IE50806B1

IE50806B1 - Pharmaceutical compositions

Info

Publication number: IE50806B1
Application number: IE36/81A
Authority: IE
Original assignee: Boots Co Ltd
Priority date: 1980-01-11
Filing date: 1981-01-09
Publication date: 1986-07-23
Also published as: ATA5481A; AT374681B; SE447450B; IN151913B; FI810056L; AU6597681A; FR2473308A1; FI76927B; DE3100191C2; GR73843B; GB2067072B; NL8100037A; LU83052A1; ES498369A0; FI76927C; DK6181A; DE3100191A1; JPS56103110A; NO810062L; NO156153C

Abstract

A sustained release pharmaceutical composition in table-t form comprises an effective amount of an orallyactive therapeutic agent, 0.8 to 1. 6% by weight of a release controlling agent and 1.0 to 7.5% by weight of an erosion promoting agent, the relative amounts of the components being such that a criticality factor calculated according to equation I lies in the range 20 to 450. Equation 1 is I wherein CF is the criticality factor, CA is the. amount of therapeutic agent per tablet in milligrams divided by the amount of release controlling agent per tablet in milligrams and CS is the amount of erosion promoting agent per tablet in milligrams divided by the amount of release controlling agent per-tablet in milligrams, Suitable therapeutic agents include acetylsalicylic acid, ibuprofen and flurbiprofen. A preferred release controlling agent is cellulose acetate phthalate and a preferred erosion promoting agent is corn starch.

Description

This invention relates to pharmaceutical compositions in tablet form in which sustained release of a therapeutic agent is obtained. The invention is particularly suitable for tablets containing anti-inflammatory agents such as acetylsalicylic acid (hereinafter referred to as ASA), indomethacin, fenoprofen, naproxen, ibuprofen and flurbiprofen which are used for example in the treatment of rheumatoid and osteoarthritis. In the treatment of these diseases it is necessary for therapeutic agents to be given for long periods. It is known that the use of aspirin in long term therapy can give rise to undesired side effects and many attempts have been made to reduce these side effects.

It is an object of the present invention to provide pharmaceutical compositions in tablet form which, on oral administration, provide delayed disintegration of the tablet, provide prolonged dissolution times for the active therapeutic agent and provide sustained blood levels of the active therapeutic agent in the patient. It has been found that these objects can be met according to the present invention by controlling the relative amounts of the therapeutic agent , a release-controlling agent and an erosion-promoting agent.

The present invention provides a sustained-release pharmaceutical composition in tablet form comprising an orally-active therapeutic agent, 0.8 to 1.6% by weight based on the total weight of the tablet of a release controlling agent and 1.0 to S0S06 7.5% by weight based on the total weight of the tablet of an erosion promoting agent, the relative amounts of the components being such that a criticality factor calculated according to equation I OF s CA 1/(CS) I wherein CF is the criticality factor, CA is the amount of therapeutic agent per tablet in milligrams divided by the amount of release controlling agent per tablet in milligrams and CS is the amount of erosion promoting agent per tablet in milligrams divided by the amount of release controlling agent per tablet in milligrams, lies in the range 20 to 450.

All percentages are expressed by weight as percentages of the total weight of the tablet. The preferred amount of release controlling agent lies in the range 1.15 to 1.6% by weight based on the total weight of the tablet and the preferred range of erosion promoting agent lies in the range 2 to 5% by weight based on the total weight of the tablet.

The criticality factor conveniently is in the range 50 to 450 and preferably lies in the range 80 to 330 and more preferably in the range 210 to 330.

The preferred release-controlling agent is cellulose acetate phthalate. Other suitable release-controlling agents include cellulose acetate derivatives disclosed in Hiatt USP 2,196,768, Shellac, zein, acrylic resins, ethyl-cellulose, hydroxypropyl-methylcellulose phthalate, sandarac and modified shellac.

