PT85880B - BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for the preparation of delayed-acting pharmaceutical compositions comprising as carrier substance a mixture of microcrystalline cellulose with hydroxypropyl methylcellulose - Google Patents

Abstract

The composition comprises an active agent in admixture with (a) microcrystalline cellulose and (b) hydroxypropyl methylcellulose wherein the weight ratio of (a) to (b) is at least 1 to 1. Aspirin is the preferred active agent.

Description

for

PROCESS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS WITH DELAYED ACTION CONTAINING A MICRO CRYSTALLINE CELLULOSE MIXTURE WITH HYDROXYPROPYL-METHYLCELLULOSE AS A VEHICLE SUBSTANCE

SANDOZ, S.A., Switzerland, industrial, headquartered in Basel, Switzerland.

B ₌ E ₌₌ § ₌ y ₌ ^ ₌ Q

The invention relates to the process for the preparation of a delayed-release pharmaceutical composition, characterized in that a pharmaceutically active agent is mixed with a) microcrystalline cellulose and b) hydroxypropyl methyl cellulose, the weight ratio being between a) and b) at least 1: 1. Aspirin (acetylsalicylic acid) is the preferred active agent.

The present invention relates to delayed-release pharmaceutical compositions.

We found surprisingly that it is possible to

a solid formulation for oral administration of delayed release using microcrystalline cellulose and hydroxypropyl methylcellulose excipients is easily accessible and widely approved.

The invention therefore offers, in one aspect, a delayed-release pharmaceutical composition comprising a pharmacologically active substance in admixture with

a) a microcrystalline cellulose and

b) hydroxypropyl-methylcellulose, the weight ratio between a) and b) being 1: 1, as a minimum.

In another aspect, the invention offers a process for the production of a delayed-release pharmaceutical composition, characterized by the fact that a pharmacologically active substance is mixed with a) microcrystalline cellulose and b) hydroxypropyl methylcellulose, the ratio being in powder form. between a) and b) of 1: 1, as a minimum.

A wide variety of pharmacologically active substances (hereinafter “agents” ’) can be used. Such agents can include water-soluble or water-insoluble compounds, and the agents can be sensitive or insensitive to moisture. The dosage of the agents can vary within wide limits.

- Representative active agents include analgesics, anti-pyretics, anti-inflammatories, antihypertamines, antihypertensives, vasodilators, tranquilizers, anti-depressants, neuroleptics, vasoconstrictors, anti-vasoconstrictors -convulsants, anti-asthmatics, et

The invention is exemplified below with reference. to acetylsalicylic acid (hereinafter ASA), although it should be understood that the invention can apply to any pharmacologically active agent.

Acetylsalicylic acid (ASA) is preferably in the form of the free acid. Alternatively, it may be in the form of a salt, for example a bare sodium salt or a calcium salt. The ASA is preferably present in the form of fine crystals, for example with a particle size of less than 40 meshes, for example from 5 to 40 meshes.

The average cellulose-microcrystalline polymerization number is preferably between approximately 200 and 2000, preferably between 200 and 300. The average molecular weights are preferably from approximately 20,000 to approximately 100,000, for example from 30,000 to 50,000. The average particle size is approximately 5 to approximately 140 microns. The particle size is preferably 20 to 100 microns, for example 80 microns. Conveniently, the specific weight is approximately 1.40 to 1.60. Mierocrystalline cellulose is advantageously obtained by means of mechanical treatment of glucose-based peptisaccharides, for example natural cellulose which has been subjected to an acid treatment.

The preferred firms are those of the AVICEL brand (Registered karce of the FMC company).

The hydroxypropyl-methylcellulose-methoxy content advantageously comprises between approximately 1% and approximately 34% by weight, preferably between approximately 19% and 30%, in particular between 19 and 24% by weight. Preferably, the hydroxypropyl content is approximately 4 to approximately 32% by weight, preferably 4 to 12% by weight.

