LU83052A1 - LONG-TERM PHARMACEUTICAL COMPOSITION AND PROCESS FOR PREPARING THE SAME - Google Patents

Description

The present invention relates to pharmaceutical compositions in the form of tablets in which a delay effect is obtained from the release of a therapeutic agent. 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, ibuprofen and flurbiprofen which are used for example in the treatment of active chronic arthritis and osteoarthritis. In the treatment of these diseases, it is necessary to give therapeutic agents for long periods of time. It is known that the use of Aspirin, in long term therapy, can cause undesirable side effects and many attempts have been made to reduce these side effects.

The object of the present invention is to provide therapeutic compositions in the form of tablets which, when administered orally, provide delayed disintegration of the tablet, provide extended dissolution times on the part of the therapeutic agent. and provide sustained blood levels of the active therapeutic agent in the patient. It has been discovered that the present invention achieves these goals by controlling the relative proportions of the therapeutic agent, an agent for regulating the release of the active ingredient, and an agent for promoting erosion.

The subject of the present invention is a pharmaceutical composition with a delayed effect, in the form of tablets, comprising an effective amount of an active therapeutic agent orally, from 0.8 to 1.6% by weight of a release of the active ingredient and from 1.0 to 7.5% by weight of an erosion-promoting agent, the relative proportions of the constituents being such that a critical factor calculated according to equation I: 35 CF (TC7TCS) 1 in where CF represents the critical factor, CA represents the quantity of therapeutic agent per tablet in mg 2 divided by the quantity of release regulating agent per tablet in mg and CS represents the quantity of erosion promoting agent per tablet in mg divided by the amount of release regulating agent per 5 mgf tablet is between 20 and 450.

All the percentages are expressed by weight, in percentages of the total weight of the tablet. The proportion by weight of agent which regulates the release of the active principle is preferably 1.15 to 1.6%, and the proportion by weight of the erosion-promoting agent is preferably from 2 to 5%.

The critical factor should have a value greater than 50 and preferably have a value of 80 to 330 and better still 210 to 330.

The agent which regulates the release of the active ingredient is preferably cellulose aceto-phthalate. Other suitable release agents include the cellulose derivatives cited in the U.S. Patent. 2,196,768 from Hiatt, shellac, zein, acrylic resins, sandaraque and modified shellac.

The preferred erosion promoting agent is corn starch. Other erosion promoting agents include rice starch, potato starch and other equivalent plant starches, starch and modified starch derivatives, cellulose derivatives and modified cellulose derivatives (eg methyl cellulose, sodium carboxymethylcellulose), alginic acid and alginates, bentonite, veagum, crosslinked polyvinylpyrrolidone, ion exchange resins as well as gums such as agar and guar, for example.

Generally speaking, ASA tablets contain 650 to 800 mg of ASA per tablet, approximately 5.0 to 13.6 mg per tablet of active ingredient release regulating agent, and approximately 13.4 to 63.8 mg per tablet of erosion promoting agent.

Other anti-inflammatory therapeutic agents can be used in pharmaceutical compositions

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I "according to the present invention. By. For example, tablets containing 400 to 600 mg of ibuprofen per tablet or 100 to 300 mg of flurbiprofen per tablet can be prepared.

The pharmaceutical compositions according to the present invention may also contain inert fillers or diluents, flow aids or tablets.

The tablets according to the present invention preferably have a hardness of 65 to 180 N depending on the scale. Schleuniger. However, it has been shown that satisfactory release characteristics of the active ingredient can be obtained with tablets of varying hardness. This facilitates large-scale tablet production, since any change in hardness produced by the tablet processing plant does not cause a significant change in release characteristics.

The compositions according to the present invention can be prepared by dissolving the liberation agent in a suitable organic solvent, in particular a lower aliphatic alcohol such as methanol, isopropanol 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 mixture of solvents, for example methylene chloride and d 'alcohol: denatured (1/1 vol / vol).