The preferred erosion-promoting agent is corn starch. Other suitable erosion-promoting agents include, rice starch, potato starch and other equivalent vegetable starches, modified starch and starch derivatives, cellulose derivatives and modified cellulose or derivatives, e.g., methylcellulose, sodium carboxymethylcellulose, alginic acid and alginates, bentonite, aluminium magnesium silicate sold under the trade mark VEEGUM, cross-linked polyvinylpyrrolidone, ion-exchange resins and gums e.g., agar, guar. 30806 ASA tablets conveniently contain 650 to 800 mg of ASA per tablet, about 5.0 to about 13.6 mg per tablet of release-controlling agent and about 13.4 to about 63.8 mg of erosion-promoting agent per tablet.

Other anti-inflammatory therapeutic agents may be utilised in the pharmaceutical compositions of the present invention. For example tablets may be prepared containing 400 to 600 mg of ihuprofen 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 a hardness on the Schleuniger scale of 6.5 to 18Kp. How15 ever it has been shown that satisfactory release characteristics can be obtained with tablets of varying hardness.

This facilitates the large scale production of the tablets because any variation in hardness produced by the tableting machinery does not cause a significant change in the release characteristics.

The present invention also provides a method of manufacturing a sustained release pharmaceutical composition in tablet form which comprises the steps of granulating a mixture of an orally active therapeutic agent and an erosion promoting agent with a solution of a release controlling agent in an organic solvent and then pressing the granules so produced into tablets, said method being characterised in that the final tablet contains 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 based on the total weight of the tablet of the erosion promoting agent and the relative amounts of the components are such that a criticality factor calculated according to equation I 1/(CS) wherein CP is the criticality factor, CA is the amount of therapeutic agent per tablet in milligrams divided by the amount of release-controlling agent per tablet in milligrams and CS is the amount of erosion-promoting agent per tablet in milligrams divided by the amount of release-controlling agent per tablet in milligrams, lies in the range 20 to 450.

Conveniently the organic solvent is a lower-aliphatic alcohol such as methanol, iso-propanol, or n-propanol, acetone and lower-aliphatic ketones such as methyl ethyl ketone, chloroform, carbon tetrachloride, ethyl acetate and non-chlorinated hydrocarbons or a solvent mixture such as methylene chloride and denatured alcohol [l:l(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-controlling agent, preferably of cellulose acetate phthalate, is added to the mixing powders in a steady stream. Mixing is continued to form a wet granular mass. The wet mass is dried to remove residual organic solvent, leaving the release-controlling agent in intimate contact with the particles of the therapeutic agent and the erosion-promoting agent. The granular mass is reduced to a suitable granule size by forcing the material through a screen and the dry granules are blended to ensure homogeneity 80306 before being compressed into tablets using a conventional rotary or single station tablet press. The tablets may then be printed directly using conventional tablet printing equipment and materials to identify the product.

Tablet identification may also be made by debossing the finished product during compression.

The invention is -illustrated by the following Examples which are not to be construed as limiting. The Examples have reference to the accompanying drawings in which:— FIG. 1 is a graphical illustration of the results of the test described in Example 7 showing mean serum levels of ASA over the first eight hours of a 24-hour study in each of two subjects receiving two 650 mg tablets as a single 1300 mg dose of ASA , the tablets being in accordance with this invention (unbroken and broken lines), as compared with a single 650 mg tablet, also in accord with the invention (alternate dot and dash line), FIG. 2 is a graphical Illustration of the results of the test described in Example 8 showing mean serum levels of salicylic acid over a 120-hour period involving multiple oral doses (nine doses-each 2 x 650 mg - 12 hours apart over a 96-hour period) of ASA tablets in accordance with this invention in eight subjects, the blood samples being taken at the hours indicated, FIG. 3 is a graphical illustration of the results of the test set forth in Example 8 and described for FIG. 2 showing serum levels of ASA, FIG. 4 is a graphical representation of the two compartment model used to produce the simulated zero-order absorption curves shovm in Figures 5 and 6, FIG. 5 is a graphical illustration of the results of a comparison between a simulated computer curve for zero order absorption of ASA (solid line) and the actual values from blood samples taken on Day 1 of treatment for subject 1 (dotted line) from Example 8, and FIG. 6 is a graphical illustration of the results of a comparison between the theoretical value for zero order absorption of ASA (solid line) in a second subject and the actual values from blood samples taken on Day 1 of treatment for subject 2 (dotted line) from Example 8.