The viscosity of hydroxypropyl methylcellulose is conveniently from approximately 15 to approximately 50 ° C cps (calculated over a 2 wt% aqueous solution at 20 ° centigrade, for example 4,000 to 50,000 cps.

average molecular weight conveniently is approximately 2,000 to 200,000, for example 90,000 to 130X).

Preferred forms of hydroxypropyl methylcellulose are obtainable under the trademarks Methocel A, K and E marketed by Dow Chemical Company, Michigan,

The weight ratio between microcrystalline cellulose and hydroxypropyl methylcellulose is advantageously between approximately 10: 1 and 1: 1, for example between 3: 1 and 1: 1, for example between 3: 1 and 2: 1.

- Preferably, the weight ratio between microcrystalline cellulose and the active substance is between 1: 5 and 1:10, for example between 1: 6 and 1: 7.5 »in particular between 1: 6.5 and 1 : 7 · The presence of a gelatinised starch is convenient. Preferably, such starch is soluble in cold water up to approximately 5% to 25%, for example from 10% to 2096 in cold water. The previously gelatinized starch is advantageously prepared by means of the starch reaction, preferably corn starch (consisting of 80% of amylopectin clusters and 20% of amylose clusters), in order to break the hydrogen bond-bridge amylose and amylopectin groupings of such corn starch.

The product conveniently contains 60% to 85% - in weight of corn starch, with the remainder being amylose and free amylopectin.

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The weight ratio between the predetermined gelatinized corn starch and hydroxypropyl methylcellulose is preferably between approximately 1: 1 and approximately 1: 5, for example approximately 1: 2.

Other ecipients can be present right away. It may be the excipients commonly used in pharmaceutical formulations, such as anti-friction agents, for example lubricants, such as acid

^_ bare stearic β magnesium stearate, gliding agents, such as silicon dioxide, non-stick agents, soluble fillers, such as lactose, edu: coloring and coloring agents.

The weight ratio between the active substance and all other excipients present is conveniently between approximately 0.2: 1 and approximately 0.4 l, for example between approximately 2: 1 and 4: 1. The hydroxypropyl methylcellulose content advantageously comprises approximately 5 to 10%, calculated on the total weight, for example from 6% to 9%, in particular from 6.5% to 8.5 ·

The pharmaceutical composition is preferably in solid form. It is preferably a unit dosage form. Such a pharmaceutical composition is conveniently in the form of a tablet.

Conveniently, the amount of acetylsalicylic acid (ASA) per unit dose is between 300 and 400 mg or between 600 and 700 mg. Such pharmaceutical compositions can be produced by techniques well known in the art.

The tablets are preferably compressed to a hardness of approximately 8 to 12 kiloponds (based on the Heberlein method).

- The bioavailability of the compositions prepared according to the invention can be determined by known methods.

In a usual test, the pharmaceutical compositions containing the acetylsalicylic acid- (ASA) of the invention are administered at 7 am, 3 pm and 25 am, or at 7 am and 7 pm. Compositions that release ASA immediately are administered at 7 am, 11 am, 3 pm, 7 pm, and 11 pm as reference compositions.

I

Determinations of free et al salicylic acid (SA) are carried out in a manner known per se by means of high-pressure liquid cmmategraphy (HPLC) (essentially as described by Hamson y col in J. Pharm. Sci. (1980) 69, 1268).

Met method for now. determination, from JJA, free.

A sample of heparinized blood is collected. Within the »15 minutes» after the blood is taken, the sinks are separated, divided into 2 portions and introduced into small polypropylene tubes that are closed with colored polypropylene plugs.

Sample »of al is acidified with 1 drop of acid from the phosphoric cone entered during a few minutes, after which they are extracted with toluene / ethyl acetate (5C5O). The extracts are analyzed using high pressure liquid chromatography (HPLC) with phase inversion with UV detection at 305 w using 3,4-dimethoxy-benzoic acid as an internal standard. The method provides a minimum quantifiable level of 0.1 microgram per milliliter of free salicylic acid (SA).

