GB2067072A - Sustained release tablets - Google Patents

Sustained release tablets Download PDF

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GB2067072A
GB2067072A GB8100522A GB8100522A GB2067072A GB 2067072 A GB2067072 A GB 2067072A GB 8100522 A GB8100522 A GB 8100522A GB 8100522 A GB8100522 A GB 8100522A GB 2067072 A GB2067072 A GB 2067072A
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sustained release
amount
agent
pharmaceutical composition
release pharmaceutical
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GB2067072B (en )
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Boots Co PLC
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Boots Co PLC
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Description

1 GB 2 067 072 A 1

SPECIFICATION

Pharmaceutical compositions This invention relates to pharmaceutical composi- 70 tions in tablet form in which sustained release of a therapeutic agent is obtained. The invention is particularly suitable fortablets containing antiinflammatory 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 forthe 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 inven tion by controlling the relative amounts of the therapeutic agent, a release-controlling agent and an erosion-promoting agent.

The present invention provides a sustained- 95 release pharmaceutical composition in tablet form comprising an effective amount of an orally-active therapeutic agent, 0.8 to 1.6% by weight of a release controlling agent and 1.0 to 7.5% by weight of an ero- sion promoting agent, the relative amounts of the components being such that a criticality factor calculated according to equation 1 CF = CA MCS) wherein CF is the criticality factor, CA is the amount of therapeutic agent pertablet in milligrams divided by the amount of release controlling agent pertablet in milligrams and CS is the amount of erosion prom Qting agent pertablet in milligrams divided by the amount of release controlling agent per tablet in mil ligrams, lies in the range 20 to 450.

All percentages are expressed by weight as per centages of the total weight of the tablet. The prefer- 115 red amount of release controlling agent lies in the range 1.15 to 1.6% by weight and the preferred range of erosion promoting agent lies in the range 2 to 5% by weight.

The criticality factor conveniently is in excess of 50 120 and preferably lies in the range 80 to 330 and more preferably in the range 210 to 330.

The preferred release-controlling agent is cellul ose acetate phthalate. Other suitable release controlling agents include cellulose acetate deriva tives disclosed in Hiatt USP 2,196,768, shellac, zein, acrylic resins, ethyl-cellu lose, hydroxypropyimethyi cellulose phthalate, sandarac and modified shellac.

The preferred erosion-promoting agent is corn starch. Other suitable erosion-promoting agents 1 include, rice starch, potato starch and other equivalent vegetable starches, modified starch and starch derivatives, cellulose derivatives and modified cellulose or derivatives, e.g., methyl-cellulose, sodium ca rboxymethylce 11 u lose, alginic acid and alginates, bentonite, veagum, cross-linked polyvinylpyrrolidone, ion-exchange resins, and gums, e.g., agar, guar.

ASAtablets conveniently contain 650; to 800 mg of ASA pertablet, about 5.0 to about 13.6 mg pertablet 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 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 ortableting aids.

The tablets of the present invention preferably have a hardness on the Schleuniger scale of 6.5 to 18Kp. However 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 compositions of the present invention may be prepared by dissolving the release-controlling agent in a suitable organic solvent such as loweraliphatic alcohols 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 in a solvent mixture such as methylene chloride and denatured alcohol [1:1 (V/V].

The therapeutic agent, in powder form is inti- mately 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 releasecontrolling agent in intimate contact with the particles of the therapeutic agent and 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 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 bythe following Exam- ples which are notto 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 2 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 involv- ing 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 80 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 shown in Figures 5 and 85 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 sub- ject 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 (dena tured, 625 mi) and methylene chloride (175 mi) pro duced by a high speed stirrer. Stirring was continued until solution was achieved.

ASA (4.375 kg, 40 meshlinch crystal, USP) and corn starch (0.2255 kg, LISP) were deaggregated through a 40 meshlinch screen into the bowl of a Hobart 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 stain- less steel trays and air dried until it could be forced through a 20 meshlinch screen. The screened granulate was further air dried to remove residual solvent. The granules were weighed, blended bytumbling, 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 (Schieuniger). Example 2 Cellulose acetate phthalate (750 9) was added slowly to the vortex of a mixture of methylene chloride (3750 mi) and ethanol (3750 mi). Stirring was continued until solution was achieved.