Example 1 Cellulose acetate phthalate (67.3 g) was added slowly to the vortex of a mixture of ethanol (denatured, 625 ml) and methylene chloride (175 ml) produced by a high speed stirrer. Stirring was' continued until solution was achieved.

ASA (4.375 kg, 40 mesh/inch crystal, USP) and corn starch (0.2255 kg, USP) were deaggregated through a 40 mesh/inch screen into the bowl of a Hobart (Trade Mark) mixer. The dry powders were mixed for five minutes at speed 1. The cellulose acetate phthalate solution was added to the mixing powders over a thirty-second period, with mixing at speed 1. Further mixing for four minutes at speed 2 was carried out to promote granulation.

The wet granular mass was discharged onto stainless steel trays and air dried until it could be forced through a 20 mesh/inch screen. The screened granulate was further air dried to remove residual solvent. The granules were weighed, blended by tumbling, and compressed on a conventional rotary tablet press using half-inch flat bevelled edge tooling to produce tablets containing 650 mg of ASA with a hardness of 8 to 10 Kp (Schleuniger).

Example 2 Cellulose acetate phthalate (750 g) was added slowly to the vortex of a mixture of methylene chloride (3750 ml) and ethanol (3750 ml). Stirring was continued until solution was achieved.

ASA (60 kg, 80 mesh per inch 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 impeller at speed 1 for two minutes. The cellulose acetate phthalate solution was poured in a steady stream onto the powders mixing at impeller speed 1 and chopper speed 1. Following addition of the solution, mixing was continued at impeller and chopper speed 2 until a suitable granular mass was obtained. The wet granular mass was spread on stainless steel ti-ays and dried in a forced convection oven at a temperature not greater than 120°F. The dry granular mass was processed through a Jackson Crockatt granulator carrying a stainless steel screen of 16 mesh/inch. The dried sized granules were blended in a drum blender for five minutes, and compressed on a conventional rotary tablet press using capsule shaped tooling to give tablets containing 800 mg of ASA with a hardness of 8 to 11 Kp (Schleuniger).

Examples 5 to 6 Four batches of tablets having the compositions set out in Table I were prepared as described in Example 1.

The disintegration time in a buffer at pH 7.5 was determined by the procedure described in the United States Pharma15 copoeia XX page 958 but omitting the discs and the release properties were determined in a buffer at pH 7.5 by the procedure described in the United.States Pharmacopoeia XX page 959 but using a modified 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 out in Table 1 which also shows the results obtained using conventional ASA tablets (Example A) and tablets (Examples B and C) in which the criticality factor is greater than required by the present invention.

The dissolution data for Examples 4 and 6 was obtained using a further batch of tablets prepared in the same manner as those used for the disintegration experiments. r-oom tn vococn v 00 CO g3R / CM O 00 v- t- O-d-OS O s < CM SO mso V cmsci mo-ox < β to cnso v- cn .-(0 03 •d a CO <0-3· οκοιη CM SCO v- CM cd inc-~ CJ LOO ο Φ S OOO OOO OOO OOO < Φ KO co o KO co o KO coo KO coo Φ Φ rd a Φ *d ft H v m v- m X— m v“ m Φ-Ρ W in © Φ Φ ft ftft β Ο Φ βΌ φ β N O Ο Φ β^ Φ β Μ O β Ο Φ kTJ Φ β N O β Ο Φ βΌ Φ b N O •Ρ to β •d I •d o co w (0 +5 Φ Φ Φ © -P -P •P β β a a bQ Q) £ β β Φ β •d *d -ΡΉ β e B β Ε-· Ο o o CO r- CM CM o a A A CO Φ ο co τι ω W β τί φ β <η Ο<Η Ο β ΦΡ W I β Ο Q CM β V to φ •Ρ Β ♦Η β Ο Κ0 •d O id^ (0 O β •d o •P -μ •d O β Φ U ft S co CO o ω CM v~ m m CM id Φ β Ο •d Ρ S β-d Φ β > *d β ft Ο W Ο Φ ο ω 0-P •d Φ •P rt •d,Q W (0 O -P ft> β to Ο β I £ -4 -4 in o mo o min OOO ο mo o in ooo IAt- O-d-v- inmx- ιηκο Ο KO v KO KO co kO KO CO £ β Λ n Λ Λ o o o o o o β <£ ©ft P < ran. β <4 (Oft <ί· Φ ft , β <3 <0 -d rt Cl, co -P < CQ-P< CQ -p < CQ-P <3 WP cQ *P <4 qwu -aJCQ O < w o *3JCQ O CQ in KO CQ ASA 800 1333 <5 minutes no pro· Starch 60 longed.

