FI76927C - FOERFARANDE FOER FRAMSTAELLNING AV EN PHARMACEUTICAL PREPARAT MED LAONGVARIG FRIGOERING AV ETT TERAPEUTISKT MEDEL I TABLETTFORM. - Google Patents

Description

76927

The invention relates to a process for the preparation of a sustained-release pharmaceutical preparation in the form of a tablet, comprising the steps of granulating a mixture of an effective amount of an orally active therapeutic agent and a wear agent. with a solution of the release control agent in an organic solvent and then compressing the granules thus prepared into tablets.

The invention is particularly suitable for the preparation of tablets containing anti-inflammatory agents such as acetylsalicylic acid (hereinafter referred to as "ASA"), indomethacin, fenoprofen, naproxen, ibu-profen and flurbiprofen, for example in the treatment of rheumatism and osteoarthritis. In the treatment of these diseases, it is necessary to administer therapeutic agents for 20 long periods of time. It is known that the use of aspirin in long-term treatment can cause undesirable side effects, and many attempts have been made to reduce these effects.

GB 1,070,492 relates to aspirin tablets which continuously release the active ingredient. It should be noted, however, that in this case, the preferred embodiments and examples relate to two-layer tablets in which one of the layers is such that it releases aspirin continuously over a long period of time. In contrast, the tablets obtained by the method of the present invention consist of only one layer and have a zero-order release property, but do not release the active ingredient immediately after taking the tablet.

U.S. Patent No. 4,012,498 discloses an invention for releasing a small amount of the first active ingredient from a tablet containing a small amount of the first active ingredient and a relatively large amount of the second active ingredient. Ko. according to the publication, this is achieved by preparing a three-component system comprising three granulations. The first of these components provides a sustained release of both active ingredients present and the other two components provide a sustained release of the active ingredients present after the release provided by the first component. This method is completely different from the method of the present invention, in which a single-component system is produced by a single granulation 10, which provides a zero-order release property of one active ingredient without immediate release of the active ingredient after taking the tablet.

U.S. Pat. No. 3,577,514 relates to sustained-release tablets containing, in addition to the active ingredient, 0.1 to 5% of a hydrochloric acid-insoluble sustained-release agent (e.g., cellulose acetate phthalate) which acts as a controlled-release agent and 5 to 15 % dispersible binder which acts as a wear promoter. However, it is essential in this known tablet that a hydrophobic dissolution retardant is also present. In contrast, the hydrophobic dissolution retardant is not used in the process of the present invention. According to the examples of U.S. Patent 3,577,514, a hydrophobic dissolution retardant is used in large quantities. Such large amounts of hydrophobic dissolution retardant are not required in the present invention, which is particularly important when a conventional drug (650 or 800 mg) is used when an active ingredient such as aspirin is used, as uncomfortably large tablets should be used if the formulation still contains a large number of other ingredients.

U.S. Pat. No. 3,773,920, claim 1,35, discloses a pharmaceutical composition comprising granules containing up to 60% of active ingredient mixed with ethylcellulose which reduces the viscosity of the release and a water-soluble polymer which increases the rate of release. The ratio of the amounts of ethyl 3,76927 cellulose to polymer can be varied to achieve the desired release rate of the active ingredient. Ko. according to the examples of the publication, the total weight of ethylcellulose and polymer is greater than the weight of the granules containing the active substance. In addition, it should be noted that these active ingredient-containing granules contain 30 to 35% by weight of a metal salt of a higher fatty acid. In contrast, the preparations prepared according to the present invention do not contain metal salts of higher fatty acids.

U.S. Patent No. 3,362,881 describes the preparation of a pharmaceutical composition by compressing a mixture of a drug, a blowing agent (dissolving agent) and a film-forming agent (release-regulating agent). However, the amounts of the various substances disclosed in this publication are not the same as the amounts of the substances used in the present invention.