ASA (60 kg, 80 mesh per inch powder, USP) and corn starch (3.0 kg, LISP) were placed in the bowl of a Littleford MGT400 mixer. The dry powders were GB 2 067 072 A 2 mixed using the impeller at speed 1 fortwo m!,-,-utes. The cellulose acetate phthalate solution was poured in a steady stream on to 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 steer trays and dried in a force 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 meshlinch. 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 3 to 6 Four batches of tablets having the compositions set out in Table 1 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 Pharmacopoeia 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 forthe disintegration experiments.

i 3 GB 2 067 072 A 3 Table 1

Example Composition Criticality Disintegration Release AmountofASA (mgltablet) Factor (C0 Time Property Released at time shown Time (Min) mg % 3 ASA 650 87 >180 minutes zero 60 189 29.1 Starch 13.4 order 180 467 71.8 CAP 10 300 640 98.5 4 ASA 650 348 >240 minutes zero 60 204 31.3 Starch 13.4 order 180 469 72.2 CAP 5 300 651 100.2 ASA 800 320 >210 minutes ze ro 60 229 28.6 Starch 40 order 180 574 71.8 CAP 10 300 783 97.9 6 ASA 650 218 >180 minutes zero 60 241 30.1 Starch 33.5 order 180 598 74.8 CAP 10 300 798 99.8 A ASA 650 Conventional >20 seconds instant Starch 65 aspirin non-buffered B ASA 800 480 60 minutes insufficient Starch 60 sustained CAP 10 release c ASA 800 1333 >5 minutes no prolonged Starch 60 in vitro d is CAP 6 integration The release properties of tablets prepared in 5 accordance with Example 5 were determined in another experiment and the results shown below obtained.

Time of Acetylsalicylic acid sample dissolved (hr) 0/6) 0.5 23.8 1 34.8 2 61.3 3 82.4 Table 2

These results, when plotted as a graph of time versus percent acetylsalicylic acid dissolved 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.

Cumulative mgASA amountASA Time Initial released by released %of Theory (hrs) pH end of time (mg) ASA released Ex. 6 Ex. 3 Ex. 6 Ex. 3 Ex. 6 Ex. 3 0-112 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 1 89.4 The level of chemical degredation 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 is promoted by elevated temperature. The reaction occurs readily and 4 GB 2 067 072 A 4 has led to the adoption by the United States Pharmacopoeia of an upper limit for the level of free salicylic acid (FSA) in ASAtablets at 0.3%.

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

Table 3

Example Time Storage Levelof FSA % 1 0 (M14 3 months 400C 0.12 0 0.06 6 months 40'C 0.14 37aCr75% 0.22 relative humidity It is widely known that, under similar conditions of storage, the limiting level of FSA, viz., 0.35/o, 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 Z 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 whiletwo 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 vacutainertube at the following times: priorto 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 hours post dose. The blood samples were analyzed for plasma salicylic acid and acetylsalicylic acid using high pressure liquid chromatography. Table 4 and FIG. 1 showthe 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/mi.

Table 4 Plasma Acetylsalicylic Acid and Salicylic Acid Values over a 24hour Period Subject No 1 2 3 Dose 1300 mg 650:mg 1300 mg mcg/M1 mcglmf mcgIM1 Study Time (hrs) ASA SA ASA SA ASA SA 0 0-1 0.1 0-1 0.1 0.1 0.1 4 0.1 0.38 G.1 0.1 G.1 0.2 0.1 0.93 0.1 0.1 0.46 0.99 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 4.30 0.30 2.45 0.61 4.07 2.5 0.61 5.55 0.25 3.08 0.51 4.99 3.0 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 microg- 11 a ram/milliliter until after eight hours. This finding is to be compared to the established half life (t = 112) of 45 twenty minutes for serum acetylsalicylic acid follow- t GB 2 067 072 A 5 ing administration of a standard 650 mg tablet.