I o to «d •d-P 'd (ΰ SOSOS The release properties of tablets prepared in accordance with Example 5 were determined in another experiment and the results shown below obtained.

Time of Acetylsalicylic acid dissolved sample(hr) (%) 0.5 23.8 1 34.8 2 61.3 3 82.4 These results, when plotted as a graph of time ι-a versus percent acetylsalicylic acid dissolved l-( give a straight line indicative of zero order release. Linear regression analysis of the data gives a correlation coefficient of 0.999, compared to a straight line value of 1.0.

The dissolution of the tablets of Example 3 and of a further batch prepared according to Example 6 were assessed in a method involving a pH change. The method was according to the United States Pharmacopoeia XX page 959 using the modification described above. The results are shown in Table 2.

Table 2 Time (hrs ) Initial PH mg ASA released by end of time Cumulative amount ASA released(mg) % of Theory ASA released Ex. 6 Ex.3 Ex. 6 Ex.3 Ex. 6 Ex.3 0-1/2 1.2 50 46 50 46 7.7 7.1 0-1 1.2 72 60 72 60 11.1 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 which occurs on storage with tablets according to the present invention is less than that occurring with conventional ASA formulations. Acetylsalicylic acid degrades to salicylic acid, and this reaction io promoted by elevated temperature. The reaction occurs readily and has led to the adoption by the United States Pharmacopoeia of an upper limit for the level of free salicylic acid (FSA) in ASA tablets at 0.3%, Tablets prepared according to Examples 1 and 5 were assayed for free salicylic acid (FSA) after storage under extreme conditions. The results are shown in Table 3Table 3 Example Time Storage Level of FSA % 1 0 - 0.04 3 months 40°C 0.12 5 0 - 0.06 6 months 40°C yrGfTM. relative humidity 0.14 0.22 It is widely known that, under similar conditions of storage, the limiting level of FSA, viz., 0.3%, would be exceeded by conventional ASA formulations.

Tablets prepared in accordance with Examples 4, 5 and 6 subjected to a drop test in a Roche friabilator. After 100 drops a weight loss of between 0.12 and 0.46 percent by weight was observed. When the test was extended to give 750 drops the edges of the tablets became worn but the tablets did not break up. A commercial sustained release aspirin tablet showed a weight of 0.85% after 100 drops and were severely worn after 750 drops.

Example 7. Serum Levels After a Single Oral Dose Tablets containing 650 mg of ASA were produced according to the method of Example 1. One human volunteer was given a single oral dose of 650 mg while two other individuals received a single dose of 1300 mg (two 650 mg tablets). Blood samples were taken from each subject via an indwelling catheter from a vein in the forearm. The samples were collected in a chilled vacutainer tube at the following times:prior to dosing and at 15, 30, 45 and 60 minutes; 1.5, 2.0, 2.5 3.0, 4.0, 8.0, 12 0, 16.0, and 24 liours por.t dose. The blood ::;unples were analyzed for plasma salicylic acid and acetylsalicylic acid using high pressure liquid chromatography. Table 4 and FIG. 1 show the results of these measurements. In figure 1 the results for subject 1 are shown as an unbroken line, those of subject 2 as an alternate dot and dash line and those of subject 3 as a broken line. The x axis represents the time in hours and the y axis the plasma'concentration of ASA in micrograms/ml. Table 4 Plasma Acetvlsalicylic Acid and Salicylic Acid Values over a 24-hour Period Subject No Dose 1 1300 mg mcg/ml 2 65Ο mg mcg/ml 3 1300 mg mcg/ml Study Time(hrs) ASA SA ASA SA ASA SA 0 0.1 0.1 0.1 0.1 0.1 0.1 X 4 0.1 0.38 0.1 0.1 0.1 0.2 X 2 0.1 0.93. 0.1 0.1 0.46 0.99 3 4 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 3.19 0.35 1.53 0.71 3.24 2.0 0.59 4.3Ο 0.30 2.45 0.61 4.07 2.5 0.61 5.55 0.25 3.08 0.51 4.99 3.0 0.46 5.70 0.35 3-29 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 11.30 12.0 0.1 17.90 0.1 3.72 0.26 19.30 16.0 0.1 8.87 0.1 3.83 0.20 14.00 24.0 0.1 0.36 0.1 2.96 0.17 9.24 The serum levels of acetylsalicylic acid were shown to peak, in all three subjects, four hours after drug ingestion. Levels did not return to 0.1 microgram/milliliter until after eight hours. This finding is to be compared to the established half Life (t=1/2) of twenty minutes for serum acetylsnlicylic acid following administration of a standard 650 mg tablet.