It is therefore an object of the present invention to provide pharmaceutical preparations in tablet form which, when used orally, cause delayed disintegration of the tablet, provide extended dissolution times for the active therapeutic agent and provide stable concentrations of the active therapeutic agent in the patient's blood. It has been found that these objects can be achieved in accordance with the present invention by adjusting the relative amounts of the therapeutic agent, the release control agent and the wear agent.

The process according to the invention for the preparation of a sustained-release pharmaceutical preparation in tablet form is characterized in that the therapeutic agent is thoroughly mixed with 1.0 to 7.5% by weight of a wear-promoting agent and the mixture is then granulated with a release-controlling solution. wherein the amount of release control agent 35 in the solution is such that the amount of release control agent in the final tablet is 0.8 to 1.6% by weight, and the relative amounts of the components are such that the criticality factor CF calculated according to Equation I is 76927

CF = A- I

1 / (CS) wherein CA is the amount of therapeutic agent per tablet in milligrams divided by the amount of release control agent per tablet in milligrams and CS is the amount of disintegrant per tablet in milligrams divided by the amount of release control agent per tablet in milligrams is 20 to 450.

All percentages are expressed as weight percentages of the total weight of the tab-10 counter. The recommended amount of the release control agent is 1.15 to 1.6% by weight and the recommended amount of the wear control agent is 2 to 5% by weight.

The criticality factor is suitably more than 50 and is preferably 80 to 330 and even more preferably 210 to 330.

15 The preferred release control agent is cellulose acetate phthalate. Other suitable release controlling agents include the cellulose acetate derivatives disclosed by Hiatt in U.S. Patent 2,196,768, shellac, seine, acrylic resins, ethylcellulose, hydroxy-20-propylmethylcellulose phthalate, sandalwood resin, and modified shellac.

The recommended anti-wear agent is corn starch. Other suitable wear aids include rice starch, potato starch and other similar vegetable starches, modified starch and starch derivatives, cellulose derivatives and modified cellulose or allyl aliphatic arthritis, polyvinyl algae, sodium carboxime-style cellulose, algin resins and gums, such as agar and guar gum.

The ASA tablets suitably contain 650 to 800 mg of ASA per tablet, about 5.0 to 13.6 mg of release control agent per tablet, and about 13.4 to 63.8 mg of disintegrant per tablet.

5,76927

For example, other anti-inflammatory therapeutic agents may be prepared as tablets containing 400 to 600 mg of ibuprofen or 100 to 300 mg of flurbiprofen per tablet.

The pharmaceutical preparations obtained according to the invention may also contain inert excipients or diluents, flow aids or tableting aids.

The tablets obtained according to the present invention have a hardness on the Schleuniger scale of 6.5 to 18 Kp. However, it has been shown that satisfactory release properties can be obtained with tablets of varying hardness. This facilitates the large-scale preparation of tablets because the possible variation in hardness caused by the tableting machine does not cause a significant change in the release properties.

According to the invention, the preparations can 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, aceto-20 and lower aliphatic ketones such as methyl ethyl ketone, chloroform, carbon tetrachloride, ethyl tetrachloride, ethyl hydrocarbons or a solvent mixture such as methylene chloride and denatured alcohol (1: 1; v / v). The therapeutic agent in powder form is thoroughly mixed with a wear agent, preferably corn starch, and a solution of a release control agent, preferably cellulose acetate phthalate, is added to the miscible powders in a continuous stream. Stirring is continued to form a wet granular mass. The wet mass is dried to remove residual organic solvent, leaving the release control agent in close contact with the therapeutic agent and the wear agent particles. The reactive mass is comminuted to a suitable grain size by forcing the material through a sieve and the dry granules are mixed to ensure homogeneity before being compressed into tablets using a conventional rotary or single station tablet press. The tablets can then be labeled directly using conventional tablet labeling equipment and materials to identify the product. Tablet identification can also be done by embossing the finished product during compression.