Example 8. 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 ASAtablet 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 representthe SA and ASA levels in the blood in micrograms/mi.

Example 9. Comparison of ASA absorption with a theoreticalzero order curve To demonstrate that the in vivo absorption characteristics of aspirin tablets prepared according to the present invention are generally zeroorder, 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 k. 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 liver 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 diag- rammatically as 5). The rate constants used in the model and shown in Figure 4 were taken from Rowland and RiegelmanJ Pharm. Sci. V6157 page 1313 (1968).

The time T required forthe entire does to be dbsorbed will limit the extent to which multiple doses overlap one another. In Figure 5 the results obtained from Subject No. 1 of Example 8 (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 Twas 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/mi.

There is reasonable agreement between the experimental and theroretical curves thus demons- trating that, in vivo there is a close approximation to zero order absorption with ASAtablets prepared according to the present invention.

6 GB 2 067 072 A 6 Table 5 Salicylic Acid Levels on Day Five, mcglmi Sub Time (hs) Post Dose No. 0 0.5 1 2 4 6 8 10 12 16 24 1 9.37 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 94.47 85.67 74.27 64.84 37.83 9.91 4 72.48 68.78 62.69 62.63 67.49 67.48 60.04 49.41 52.85 40.19 16.87 38.37 32.39 31.42 30.78 28.39 34.27 33.51 34.42 35.16 31.37 12.16 6 22.85 24.81 25.26 28.80 28.09 30.22 29.61 30.54 36.95 15.36 2.70 7 11.98 14.53 15.98 20.90 24.47 33.42 35.19 35.47 34.07 10.35 0.40 8 10.65 12.04 13.98 16.57 18.61 24,01 19.52 15.93 15.58 13.78 3.59 Mean 38.73 38.67 39.60 42.26 42.54 49.02 44.31 41.50 40.62- 29.03 11.31 - t SEM 10.45 10.10 10.34 10.64 10.09 10.74 9.30 8.70 8.97 7.93 5.01 Table 6 Acetylsalicylic Acid Levesi on Day Five, mcg/mi Sub Time (hs) Post Dose No. 0 0.5 1 2 4 6 8 10 12 16 24 1 0.15 0.39 0.43 0.47 0.49 0.31 0.34 0.46 0.22 0.18 0.09 2 0.81 1.07 1.97 0.76 0.47 0.32 0.28 6.47 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 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 0.28 0.16 0.09 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 0.86 0.80 0.62 0.43 0.33 0.19 0.13 0.16 0.09 Mean 0.58 0.81 0.67 0.54 0.43 0.32 0.31 0.23 0.16 0.10 -t SEM 0.08 0.18 0. 51 0.08 0.08 0.04 0.54 0.04 0.02 0.01 Example 10

Cellulose acetate phthalate (50 g) was added slowlyto a rapidly stirred mixture of ethanol (620 mi) 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 underthe trade name Emcompress (0.75 kg) and corn starch (0.155 kg) which had been thoroughly mixed. the wet granular mass was airdried on stainless steel trays, passed through a 14 meshlinch screen and dried furtherto remove all solvent.

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

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

The granules were compressed on a conventional rotary tablet press using half-inch fl at-beve lied 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 releasecontrolling agent and erosion promoting agent 1.44 and 4.46, repsectively.

Tablets produced from granules prepared as described 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 37C.

Hardness Mean disintegration Kp time Imins) 4.14 >235 8.54 >275 10.86 >240 A conventional lbuprofen tablet disintegrates in less than one minute and a sugar coated tablet disintegrates within five to terrminutes.

In vitro dissolution. tests (United States Phar- macopoeia XX page 959) showthat 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.

1 7 GB 2 067 072 A 7 Amountibuprof en dissolved (mg.) Conventional tablet Timel Ex. 10 (pH 7.5) (pH 6. 8) mins After3 months After 3 months i. nitial storage at 40'C initial storageat400C 277 62 - - 318 110 68 63 365 163 100 99 383 248 169 163 219 217 240 2 65 274 tl 155 153 8.4 41.3 In the above results ti 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 give a correlation coefficient 0.996 thus indicating zero order dissolution in vitro.

