LU87009A1 - SUSTAINED RELEASE PHARMACEUTICAL COMPOSITIONS - Google Patents

Description

'......' rRA \ D -: ./ .'F: Ϊ.ΓΛΞ, FOT .. 'RG

i .-.! **> * M. nFeur k NFFsire; ”R ..., .¾¾ - · '· * ~ i' ·’ 'V-t. ·> ,? £; . y ·· ^ ... of: Τ. ·: ο. · .ττ, =: e; desQassesMc * ennes ....... . j ζρ: -Ζ. ·: ζί5 Sr ~ L? Intellectual Property

..W * rc - I ö LUXEMBOURG

(σ 4 <££ T

Patent Application --r - ^ & z. .......................... ........................ .................................................. ... ............................................... .................................................. ........... / 3) I. Request

The company known as: SANDOZ S .A., Lichtstrasse 35, ΏΡ-4002 Basel, Switzerland ".} Represented by Mr. Louis EMRINGER, lawyer, residing in Luxembourg., Acting in his capacity as agent__________ - ........ .............-................................ — ... ..............------------------------------------ ---------------------------------------------------------- -----------------------------------— (3) deposit (s) this ... if x oc tobre .1 9 ü 0 - qua tr e - vinq t-sept __________________________________________________ {4¾ at ................... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: L this request for obtaining a patent for an invention concerning: - ............................. .................................................. .......................................... — ....... ..................-.....—------------------------- ---------------------------- (5) ................... ... Compositions ..... pharmaceuticals ...... â ... Ί i bérati on pfol o ngêe ______________________________ ______ 2. description in language _______________ ____________________ of the invention in triplicate; 3 ............................. / / .................. drawing boards, in triplicate; 4. the receipt of the taxes paid to the Registration Office in Luxembourg, 6 ._ .. Q..C..t 0 b.I e ._. L 987 .........; 5. the delegation of power, dated ......... JËîËËë ................._............. ................. on ......... September 30, 198? 6. the successor document (authorization); claims (s) for the above patent application the priority of one (s) request (s) from {7) ._...................... ................................? re.vet: ............. ......................................: ......... filed ( s) in (8) ....._________________________ on (9) ... 9. October 1986 _______ under N ° (10) ............ ^ 6? 4213 ... .................................................. ... ................................. .............. ...... ......................

on behalf of (11) SANDOZ CANADA INC. , Dorval, Quebec H9R 4P5, Canada élitf elect) domicile for him (her) and, if designated, for his agent, in Luxembourg 141., Mr. £ .. Albert.

A den 2..6.5.2 Luxembourg ........................ - ................ .................................................. ......... (32 s requests (s) the grant of a patent for the invention for the subject described and represented in the abovementioned appendices, with postponement of this grant to ....... ..... six ................... ......................... ......................................... months. <13)

The depositor / agent: ......... r ^ ro ..... Κ ...... Λ ...... .............. .................................................. ........ /.'4; ^ ~ II. Deposit Minutes

The above application for a patent for invention has been filed with the Ministry of the Economy and Middle Classes. Intellectual Property Service in Luxembourg, dated: & npr ““ tiU, ι88ί ·.

___ 'V * G; . ’· Pr. The Minister of Feconomics and the Middle Classes.

\; at ......................... hours' / - V jf. d. / I £ VF rfLFT 'e | The head of the department Intellectual property.

A0l K * 2® “· _ï> y ·; -— · i___________________ l / \ _________ EXPLANATIONS RELATING TO THE FORM!> £ EFF./·* v 'Ί:; b iiju "Dernandc de certiiroat ut ^.-V -., cv · ·.: fv · ύ. faeve;; vi:. ^; palNo ............ dtl ..... ...... ~ ~ C2 r. Ie r .-. R * r. - y ~: dud ^ naîiiit'Ur. When ceiip-wi ς ·> ':; · - *. -.- ». R1 - ~ * laughs. "bric suedrose of the social siect, when I cicnanûcuî c" - _ir ..: '-_ T -..- rru. v.sz = xz -' 100-6970 CLAIMING THE PRIORITY of the patent application

In Great Britain_

October 9, 1986_

DESCRIPTIVE MEMORY

filed in support of an application for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: Pharmaceutical compositions with sustained release

The present invention relates to new sustained release pharmaceutical compositions.