The invention is illustrated by the following examples, which are not to be construed as limiting. The examples refer to the accompanying drawings, in which Figure 1 is a graphical representation of the results of the experiment described in Example 7, showing mean serum ASA levels during the first 8 hours of a 24-hour study in two patients receiving two 650 mg tablets as one 1300 mg: n ASA dose of tablets according to the present invention (solid and dashed line) compared to one 650 mg tablet which was also according to the invention (dotted line).

Figure 2 is a graphical representation of the results of the experiment of Example 8 showing the mean serum concentrations of salicylic acid over 120 hours involving multiple oral doses (9 doses, 2 x 650 mg each, every 12 hours over 96 hours) of the ASAs of this invention. tablets in eight patients when blood samples were taken at the indicated hours.

Figure 3 is a graphical representation of the results of the experiment shown in Example 8 and described in connection with Figure 2, which show serum ASA levels.

Figure 4 is a graphical representation of a two-compartment model used to provide the simulated zero-order absorption curves shown in Figures 5 and 6.

Figure 5 is a graphical representation of the results of a comparison performed between a simulated computer curve of zero order ASA absorption (solid line) and actual values obtained from blood samples taken on the first day of treatment from Example 8 patient 1 (dashed line) and 35 Figure 6 is a graphical representation of the results of a comparison performed between the theoretical value (solid line) of zero-order absorption of ASA 76927 in another patient and the actual values obtained from blood samples taken on the first day of treatment from Example 8 patient 2 (dashed line). .

5 Example 1

Cellulose acetate phthalate (67.3 g) was slowly added to a vortex of a mixture of ethanol (denatured, 625 mL) and methylene chloride (175 mL). Stirring was continued until a solution was reached.

10 ASAs (4.375 kg, 0.42 mm crystals, USP) and corn starch (0.2255 kg, USP) were ground through a 0.42 mm sieve in a Hobart mixer bowl. The dry powders were mixed for five minutes at speed 1. The cellulose acetate phthalate solution was added to the blended powders over 30 seconds with stirring at speed 1. Further mixing for four minutes at speed 2 was performed to promote granulation.

The wet granular mass was emptied onto stainless steel plates and air dried until it could be forced through a 0.84 mm sieve. The screened granular mass was further air dried to remove residual solvent. The granules were weighed, mixed by drumming and compressed on a conventional rotary tablet press using a 12.7 mm flat round-edged tool to prepare tablets containing 650 mg of ASA and having a hardness of 8-10 Kp (Schleuniger).

Example 2

Cellulose acetate phthalate (750 g) was slowly added to a vortex of a mixture of methylene chloride (3750 mL) and ethanol (3750 mL). Stirring was continued until a solution was reached.

ASA (60 kg, 0.17 mm, powder, USP) and corn starch (3.0 kg, USP) were placed in a plate of a Littleford MGT 400 mixer. The dry powders were mixed using 35 paddle mixers at speed 1 for two minutes. The cellulose 8 76927 acetate phthalate solution was poured in a continuous stream onto the powders, which were mixed at a blade speed of 1 and a shredder speed of 1. After the addition of the solution, stirring was continued at a blade and shredder speed of 2 until a suitable granular mass was obtained. The wet granular mass was applied to stainless steel plates and dried in a forced rotary oven at a maximum temperature of 49 ° C. The dry granular mass was passed through a Jackson Crockatt granulator with a 1.19 mm 10 stainless steel screen. The dried, graded granules were mixed in a tumbler mixer for five minutes and compressed on a conventional tablet press using a capsule-shaped tool to obtain tablets containing 800 mg of ASA and having a hardness of 8-11 Kp 15 (Schleuniger).