Examples 11 and 12 Tablets containing fl urbiprofen, (2 - (2 - fluoro - 4 - biphenylyi) - propionic acid, were prepared by adding a solution of cellulose acetate phthalate to a 60 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 furtherto remove organic sol vent. 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.

CAPsolution Cellulose acetate phthalate Ethanol denatured Methylene chloride Othercomponents Flubiprofen Emcompress Corn Starch Weight of flurbiprofen pertablet

Hardness of tablet (Kp) CIF % release controlling agent %erosion promoting agent EX. 11 99 mi 60 mi Ex. 12 8.339 mi 55 mi 300 g 100 g 240 g 400 g 18.6 g 17.29 300 mg 100 mg 80 8.7 -t 1.2 25 1.58 3.27 7.14 -t 0.54 25 1.58 3.27 The mean disintegration times of the tablets of Examples 11 and 12 in a buffer at pH 7.5 were deter- mined by the method described on page 958 of the United States Pharmacopoeia XX The results obtained are shown below.

Mean disintegration time (mins) Residue (%) Ex. 11 Ex. 12 >300 >360 3.7 4.9 The dissolution of flurbiprofen over a period of time from the tablets of Examples 11 and 12 as 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.

Time (hours) 1 2 3 4 7 %flurbiprofen dissolved Ex. 11 Ex. 12 9.6 10.6 22.5 17.1 29.3 24.7 34.8 28.8 44.8 35.1 56.9 47.7 74.0 68.5 A plot of the percentage of flurbiprofen dissolved againsttime 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. indicaters that no flurbiprofen could be detected.

8 GB 2 067 072 A 8 Table 7

Flurbiprofen concentrations in plasma mcgImL Time Volunteer 1 Volunteer2 Volunteer3 Volunteer4 (hrs) A 8 A a A 8 A 8 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 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 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 N D ND j ND ND i N D 0.2 N D 0.2 ND Although the foregoing Examples evidence the application of the present invention to various orally-active therapeutic agents or medicaments to provide controlled-release tablets thereof, the inven tion 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 contro lled-rel ease tabletting of any orally active medicament, although is preferably in the tabletting of medicaments of an acidic nature, especially aspi rin and nonsteroidal arylalkanoic acid anti inflammatory agents, including their salts, esters, anhydrides, and other derivatives, as previously dis closed. These compounds are antipyretics, analges ics, and anti-inflammatory agents. Other representa tive type of orally active medicaments which may be 60 incorporated into sustained-release tablets accord ing to the invention include sedatives, stimulants, antibiotics, antispasmodics, nutritional agents, hematinics, anthelmintics, expectorants, hormones of various types including adrenocorticosteroids, androgenic steroids, estrogenic steroids, progesta tional steroids, and anabolic steroids, nonsteroidal counterparts of the foregoing, psychic energizers and antiviral agents.

Claims (18)