The therapeutic agent, in powder form, is intimately mixed with the erosion-promoting agent, preferably corn starch, and the solution of agent regulating the release of the active principle, preferably d cellulose acetate phthalate is added continuously to the powders being mixed. The mixing is continued so as to obtain a wet granular mass. The wet mixture is dried to remove the residual organic solvent, leaving the agent for release of the active ingredient in intimate contact with the particles of the therapeutic agent and the promoter agent. erosion. The granular mass is reduced to granules of suitable size, forcing the material through a sieve, and the dry granules are mixed in order to ensure their homogeneity before being transformed into tablets using a tablet press. classic, rotary or single compression station. The tablets can then be directly subjected to a printing operation using a conventional printing facility for 10 tablets and conventional materials allowing the product to be identified. Compresses can also be identified by intaglio printing of the final product during compression.

The following nonlimiting examples are given by way of illustration of the present invention. The examples relate to the appended drawing, given solely by way of example, in which: - FIG. 1 is a graphic illustration of the results of the test described in Example 7, showing the mean serum levels of ASA during the first 8 hours of a 24-hour study in two subjects each receiving two 650 mg tablets under the form of a single dose of 1300 mg of ASA, said tablets being prepared according to the invention (solid line and broken line) by comparison with a single tablet of 650 mg, also according to the invention (dot line and dashes); - Fig. 2 is a graphic illustration of the results of the test described in Example 8, indicating the average serial levels of salicylic acid during a period of 120 hours including multiple doses taken orally ( nine doses of 2 x 650 mg each, every 12 hours, for a period of 96 hours) of ASA tablets according to the invention from 8 subjects, the blood samples being taken at the times (hours) indicated. 35 - Fig.3 is a graphic illustration of the results of the test reported in Example 8 and described in connection with Fig.2, indicating the serum ASA levels; k 5 - Fig.4 is a graphical representation of the two-compartment model used to obtain the simulated absorption curves of zero order illustrated in Fig.5 and 6? 5 - Fig.5 is a graphic illustration of the results of a comparison made between a simulated computer curve for zero order ASA absorption (solid line) and the values actually obtained on pre-

Blood samples taken on day 1 of treatment on subject 1 (broken line) of Example 8; and FIG. 6 is a graphic illustration of the results of a comparison carried out between the theoretical value of an absorption of ASA of zero order (solid line) in a second subject and the values actually obtained on blood samples. performed on day 1 of the treatment on subject 2 (broken line) of Example 8. Example 1

Slowly poured 67.3 g of cellulose aceto-phthalate onto the vortex of a mixture of ethanol (denatured; 20,625 ml) and methylene chloride (175 ml) produced by a high speed agitator. Continue to agitate until complete dissolution.

4.375 kg of ASA (0.42 mm crystals; USP) and 0.2255 kg of ÜSP corn starch are broken up through a 25 mesh screen with 0.42 mm opening, dropping them into the bowl of a Hobart mixer. mix the dry powders for 5 minutes at speed # 1. The cellulose aceto-phthalate solution is added to the powders subjected to the mixture, in 30 seconds, while mixing at speed No. 30 1. Mixing is continued for 4 minutes at speed No. 2 in order to cause granulation .

The wet granular mass is poured onto stainless steel trays and air dried until it can be forced to pass through a 35 mesh screen with 0.84 mm opening. After passing through the sieve, the granular product is dried with air, to remove the solvent. The granules are weighed, mixed in ts \ 6 causing them to tilt, and compressed using a conventional rotary tablet press using 12.7 mm flat beveled tools to obtain tablets containing 650 mg of ASA and having a hardness of 5 80 to 100 N (Schleuniger).

Example 2

750 g of cellulose acetate phthalate are slowly poured onto the vortex of a mixture of 3750 ml of methylene chloride and 3750 ml of ethanol. Stirring is continued until complete dissolution.