Examples 3-6

Four batches of tablets having the compositions shown in Table I were prepared as described in Example 1. The disintegration time in a buffer solution having a pH of 7.5 was determined by the procedure described in

United States Pharmacopoeia XX, page 958, but excluding discs and release properties were determined in buffer at pH 7.5 by the procedure described in United States Pharmacopoeia XX, page 959, but using a modified modification of the device described as device 1. , where the propeller agitator is mounted on a shaft above the drum. The results of these experiments are shown in Table 1, which also shows the results obtained using conventional ASA tablets (Example A) and 30 tablets (Examples B and C) with a criticality factor higher than that required by this invention. The dissolution results of Examples 4 and 6 were obtained using a new batch of tablets prepared in the same manner as used for the disintegration experiments.

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10 76927

The release properties of the tablets prepared according to Example 5 were determined in a second experiment and the results shown below were obtained.

5 Sampling time Acetylsalicylic acid (h) dissolved - 0/5 23.8 1 34.8 2 61.3 10 3 82.4

Plotting these results on a graph showing time as a function of the percentage of acetylsalicylic acid dissolved gives a straight line indicating zero release. Linear regression analysis of the results gives a correlation coefficient of 0.999 compared to a straight line value of 1.0.

The dissolution of the additional batch of tablets prepared according to Example 3 and Example 6 was confirmed by a method involving a change in pH. The method was in accordance with page 959 of the United States Pharmacopoeia using the modification described above. The results are shown in Table 2.

Table 2 25 -

Time Initial mg of ASA released-% of theoretically released (h) pH nut over time- cumulative A3A of accumulated AAA lative _ amount_ _ _Ex. 6 Example 3 Example 6 Example 3 Example 6 Example 3 30 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 30.3 24.0 3-6.5 7.5 410 425 607 581 93.4 89.4 11 76927

The level of chemical disintegration that occurs upon storage with the tablets of this invention is lower than that achieved with conventional ASA formulations. Acetylsalicylic acid decomposes into salicylic acid and this reaction is promoted by elevated temperature. The reaction is easy and has led the United States Pharmacopoeia to adopt an upper limit of 0.3% for free salicylic acid (FSA) levels in ASA tablets.

Tablets 10 prepared according to Examples 1 and 5 were analyzed for free salicylic acid (FSA) after storage under extreme conditions. The results are shown in Table 3.

Table 3 15

Example Time Storage FSA level,% 10 - 0.04 3 40 ° C 0.12 months 20 5 0 - 0.06 6 40 ° C 0.14 months 37 ° c / 75 »relative humidity 1 2 3 4 5 6 2

It is widely known that under similar storage conditions, the limiting level of FSA, namely 0.3% above 4, is achieved with conventional ASA formulations. Tablets prepared according to Examples 4, 5 and 6 were subjected to a drop test in a Roche brittle device. After one hundred drops, a weight loss of 0.12-0.46% by weight was observed. When the experiment was extended to 750 drops, the edges of the tablets wore broken, but the tablets did not break. The commercial sustained-release aspirin tablet showed 0.85% weight loss and was severely worn after 750 drops.

76927 12

Example 7

Serum concentrations after a single oral dose

Tablets containing 650 mg of ASA were prepared according to the method of Example 1. One volunteer received a single oral dose of 650 mg, while the other two subjects received 1300 mg as a single dose (two 650 mg tablets). Blood samples were taken from each patient from the forearm vein through 10 catheters in it. Samples were collected in a refrigerated vacuum container at the following times: before dosing and at 15.30, 45, and 60 minutes; 1.5, 2.0, 2.5, 3.0, 4.0, 4.0, 8.0, 12.0, 16.0 and 24 hours after dosing. Blood samples were analyzed for plasma salicylic acid and acetyl-salicylic acid using high performance liquid chromatography. Figure 1 shows the results of patient 1 as a solid line, the results of patient 2 as a dotted line, and the results of patient 3 as a dashed line, the x-axis representing time in hours and the y-axis representing the plasma concentration of ASA in micrograms / ml.