Method for the determination of total total SA is determined from urine as salicylic acid. Each test of 1 ml of urine is mixed with 1 ml of concentrated hydrochloric acid, closed and heated to 98 ° C for 16 hours, after which the tests are allowed to cool. 1 ml of acetonitrile containing the internal standard is added to them »The samples are subjected to HPLC analysis and salicylic acid (SA) is determined by ultraviolet spectroscopy at 313 mm.

The bioavailability tests are carried out advantageously for 8 days, with minimum. Other details can be deduced from the tests described below. As concen

Medium salicylation strains show an unexpectedly high bioavailability of free blood salicylate from the pharmaceutical compositions of the invention, in particular at therapeutic anti-inflammatory levels.

The tests described below show the nullity of the ASA kinetics, since the AUG 0-8 hours for the free salicylate for a dose of 3.9 grams of ASA (130G mg ASA administered 3 times a day in Test A) in a dose of 3.9 d® ASA is disproportionately higher than that for 2.6 g ASA (1300 mg administered twice daily in Trial B). Urine excretion data show that for doses of 2.6 g ASA and 3.9 g ASA, the excretion-cumulation of total SA is similar and dose independent.

These results suggest that at high-doses of ASA in which an anti-inflammatory effect occurs there is a constant saturation of the metabolic access pathways (as demonst the cumulative urine excretion values-regardless of the dose). We found that the concentration of free salicylic acid SA in the plasma increases disproportionately in relation to the dose in high doses of ASA (acetylsalicylic acid) <We believe that this may be due to a combination of the release effect of acetylsalicylic acid (ASA ) unbound and the relationship between o-salicylic acid bound with -a · protein and unalloyed salicylic acid in plasma. When the metabolism is saturable, the release should decrease, but when the protein-binding is saturated, the release-increase. Therefore, the steady state concentration of free salicylic acid may depend on the magnitude of each of the effects mentioned above.

The pharmaceutical compositions of the invention have a longer half-life elimination (for example above 9 hours) than that of immediate release ASA pharmaceutical compositions. In the case of ASA release compositions

/ immediate, large minimum / maximum acid ratios of free salicylic acid may occur, which can cause periods of increased SA metabolism resulting in lower steady state levels.

The pharmaceutical compositions of the invention, on the other hand, provide therapeutic SA concentrations at lower daily doses than immediate release ASA pharmaceutical compositions, and have a lower potential for gastro intestinal irritation.

The pharmaceutical compositions of the invention can be administered for all indications for which the ASA is used, in particular in the treatment of rheumatism pain, arthritis, lumbago, neuralgia, neuritis, sciatica-and bur site (anti-inflammatory indications) , ischemic attacks of fever and brain.

For anti-inflammatory indications, satisfactory results are obtained with a dose of approximately 600 to 1300, for example 650 to 1300 mg of ASA administered every 8 to 12 hours.-The daily doses contemplated are approximately 2.6 and approximately 3.9 g.-The doses indicated as analgesics and anti-pyretics are comprised between approximately 300 and approximately 700 mg, for example from 325 to 650 milligrams. For rheumatic fever, daily doses comprise 100 mg of ASA / Eg body weight which can be administered in divided doses, - every 8 to 12 hours to stop pain, swelling or fever. In ischemic brain attacks, an indicated dose comprises 650 mg given 12 hours.

In another aspect, the present invention offers one with a solid pharmaceutical position intended for oral administration, which comprises at least 3CG mg of acetylsalicylic acid in the form of delayed release and capable of proporeiv

in the steady state by administration of a daily dose of 2.6 g of acetylsalicylic acid, in divided doses, 2 to 3 times a day, at a concentration of ealicylic-free acid in the blood plasma significantly higher than the concentration. ' It is obtained with the administration of the immediate release acetylsalicylic acid tablets administered in an equal daily dose in divided doses administered every 4 hours.