60 kg of powdered ASA (USP; grain size of 0.177 mm) and 3.0 kg of starch and USP corn are introduced into the bowl of a Littleford MGT 400 mixer. The dry powders are mixed using the rotor speed # 1 for two minutes. The cellulose aceto-phthalate solution is poured continuously onto the powders, while mixing at a speed of rotor no. 1 and a speed of chopper no. After adding the solution, mixing is continued by operating the rotor and the chopper at speed # 2, until an appropriate granular mass is obtained.

The wet granular mass is spread on stainless steel trays and dried in a forced convection oven at a temperature not higher than 49 ° C. The dry granular mass is treated using a Jackson Crockatt granule conversion device carrying a stainless steel screen with a mesh size of 1.19 mm. After the granules of the desired dimensions have dried, they are mixed in a drum mixer for 5 minutes and compressed using a conventional rotary tablet press using a capsule-shaped apparatus in order to obtain tablets containing 800 mg of ASA and having a hardness of 80 to 110 N (Schleuniger). Examples 3 to 6

Four batches of tablets having the compositions indicated in Table 1 are prepared, as described in Example 1. The disintegration time in a buffer at pH 7.5 is determined in accordance with the operating protocol described in

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^ Γ Ό Ό Ό Ό Ό Ό I y ëS 'f £ * p · ρ ο ί τΐ u <; -h u rtl-H <-hu <· _i cj i Çj P, §. 2 § ws &; cosat /) Ea m ë os ft wëa - ^ j 1 -1 6 i ω (uoj XHC m ht m co ^ «U {U -1 8 page 958 of the United States Pharmacopoeia XX, but without disks, and release properties are determined in pH 7.5 buffer as described on page 959 of United States Pharmacopoeia XX, 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 reported in Table 1 which also indicates the results obtained using conventional ASA tablets (exem-10 pie A) as well than tablets (Examples B and C) in which the critical factor is higher than required by the present invention. The dissolution characteristics for Examples 4 and 6 were obtained using another batch of tablets prepared in the same manner as 15 those used for the disintegration tests.

The release properties of tablets prepared as in Example 5 were determined in another test and the results obtained are reported below:

Blood test Acetylsalicylic acid dissolved 20 (hours) (%) 0.5 23.8 1 34.8 2 61.3 3 82.4 25 These results, when plotted on a graph showing time as a percentage acetylsalicylic acid dissolved, give a straight line indicating zero order release. Analysis of the results by linear regression gives a coefficient of corelation 30 of 0.999, compared with a value of 1.0 for the straight line.

The dissolution characteristics of the tablets of Example 3 and of another batch prepared as described in Example 6 are evaluated according to a procedure involving a variation in pH. This is the operating protocol described on page 959 of the United States Pharmacopoeia XX, 9 with the variant described above. The results obtained are reported in Table 2.

Table 2

Time J pH mg of ASA released Cumulative quantity Percentage 5 (hours) initial after the lapse of ASA released from ASA released time (mg) compared to _____the theory | Ex.6 Ex.3 Ex.6 j Ex.3 Ex.6 Ex.3 0- 1/2 1.2 50 46 50 46 7.7 7.1 10 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 degree of chemical degradation which occurs on storage with respect to the tablets according to the present invention is less than that which occurs with conventional ASA compositions. Acetyl salicylic acid degrades to salicylic acid, and this reaction is favored by high temperatures. The reaction is easily carried out and has led the Pharmacopoeia of the USA. to adopt an upper limit of 0.3% for free salicylic acid (FSA) contained in the tablets based on ASA.

Tablets prepared as described in Examples 1 and 5 were titrated to know their content of free cyclic salic acid (FSA) after storage under extreme conditions. The results obtained are reported in Table 3.

TABLE 3

Example Storage time FSA content,% 30 1 0 - 0.04 3 months 40 ° C 0.12 50 - 0.06 6 months 40 ° C 0.14 37 ° C / humidity 35! 75% relative 0.22 _I ____ i-

It is well known that, under similar storage conditions, the limit level of 0.3% of FSA would be exceeded 1 ° by conventional compositions based on ASA.