The Applicant has surprisingly found that solid sustained release formulations 5 which can be administered orally, using already available and well known excipients, microcrystalline cellulose and hydroxypropyl methylcellulose, can be prepared.

The subject of the present invention is therefore a sustained-release pharmaceutical composition comprising a pharmacologically active substance in combination with a) microcrystalline cellulose and b) hydroxypropyl methylcellulose, the weight ratio of component a) to component b) being at least 1 to 1, with the proviso that the active substance is also in association with pregelatinized starch when the active substance is other than acetylsalicylic acid in free form or in the form of a salt.

In the pharmaceutical compositions of the invention, a wide variety of pharmacologically active substances can be used. They may be soluble or insoluble compounds in water. These substances may or may not be sensitive to moisture. The dose of active substance in the pharmaceutical compositions of the invention can vary within wide limits.

Representative active substances include analgesics, antipyretics, antiinflammatories, antihistamines, antihypertensives, vasodilators, tranquilizers, antidepressants, neuroleptics, vasoconstrictors, antispasmodics, antiasthmics, etc.

The invention is illustrated below with reference to acetylsalicylic acid, but it goes without saying that it can be applied to any other active substance.

Acetylsalicylic acid is preferably in the form of free acid; it can also be in the form of a salt, for example a sodium or calcium salt. The acetylsalicylic acid is preferably in the form of fine crystals, for example having a particle size less than 40 mesh, 2 ranging for example between 5 and 40 mesh.

The average degree of polymerization of the microcrystalline cellulose is preferably between approximately 200 and 2000, more preferably between 200 and 300. The preferred average molecular weights are between approximately 20,000 and approximately 100,000, for example between 30,000 and 50,000. The average particle size is preferably between about 5 and about 140 microns.

The particle size is preferably between 20 and 100 microns, for example 80 microns. The specific mass is advantageously between approximately 1.40 and 1.60. Microcrystalline cellulose is advantageously obtained by mechanical treatment of glucose-based polysaccharides, for example natural cellulose, optionally with acid treatment. The preferred forms are those sold under the trademark AVICEL 15 by FMC Corporation.

The content of methoxy groups in hydroxypropyl-methyl-cellulose is advantageously between approximately 15 and approximately 34% by weight, more preferably between approximately 19 and 30, particularly between 19 and 24% by weight. The content of hydroxypropyl groups is preferably between about 4 and about 32% by weight, more preferably between 4 and 12% by weight.

The viscosity of the hydroxypropyl methylcellulose is advantageously between approximately 15 and approximately 50,000 cps (2% by weight aqueous solution at 20 degrees centigrade), for example between 4000 and 50,000 cps.

The average molecular weight is advantageously between approximately 20,000 and 200,000, for example between 90,000 and 130,000.

The preferred forms of hydroxypropyl methylcellulose are those sold under the trademarks Methocel A, K and E by DOW Chemical Company, Michigan, USA.

»3

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

The weight ratio of microcrystalline cellulose to the active substance is preferably between 1: 5 and 1:10, more preferably between 1: 6 and 1: 7.5, in particular between 1: 6.5 and 1: 7 . Advantageously, pregelatinized starch is present. The starch is advantageously soluble up to a percentage of between 10 approximately 5 to 25, for example between 10 and 20% by weight in cold water. The pregelatinized starch is obtained by modification of the starch, preferably corn starch (based on 80% of amylopectin residues and 20% of amylose residues) in order to break the hydrogen bond between the residues amyloidosis and amylopectin. The product advantageously contains from 60 to 85% by weight of corn starch, the remainder consisting of free amylose and tamylopectin.

The weight ratio of pregelatinized starch to hydro-xypropyl-methylcellulose is preferably between approximately 1: 1 and approximately 1: 5, and is for example approximately 1: 2.

Other excipients can also be present in the compositions of the invention. They may be excipients usually used in pharmaceutical formulations, such as anti-friction agents, for example lubricants such as stearic acid or magnesium stearate, and flow agents such as silica, anti-adhesion agents, soluble fillers such as lactose, flavoring agents and colorings.

4

The weight ratio of the active substance to the other excipients present is advantageously between approximately 0.2: 1 and approximately 0.4: 1, more preferably between approximately 2: 1 and 4: 1. The hydroxypropyl methylcellulose content is advantageously between 5 and 10% of the total weight of the formulation, for example between 6 and 9 Si, in particular between 6.5 and 8.5%.

