BE1018280A3 - EXTENDED RELEASE NIMESULIDE COMPOSITION. - Google Patents

Abstract

A protease-release pharmaceutical composition of nimesulide containing nimesulide as an active ingredient, a sustained release additive and L-arginine.

Description

"Composition of sustained release nimesulide

The present invention relates to a sustained release pharmaceutical composition of nimesulide containing nimesulide as an active ingredient and a sustained release additive.

Nimesulide (also known as n- (4-nitro-2-phenoxyphenyl) methanesulfonamide or as 4-nitro-2-phenoxymethane-2-sulfoanilide) is a drug (cycloxygenase inhibitor [ COX] preferentially of type 2) well known used in the treatment of diseases or inflammatory conditions, and which has analgesic and antipyretic properties. This compound, however, is very sparingly soluble in water and also has a weakly acidic character, with a pKa of about 6.5.

This nonsteroidal anti-inflammatory drug (NSAID), therefore, behaves as a weak acid with very low water solubility (approximately 0.01 mg per ml) has a pH dependent solubility. Attempts to increase its aqueous solubility have been published in particular, a study published by G. Piel, B. Pirotte, I. Delneuville, P. Neven, G. Llabres, J. Delarge and L. Delattre in J. Pharm. Sci., 86 (1997), page 475 to 480 under the title "Study of the Influence of both cyclodextns and L-lysine on the aqueous solubility of nimesulide, isolation and charactehzation of nimesulide-L-lysine-cyclodextrin complexes.

A controlled release nimesulide composition is known from WO 01/22791. Such a composition has the advantage of allowing an assay at a rate of once a day, which is more practical in the treatment of inflammatory diseases, both acute and chronic.

The composition according to WO 01/22791 comprises nimesulide as active substance and one or more sustained-release materials as well as excipients. This composition is in the form of a bilayer tablet which has a first layer which allows rapid release of the active substance (nimesulide) and a second layer which allows a sustained release of nimesulide. According to WO 01/22791, sustained-release polymers are preferably hydrophilic in nature and are present as a fast and slow hydration polymer mixture. Unfortunately, the step of compressing the two layers to form a bilayer tablet using a suitable machine is a delicate step. In addition, no solution to improve the solubility and therefore the bioavailability of nimesulide has been provided according to WO 01/22791.

Nimesulide is a cox-2 selective anti-inflammatory drug that, although less gastric toxic than some nonsteroidal anti-inflammatory drugs, still has a relatively high degree of gastric toxicity. In addition, some cases of fulminant hepatitis have been reported for this anti-inflammatory.

From WO 95/34533 there is known a nimesulide L-lysine salt which has been prepared to increase the aqueous solubility of nimesulide to about 5 to 7.5 mg per ml.

To obtain a sustained-release composition, it is necessary that the composition already allows a gradual release into the stomach for a better prolonged effect and it is necessary that the bulk of the composition is absorbed in the intestinal part of the digestive tract, substantially constant over time. It has been imagined to manufacture a sustained-release composition using a nimesulide-L-lysine salt according to WO 95/34533, although intuitively it seemed unlikely that a composition comprising nimesulide under more soluble form may be suitable for a sustained release composition. Unfortunately, as can be seen from Comparative Example 1, it has not been possible to manufacture tablets with a sustained release composition comprising nimesulide-L-lysine salt for technological reasons.

In addition, the addition of cyclodextrin (see Comparative Example 2) which is known to increase the solubility of nimesulide has also not given a satisfactory result in the development of a sustained release composition.

The object of the invention is therefore to provide a sustained-release pharmaceutical composition of nimesulide in which gastric toxicity as well as hepatic toxicity are reduced. In addition, an object of the invention is to provide a composition which prolongs the release of nimesulide in the intestinal part, more particularly a composition in which the solubility of nimesulide is improved.