Example a Serum levels following multiple oral doses ASA tablets prepared according to the method of Example 1 were administered orally to eight healthy volunteers in doses of 1300 mg (two 650 mg tablets) twice-a-day at 0800 and 2000 hours for nine consecutive doses, the last dose being given on the 96th hour, to determine the steady-state pharmacodynamics of the ASA tablet formulation of this invention. Blood samples were taken from the subjects at predetermined time intervals during the course of the study.

The blood samples were analyzed by high performance liquid chromatography for levels of salicylic acid and acetylsalicylic acid. Individual blood levels of salicylic acid and acetylsalicylic acid found on Day five of the study are shown in Tables 5 and 6. Graphical representation of the mean blood levels for salicylic acid and acetylsalicylic acid for the entire study are shown in FIGS 2 and 3, respectively. In these figures the figures on the x axis represent the time in hours and the figures on the y axis represent the SA and ASA levels in the blood in micrograms/ml. Example 9. Comparison of ASA absorption with a theoret20 ical zero order curve To demonstrate that the in vivo absorption characteristics of aspirin tablets prepared according to the present invention are generally zero-order, results from subjects 1 and 2 of Example 8 were compared to the predicted results calculated by a computer. The computer calculations were . .based on a two compartment model with first order metabolism. The model is shown diagrammatically in Figure 4. The model assumes that the total dose D is absorbed at a constant rate k0 over a period of time T. At the end of the time T all. the dose will have been absorbed. The model also assumes that 60% of the ASA passes the livei' 2 unhydrolysed before passing into a central compartment 3 which has an apparent volume of distribution of 6.3 litres. The acetylsalicylic acid may pass reversibly from the central compartment 3 to body tissue (shown as 4) or may be removed irreversibly as metabolites (shown diagrammatically as 5). The rate constants used in the model and shown in Figure 4 were taken from Rowland and Riegelraan J. Pharm, Sci, Vol 57 page 131’ (1968).