The pharmaceutical composition of the invention is preferably in solid form. It is preferably in the form of a unit dose, advantageously in the form of tablets. The amount of acetylsalicylic acid per unit dose is advantageously between 300 and 400 mg or between 600 and 700 mg.

The pharmaceutical compositions of the invention can be prepared according to methods known in the art, by mixing the active substance with components a) and b) and optionally the other excipients.

The tablets are obtained by compression, making it possible to reach a hardness preferably between approximately 8 and 12 kg (determined according to the Heberlein method).

The bioavailability of the compositions of the invention can be determined according to the usual methods.

In a typical test, the pharmaceutical compositions based on acetylsalicylic acid of the invention are administered at 7:00 a.m., 3:00 p.m., 11:00 p.m. or 7:00 a.m. and 7:00 p.m. . The immediate release compositions of acetylsalicylic acid are administered at 7 a.m., 11 a.m., 3 a.m., 7 p.m. and 11 p.m. as reference formulations.

Free and total salicylic acid can be determined according to the usual methods, by liquid chromatography (HPLC, essentially as described by Hamson et al., In J. Pharm. Sci. (1980) 69 1268).

5 Γ Method for detecting free T salicylic acid

Heparinized blood samples are collected. Within 15 minutes of drawing the blood, the plasma is distributed in two polypropylene tubes sealed with colored and coded poly-5 propylene caps.

For a few minutes, 0.5 ml samples are acidified with 1 drop of concentrated phosphoric acid and extracted with toluene / ethyl acetate (50:50). The extracts are analyzed by reverse phase liquid chromatography (HPLC) with phase 10 detection at 305 mm UV using 3,4-dimethoxy benzoic acid as internal standard. The method gives a minimum quantifiable rate of 0.1 micrograms per ml of free salicylic acid.

Total Salicylic Acid Detection Method Total salicylic acid is determined from the urine as salicylic acid. Each 1 ml urine sample is mixed with 1 ml concentrated hydrochloric acid, the mixture is sealed and heated for 16 hours at 98 ° C. The sample is allowed to cool. 1 ml of acetonitrile containing the internal standard is added. The samples are subjected to analysis by liquid chromatography (HPLC) and the salicylic acid is detected by UV spectroscopy at 313 mm.

The bioavailability tests are preferably continued for at least 8 days. Other details are revealed at the end of the tests described below. The average salicylate concentrations determined reveal a high and unexpected availability of free salicylate in the blood with the pharmaceutical compositions of the invention, in particular at therapeutic levels as an anti-inflammatory.

The tests as described below show a non-linear kinetics of acetylsalicylic acid since the AUC (area under the curve) from 0 to 8 hours of free salicylate for a dose of 3.9 g of acetylsalicylic acid (1300 mg of acetylsalicylic acid administered 3 times a day in trial A) is disproportionately higher than for a dose of 2.6 g 6 of acetylsalicylic acid (1300 mg administered 2 times a day in test B). Data on urine elimination show that for doses of 2.6 g acetylsalicylic acid and 3.9 g acetylsalicylic acid, the cumulative elimination of total salicylic acid is similar and independent of the dose.

These results suggest that at high doses of acetylsalicylic acid in which the anti-inflammatory effect is manifested, a constant saturation of the metabolism occurs (as indicated by the cumulative urine elimination values which are independent of the dose). We have found that at high doses of acetylsalicylic acid, the concentration of free salicylic acid in the plasma increases disproportionately with respect to the dose. This may be due to a combination of the clearance effect of unbound acetylsalicylic acid and the ratio of protein bound salicylic acid to unbound salicylic acid in plasma. When the metabolism can be saturated, the clearance effect should decrease, but when the protein binding is saturated, the clearance effect increases. Therefore, the steady-state concentration of Tiber salicylic acid may depend on the magnitude of each of these two effects.

The pharmaceutical compositions of the invention have a longer elimination half-life (for example greater than 9 hours) than that of the immediate-release pharmaceutical compositions of acetylsalicylic acid. In the case of immediate-release acetylsalicylic acid compositions, large differences in the ratio of free salicylic acid may occur which can cause periods of increased metabolism of salicylic acid resulting in lower levels of d 'balanced. The pharmaceutical compositions of the invention, on the other hand, give therapeutic concentrations of salicylic acid, at lower daily doses than the pharmaceutical compositions of immediate-release acetylsalicylic acid, and have a lower potential for gastrointestinal irritation. .