Conveniently, the pharmaceutical composition contains 300 to 700 mg of acetylsalicylic acid (ASA) and has a dissolution rate at 37% in water of between 15 and 40% in one hour, and not less than 70% in 8 hours.

Preferably, between 20 and 3% · are released in one hour. Conveniently, in 8 hours, the release will comprise 70 to 90%, for example 80 to 90%.

The following Examples illustrate the invention.

In the Examples:

Microcrystalline cellulose has a molecular weight of 30,000 to 50,000; an average particle size of 30 to 100 microns; a specific weight of 1.55; a volume of 0.30 to 0.80. The material used was Avicel PE 102 (registered marsa) marketed by KdO Corporatinn, marcus lonk, USA. This material agrees with the las specifications for microcrystalline cellulose in the USF / National Formulai? Y XXI.

Hydroxypropyl methylcellulose 2208 has an average molecular weight number of 12,000; a viscosity of approximately 15,000 cps; 19% - by weight of methoxy content and 4% - 12% by weight of hydroxypropyl content. The brand lúethocel K15i5 Premuim (registered trademark) used by Dow Ohemical Oompany, hichigan, EDA was used. Agrees with the specifications given for hydroxypropylmethylcellulose 2208 in U3P Xxl.

~ Pre-gelatinized starch - β is a modified corn starch which comprises 5% amylose, 15% amylopectin and 8% unchanged corn starch. It is partially soluble in cold water. It used Starch 1500 (registered trademark) material marketed by Qolorcon Inc., West Point, Pennsylvania, USA. Agrees with the specifications given for pregelatinized starch in USP / National Formulary XXI.

colloidal silicon dioxide was Cab-0-Sil- (registered trademark) marketed by Cabet Oorpnration, Boston, Mass. USA. Agrees with the specifications given in I USP / National Formulary XXI.

acetylsalicylic acid ASA was used in the form of 40 mesh crystals. The immediate-release formulation used as a reference in bioavailability tests was Bayer Aspirin (registered trademark).

- Further specifications for the products indicated above can be found in Manufacturer’s brochures and Lexikon der Hilfsstoffe by H.P.Fiedler, 2 &. Edition 1981, Editio Cantor, Aulendorf, EFA.

All other ingredients used are in accordance with USP XXI specifications.

I ΕηηΜΡΙΟ 1: Tablets containing 325 mg, ASA mg / cnmpressed

ASA 525,000

Microcrystalline cellulose 47,500 Hydroxypropyl methylcellulose 27 »625 Pre-gelatinized starch 22,100 Stearic acid 2,125 Colloidal silicon uoxide 0.650

A charge for the preparation of 1 million tablets is prepared as follows:

- The quantities indicated above are multiplied by 1 million, for example, 525 kg of acetylsalicylic acid are used. 50 kg of acetylsalicylic acid are mixed with silicon dioxide, the remaining products ^ acetylsalicylic acid, hydroxypropyl methylcellulose, silicon dioxide / acetylsalicylic acid, microcrystalline cellulose and pregelatinized starch are introduced, - alternately, in a double bushing mixer at 50 feet from nozzles. mix for 15 minutes, then 40 kg of mixture are collected and the remaining mixture is passed through a 2nd mesh stainless steel sieve (opening size: 1.00 mm; wire diameter 0.65 mm) on an oscillating granulator. The 40 kg of the mixture to be sieved is mixed for 5 minutes with stearic acid, then the mixture is sieved through a 2C mesh stainless steel sieve as described above, on an oscillating granulator, and mixing with the previously sieved mixture, mix for 15 minutes in rotating movements to produce a granulate. The granulate is then compressed into tablets in a rotary tablet press.

tablet has a weight of 425 W5J a thickness of 4.68 - 4.85 mm; a hardness of 8-12 kiloponds (Heierer method). Dissolution rate data in cold water at 37 ° C. . _.