For this purpose, the composition according to the invention, containing nimesulide as an active ingredient in a proportion ranging from 40 to 60% by weight relative to the total weight of the composition and at least one release additive. in the range from 10 to 40% by weight relative to the total weight of the composition is characterized in that it further comprises an amount of L-arginine in a proportion of between 10 and 40% by weight. weight relative to the total weight of the composition.

Since L-arginine is a nitrogen monoxide (NO) group donor, it enhances the gastro-protective effect of the selective COX-2 anti-inflammatory drug nimesulide. In addition, L-arginine has been shown to be a hepatoprotective substance. In addition, L-arginine is a substance that improves the solubility of nimesulide by its alkaline character.

Surprisingly and relatively unexpectedly, it has been shown that the sustained-release nimesulide composition according to the invention allows a better absorption into the body of nimesulide, since the release began in the stomach and continued, still substantially constant in the intestine to act for a long time and sustained against inflammation, in comparison with the pharmaceutical composition sustained release nimesulide such as that known from WO 01/22791, which must include a very fast release layer in order to counteract the gastric environment of the stomach, unfavorable to the release of nimesulide.

Advantageously, said sustained-release additive is chosen from the group of hydroxypropyl methylcellulose, xanthan gum, ethylcellulose, hydrogenated castor oil, glycerol behenate, their derivatives and their mixtures. Preferably, said at least one sustained release additive is glycerol behenate.

In a particular embodiment, the composition further comprises one or more lubricants selected from the group consisting of sodium stearyl fumarate, glycerol palmitostearate, hydrogenated castor oil, stearic acid, magnesium stearate, their derivatives and their mixtures and is preferably magnesium stearate, in a proportion ranging from 1 to 5% by weight relative to the total weight of the composition.

Magnesium stearate improves the lubricating qualities of the composition according to the invention and thus facilitates the manufacture of the composition, in particular when it is in the form of tablets.

In a particular form of the invention, the sustained-release pharmaceutical composition of nimesulide further comprises one or more diluents, in a proportion ranging from 10 to 40% by weight relative to the total weight of the composition. The diluent is preferably selected from the group consisting of lactose monohydrate, microcrystalline cellulose, their derivatives and mixtures thereof.

In a particularly preferred form according to the invention, the composition comprises from 5 to 10% by weight relative to the total weight of the lactose monohydrate composition and from 3 to 8% by weight relative to the total weight of the microcrystalline cellulose composition. . Microcrystalline cellulose is a binder that promotes compression during the manufacturing process of the composition according to the invention.

Advantageously, in a particularly preferred embodiment, the nimesulide sustained release composition according to the invention further comprises one or more surfactants in a proportion ranging from 1 to 5% by weight relative to the total weight of the composition. Said one or more surfactants are selected from the group consisting of sodium lauryl sulphate, sodium docusate, their derivatives and mixtures thereof, and is preferably sodium docusate, as it facilitates wetting by aqueous digestive fluids and gives results. higher than sodium lauryl sulphate.

In a particular form of the invention, the composition according to the invention comprises five mini-tablets (multi-unit form) having a weight of about 80 mg and being packaged in a conventional digestible capsule. In this way, if the capsule is ingested as such, when it reaches the stomach, the capsule is digested and the gastric juices have access to the five mini tablets of sustained release composition of nimesulide according to the invention. Therefore, the contact surface between the outer wall of said mini-tablets and the gastric juices is greatly increased and the release of nimesulide begins in the gastric medium where the pH is particularly unfavorable to the solubilization of nimesulide. However, according to the invention since nimesulide is at least partially in the form of an L-arginine-nimesulide salt, the solubilization of nimesulide is less dependent on the pH of the digestive fluids. The use of a multi-unit form (mini-tablets combined in a capsule) is particularly interesting because it makes it possible to easily carry out dose-response studies and then to choose the most appropriate dose of sustained-release nimesulide (40, 80, 120, 160 or 200 mg nimesulide) for the desired clinical effect.