13 76927

Table 4

Plasma acetylsalicylic acid and salicylic acid values over 24 hours 5___i________ 1 2 3 ~ Patient 1300 mg 650 mg 1300 mg No. ^ g / ml / vg / ml / Ag / ml

Dose_:--------

Review period ASA SA ASA SA ASA SA

10 0 0.1 0.1 0.1 0.1 0.1 0.1 1/4 0.1 0.38 0.1 0.1 0.1 0.2 1/2 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 15 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 SO 0.68 8.89 0.38 4.27 0.97 10.70 20 '' 9 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 25

Serum concentrations of acetylsalicylic acid were shown to be maximal in all three patients four hours after ingestion. Concentrations returned to 0.1 μg / ml in 2Q only after eight hours. This finding should be compared to the established 20-minute half-life (t = 1/2) with acetylsalicylic acid serum levels after ingestion of a standard 650 mg tablet.

76927 14

Example 8

Serum Concentrations After Multiple Oral Doses ASA tablets prepared according to the method of Example 1 5 were orally administered to eight healthy volunteers at doses of 1300 mg (two 650 mg tablets) twice daily at 8:00 and 20:00 in nine consecutive doses, with the last dose was administered at 96 hours to determine the steady state pharmacodynamic properties of the ASA-10 tablet formulation of this invention. Blood samples were taken from individuals at predetermined intervals during the study. Blood samples were analyzed by high performance liquid chromatography for salicylic acid and acetylsalicylic acid concentrations. The individual blood concentrations of salicylic acid and acetylsalicylic acid observed on the fifth day of the study are shown in Tables 5 and 6. A graphical representation of the mean blood concentrations of salicylic acid and acetylsalicylic acid throughout the study is shown in Figures 2 and 3, respectively. In these figures, the x-axis numbers promote time in hours and the y-axis numbers represent blood SA and ASA levels in micrograms / ml.

Example 9 Comparison of ASA absorption with a theoretical zero order curve

In order to show that the in vivo absorption properties of the aspirin tablets prepared according to the present invention are generally non-zero, the results obtained from individuals 1 and 2 of Example 30 were compared with the machine-calculated, predictable results. Computer calculations were based on a two-compartment model with first-order metabolism. The model is shown schematically in Figure 4. The model assumes that the total dose D-35 is absorbed at a constant rate KQ over the period T.

15 76927

At the end of time T, the entire dose should be absorbed. The model also assumes that 60% of the ASA passes through the liver 2 unhydrolyzed before entering the central compartment 3 with an apparent volume of distribution of 6.3 liters.

Acetylsalicylic acid can travel reversibly from central compartment 3 to body tissue (shown at number 4) or can be reversibly removed as metabolites (shown schematically at number 5). The rate constants used in the model and shown in Figure 4 were taken from the article by Rowland and 10 Riegelman1 in J. Pharm. Sci. Butter. 57 (1968), page 1313.

The time T required to absorb the entire dose limits the amount by which multiple doses overlap. In Fig. 5, the results obtained from Example No. 15 No. 1 (dashed line) of Example 8 are shown in Fig. 6 and compared with a computer-generated curve (solid line) obtained when T was given a value for six hours. In Figures 5 and 6, the x-axis numbers represent time in hours and the y-axis numbers represent ASA concentrations in blood at 20 micrograms / ml.

There is a reasonable agreement between the experimental and theoretical curves, indicating that there is an in vivo near-absorption approximation with ASA tablets prepared in accordance with this invention.

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76927 18

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 thoroughly mixed mixture of ibuprofen, 2- (4-iso-butylphenyl) propionic acid, (2.5 kg), dicalcium phosphate dihydrate sold under the tradename Emcompress (0.75 kg) and corn starch (0.155 kg). mixed. The wet granular mass of air-10 was dried on stainless steel plates, passed through a 14 mesh screen and further dried to remove all solvent.