Tablets prepared as described in Examples 4, 5 and 6 were subjected to a drop resistance test in a "Roche friabilator" device for evaluating the friability. After 100 falls, there is a weight loss of between 0.12 and 0.46%. When the test is extended to 750 drops, the edges of the tablets show signs of wear, but the tablets do not break. A commercially available Aspirin retarded tablet has a weight loss of 0.85% after 100 falls and is very worn out after 750 falls.

Example 7

Serum levels after a single oral dose

Tablets containing 650 mg of ASA are prepared by operating as described in Example 1. A volunteer is made to absorb a single dose of 650 mg orally while two other subjects absorb a single dose of 1300 mg (two 650 mg tablets). Blood samples are taken from each subject, using an indwelling catheter in a vein in the forearm. The blood is collected in a refrigerated "vacutainer" tube at the following times: before taking the drug and after 15, 30, 45 and 60 minutes, and after 1.5, 2.0, 2.5, 3, 0, 4.0, 8.0, -12.0, 16.0 and 24 hours after absorption of the drug. The blood samples are subjected to an analysis of the salicylic acid and acetylsalicylic acid content of the plasma by high pressure liquid chromatography. The results of these measurements are reported in Table 4 and 1 in Fig.l. In Fig.l the results relating to subject no. 1 are indicated by a solid line, those relating to subject 2 by alternating dots and lines, and those relating to subject 3 by a broken line. The x-axis represents time in hours and the y-axis represents the plasma concentration of ASA, in micrograms 35 per ml.

.

11 TABLE 4.

Plasma acetylsalicylic acid and salicylic acid levels within 24 hours

Subject n °: 1 2 3 5 Dose: 1300 mg 650 mg 1300 mg mcg / ml mcg / ml mcg / ml

Study time

(hours) ASA SA ASA SA ASA SA

0 0.1 0.1 0.1 0.1 0.1 0.1 10 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 1.5 0.37 3.19 0.35 1.53 0.71 3.24 15 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 20 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

Serum acetylsalicylic acid levels peak in all three subjects 4 hours after ingestion of the drug. Levels only return to 0.1 mcg / ml after 8 hours. This result should be compared with the established half-life (t = 1/2) of 20 minutes for the serum acetylsalicylic acid level after administration of a standard 650 mg tablet.

30 Example 8

Serum levels after multiple oral doses

ASA tablets prepared as described in Example 1 are administered orally to 8 healthy volunteers, at doses of 1300 mg (2 tablets of 650 mg) twice a day at 0800 and 2000 hours, nine times Then, the last dose being administered at the 96th hour, in order to determine the pharmacodynamic properties in a permanent diet of the ASA tablets according to the invention. Blood samples are taken from the subjects at predetermined time intervals during the study. The blood samples are analyzed by high performance liquid chromatography in order to determine their level of salicylic acid and acetylsalicylic acid. The individual blood levels of salicylic acid and acetylsalicylic acid obtained on the 5th day of the study are reported in Tables 5 and 6. The graphical representation of the average blood levels of salicylic acid and acetylsalicylic acid for the study the whole is shown respectively in Fig. 2 and 3. In these Fig., the values indicated on the x-axis represent the time in hours and the values indicated on the y-axis represent the rates of SA and ASA in the blood, in mcg / ml.

Example 9

Comparison of ASA absorption with a theoretical zero order curve

In order to demonstrate that the in vivo absorption-2Q ption characteristics of the ASA tablets prepared according to the present invention are generally of zero order, the results obtained with subjects 1 and 2 of Example 8 are compared with the results forecast calculated by a computer.