During digestion, thanks to peristalsis, the sustained release nimesulide composition according to the invention passes into the small intestine where the pH is from about 5 to 6 or even up to 8, in which the solubilization of nimesulide is more favorable. In addition, since it is in the small intestine that the absorption of the active substances takes place preferentially, it is particularly preferable that the solubilization of nimesulide be long and prolonged in this place in order to optimally diffuse into the systemic circulation.

Other embodiments of the composition according to the invention are indicated in the appended claims.

Other features, details and advantages of the invention will emerge from the description and examples given below, without limitation and with reference to the appended figures.

FIG. 1 illustrates the kinetics of dissolution of the nimesulide composition according to example 1 at pH 7.4 and at 100 rpm.

Figure 2 illustrates the dissolution profiles obtained with 5-7.5 and 10% film-coated tablet cores of a 5% HPMC (hydroxypropyl methylcellulose) SURELEASE film (METHOCEL 5 mPa.s).

FIG. 3 illustrates the influence of the pH of the dissolution medium on the in vitro dissolution kinetics of the nimesulide composition obtained in example 2 at pH 7.4 and at 100 rpm.

FIG. 4 illustrates the influence of the percentage of hydroxyethylcellulose (NATROSOL 250HX) on the in vitro dissolution kinetics of the nimesulide composition obtained in Example 2 at pH 7.4 and at 100 rpm.

Figure 5 illustrates release kinetics of a composition obtained in Example 3 in which the mixed matrix agent contained CUTINA HR and hydroxypropyl methylcellulose.

FIG. 6 illustrates a kinetics of dissolution of the composition according to the invention at pH 1.2.

FIG. 7 illustrates a kinetics of dissolution of the composition according to the invention at pH 5.5.

FIG. 8 illustrates a kinetics of dissolution of the composition according to the invention at pH 6.8.

FIG. 9 illustrates a kinetics of dissolution of the composition according to the invention at pH 7.4.

Figure 10 illustrates dissolution kinetics of a nimesulide composition with L-lysine and HPMC-K4M.

Figure 11 illustrates dissolution kinetics of a nimesulide composition with L-lysine and HPMC-K15M.

Figure 12 illustrates dissolution kinetics of a nimesulide composition with L-lysine and HPMC-K100M. Detailed description of the invention.

Nimesulide (N-4'-nitro-2'-phenoxyphenyl methanesulfonamide) is a nonsteroidal anti-inflammatory drug (NSAID) that behaves like a weak acid with low water solubility ("0.01 mg / ml"). ) whose solubility is pH-dependent.

When nimesulide is prescribed as an anti-inflammatory, the recommended daily dose is usually 200 mg or a multiple of it. As mentioned previously, the development of a sustained-release oral form containing 200 mg of nimesulide allows a simplification of the dosage since the treatment can be limited to a single daily dose and will therefore increase the attendance rate. treatment; pharmacokinetic and adherence. In addition, the elimination half-life time of nimesulide which is between 3.2 and 6 hours justifies the development of a sustained-release oral form. In addition, according to the invention, a formulation of a multi-unit system allowing a better dispersion in the intestinal tract than a monolithic form has been developed. This multi-unit formulation also avoids high local concentrations of nimesulide. In addition, this multi-unit formulation offers the advantage of being able to easily fragment the dose in order to establish a better dose-response relationship. In addition, when packaging the mini-tablets in capsule, if there is a need to condition by 2 or 5, the flexibility of the multi-unit form allows it easily without changing the preparation steps but only the conditioning step.

Advantageously, since nimesulide is poorly soluble in water, an alkaline substance, L-arginine has been associated with it in order to improve its solubility and therefore its availability for the organism, while inhibiting its dissolution by means galenics to obtain a sustained release formulation.

As an alkaline pH modifier, L-arginine is of great interest as a NO donor since synthesis of NO-releasing NSAIDs would produce derivatives with fewer gastrointestinal side effects as well as hepatic level.

For each nimesulide sustained release composition or other comparative composition used in the context of the present invention, a conventional in vitro dissolution method was used: This method is described in the European and American Pharmacopoeia and uses a 100 t rotating pallet / min in a pH 7.4 medium containing 3% POLYSORBATE 80 to ensure the "sink" conditions because nimesulide is a poorly soluble active substance.