1. A sustained release pharmaceutical composi tion in tablet form comprising an effective amount of an orally-active 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 rela tive amounts of the components being such that a criticality factor calculated according to equation 1 CA CF= MCS) wherein CIF 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 1 80 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 and the amount of erosion promoting agent lies in the range 2 to 5% by weight.
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. 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 composi- tion as claimed in any one of the preceding claims wherein the release controlling agent comprises cellulose acetate phthalate, cellulose acetate derivatives, shellac, zein, acrylic resin, ethylcellulose, hydroxypro pyImethylcel 1 u lose phthalate, sandarac, or modified shellac; and wherein the erosionpromoting agent comprises corn starch, rice starch, potato starch and other vegetable starches, modified starch, starch derivatives, cellulose, cellulose derivatives, modified cellulose, modified cellulose deriva- tives, alginic acid, alginates, bentonite, veagum, 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 anyone of claims 3,4 or5 wherein Q A f 9 tfie therapeutic agent is acetylsalicylic acid.
10. A sustained release pharmaceutical composition as claimed in claim 8 or claim 9 wherein the aimount of acetylsalicylic acid per tablet is 650 to 800 5 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 composi- tion as claimed in claim 8 wherein the amount of flurbiprofen per tablet is 100 to 300 mg.
13. A method of manufacturing a sustained released pharmaceutical composition in tablet form comprises the steps of granulating a mixture of an effective amount 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 characterisedin that the final tablet contains 0.8 to 1.6% by weight of the release controlling agent and 1.0 to 7.5% by weight of the erosion promoting agent and the relative amount of the components are such that a criticality factor calculated according to equation 1 CA CIF = 1ACS) 1 wherein C17 is the criticality factor, CA is the amount of therapeutic agent pertablet in milligrams divided by the amount of relase controlling agent pertablet in milligrams and CS is the amount of erosion prom- oting agent pertablet in milligrams divided by the amount of release controlling agent pertablet in milligrams, lies in the range 20 to 450.
14. A method of manufacturing a sustained release composition 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 composition as claimed in claim 3 substantially as hereinbefore described 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 composition as claimed in claim 14 substan- tially 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 described with reference to Examples 10 to 12.
Printed for Her Majesty's Stationery Office by The Tweeddale Press Ltd., Berwick-upon-Tweed, 1981. Published at the Patent Office, 25 Southampton Buildings, London, WC2A lAY, from which copies may be obtained.
GB 2 067 07? A 9
GB8100522A 1980-01-11 1981-01-08 Sustained release tablets Expired GB2067072B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US11143080 true 1980-01-11 1980-01-11
US06194453 US4308251A (en) 1980-01-11 1980-10-17 Controlled release formulations of orally-active medicaments

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GB2067072A true true GB2067072A (en) 1981-07-22
GB2067072B GB2067072B (en) 1983-08-10

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GB8100522A Expired GB2067072B (en) 1980-01-11 1981-01-08 Sustained release tablets

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JP (1) JPS56103110A (en)
BE (1) BE886998A (en)
CA (1) CA1140466A (en)
DE (1) DE3100191C2 (en)
DK (1) DK6181A (en)
ES (2) ES498369A0 (en)
FI (1) FI76927C (en)
FR (1) FR2473308B1 (en)
GB (1) GB2067072B (en)
LU (1) LU83052A1 (en)
NL (1) NL8100037A (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0061217A2 (en) * 1981-03-19 1982-09-29 PHARMATEC S.p.A. Ibuprofen-containing sustained release pharmaceutical composition
EP0134290A1 (en) * 1983-08-16 1985-03-20 Verex Laboratories, Inc. Constant release rate solid dosage theophyllineformulation
EP0134289A1 (en) * 1983-08-16 1985-03-20 Verex Laboratories, Inc. Constant order release, solid dosage indomethacin formulation and method of treating arthritis and other inflammatory conditions
EP0138216A2 (en) * 1983-10-14 1985-04-24 Sumitomo Pharmaceuticals Company, Limited Sustained-release IFN preparation for parenteral administration
EP0234670A3 (en) * 1986-01-18 1988-01-13 The Boots Company Plc Sustained-release pharmaceutical formulation containing xanthan gum
EP0280571A2 (en) * 1987-02-27 1988-08-31 Eli Lilly And Company Sustained release matrix formulations
US4849141A (en) * 1985-12-27 1989-07-18 Sumitomo Pharmaceuticals Company, Limited Method for producing sustained release formulation
US4855134A (en) * 1983-10-14 1989-08-08 Sumitomo Pharmaceuticals Company, Limited Sustained-release preparation
US4968508A (en) * 1987-02-27 1990-11-06 Eli Lilly And Company Sustained release matrix
US5021241A (en) * 1983-10-14 1991-06-04 Sumitomo Pharmaceuticals Company, Limited Long-term sustained-release preparation
US5385738A (en) * 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2496082A (en) * 1947-05-24 1950-01-31 Ashenfelter William Scaffold structure
JPH0530810B2 (en) * 1983-06-07 1993-05-11 Asahi Chemical Ind
JPH0662404B2 (en) * 1983-06-14 1994-08-17 シンテックス・ファーマシユーテイカルズ・インターナシヨナル・リミテツド Controlled release naproxen and naproxen sodium tablets