The computer calculations are based on a two compartment model with first order metabolism. The model is shown schematically in Fig. 4. The model assumes that the total dose D is absorbed at one time. constant size kQ over a period of time T. At the end of time T the whole dose will have been absorbed. The model also assumes that 60% of the ASA passes the liver 2 without being hydrolyzed, before passing into a central compartment 3 which has an apparent volume of distribution of 6.3 liters. Acetylsalicylic acid can reversibly pass from the central compartment 3 to the tissues of the organism (indicated in 4) or can be irreversibly eliminated in the form of metabolites (indicated diagrammatically in 5). The speed constants used in / 13.

model and shown in Fig. 4 are those of Rowland and Riegelman, J. Pharm. Sei. Flight. 57, page 1313 (1968).

The time T required for absorption of the entire dose is limited. : the degree of overlap between multiple doses.

5 In Fig. 5, the results obtained with subject no. 1 of Example 8 (broken line) are compared with the curve from the computer (solid line) obtained when T is given a value of 16 hours. The results obtained with subject 2 of Example 8 (broken line) are shown in Fig. 6 and are compared with the curve from the computer (solid line) obtained when T is given a value 6 hours. In Figs. 5 and 6, the values indicated on the x-axis represent the time in hours and the values indicated on the y-axis represent the blood levels of ASA in mcg / ml.

There is reasonable conformity between the experimental and theoretical curves, which demonstrates that, in vivo, the absorption is practically zero order in the case of the ASA tablets prepared in accordance with the present invention.

Example 10

50 g of cellulose acetate phthalate are slowly added to a rapidly stirred mixture of 620 ml of ethanol and methylene chloride. Stirring is continued until a solution is obtained. This solution is added to a mixture of ibuprofen (2- (4-isobutylphenyl) -propionic acid; 2.5 kg), dicalcium phosphate dihydrate supplied under the trade name Emcompress (0.75 kg) and 0.155 kg of starch of corn that have been thoroughly mixed. The wet granular mass is dried in air on stainless steel trays, passed through a 1.41 mm mesh screen and continued to dry to remove all of the solvent.

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The mixture of granules is obtained with a yield of 98.4%. The flow properties of the ëva-5 granules read from Carr (Brit. Chem. Eng., 15, 1541-1549, 1970) are found to be good to fair.

The granules are compressed using a conventional rotary tablet press, using a flat bevel apparatus of 12.7 mm, in order to obtain tablets containing 10 mg of ibuprofen and having a hardness of 80 to 120 N (Schleuniger).

The CF for this example is 155 and the percentages of agent for regulating the release of the active principle and of agent for promoting erosion are respectively 1.44 and 4.46.

Tablets obtained from granules prepared as described above are compressed until different hardnesses are obtained and the resulting tablets are subjected to disintegration tests (Pharmacopoeia of the EUA XX, page 959) in a buffer at pH 7, 5 to 37 ° C.

Hardness J Average de-Schleuniger disintegration time (minutes) 41.4> 235 * 85.4> 275 25 108.6> 240

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

In vitro dissolution tests (Pharmacopoeia of 30 EUA XX swimming 959) show that the tablets of example lô (Schleuniger hardness of 108.6 N) cause a sustained-release release of ibuprofen, when compared with classic ibuprofen tablets. Each test was repeated six times.

35 In the following table, es * "time required for the dissolution of 50% of ibuprofen. The results au_ / '' ..........” · ..... · 16 end of 3 months of storage show that the tablets of the present example have good storage stability.

The results obtained with the tablets of Example 10 not stored give a straight line when the quantity of dissolved ibuprofen is plotted on a graph as a function of time. The linear regression analysis on the results gives a correlation coefficient of 0.996 which indicates a zero order dissolution in vitro.