7

The pharmaceutical compositions of the invention can be administered for all the indications for which acetylsalicylic acid is recommended, in particular rheumatic pain, arthritis, lumbago, neuralgia, neuritis, sciatica and bursitis (anti indications -inflammatory), fever and ischemic attacks of the brain.

For indications as an anti-inflammatory, a dose of between about 600 and 1300 mg, for example between 650 and 1300 mg of acetylsalicylic acid every 8 to 12 hours gives satisfactory results. The appropriate daily doses are between about 2.6 and about 3.9 g. The recommended doses for an analgesic and antipyretic effect are between approximately 300 and approximately 700 mg, for example between 325 and 650 mg. For action against rheumatic fever, daily doses of 15,100 mg of acetylsalicylic acid / kg can be administered in divided doses every 8 to 12 hours to combat pain, swelling and fever. For ischemic attacks of the brain, the indicated dose is 650 mg every 12 hours.

According to another aspect, the subject of the invention is a solid pharmaceutical composition which can be administered orally comprising at least 300 mg of acetylsalicylic acid in a sustained-release form which, after administration of a daily dose of 2.6 g of acetylsalicylic acid in divided doses 2 to 3 times a day, may give steady state 25 free salicylic acid plasma levels higher than those obtained at steady state after administration of tablets. immediate release acetylsalicylic acid at the same daily dose and in fractional form every 4 hours.

The pharmaceutical composition advantageously contains a dose of acetylsalicylic acid of between 300 and 700 mg and has a dissolution rate in water at 37 ° C of between 15 and 40% after one hour and greater than 70% at after 8 hours.

Preferably, 20 to 35% of the active substance is released after one hour, and more preferably from 70 to 90%, for example from 80 to 90% are released after 8 hours.

8

The following examples illustrate the present invention without in any way limiting its scope.

In these examples, the microcrystalline cellulose has a molecular weight of between 30,000 and 50,000; the average particle size is between 30 and 100 microns; the specific mass is 1.55; the packing volume is between 0.30 and 0.80; the product used is marketed under the brand Avicel PH 102 by the company FMC, Marcus Hook, USA. It meets the prescriptions given for the one dares microcrystalline 10 in the American Pharmacopoeia USP XXI.

Hydroxypropyl-methylcellulose 2208 has an average molecular weight of 120,000; the viscosity is approximately 15,000 cps; the content of methoxy groups is between 19 and 24% and the content of hydroxypropyl groups is between 4 and 12%; the product used is that sold under the brand Methocel K15M Premium by the company Dow Chemical, Michigan, USA. It meets the prescriptions given for hydroxypropyl-methylcellulose 2208 in the American Pharmacopoeia USP XXI.

The pregelatinized starch is a modified corn starch and comprises 5% amylose, 15% amylopectin and 80% unmodified corn starch. It is partially soluble in cold water. The product used is marketed under the brand Starch 1500 by the company Colorcon Inc., West Point, Pennsylvania, USA. It meets the prescriptions given for pregelatinized starch in the American Pharmacopoeia USP XXI.

Colloidal silica is that sold under the brand name Cab-0-Si1 by the company Cabot Corporation, Boston, Mass.

USA. It meets the prescriptions given in the American Pharmacopoeia USP XXI.

The acetylsalicylic acid used has 40 mesh crystals. The immediate-release formulation used as a reference in the bioavailability tests is marketed under the brand Aspirin by the company Bayer.

Further information for the above products is available in the manufacturers' brochures and in Lexikon der Hilfsstoffe by H.P. Fiedler, second edition 1981, Edition Cantor, Aulendorf, Federal Germany.

All the other products used meet the pres-5 criteria given in the American Pharmacopoeia USP XXI.