The operating conditions of the in vitro test are described below:

Medium: 1000.0 ml 50 mM phosphate buffer pH 7.4 containing 3% POLYSORBATE 80 (SINK conditions) and having an ionic strength of 0.2

Assay: in-line UV absorption (398 nm) at times 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105 minutes and at 2, 3, 4, 5, 6 and 7 o'clock , 8h, 9h and 10h.

Apparatus: SOTAX® AT7 (available from Sotax Corporation) comprising a rotating pallet at a rotation speed of 100 revolutions per minute.

EXAMPLE 1 Production of mini-film-coated tablets

Small biconvex tablets with a diameter of 5.5 mm and a radius of curvature of 3.5 mm comprising nimesulide (available for example from the company Erregierre SPA - Italy), a surfactant (sodium docusate - at a rate of 1% by weight relative to the weight of nimesulide) and L-arginine (at a rate of 30% by weight relative to the weight of nimesulide) were manufactured in the following manner.

1000 g of nimesulide and 300 g of L-arginine were weighed and introduced into the tank of a Gral-10 mixer, available for example from the company GEA-Colette, equipped with a blade with 3 branches. It was mixed for 10 minutes at 100 rpm. Hot sodium docusate was dissolved in 130 g of purified water to form a suspension of sodium docusate upon cooling, and this suspension of sodium docusate was added to the nimesulide / L-arginine mixture at a rate of 20 g / min. The stirring of the main mixing arm is 100 rpm.

When all the suspension of docusate Na was added, the chopper was rotated at 1500 rpm for 10 min. The granulate was then placed in the oscillating granulator (for example available from Erweka) on a 1 mm mesh screen and then on a 630 μm mesh screen. The granulate thus obtained was dried in a fluidized air bed at 40 ° C.

Two control tests were carried out on this granule. This is a granulometric analysis presented in Table 1 and a water content analysis presented in Table 2 using the Karl-Fisher method. Five batches (from 1 to 5) of mini-tablets were manufactured for validation. For batches 4 and 5, a larger quantity of liquid was added during the granulation, ie 160 g in total.

Table 1

As can be seen in Table 1, the particle size distribution of the granules thus formed is fairly reproducible.

Table 2

As can be seen in Table 2, the water content of the granules thus formed is reproducible.

These granules were then mixed with an outer phase composed of microcrystalline cellulose (AVICEL PH-102) and magnesium stearate. The composition is described below in Table 3. The microcrystalline cellulose AVICEL is for example available from FMC Corporation.

Table 3

As shown in the graph in Figure 1, these tablets release nimesulide very rapidly (approximately 100% dissolved after 30 minutes).

In order to gradually release nimesulide, the coating of these tablets with a film of filmogen insoluble in digestive juices but nevertheless permeable and optionally containing a pore-forming excipient (HPMC, PEG 4000) to modulate the release nimesulide was appropriate.

The tablets were film coated with a SURELEASE latex available from Colorcon Ltd Company containing ethylcellulose as a film-forming polymer controlling the release of nimesulide.

The lamination operation was carried out on a load of 500 g of these tablets in a HI-COATER HCT Mini turbine, available from Lödige. The rotational speed of the turbine was between 18 and 20 rpm. The inlet temperature was between 60 and 64 ° C while the exit temperature was in the range of 38 to 40 ° C. The spray pressure was 2 bar and the flow rate of the film-coating suspension was 5 to 6 g / min.

Previously manufactured tablets have been film coated using various formulations A to D.

Formulation A comprises 300 g of SURELEASE latex, 3.75 g of hydroxypropyl methylcellulose (METHOCEL E5 available from Dow Chemical Corporation) and 200 g of purified water. The amounts of formulation A applied to the aforesaid tablets (expressed in% by dry weight of applied film relative to the final weight of the tablet) were 5 to 7.5% and 10%.