Γ Amount of ibuprofen dissolved (mg). ! ---- 10 htenps in Classic tablet

State) Example 10 (pH 7.5) fpH 68, i - -: | After 3 months After 3 months

] initial storage at 40 ° C initial storage at 40 ° C

l> _____. ________ 10 - 277 62 15 20 - 318 110 30 68 63 365 163! 60 100 99 383 248 120 169 163 180 219 217 20 240 265 274 t1 / 2 155 153 8.4 41.3

Examples 11 and 12

Tablets containing flurbiprofen (2- (2-fluoro ~ 4-biphenylyl) -propionic acid) are 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 is dried in air, passed through a sieve and dried again so as to remove the organic solvent. Magnesium stearate (0.5% relative to the total weight of the granules) is added and the granules are transformed into tablets. The compositions of Examples 11 and 12 are indicated below:

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APC Ex .il Ex.12 solution

Cellulose aceto-phthalate 9g 8.33 g

Denatured ethanol 60 ml 55 ml

Methylene chloride 60 ml 55 ml 5 Other constituents

Flurbiprofen 300g 100g

Emcompress 240 g 400 g

Corn starch 18.6 g 17.2 g

Weight of flurbiprofen 10 per tablet 300 mg 100 mg

Schleuniger hardness of the tablets (N) 87+ 12 71.4+ 5.4 CF 25 25

Active release agent,% 1.58 1.58 15 Erosion promoting agent,% 3.27 3.27

The average disintegration times of the tablets of Examples 11 and 12 in a buffer at pH 7.5 are determined according to the procedure described on page 958 of the

U.S. Pharmacopoeia XX. The results obtained are shown below:

Ex.11 Ex.12

Average disintegration times (minutes) 300 360 Residue (%) 3.7 4.9 25 The dissolution of flurbiprofen for a certain period of time is evaluated from the tablets of Examples 11 and 12 using the installation described on p. .959 of the USA Pharmacopoeia XX. A phosphate buffer at pH 6.8 is used. The test is repeated 6 times and the average value of the amount of active material released is indicated below:

Time (hours) Percentage of dissolved flurbiprofen

Ex. 11 Ex. 12 1 9.6 10.6 35 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 40 10 74.0 68.5 18

When we carry / on a graph, the percentage of flurbiprofen dissolved as a function of time for each of these series of results, we obtain a straight line which indicates that there is, in each case, a mechanism of order 5 zero . The application of a regression analysis to the results gives a co r elation coefficient of 0.993 for example 11 and 0.999 for example 12.

For comparison, a conventional flurbiprofen tablet, containing 100 mg of flurbiprofen, when subjected to the same test is completely dissolved in approximately one hour.

The tablets of Example 12 are used in a test in which the level of flurbiprofen in the plasma is measured in 4 volunteers after administration of a single dose of drug, the results obtained being reported in columns A of Table 7. The Results obtained with a standard 100 mg flurbiprofen tablet used in a similar trial with the same volunteers are reported in columns B of Table 7. ND indicates that '20 cannot detect flurbiprofen.

_TABLE 7_

Concentrations of flurbiprofen in plasma, ncg / ml

Tenps (hours) Volunteer 1 Volunteer 2 Volunteer 3 Volunteer <

25__A__B A__B A 1 B AB

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 d 5.8 7.2 30 4 4 , 8 6.4 10.3 6.5 7.7 6.0 d 5.3 5.5 5 4.1 4.6 7.3 4.7 5.7 4.8 d 4.5 3.7 6 3.4 3.7 5.6 4.0 4.6 3.7 d 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

35 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

__! - L—-

U

19

Although the above examples illustrate the application of the present invention to various therapeutic agents or oral active medicaments in order to present them in the form of tablets releasing them in a controlled manner over time, The invention is not limited to the presentation in the form of tablets of the medicaments particularly described in the examples.