The time T required for the entire dose to be absorbed will limit the extent to which multiple doses overlap one another. In Figure 5 the results obtained from Subject No. 1 of Example 0 (dotted line) are compared with the computer generated curve (solid line) produced when T was given the value of 16 hours. The results obtained from Subject No. 2 of Example 8 (dotted line) are shown in Figure 6 and are compared with the computer generated curve (solid line) produced when T was given the value of six hours. In Figures 5 and 6 the figures 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 reasonable agreement between the experimental and theoretical curves thus demonstrating that, in vivo there is a close approximation to zero order absorption with ASA tablets prepared according to the present invention Table 5 Salicylic Acid Levels on Oay Five, mcg/ml Sub No. 0 Timo (hrs) Post Dose 24 0.5 1 2 4 6 8 10 12 16 5 1 9.57 9.98 10,05 10,93 13.38 18.33 15.03 12.73 10.41 8.31 1.58 2 63.85 68.23 73.98 77.12 72.08 89.96 75.93 79.22 85.07 75.04 43.32 3 80.3 78.57 83,41 90.31 87,82 M.47 85.67 74.27 64.84 37.83 9.91 4 72.48 68.78 62.69 62.63 67.49 67.40 60.01 49.41 52.85 40.19 16,87 5 38.37 32.39 31.42 30.78 28.39 34.27 33.51 34.42 35.16 31.37 12,16 10 6 22.85 24.81 25.26 28.80 28.09 30.22 29.61 30.54 36.95 15.36 2.70 7 11.93 14.53 15.98 20.90 24.47 33.42 35.19 35.47 34.07 10.35 0.40 δ 10.65 12,04 13.98 16.57 18.61 24.01 19.52 15.93 15.58 13.78 3.59 Mean 30.73 38.67 39.60 42.26 42.54 49.02 44.31 41,50 40,62 29.03 11.51 iSEM 10.45 10.10 10.34 10.64 10.09 10.74 9.30 8.70 8.97 7.93 5.01 Table 6 Acqfylsal Icytlc Acid Levels on Oay Five, mcg/nl Sub No. 0 0.5 1 Timo (hrs) Post Ooso 12 16 24 2 4 6 8 10 1 0.15 0.39 0.43 0.47 0.49 0.31 0.34 0.46 0,22 0.18 0.09 20 2 0.81 1.07 1.97 0.76 0.47 0.32 0.28 - 0.47 0.28 0.16 0.09 3 0.79 0.76 0.75 0.66 0.40 0.28 0.05 0,05 0.05 0.05 0.10 4 1.08 0.65 0.88 0.65 0.95 0.63 0.43 0,26 0.43 0.26 0.09 5 0.74 0.59 0.49 0.55 0.32 0.89 0.43 0.24 0.25 0.23 0.18 6 0.23 0.80 0.62 0.89 0,35 0,31 0.43 0.46 0.20 0.16 0.09 25 7 0.15 0.41 0.50 0.54 0.75 0.28 0.30 0.37 0.19 0.08 0.09 8 0.65 0.65 0.06 0.80 0.02 0.43 0.33 0.19 0.13 0.16 0.09 Moan 0.58 0.67 0.81 0.67 0.54 •0.43 «.32 0.31 0.23 0.16 0.10 iSEM 0.12 0.08 0.18 0.51 0.00 0.00 t>.04 0.54 0.04 0.02 0.01 Example 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 corn starch (0.155 kg) which had been thoroughly mixed. The wet granular mass was air-dried on stainless steel trays, passed through a 14 mesh/inch screen and dried further to remove all solvent.

A quantity of dried granule of about 0.05 kg was withdrawn from the bulk and blended with a colloidal silicon dioxide sold under the trade name Aerosil (Registered Trade Mark) 200 (0.5% based on total weight of granules). This preblend was then mixed with the bulk of the granules for ten minutes.

The blended granules were obtained in a yield of 98.4%. The flow properties of the granules assessed hy the method of Carr (Brit. Chem. Eng. 15, 1541-1549, 1970) were found to be fair to passable.

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

The CF for this example is 155 and the percent by weight of release-controlling agent and erosion promoting agent 1.44 and 4.46, respectively.

Tablets produced from granules prepared as described 30 above were compressed to different hardness and the resulting tablets subjected to disintegration tests (United States Pharmacopoeia XX page 959) in a buffer at pH 7.5 at 37°C.

Hardness Mean disintegration Kp time (mins) A. 14 >235 8.54 >275 10.86 >240 A conventional ibuprofen tablet disintegrates in less than one minute and a sugar coated tablet disintegrates within five to ten minutes.

In vitro dissolution tests (United States Pharmacopoeia XX page 959) show that the tablets of Example 10 (Hardness 10.86 Kp) do cause a sustained release of the ibuprofen when compared to conventional ibuprofen tablets. Each experiment was repeated six times.

Time/ mins Amount ibuprofen dissolved (mg.) Ex. 10 (pH 7.5) Conventional tablet (pH 6.8) initial After 3 months storage at 40°C initial· After 3 months storage at 40°C 10 - - 277 62 20 - - 318 110 30 68 63 365 163 60 100 99 383 248 120 169 163 180 219 217 240 265 274 155 153 8.4 41.3 In the above results t^ is the time taken for 50% of the ibuprofen to dissolve. The results after three months storage show that the tablets of the present Example have good storage stability.

The results for the tablets of Example 10 which had not been stored give a straight line when the amount of ibuprofen dissolved is plotted against time. Linear regression analysis on the results gave a correlation coefficient Ο.996 thus indicating zero-order dissolution in vitro.