Formulation B is identical to Formulation A except that it comprises 7.5 g of hydroxypropylmethylcellulose (METHOCEL E5). The amounts of formulation B applied to the aforesaid tablets (expressed in% by dry weight of applied film relative to the final weight of the tablet) were 10 to 15% and 20%.

Formulation C is identical to formulation B except that it comprises 7.5 g of PEG 4000. The amounts of formulation C applied to the above-mentioned tablets (expressed in% by dry weight of film applied relative to the weight tablet) were 7.5 to 10% and 15%

Formulation D was carried out by the application of a sub-layer composed of a mixture of METHOCEL E5. and PEG 4000 (5 mg / tablet) and then by applying a mixture of latex SURELEASE and PEG 4000 to 15% by weight relative to the weight of polymer SURELEASE. The amounts of formulation D applied to the above-mentioned tablets (expressed in% by dry weight of applied film relative to the final weight of the tablet) were 5 to 7.5% and 10%. According to the dissolution kinetics obtained, difficulties to slowly release the nimesulide incorporated in these film-coated tablets were encountered: there is a sudden release from the tablet wafer after a latency time of 1 to 3 hours depending on the amount of film applied.

The ethylcellulose film is not sufficiently elastic to uniformly coat biconvex tablets so that cracks appear at the tablet wafer where the film thickness is the lowest.

As can be seen in FIG. 2, the dissolution profiles obtained with the film tablet cores by 5, 7.5 and 10% by weight of a SURELEASE film relative to the weight of the composition containing 5% by weight. HPMC (METHOCEL E5) are not optimal. It can be seen that after a latency that increases with the percentage of film applied, the release of nimesulide is very fast following the fragility of the film at the edges of the tablet. This profile does not correspond to that of a progressive release form of the active substance.

EXAMPLE 2-Mini-Matrix Tablets with Hydrophilic Matrix

As mentioned above, according to the invention there is provided a sustained-release composition of nimesulide, in the form, for example, of mini-tablets each containing 40 mg of nimesulide in combination with L- arginine; to obtain a dose of 200 mg, 5 mini-tablets dosed at 40 mg of nimesulide and weighing about 80 mg will be introduced into a capsule No. 0.

The matrix excipients used were hydroxypropyl methylcellulose varieties of different viscosities (HPMC K4M, K15M and K100M), xanthan gum and hydroxyethylcellulose (NATROSOL 250 HX Pharm - available from AQUALON, which is a hydroxyethyl cellulose). a relatively high viscosity of 9000 mPa.s for a 2% solution at 20 ° C).

Matrix tablets were manufactured using a granule containing different concentrations of L-arginine (10% -30% and 56.5% by weight based on the weight of nimesulide) as a pH modifier; the granule is prepared in a granulator mixer GRAL 10. A

this granulate, various types of HPMC (METHOCEL K4M, K15M and K100M) were added in external phase.

The granule containing 10% L-arginine by weight relative to the weight of nimesulide exhibited a slow release kinetics of nimesulide from the tablets, particularly in view of the half-life time of nimesulide. The granule containing 56.5% L-arginine (stoichiometric amount) by weight relative to the weight of nimesulide generated sticking problems to the punches. These two compositions were discarded.

The granule containing 30% L-arginine by weight relative to the weight of nimesulide had the composition shown in Table 4. These tablets were manufactured on a rotary press for example available from the company GEA Courtoy by applying a single value of force compression:

Table 4

Dissolution tests of this composition shown in Table 4 were carried out at different pHs according to the procedure mentioned above. The results are illustrated in Figure 3. As can be seen, at pH 1.2 and pH 7.4, good reproducibility of dissolution rates was observed. On the other hand, at pH 5.5 and 6.5, the standard deviations are high and sometimes very high (20%).

With this same granule containing 30% L-arginine compared to nimesulide, we also realized the same type of formulation with HPMC K4M and HPMC K100M; sticking problems with punches were encountered, and this composition was discarded. In addition, it has also been realized according to the invention, matrix tablets using, as matrix agent xanthan gum at a percentage ranging from 4 to 16.75%: Unfortunately, the kinetics of release is too slow.