EXAMPLE 1: £ oms_s à 32_5_mçj_ d / ^ cjde acetalsalicylic mg / tablet

Acetylsalicylic acid 325,000

Microcrystalline cellulose 47,500 10 Hydroxypropyl-methylcellulose 27,625

22,100 pregelatinized starch

Stearic acid 2.125

Colloidal silica 0.650

The batch for preparing 1 million tablets is formulated as follows:

The above quantities are multiplied by 1 million, for example using 325 kg of acetylsalicylic acid. 50 kg of acetylsalicylic acid are mixed with the silica. The remaining acetylsalicylic acid, hydroxypropyl methylcellulose, silica / acetylsalicylic acid, microcrystalline cellulose and pregelatinized starch are introduced into a mixer of about 850 liters. Mix for 15 minutes. 40 kg of the mixture are then removed. The remainder of the mixture is passed through a 20 mesh stainless steel screen (opening size: 1.00 mm; wire diameter: 0.63 mm) over an oscillating granulator. The 40 kg of the unsifted mixture is mixed for 5 minutes with stearic acid, passed through a 20 mesh stainless steel sieve as described above with the oscillation granulator and added to the previously sieved mixture . It is mixed by free fall for 15 minutes so as to obtain granules. The granule is then transformed into tablets using a rotary machine intended to manufacture tablets. Tablets of 425 mg are obtained, with a thickness of between 4.68 and 4.85 mm, and of hardness between 8 and 12 kg (Heberlein method).

10

Dissolution in water at 37 ° C (average of 6 tablets): Percentage of acetylsalicylic acid release Lot 1 Lot 2 1 hour 23.1 30.3 5 2 hours 39.4 45.4 3 hours 51.2 57 , 0 4 hours 61.4 65.9 6 hours 72.5 76.5 8 hours 80.7 86.6 10 12 hours 87.1 93.6 EXAMPLE 2: 650 mg d / acetic acid '£ yJM £ ue

Similar to that described in Example 1, tablets are prepared each containing: mg / tablets Acetylsalicylic acid 650.00

Microcrystalline cellulose 95.00

Hydroxypropyl-methylcel1ulose 55.25

Pregelatinized starch 44.20

Stearic acid 4.25 20 Colloidal silica 1.30

The batch includes 500,000 tablets. The resulting tablets each have a weight of 850 mg and a thickness of between 6.25 and 6.40 mm.

Dissolution in water at 37 ° C (average of 6 tablets): 25 Percentage of acetylsalicylic acid release

Lot 1 Lot 2 1 hour 21.5 26.8 2 hours 34.4 39.9 3 hours 44.2 49.8 30 4 hours 53.4 57.7 6 hours 66.1 69.0 8 hours 75.7 77.1 12 hours 86.9 85.7 11

Test A:

BiodispondibiUté at steady state of 1300 mg of acetylsalicylic acid in the form of a pharmaceutical composition according to the invention, administered 3 times a day. The pharmaceutical composition of the invention is administered as described in Example 2 (tablet .a 650 mg of acetylsalicylic acid) has 12 healthy male volunteers, 2 tablets at 7 am, 3 pm and 11 pm from the 1st to the 8th day and at 7.10 am on the 9th day. The total daily dose is 3.9 g of acetylsalicylic acid.

An immediate release formulation is administered in the form of tablets dosed at 325 mg at a rate of 2 tablets every 4 hours from 7 am to 11 pm in the evening from the 1st to the 8th day 15 and at 7 am and 11 am morning of the 9th day. The total daily dose is 3.25 g of acetylsalicylic acid.

Each patient receives both formulations in a 9-day study in a randomized fashion. The elimination period at the end of the study is 6 days.

20 Blood samples are taken on the 8th day at 7 am (pre-dose) and at 11 am (pre-dose) and on the 9th day at 7 am (pre-dose) and 1, 2, 3, 4 (pre-dose in the case of an immediate release formulation), 5, 6, 8, 10 and 12 hours after the administration of the drug at 7 am.

The statistical evaluation obtained for the two formulations on the 8th and the 9th day indicates that the two have reached steady state for the bioavailability study carried out on the 9th day.

