalate , cellulose acetate derivatives, shellac, zein, acrylic resins, ethylcellulose, hydroxypropylmethylcellulose phthalate, sandarac or modified shellac, and (c) 1.0 to 7.5% by weight, based on the total weight of the tablet, of an erosive agent selected from maize starch , rice starch, potato starch or other vegetable starch species, modified starch, starch derivative, cellulose, cellulose derivative, modified cellulose, modified cellulose derivative, alginic acid, alginates, bentonite, aluminum magnesium silicate, relative vinyl antacid such that a critical factor is calculated according to the equation I cF = cA 1 l / (cs) wherein CF is the critical factor, CA is the amount of therapeutic agent per tablet in mg divided by the amount of release control agent per tablet in mg and CS is the amount of erosion promoting agent per tablet in mg divided by the amount of release controlling agent per mg tablet in mg and is in the order of 20 to 450. 2. A sustained release pharmaceutical composition according to claim 1, wherein the amount of release control agent is in the order of 1.5 to 1.6% by weight and the amount of erosion promoting agent is in the order of 2 to 5% by weight. A sustained release pharmaceutical composition according to any one of the preceding claims, characterized in that the critical factor is in the order of 50 to 450; Sustained release pharmaceutical composition according to any one of the preceding claims, characterized in that the critical factor is in the order of 80 to 330. Sustained release pharmaceutical composition according to any one of the preceding claims, characterized in that the critical factor is in the order of 210 to 330. Sustained release pharmaceutical composition according to any one of the preceding claims, characterized in that the release controlling agent is cellulose acetate phthalate and the erosion promoting agent is corn starch. A sustained release pharmaceutical composition according to any one of the preceding claims, characterized in that the therapeutic agent is acetylsalicylic acid, ibuprofen or flurbiprofen. Sustained release pharmaceutical composition according to any one of claims 3, 4 or 5, characterized in that the therapeutic agent is acetylsalicylic acid. A method of preparing a sustained release tablet pharmaceutical composition comprising the steps of granulating a mixture of an orally active therapeutic agent and an erosion promoting agent selected from corn starch, rice starch, potato starch and other vegetable starch species, modified starch , starch derivatives, cellulose, cellulose derivatives, modified cellulose, modified cellulose derivatives, alginic acid, alginates, bentonite, aluminum magnesium silicate, crosslinked polyvinylpyrrolidone, ion exchange resins or adhesives, with a solution of a liberating cellulate thulacate; zein, acrylic resins, ethylcellulose, hydroxypropylmethylcellulose phthalate, sandarac or modified shellac, in an organic solvent and then pressing the granules so prepared into tablets, which method is characterized in that the final tablet contains 0.8 to 1.6% by weight, based on the total weight of the tablet, of the release control agent and 1.0 to 7.5% by weight, based on the total weight of the tablet, of the erosion-promoting agent and that the relative amounts of the components are such that a critical factor is calculated according to the equation I CF CA l / (CS) where CF is the critical factor, CA is the amount of therapeutic agent per tablet in mg divided by the amount of release-controlling agent per tablet in mg and CS is the amount of erosion-promoting agent per tablet in mg divided by the amount of release-controlling agent per tablet in mg, and is in the range of 20 to 450.