(medium term 6 tablets).

A8A release percentage

- Sample 1 Sample 2 hour 25.1 50.3 hours 59.4 45.4 hours 51.2 57, the hours 61.4 65.9 hours 72.5 76.5 hours 80.7 86.6 hours 87.1 95.6

ex ^ flo a

Pills containing 650 WS of ASA segujn

In a manner analogous to that described in Example 1, tablets are produced each containing

tes:

mg / eaten

ASA 650,000

Microcrystalline cellulose 95 »000

Hydroxypropyl methylcellulose55,25

Pre-gelatinized starch44,2c

Stearic acid -4.25

Coloiaal silicon dioxide1,30

Mixing drum size calculated to 500,000 tablets. The resulting tablets each have a weight of 850 mg and a thickness of 6.25 to 6.40 mm.

Compressed speed data) in water at 37 ⁿ ^ · dissolution (mean value 6

Release of ASA%

Sample 1 Sample 2 hour 21.5 26.8 h «ras 34.4 39.9 h * ras 44.2 49.8 hours 53 »4 57.7 hours 66.1 69.0 hours 75.7 77.1 hours 86.9 85.7

TEST A;

Steady state bioavailability of 1300 mg ASA according to the invention, administered 3 times a day

The pharmaceutical composition of the invention described in Example 2 (tablets with 650 mg ASA) - was administered in a dose of 2 tablets to 12 healthy, voluntary men, at 7 am, 15 logs at 23 pm on days 1 - 8, and at 7 am on day 9 »The total daily dose ASA was 3» 9 g ·

A composition with immediate release was administered in a dose of 325 mg tablets every 4 hours from 7 am to 11 pm on days 1 - 8 and at 7 am and 11 pm on day 9 · The total daily dose was 5 »25 g ASA *

Each person who took part in the trial received both formulations in a 9-day study session in any sequence.

wash-out period at the end of the study-session lasted 6 days.

On day 8 in the morning blood samples were taken at 7 am (pre-dose), at 11 am (pre-dose) and on day-9 at 7 am (pre-dose) -and 1, 2, 3, 4 (pre-dose in the case of the immediate release composition) and at 5 »6, 8, 10 and 12 hours after administration at 7 am.

The statistical evaluation for the two formulations on days 8 and 9 indicates that both were in steady state steady state for the bioavailability study that was to be carried out on day 9 · the results obtained in relation to the determination of selicylate

EERENCE free in blood plasma are as follows (R immediate release formulation).

RESULTS Day 9 steady state Mean plasma salicylate concentrations mcg / ml

Time followed by blood taking (hour)

1.00

2.00

3.00

4.00

5.00

6.00

8.00

10.00

12.00

3.9 g / Day

EA1OLC 2 x 650 mg q8h

113.90 + 56.14 *

117.91 + 56.02 *

114.17 + 57.27 *

118.58 + 61.07 *

117.15 + 59.25 *

115.66 + 58.85 *

111.82 + 57.34 *

94.20 + 57.19 *

82.82 + 49.36 *

68.11 + 52.07 *

3.25 g / Day £ OFFER x 325 mg q4h

56.29 + 36.90

68.55 + 37.07

72.53 + 31.12

68.54 + 39.81

54.49 + 32.29

67.02 + 27.50

64.28 +21.55

54.57 + 29.53

41, -94 + 26.46

30.02 +23.23

The two formulations differ statistically at the level of% or higher

Pharmacokinetic evidence for Salicylate in steady-state (day 9) liÀ-uttxPLC 2 x 650 mg qSh

0-8 hr AUC (mcg-hrs / mL) 902.35 + 456.88 * ^ max (mcg / mL) 128.00 + 60.54 * ^T max (hours) 3.08 + 1.51 1/2 (hours) 10.15 + 5.38 * ^K el (hours ” ¹ ) ¹ ) 0.09 + 0.04 *

reference x 325 mg q4h

510.26 + 227.46

83.81 + 33.20

3.42 +1.88

5.00 +2.37 ’

0.17 +0.09 ’m Statistically different at a level of% or higher. Calculation of numbers after the second dose.