The results of the determinations of free plasma salicylate are as follows: (REFERENCE = immediate release formulation): - 12 Results: 9th day (steady state)

Average salicylate concentrations in blood plasma (mcg / ml) 5 3.9 g / day 3.25 g / day

Blood test EXAMPLE 2 REFERENCE

_ (hour) _ 2 x 650 mg / 8 hours 2 x 325 mq / 4 hours 0 113.90 ± 56.14 * 56.29 ± 36.90 1 117.91 ± 56.02 * 68.55 ± 37, 07 10 2 114.17 ± 57.27 * 72.53 ± 31.12 3 118.58 ± 61.07 * 68.54 ± 39.81 4 117.15 ± 59.25 * 54.49 ± 32.29 5 115.66 ± 58.85 * 67.02 ± 27.50 6 111.82 ± 57.34 * 64.28 ± 21.55 15 8 94.20 ± 57.19 * 54.57 ± 29.53 10 82.82 ± 49.36 * 41.94 ± 26.46 12 68.11 ± 52.07 * 30.02 ± 23.23 * The two formulations differ statistically by 5% or more. Pharmacokinetic indices for steady state salicylate 20 (9th day)

EXAMPLE 2 REFERENCE

2 x 650 mq / 8 hours 2 x 325 mq / 4 hours AUC 0-8 hours 902.35 ± 456.88 * 510.26 ± 227.46 (mcg-hours / ml) 25 Cmax (mcg / ml) 128, 00 ± 60.54 * 83.81 ± 33.20

Tmax (hours) 3.08 ± 1.51 3.42 ± 1.88 ti / 2 (hours) 10.15 ± 5.38 * 5.00 ± 2.37 "

Kei (hours -1) 1) 0.09 ± 0.04 * 0.17 ± 0.09 "* Statistical difference of 5% or more.

30 "Calculated on the figures after the second dose.

1) Constant elimination of AUC relative between 0 and 8 hours {%) 177.26 ± 57.61

Relative Cmax (%) 153.18 ± 47.92 13

Evaluation of the results The statistical evaluation of the steady-state salicylate concentrations in the blood plasma using the appropriate statistical tests reveals significantly higher plasma concentrations for the formulation of Example 2 at each time. The increase in free plasma salicylate levels is greater than expected even if a dose of 3.9 g of the reference formulation is administered. The statistical evaluation shows that the mean AUC from 0 to 8 hours and the mean Cmax are significantly higher for the formulation of Example 2. The adjustment of the mean AUC from 0 to 8 hours to a dose of 3.9 g for each product gives a relative bioavailability of the formulation of Example 2 of the invention estimated at 147% of that of the reference product. The formulation of Example 15 2 of the invention has a significantly longer half-life and a

Kei weaker.

The total concentration of salicylate in the urine is determined over a 24-hour period on the 9th day. The values obtained for the formulation of Example 2 are 1488.42 ± 20.531.08 mg and 1265.97 ± 572.16 mg for the reference formulation. These values are similar.

Test B:

Bioavailability at steady state of 1300 mg of acetylsal.y-cylic acid in the form of a pharmaceutical composition according to Tin-25 vention, administered twice a day

The formulation of Example 2 (650 mg tablet of acetylsalicylic acid) is administered to 6 healthy male volunteers (three of them participated in trial A above) at the rate of 2 tablets of 7 in the morning and 7:30 a.m. for 8 days with a final dose at 7 a.m. on the 9th day. The total dose of acetylsalicylic acid is 2.6 g. The protocol is identical to that described above, except for the lower dose.

Statistical evaluation on the 8th and 9th day indicates that the steady state is reached on the 9th day.

»14 4

The results obtained over a period of 12 hours after the administration of the drug are indicated below: 9th day (steady state) average concentration of salicylate in the blood plasma (mcg / ml)

Blood sample Example 2 _ (hour) _ 2 x 650 mg / 12 hours 0 49.70 ± 21.16 1 54.82 ± 22.75 10 2 58.72 ± 22.53 3 62.19 ± 23.31 4 59.90 ± 23.18 5 55.87 ± 25.84 6 55.18 ± 22.04 15 8 47.22 ± 24.77 10 42.98 ± 24.19 12 34.72 ± 20.09 L 'AUC from 0 to 8 hours is 446 ± 182.46 mcg / hour / ml. The Cmax is 20 of 64.11 ± 21.78 (mcg / ml).

The results indicate that a dose of 2.6 g of acetylsalicylic acid administered at the rate of 1300 mg twice a day in the form of a formulation according to the invention gives free plasma salicylate levels comparable to a dose of 3 , 25 g 25 acetylsalicylic acid administered at a rate of 650 mg 5 times a day in the form of an immediate-release formulation.