An amount of about 0.05 kg of dried granule was removed from the bulk and mixed with colloidal silica sold under the tradename Aerosil 200 (0.5% of the total weight of the granules). This premix was then mixed with the bulk of the granules for ten minutes.

The mixed granules were obtained in 98.4% yield. By the method of Carr ^ Brit. Chem. Eng. 15 (1970), ss. 1541-1549 ^ 20 certain flow properties were found to be moderately satisfactory.

The granules were compressed on a conventional rotary tablet press using a 12.7 mm flat, rounded edge tool to give tablets containing 400 mg of ibuprofen and having a hardness of 8-12 Kp (Schleuniger).

The criticality factor in this example is 155 and the weight percent of release control agent and wear agent is 1.44 and 4.46%, respectively.

The tablets obtained from the granules prepared as described above were compressed to different hardnesses and the obtained tablets were subjected to disintegration tests (United States Pharmacopoeia XX, page 959) in pH 7.5 buffer at 37 ° C.

76927 19

Hardness Kp Average disintegration time _ (min) _ 4.14> 235 8.54> 275 5 10.86> 240

A conventional ibuprofen tablet disintegrates in less than one minute and a sugar-coated tablet in 5-10 minutes.

In vitro dissolution experiments (United States Pharmacopoeia XX, page 959) show that the examples of Example 10 (hardness 10.80 Kp) do indeed cause sustained release of ibupropene compared to conventional ibuprofen tablets. Each experiment was repeated six times.

15

Time Dissolved ibuprofen amount (mg) ______ ^ 11 Example 10 (pH 7.5) Conventional tablet _ (pH 6.8) _

At the beginning of 3 months of storage- At the beginning of 3 months after storage at 20 40 ° C at 40 ° C 10 - - 277 62 20 - - 318 110 30 68 63 365 163 60 100 99 383 248 25 120 169 163 180 219 217 240 265_274____ t1 / 2 155 153 8.4 41.3 30

In the above results, t 1/2 is the time taken for ibuprofen to dissolve by 50%. The results after three months of storage show that the tablets of this example have good storage stability.

The results of the non-stored tablets of Example 10 give a straight line when the amount of dissolved ibuprofen is plotted as a function of time. Linear regression analysis of the results gave a correlation coefficient of 0.996, indicating zero-order dissolution in vitro.

Examples 11 and 12

Tablets containing flurbipropene [2- (2-fluoro-4-biphenyl) 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, screened and further dried to remove the solvent. Magnesium stearate (10.5% of the total weight of the granules) was added and the granules were tableted. The compositions of Examples 11 and 12 are shown below.

CAP solution Example 1 Example 12

Cellulose acetate phthalate 9 g 8.33 g

Ethanol, denatured 60 ml 55 ml

Methylene chloride 60 ml 55 ml

Other components

Flurbiprofen 300 g 100 g

Emcompress 240 g 400 g

Corn starch 18.6 g 17.2 g

Flurbiprofen weight per tablet 300 mg 100 mg

Tablet hardness (Kp) 8.7 + 1.2 7.14 + 0.54 CF 25 25

Release control agent,% 1.58 1.58

Abrasive agent,% 3.27 3.27

The mean disintegration times of the tablets of Examples 11 and 12 in pH 7.5 buffer were determined by the method described on page 958 in United States Pharmacopoeia XX. The results obtained are shown below.

Example 11 Example 12

Mean decomposition time (min)> 300> 360 Residue (%) 3.7 4.9 21 76927

The dissolution of flurbiprofen over a period of time from the tablets of Examples 11 and 12 was confirmed using the equipment described on page 959 of the United States Pharmacopoeia XX. Phosphate buffer 5 having a pH of 6.8 was used. The experiment was repeated six times and the average amount of active substance released is shown below.