1) Relative elimination constant 0-8 hours AUC (%)

Relative C _maXt (%)

177.26 + 57.61

153.18 + 47.92 f tf

Evaluation results «m« w · »· *» · »· *» · »Mm» * ·· * ·

- Statistical evaluation of plasma steady state concentrations in the plasma steady state using appropriate statistical research methods showed significantly higher plasma concentrations for the Example 2 compositions at all times »0 increase in salicylate levels free in plasma is higher than expected even when administered - at a dose of 3.9 g of the reference formulation. The statistical evaluation showed that the average AUO 0-8 hours and the ^C max. mean values were significantly higher for the formulation of Example 2. c adjusting the mean-AUG 0-8 hours in a 3 »9 g / dose for each product provides an estimated relative availability of the formulation of the invention shown in Example 2 of 147 / in comparison with the reference position. The formulation of temple 2 prepared according to the invention showed a significantly broader half-life value and a reference IL. . ⁶¹ smaller than the composition The total urine salicylate concentration was measured for 24 hours on day-9. The results obtained for the reference composition were 216> 97 + 572.16 mg. hese _the values are similar.

TEST B;

Stable bioavailability of 1300 mg ASA according to the invention administered twice daily

The formulation of Example 2 (650 mg ASA tablet) was administered in doses of 2 tablets each time to 6 healthy men, volunteers. J from such volunteers had completed the previous Essay A, in which they had received a dose at 7 am and another at 7 pm for 8 days with a final dose at 7 am on day 9 · The total daily dose? .

of ASA comprised 2.6 g.- The protocol was the same as that discussed above, except for the lower dose.

The statistical evaluation of day 8 and day 9 rn ^ strí. etate was reached on day 9 «results obtained up to 12 hours after admj, active substance, are listed below!

that steady

Time followed by blood taking (hour)

1.0

2.0

3.0

4.0

5.0

6.0

8.0

10.0

12.0

Day 9 (steady state) Average concentration of Salicylate m plaema Example 2 x 650 mg q! 2h.

49.70

54.82

58.72

62.19

59.90

55.37

55.18

47.22

42.98

34.72

21.16

22.75

22.53

23.31

23.18

25.84

22.04

24.77

24.19

20.09 +

i +

± +

+ +

+ ♦

+

The 0-8 hour AUC was calculated as

446 + 182.46 mcg-hours / ml.

C _mav . 64.11 + 21.78 (mcg / ml).

IH&JC a ***

The results show that the 2.6 g dose of ASA administered in doses of 1 JCO mg ASA, twice a day, in a formulation according to the invention, offers free plasma levels of free de-salicylate comparable to those immediate release formulations in a dose of 3.25 g ASA, administered in doses of 65C mg ASA 5 times a day.

Total urine SA concentrations were also measured over 24 hour time periods. The total cumulative portion of SA was 1 $ 22 + 162 mg. This value is similar to the values found in Test A.

7 /

Claims (4)