In addition, as a matrix agent, NATROSOL 250 HX Pharm (hydroxyethylcellulose with a relatively high viscosity of 9000 mPa.s for a 2% solution at 20 ° C) was also used. The percentages of NATROSOL tested are 8.5, 11 and 16.75%.

The results of the dissolution test are illustrated in FIG. 4. As can be seen, the in vitro release profile at pH 7.4 of nimesulide from the tablets containing 8.50% NATROSOL 250 HX is quite satisfactory although the standard deviations are very high: this is the reason why this type of formulation was not retained.

EXAMPLE 3-Matrix mini-tablets with mixed matrix

We have tried a mixed matrix agent formulation containing CUTINA HR for example available from Henkel and HPMC K4M (15 / 7.5) (A) or HPMC K100M (15 / 7.5) (B) unfortunately, as can be seen in Figure 5, the release kinetics are too fast to meet the requirement of sustained release.

As a result, the amount of CUTINA HR has been increased up to 30% which is the percentage from which release kinetics become too slow. Unfortunately, no composition allowing to obtain a satisfactory flow during the granulation could be obtained and the mixed matrices were therefore discarded.

EXAMPLE 4 Lipoprote Matrix Mini-Tablets

A granule of nimesulide, sodium docusate and L-arginine was manufactured. Then, an external phase consisting mainly of CUTINA HR was added to the granule: the results obtained are unsatisfactory in terms of technology because the flow of the tablet mixture is low and the weight variation coefficient of the tablets is greater than 2%. . A thermoplastic granulation with the same formulation (CUTINA HR as a thermoplastic agent) was also tried, but without success, indeed, this mixture was sticking to the walls of the mixer-granulator tank and there was en masse in the tank.

To obtain a good flow of the mixture to be compressed, tests were carried out by replacing CUTINA HR with a lipid excipient of higher granulometry: COMPRITOL ATO 888 (glycerol behenate, for example available from Gattefossé).

After several tests, in which the proportions of COMPRITOL ATO 888, lactose DCL15 (for example available from DMV) and microcrystalline cellulose (AVICEL PH 200) were modified, the formulation shown in Table 5 was retained.

Table 5.

Several batches (approximately 1.5 kg) of tablets according to the invention have thus been manufactured in order to be able to test the characteristics of these tablets. For this purpose, 982.5 g of granules obtained according to the beginning of Example 1 (composed of Nimesulide, L-arginine and sodium Docusate) were weighed.

Then 300 g of glycerol behenate, 127.5 g of lactose monohydrate, 75 g of microcrystalline cellulose were weighed. All these constituents were introduced into the tank of the Collette Gral-10 mixer equipped with a blade with 3 branches and mixed for 5 minutes at 100 rpm.

Fifteen grams of magnesium stearate were weighed and added to the mixture in the Gral-10 tank and mixed for 1 minute at 100 rpm.

The compression was carried out by progressively introducing the mixture obtained into the feed shoe of a GEA Courtoy rotary press equipped with 5,5 mm concave punches. The setting of the press was carried out so that the weight of the tablets was 80.0 mg and their hardness was close to 35 N.

Several control tests were then carried out on these tablets: - Crush strength, presented in Table 6, - Weight regularity, presented in Table 7, - Dissolution tests at different pH (1.2 - 5.5 - 6.8 - 7.4)

Three batches of tablets were made to demonstrate the reproducibility and reliability of the manufacturing process. The three lots bear the following batch number: 6, 7, and 8. A fourth lot, numbered 9 (prepared from the granule of lot 5) was then made. We made the manufacturing on the rotary press without any technological problem and the tablets were subjected to the dissolution test at pH 7.4.

Table 6

As can be seen in Table 6, the tablets have a crush strength of between 30 and 35 N, which is a very suitable resistance value for mini-tablets such as those made in the context of the present invention. .