In this respect, the invention can be very widely varied and applied to presentation in the form of award-winning tablets releasing their active principle in a controlled manner and containing any active drug orally, although particularly suitable for presentation in the form of tablets of acidic drugs, in particular based on acetylsalicylic acid and non-steroidal anti-inflammatory agents of arylalkanoic acid type, including their salts, esters, anhydrides and others derivatives, as previously indicated. These compounds are antipyretic, analgesic and anti-inflammatory agents. As other types of oral active medicaments which can be incorporated into tablets with a delayed or prolonged effect according to the invention, mention will be made of painkillers, stimulants, antibiotics, antispasmodics, nutritional agents, antianemics, anthelmintics , antispasmodics, expectant drugs, hormones of various types, including adrenocorticosteroids, androgenic steroids, estrogenic steroids, progestin steroids and anabolic steroids *, as well as non-steroidal derivatives of the foregoing, psychotonic and anti-viral agents.

l ·

Claims (13)

1. Pharmaceutical composition with prolonged or delayed effect, in the form of tablets, comprising an effective amount of an active therapeutic agent orally, from 0.8 to 1.6% by weight of a regulatory agent for the release of active ingredient and from 1.0 to 7.5% by weight of an erosion-promoting agent, the relative proportions of the constituents being such that a critical factor calculated according to equation I: 1 ° CP = - X 1 / (CS) in which CF represents the critical factor, CA represents the quantity of therapeutic agent per tablet in mg divided by the quantity of release regulating agent per tablet in mg and CS represents the quantity of agent erosion promoter per mg tablet divided by the amount of release regulating agent per mg tablet, between 20 and 450. * 2. Composition according to claim 1, charac-. sée in that the amount of agent regulating the release of the active ingredient is 1.15 to 1.6% by weight and the amount of erosion promoting agent is 2 to 5% by weight . 3. Composition according to claim 1 or 2, characterized in that the critical factor is between 25 50 and 450. 4. Composition according to any one of the preceding claims, characterized in that the critical factor is between 80 and 330. 5. Composition according to any one of the preceding claims, characterized in that the critical factor is between 210 and 330. 6. Composition according to any one of the preceding claims, characterized in that the agent for regulating the release of the active principle is cellulose acetate phthalate, a cellulose acetate derivative, shellac, zein, acrylic resin, ethylcellulose, hydroxypropylmethylcellulose phthalate, sandarague or modified shellac; the erosion promoting agent is corn starch, rice starch, potato starch or other vegetable starches, modified starch, starch derivative, cellulose , a cellulose derivative, modified cellulose, a modified cellulose derivative, alginic acid, an alginate, bentonite, veagum, crosslinked polyvinylpyrrolidone, an ion exchange resin or a gum. 7. Composition according to any one of the preceding claims, characterized in that the agent regulating the release of the active principle is cellulose aceto-phthalate and the agent promoting erosion is 'corn starch. 8. Composition according to any one of the preceding claims, characterized in that the therapeutic agent is acetylsalicylic acid, ibuprofen or flurbiprofen. 9. Composition according to any one of Claims 3, 4 or 5, characterized in that the therapeutic agent is acetylsalicylic acid. 10. Composition according to claim 8 or 9, characterized in that the amount of acetylsalicylic acid is from 650 to 800 mg per tablet. 11. Composition according to claim 8, characterized in that the amount of ibuprofen is 400 to 600 mg * per tablet. 12. Composition according to claim 8, characterized in that the amount of flurbiprofen is 100 to 300 mg per tablet. 13. Process for the preparation of a pharmaceutical composition with long-lasting or delayed effect, in the form of tablets, according to which a mixture of an effective amount of an active oral therapeutic agent and a promoter agent is converted into granules of erosion with a solution of a regulating agent for the release of the principle ^ - ·. te 22 active in an organic solvent, then the resulting granules are pressed into tablets, characterized in that the final tablet contains 0.8 to 1.6% by weight of the agent regulating the release of the active principle, and from 1.0 5 to 7.5% by weight of the erosion-promoting agent and the relative proportions of the constituents are such that a critical factor calculated according to equation I: CF = - I 1 / (CS) Where CF represents the critical factor, CA represents the amount of therapeutic agent per tablet in mg divided by the amount of release agent per tablet in mg and CS represents the amount of erosion promoting agent per tablet in mg divided by the quantity of agent for regulating the release of the active principle per tablet in mg, ie between 20 and 450. VAJvUoj "i