1§. - process for the preparation of a delayed-release pharmaceutical composition, characterized by the fact that a pharmacologically active agent is mixed with * a) cellulose-microcrystalline and b) with hydroxypropyl methylcellulose, the weight ratio being between a) and b ) ual i _o at least 1 to 1. 2e. Process according to claim 1, characterized in that the active agent is acetylsalicylic acid. 3rd. Process according to claim 2, characterized in that unit dosage forms of _t are prepared which contain from 3op to 700mg of acetylsalicylic acid. air. Process for the preparation of a composition according to claim 3, characterized in that the amount of acetylsalicylic acid is 525 mg. - 5-. Process for the preparation of a composition according to claim 3, characterized in that the amount of acetylsalicylic acid is 65%. õ £. Process for the preparation of a composition according to any one of claims 1 to 5, characterized in that the microcrystalline cellulose has an average polymerization number between approximately 2CO and 2,000. 7. A process for the preparation of a composition according to any one of claims 1 to 6, characterized in that the average molecular weight of microcrystalline cellulose is approximately 2% CCO to 100,000. ^- --83.- process for the preparation of a composiçãr according to any of claims 1 to 6, characterized in that the average molecular weight of microcrystalline cellulose is approximately 3C 000-50000. Process for the preparation of a composition according to any of claims 1 to 8, characterized in that the density of the microcrystalline cellulose is comprised between 1.4C and 1.60. -103. Process for the preparation of a composition according to any one of claims 1 to 9, characterized in that the methoxy content of hydroxypropylmethylcellulose is approximately 14% to approximately 34% by weight. -lis. - process for the preparation of a composition according to any of claims 1 to 10, characterized in that the methoxy content of hydroxypropyl methylcellulose is from 19% to 24% by weight. -12 ». Process for the preparation of a composition according to any one of claims 1 to 11, characterized by | characterized by the fact that the hydroxy content of hydroxypropyl-me. Tylcellulose will be approximately 4% to approximately 32% by weight. -133. - For the preparation of a composition according to any one of claims 1 & 12, characterized in that the hydroxy content of hydroxypropyl-m-tylcellulose is approximately 4% to approximately 12% by weight. -14½. Process for the preparation of a composition according to any one of claims 1 to 12, characterized in that the viscosity of the hydroxypropyl methylcellulose is approximately 15 cps to approximately 5 000 000 cps (measured in an aqueous solution to 2% by weight, to 202. centrifuged). · -15 ^to - Process for the preparation of a composition, according to claim 14, characterized by the fac, to the viscosity of the methylcellulose hydroxypropyn-opil COO be 4 50 000 cps. 16s ?. Process for preparing a composition according to any one of claims 1 to 15, characterized in that the average molecular weight of hydroxypropyl methylcellulose is approximately 2 ^A 000 to 200 000. 17 *. - process for the preparation of a composition according to any of claims 1 to 16, characterized in that the average molecular weight of hydroxypropyl methylcellulose is 9C 000 to 130 000. lQê. - process for preparing a composition according to any of claims 1 to 17, characterized in that the weight ratio between microcrystalline cellulose and hydroxypropyl methylcellulose is comprised between 10: 1 and 1: 1. -19®. Process for the preparation of a composition according to any of claims 1 to 18, characterized in that the weight ratio between microcrystalline cellulose and hydroxypropyl methylcellulose is 3; ]. to 1: 1. Process for the preparation of a composition according to any of claims 1 to 19, characterized in that the weight ratio between the microcrystalline cellulose and the active agent is comprised between 1: 5 β ι; 10. 21a. Process for the preparation of a composition according to any one of claims 1 to 2, characterized in that the weight ratio between the microcrystalline cellulose and the active agent is between 1; 6 and 1: 7.5. • 22 *. Process for the preparation of a composition according to any of claims 1 to 21, characterized in that it comprises gelatinized starch. -2js. Process for the preparation of a composition according to any one of claims 1 to 22, characterized in that the weight ratio between the previously gelled starch and the hydroxypropyl methylcellulose is between approximately 1: 1 and approximately 1 : 5. -24fc. Process for the preparation of a composition according to any one of claims 1 to 2, characterized in that the weight ratio between the active agent and all other excipients present is between 2; 1 and 4: 1. 25- · --process for the preparation-of a com; The composition according to any one of claims 1 to 24, characterized in that it is in the form of a tablet obtained by compression to a hardness of approximately 5.6 to 5 »4 kilograms. 261. - Process for the preparation of a solid pharmaceutical composition-intended for administration-orally, characterized by the fact that it comprises at least 5 <* C · mg of acetylsalicylic acid (ASA) in the form of delayed release and being able to provide a stationary staircase