Table 7

As can be seen from Table 7, the tablets have a weight regularity around the target value of 80 mg and a satisfactory coefficient of variation. Therefore, the desired regularity of weight of the tablets has been achieved by the composition according to the invention.

The dissolution tests were then carried out according to the procedure described above at different pH using dissolution media 1 to 4. The results obtained for these dissolution tests are respectively presented in Tables 8, 9, 10, and 11 and Figures 6, 7, 8 and 9.

Dissolution medium 1: Buffer at pH 1.2 before an ionic strength of 0.2.

For 7 liters of buffer, 49 ml of 12 M HCl was mixed with 47.05 g of NaCl and 210 g of POLYSORBATE 80. The mixture was then stirred until complete dissolution. The pH was then checked using a conventional pH probe.

Dissolution medium 2: Buffer at pH 5.5 before an ionic strength of 0.2

For 7 liters of buffer, 73.55 g of citric acid monohydrate was mixed with 32.71 g of NaOH and 210 g of POLYSORBATE 80. The mixture was then stirred until complete dissolution. The pH was then checked using a conventional pH probe.

Dissolution medium 3: pH 6.8 buffer before an ionic strength of 0.2

For 7 liters of buffer, 47.63 g of KH 2 PO 4 was mixed with 6.27 g of NaOH, 43.04 g of NaCl and 210 g of POLYSORBATE 80. The mixture was then stirred until complete dissolution. The pH was then checked using a conventional pH probe.

Dissolution medium 4: Buffer pH 7.4 before an ionic strength of 0.2

For 7 liters of buffer, 47.63 g of KH 2 PO 4 was mixed with 10.95 g of NaOH, 29.37 g of NaCl and 210 g of POLYSORBATE 80. The mixture was then stirred until complete dissolution. The pH was then checked using a conventional pH probe.

Table 8

These results have been plotted in FIG. 6. As can be seen, even at pH 1.2, which is particularly unfavorable for the dissolution of nimesulide (acidic compound) and which simulates the gastric pH, the dissolution of nimesulide occurs. already and is very weak, allowing a really prolonged release of nimesulide, which begins very slightly already in the stomach.

Table 9

These results have been plotted in Figure 7. As can be seen, at pH 5.5 which is still somewhat unfavorable to the dissolution of nimesulide (acid compound) and which simulates the pH of the beginning of the small intestine the dissolution of nimesulide occurs relatively steadily, but increasing over time, allowing a truly prolonged release of nimesulide which therefore begins already in the stomach and continues in the small intestine.

Table 10

These results have been plotted in Figure 8. As can be seen, at pH 6.8 which simulates the pH of the small intestine medium, the dissolution of nimesulide occurs relatively satisfactorily, despite differences in values between the different lots. However, this dissolution is appropriate to allow a truly prolonged release of nimesulide which therefore begins already in the stomach and continues in the small intestine.

Table 11

These results have been plotted in Figure 9. As can be seen, at pH 7.4, the dissolution of nimesulide occurs satisfactorily, and constant. This dissolution profile of the composition according to the invention is suitable for confirming a really prolonged release of nimesulide which therefore begins already in the stomach and which continues in the small intestine ensuring a systemic diffusion of nimesulide.

In addition, on the chosen formulation, we also studied the influence of the beginning, the middle or the end of the compression and the influence of carrying out the dissolution test on 1.2 or 5 tablet (s) in the medium at pH 7.4. No significant influence of these two parameters could be demonstrated.

COMPARATIVE EXAMPLE 1 Mini-Matrix Tablets with Hydrophilic Matrix Containing L-Ivsine

As mentioned at the beginning, some tests were carried out with a nimesulide composition containing L-lysine in the form, for example, of mini-tablets each containing 40 mg of nimesulide in combination with L lysine. L-lysine is, like L-arginine, an alkaline substance.