SOSOS 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 trade name Emcompress) and corn starch. The wet mass was air dried, screened and dried further to remove organic solvent. Magnesium stearate (0.5 % of the total weight of granules) was added and the granules tableted. The compositions of examples 11 and 12 are given below. CAP solution Ex.11 Ex.12 Cellulose acetate phthalate 9 g 8.33 g Ethanol denatured 60 ml 55 ml Methylene chloride 60 ml 55 ml 15 Other components Flurbiprofen •500 g · 100 g Emcompress 240 g 400 g Corn Starch 18.6 g 17.2 g 20 Weight of flurbiprofen per tablet 300 mg 100 mg Hardness of tablet (Kp) 8,7 ± 1.2 7.14±0.54 CF 25 25 % release controlling agent 1.58 1.58 25 % erosion promoting agent 3.2+ 3.27 Tlie mean disintegration times of the tablets of Examples 11 and 12 in a buffer at pH 7.5 were determined by the method described on page 958 of the United States Pharmacopoeia XX. The results obtained are shown below.

Ex.11 Ex.12 Mean disintegration time >300 >360 (mins) Residue (%) 3.7 4.9 The dissolution of flurbiprofen over a period of time from 10 the tablets of Examples 11 and 12 was assessed using the apparatus described on page 959 of the United States Pharmacopoeia XX. A phosphate buffer at pH 6.8 was used. The experiment was repeated six times and the mean value of the. amount of active material released is given below. 15 Time(hours) % flurbiprofen dissolved Ex.11 Ex.12 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 10 74.0 68.5 SOSOS A plot of the percentage of flurbiprofen dissolved against time for each of these sets of results gave a straight line indicating that a zero—order mechanism is operating in each case. Application of regression analysis to the data gives a correlation coefficient of 0.993 for Example 11 and 0.999 for Example 12.

By way of comparison a conventional flurbiprofen tablet containing 100 mg of flurbiprofen in the same test showed complete dissolution in about 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 columns headed A in Table 7. The results obtained with a conventional 100 mg. flurbiprofen tablet used in a similar experiment with the same volunteers are shown in the columns headed B in Table 7. N.D. indicates that no flurbiprofen could be detected.

Table 7 Time (hrs) Flurbiprofen concentrations in plasma mcg/ml. Volunteer 1 Volunteer 2 Volunteer 3 Volunteer 4 A B A B A 3 A B 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./ 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 1.6 1.3 1.6 1.4 2.8 1.0 24 0.5 0.2 0.2 0.2 0.3 0.3 0.4 ND 30 ND ND t ND ND 0.2 _ ND 0.2 ND 80806 Although the foregoing Examples evidence the application of the present invention to various orally-active therapeutic agents or medicaments to provide controlledrelease tablets thereof, the invention is not limited to the tabletting of the specific medicaments of the Examples.

In this aspect, the invention can be varied widely and is applicable for the controlled-release tabletting of any orally active medicameht, although is preferably in the tabletting of medicaments of an acidic nature, especially aspirin and nonsteroidal arylalkanoic acid anti-inflammatory agents, including their salts, esters, anhydrides, and other derivatives, as previously disclosed. These compounds are antipyretics, analgesics, and anti-inflammatory agents.

Other representative types of orally active medicaments which may be incorporated into sustained-release tablets according to the invention include sedatives, stimulants, antibiotics, antispasmodics, nutritional agents, hematinics, anthelmintics, expectorants, hormones' of various types including adrenocorticosteroids, androgenic steroids, estrogenic steroids, progestational steroids, and anabolic 20 steroids, nonsteroidal counterparts of the foregoing, psychic energizers and antiviral agents. 806

Claims

1. /(CS) wherein CF is the criticality factor, CA is the amount of therapeutic agent per tablet in milligrams divided by the amount of release-controlling agent per tablet in 1) A sustained release pharmaceutical composition in tablet form comprising an orally-active therapeutic agent, 0.8 to 1,6% by weight based on the total weight of the tablet of a release-controlling agent and 1.0 to 7.5% by weight based on the total weight of the tablet of an erosion-promoting agent, the relative amounts of the components being such that a criticality factor calculated according to equation I CA CF = 1/(CS) 1 wherein CF is the criticality factor, CA is the amount of therapeutic agent per tablet in milligrams divided by the amount of release controlling agent per tablet in milligrams and CS is the amount of erosion promoting agent per tablet in milligrams divided.by the amount of release controlling agent per tablet in milligrams, lies in the range 20 to 450.