Time (h) Dissolved flurbiprofen,%

Example 11 Example 12 10 - 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

The percentage of dissolved flurbiprofen as a function of time in each of these sets of results gave a straight line, indicating that there is a zero-order mechanism in each case. Using regression analysis on the results gives a correlation coefficient of 0.993 in Example 11 and 0.999 in Example 12.

2 ^. By comparison, a conventional flurbiprofen tablet containing 100 mg of flurbiprofen in the same experiment showed complete dissolution in about one hour.

The tablet of Example 12 was used in an experiment measuring the plasma concentration of flurbiprofen in four volunteers after a single dose and the results are shown in the columns labeled A in Table 7. The results obtained with a conventional 100 mg flurbiprofen tablet used in the same experiment in the same volunteers are shown in B in the heading columns of Table 7. ND means that 76927 22 flurbiprofen could not be detected.

Table 7 5 Flurbiprofen plasma concentrations, μg / ml

Time Optional 1 Optional 2 Optional 3 Optional 4 ^ A_B_A_B_A S_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 10 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 5.0 4.0 4.6 3.7 3.6 3.1 15 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 ND ND 0.2 ND 0.2 ND 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Although the above examples demonstrate the applicability of the present invention to various orally active therapeutic agents or drugs to provide controlled release tablets therefrom, the invention is not limited to the tableting of the specific drugs of the 5 examples. At this point, the invention can be varied widely and is applicable to the controlled release tableting of any orally active drug, although it is directed to drugs of a more acidic nature, in particular aspirin and non-steroidal arylalkanoic anti-inflammatory agents. , such as for the tableting of the salts, esters, 12 anhydrides and other derivatives disclosed above. These compounds include antipyretics, 14 analgesics, and anti-inflammatory agents.

15

Other representative types of orally active drugs that can be incorporated into the sustained release tablets of the invention include sedatives, tonics, antibiotics, anticonvulsants, nutrients, hematin drugs, anthelmintics, antitussives, various types of hormones. 5 adrenocorticosteroids, androgenic steroids, estrogenic steroids, progestational steroids, and anabolic steroids, non-steroidal counterparts of the aforementioned, psychic stimulants, and viral antibodies.

Claims (8)

24 7 6 9 2 7 A process for preparing a sustained release pharmaceutical formulation in tablet form, comprising the steps of granulating a mixture of an effective amount of an orally active therapeutic agent and a disintegrant with a solution of a controlled release agent in an organic solvent and then compressing the thus prepared 10 and granules for tablets, characterized in that the therapeutic agent is thoroughly mixed with 1.0 to 7.5% by weight of the disintegrant and the mixture is then granulated with a solution of the release control agent, the amount of the release control agent in the solution 15 being such that the amount of release control agent in the final tablet is 0.8 to 1.6% by weight, and the relative amounts of the components are such that the criticality factor CF, calculated according to Equation I, Process according to Claim 1, characterized in that the amount of release control agent is from 1.15 to 1.6% by weight and the amount of wear-promoting agent is from 2 to 5% by weight. 2. CF = - I 1 / (CS) wherein CA is the amount of therapeutic agent per tablet in milligrams divided by the amount of release control agent per tablet in milligrams and CS is the amount of disintegrant per tablet in milligrams divided by the amount of release control agent per tablet in milligrams, is 20 - 450. Method according to Claim 1 or 2, characterized in that the criticality factor is 50 to 35,450. Method according to any one of the preceding claims, characterized in that the criticality factor is 80 to 330. 25 76927 Method according to any one of the preceding claims, characterized in that the criticality factor is 210 to 330. Process according to any one of the preceding claims, characterized in that the release-regulating agent is cellulose acetate phthalate and the wear-promoting agent is maize starch. Process according to any one of the preceding claims, characterized in that the therapeutic agent is acetylsalicylic acid, ibuprofen or flurbiprofen. A method according to claim 3, characterized in that the therapeutic agent is acetylsalicylic acid. 26 Patentkrav 7 6 9 2 7