The matrix excipients used were varieties of hydroxypropyl methylcellulose of different viscosities (HPMC K4M, K15M and K100M), xanthan gum and hydroxyethylcellulose (NATROSOL 250 HX Pharm - hydroxyethylcellulose with a relatively high viscosity of 9000 mPa. s for a 2% solution at 20 ° C).

Matrix tablets were manufactured using a granulate containing 30% by weight of L-lysine relative to the weight of nimesulide, prepared in a granulator-granulator GRAL 10. To this granule, various types of HPMC (METHOCEL K4M, K15M and K100M) were added in the external phase.

The granule containing 30% L-lysine by weight based on the weight of nimesulide had the composition shown in Table 12.

Table 12

Dissolution tests of these compositions shown in Table 12 were performed in vitro at pH 7.4 and 100 rpm and the results are shown in Figures 10 to 12 (respectively K4M, K15M and K100M).

As can be seen, the kinetics of release was too slow, irrespective of the viscosity of the added hydroxypropyl methylcellulose.

In order to improve the in vitro release profile of nimesulide, tablets were manufactured by adding in the external phase an equal parts mixture of HPMC and microcrystalline cellulose to the nimesulide / lysine granule: the release kinetics correspond to the expected profile; unfortunately, technological problems have been encountered during scaling up, namely a large sticking to the punches regardless of the compressive force applied. It is therefore not possible to produce this composition.

COMPARATIVE EXAMPLE 2

In order to increase the aqueous solubility of nimesulide, a nimesulide granulate containing hydroxypropyl-β-cyclodextrin (HP-β-CD) was also made.

For technological reasons (heating of the granule, clogging of the oscillating sieve) this type of formulation was quickly abandoned.

It is understood that the present invention is in no way limited to the embodiments described above and that many modifications can be made without departing from the scope of the appended claims.

Claims (8)

1. A sustained release pharmaceutical composition of nimesulide containing nimesulide as an active ingredient in a proportion ranging from 40 to 60% by weight relative to the total weight of the composition and at least one sustained release additive in a proportion in the range from 10 to 40% by weight relative to the total weight of the composition, characterized in that it further comprises an amount of L-arginine in a proportion of between 10 and 40% by weight per relative to the total weight of the composition. . · The nimesulide sustained release pharmaceutical composition according to claim 1, wherein said at least one sustained release additive is selected from the group consisting of hydroxypropyl methylcellulose, xanthan gum, hydroxyethylcellulose, hydrogenated castor and glycerol behenate, their derivatives and mixtures thereof and is preferably glycerol behenate. 3. Pharmaceutical sustained-release composition of. Nimesulide according to claim 1 or 2, further comprising one or more lubricants selected from the group consisting of sodium stearyl fumarate, glycerol palmitostearate, hydrogenated castor oil, stearic acid, magnesium stearate, their derivatives and mixtures thereof and preferably magnesium stearate in a proportion of from 1 to 5% by weight relative to the total weight of the composition. 4. Pharmaceutical sustained-release nimesulide composition according to any one of claims 1 to 3, further comprising one or more diluents in a proportion ranging from 10 to 40% by weight relative to the total weight of the composition. The nimesulide sustained release pharmaceutical composition according to claim 4, wherein said one or more diluent is selected from the group consisting of lactose monohydrate, microcrystalline cellulose, and their derivatives and mixtures thereof. 6. Composition according to claim 5, comprising from 5 to 10% by weight relative to the total weight of the lactose monohydrate composition and from 3 to 8% by weight relative to the total weight of the microcrystalline cellulose composition. 7. Pharmaceutical sustained-release composition of nimesulide according to any one of the preceding claims, further comprising one or more surfactants in a proportion ranging from 1 to 5% by weight relative to the total weight of the composition, selected from the group consisting of sodium lauryl sulphate, sodium docusate, their derivatives and mixtures thereof and is preferably sodium docusate. 8. A sustained release pharmaceutical composition of nimesulide according to any one of the preceding claims, wherein five mini-tablets having a weight of about 80 mg of said composition are packaged in a conventional digestible gelatin.