2. ) A sustained release pharmaceutical composition as claimed in claim 1 wherein the amount of release controlling agent lies in the range 1.15 to 1.6% by weight based on the weight of the tablet and the amount of erosian-pranoting agent lies in the range 2 to 5% by weight based on the total weight of the tablet.

3. ) A sustained release pharmaceutical composition as claimed in either of the preceding claims wherein the criticality factor lies in the range 50 to 450.

4. ) A sustained release pharmaceutical composition as claimed in any one of the preceding claims wherein the criticality factor lies in the range 80 to 330.

5. Calculated according to equation I 5) A sustained release pharmaceutical composition as claimed in any one of the preceding claims wherein the criticality factor lies in the range 210 to 330.

6. ) A sustained release pharmaceutical composition as claimed in any one of the preceding claims wherein the release controlling agent comprises cellulose acetate phthalate, cellulose acetate derivatives, shellac, zein, acryl ; c resins, ethylcellulose, hydroxypropylmethylcollulose phthalate;, sandarac, or modified shellac; and wherein the erosion-promoting agent comprises corn starch, rice starch, potato starch and other vegetable starches, modified starch, starch derivatives, cellulose, cellulose derivatives, modified cellulose, modified cellulose derivatives, alginic acid alginates, bentonite, aluminium magnesium silicate, cross-linked polyvinyl pyrrolidone, ion exchange resins or gums.

7. ) A sustained release pharmaceutical composition as claimed in any one of the preceding claims wherein said release-controlling agent is cellulose acetate phthalate and said erosion-promoting agent is corn starch.

8. ) A sustained release pharmaceutical composition as claimed in any one of the preceding claims wherein the therapeutic agent is acetylsalicylic acid, ibuprofen or flurbiprofen.

9. ) A sustained release pharmaceutical composition as claimed in any one of claims 3, 4 or 5 wherein the therapeutic agent is acetylsalicylic acid.

10. Milligrams and CS is the amount of erosion-promoting agent per tablet in milligrams divided by the amount of release-controlling agent per tablet in milligrams, lies in the range 20 to 450. 10) A sustained release pharmaceutical composition as claimed in claim 8 or claim 9 wherein the amount of acetylsalicylic acid per tablet is 650 to 800 mg.

11. ) A sustained release pharmaceutical composition as claimed in claim 8 wherein the amount of ibuprofen per tablet is 400 to 600 mg.

12. ) A sustained release pharmaceutical composition as claimed in claim 8 wherein the amount of flurbiprofen per tablet is 100 to 300 mg.

13. ) A method of manufacturing a sustained release pharmaceutical composition in tablet form comprises the steps of granulating a mixture of an orally active therapeutic agent and an erosion-promoting agent with a solution of a release-controlling agent in an organic solvent then pressing the granules so produced into tablets, eaid method beinc characterised in that the final tablet contains 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 based on the total weight of the tablet of the erosion-promoting agent and the relative amounts of the components are such that a criticality factor

14. ) A method of manufacturing a sustained release com15 position as claimed in claim 13 wherein the criticality factor lies in the range 50 to 450 and the therapeutic agent is acetylsalicylic acid.

15. ) A sustained release pharmaceutical compositon as claimed in claim 3 substantially as hereinbefore described 20 with reference to Examples 1 to 9.

16. ) A sustained release pharmaceutical composition as claimed in claim 1 substantially as hereinbefore described with reference to Examples 10 to 12.

17. ) A method of manufacturing a sustained release compos25 ition as claimed in claim 14 substantially as hereinbefore described with reference to Examples 1 to 9.

18. ' A method of manufacturing a sustained release composition as claimed in claim 13 substantially as hereinbefore describee with reference to Examples 10 to 12. F.R. KELLY S CO. AGENTS FOR THE APPLICANTS. THE BOOTS COMPANY LIMITED