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US2953497A (en) * 1953-06-03 1960-09-20 Howard A Press Therapeutic tablets
NL265428A (en) * 1960-06-06
US3577514A (en) * 1968-06-10 1971-05-04 Pfizer Sustained release pharmaceutical tablets
US3773920A (en) * 1971-07-14 1973-11-20 Nikken Chemicals Co Ltd Sustained release medicinal composition
US3906086A (en) * 1971-07-19 1975-09-16 Richard G Powers Timed-release aspirin
GB1500300A (en) * 1975-01-06 1978-02-08 Ciba Geigy Ag Pharmaceutical preparation for the treatment of circulatory disorders
JPS5411226A (en) * 1977-06-24 1979-01-27 Shin Etsu Chem Co Ltd Disintegratable granule

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0061217A3 (en) * 1981-03-19 1983-04-20 PHARMATEC S.p.A. Ibuprofen-containing sustained release pharmaceutical composition
EP0061217A2 (en) * 1981-03-19 1982-09-29 PHARMATEC S.p.A. Ibuprofen-containing sustained release pharmaceutical composition
EP0134289A1 (en) * 1983-08-16 1985-03-20 Verex Laboratories, Inc. Constant order release, solid dosage indomethacin formulation and method of treating arthritis and other inflammatory conditions
EP0134290A1 (en) * 1983-08-16 1985-03-20 Verex Laboratories, Inc. Constant release rate solid dosage theophyllineformulation
US5081156A (en) * 1983-10-14 1992-01-14 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release preparation
EP0138216A2 (en) * 1983-10-14 1985-04-24 Sumitomo Pharmaceuticals Company, Limited Sustained-release IFN preparation for parenteral administration
EP0138216A3 (en) * 1983-10-14 1985-10-30 Sumitomo Chemical Company, Limited Sustained-release preparation
US5021241A (en) * 1983-10-14 1991-06-04 Sumitomo Pharmaceuticals Company, Limited Long-term sustained-release preparation
US5385738A (en) * 1983-10-14 1995-01-31 Sumitomo Pharmaceuticals Company, Ltd. Sustained-release injection
US4855134A (en) * 1983-10-14 1989-08-08 Sumitomo Pharmaceuticals Company, Limited Sustained-release preparation
US4849141A (en) * 1985-12-27 1989-07-18 Sumitomo Pharmaceuticals Company, Limited Method for producing sustained release formulation
US5415871A (en) * 1986-01-18 1995-05-16 The Boots Company Plc Therapeutic agents
EP0234670A3 (en) * 1986-01-18 1988-01-13 The Boots Company Plc Sustained-release pharmaceutical formulation containing xanthan gum
US4968508A (en) * 1987-02-27 1990-11-06 Eli Lilly And Company Sustained release matrix
EP0280571A2 (en) * 1987-02-27 1988-08-31 Eli Lilly And Company Sustained release matrix formulations
EP0280571A3 (en) * 1987-02-27 1989-01-04 Eli Lilly And Company Sustained release matrix formulations

Also Published As

Publication number Publication date Type
ES498369A0 (en) 1982-06-01 application
ES498369D0 (en) grant
DK6181A (en) 1981-07-12 application
FI810056A (en) application
ES8301629A1 (en) 1982-12-16 application
FR2473308A1 (en) 1981-07-17 application
BE886998A (en) 1981-07-08 grant
FI810056L (en) 1981-07-12 grant
ES8205353A1 (en) 1982-06-01 application
JPS56103110A (en) 1981-08-18 application
NL8100037A (en) 1981-08-03 application
ES509179D0 (en) grant
DE3100191C2 (en) 1988-09-01 grant
FI76927B (en) 1988-09-30 application
GB2067072B (en) 1983-08-10 grant
LU83052A1 (en) 1982-09-10 application
FI76927C (en) 1989-01-10 grant
ES509179A0 (en) 1982-12-16 application
CA1140466A1 (en) grant
BE886998A1 (en) grant
CA1140466A (en) 1983-02-01 grant
FR2473308B1 (en) 1985-07-19 grant
DE3100191A1 (en) 1981-12-10 application

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