Concentrations of total salicylic acid in the urine are also determined over a 24-hour period. The cumulative total salicylic acid is 1322 ± 162 mg. This value is similar to the values found in test A.

Claims (23)

15 1. A sustained release pharmaceutical composition, characterized in that it contains a pharmacologically active substance in combination with a) microcrystalline cellulose and b) hydroxypropyl methylcellulose, the weight ratio of component a) to component b ) being at least 1 to 1, with the proviso that the active substance is also in association with pregelatinized starch when the active substance is other than acetylsalicylic acid in free form or in the form of a salt. 2. A pharmaceutical composition according to claim 1, characterized in that the active substance is acetylsalicylic acid. 3. A pharmaceutical composition according to any one of claims 1 or 2, characterized in that it is in the form of tablets. 4. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that the amount of acetylsalicylic acid per tablet is between 300 and 700 mg. 5. A pharmaceutical composition according to claim 20 4, characterized in that the amount of acetylsalicylic acid is 325 mg. 6. A pharmaceutical composition according to claim 4, characterized in that the amount of acetylsalicylic acid is 650 mg. 7. A pharmaceutical composition according to any one of claims 1 to 6, characterized in that the microcrystalline cellulose has an average degree of polymerization of between approximately 200 and 2000. 8. A pharmaceutical composition according to any one of claims 1 to 7, characterized in that the average molecular weight of microcrystalline cellulose is between about 20,000 and 100,000. 9. A pharmaceutical composition according to any one of claims 1 to 8, characterized in that the content of methoxy groups of 11 hydroxypropyl methylcellulose is between "" * 16 between about 15 and about 34% by weight. 10. A pharmaceutical composition according to any one of claims 1 to 9, characterized in that the content of hydroxypropyl groups of the hydroxypropyl-methylcellulose is between about 4 and about 32% by weight. 11. A pharmaceutical composition according to any one of claims 1 to 10, characterized in that the viscosity of the hydroxypropyl-methylcellulose is between 4000 and 50,000 cps. 12. A pharmaceutical composition according to any one of claims 1 to 11, characterized in that the average molecular weight of hydroxypropyl-methylcellulose is between 90,000 and 130,000. 13. A pharmaceutical composition according to any one of claims 1 to 12, characterized in that the weight ratio of microcrystalline cellulose to hydroxypropyl-methyl-cellulose is between 10: 1 and 1: 1. 14. A pharmaceutical composition according to any one of claims 1 to 12, characterized in that the weight ratio of microcrystalline cellulose to hydrocypropyl-methyl cellulose is between 3: 1 and 1: 1. 15. A pharmaceutical composition according to any one of claims 1 to 14, characterized in that the weight ratio of microcrystalline cellulose to the active substance is between 1: 5 and 1:10. 16. A pharmaceutical composition according to any one of claims 1 to 15, characterized in that it contains pregelatinized starch. 17. A pharmaceutical composition according to claim 30 16, characterized in that the weight ratio of pregelatinized starch to hydroxypropyl methylcellulose is between approximately 1: 1 and approximately 1: 5. »* * * 17 18. A pharmaceutical composition according to any one of claims 1 to 17, characterized in that the weight ratio of the active substance to all the other excipients present is between 2: 1 and 4: 1. 19. A pharmaceutical composition according to any one of claims 1 to 18, characterized in that it is in the form of tablets obtained by compression making it possible to reach a hardness of approximately 8 to 12 kg. 20. A solid pharmaceutical composition for oral administration, characterized in that it comprises at least 300 mg of acetylsalicylic acid in a sustained-release form which, after administration of a daily dose of 2.6 g of acid acetylsalicylic in divided doses 2 to 3 times a day, may give steady state plasma free salicylic acid levels higher than those obtained at steady state after administration of acetylsalicylic acid tablets immediate release at the same daily dose and in divided form every 4 hours. 21. A pharmaceutical composition according to claim 20 20, characterized in that the pharmaceutical composition contains 300 to 700 mg of salicylic acid and has a dissolution rate in water at 37 ° C between 15 and 40% at the end 1 hour and more than 70% after 8 hours. 22. A pharmaceutical composition according to claim 25 20 or 21, characterized in that the composition is in the form of a tablet. 23. A pharmaceutical composition according to any one of claims 20 to 22, characterized in that it exhibits at least one of the characteristics specified in any one of claims 1 to 19.