WO1995016451A1

WO1995016451A1 - Tablets for the controlled release of 4-asa

Info

Publication number: WO1995016451A1
Application number: PCT/FR1993/001236
Authority: WO
Inventors: Franck Arno Gouchet; Hatem Fessi; Francis Puisieux
Original assignee: Franck Arno Gouchet; Hatem Fessi; Francis Puisieux
Priority date: 1992-06-22
Filing date: 1993-12-14
Publication date: 1995-06-22

Abstract

The present invention relates to a new galenic form of amino-4-hydroxy-2-benzoic acid, which is a potent non steroid anti-inflammatory substance known as 4-ASA. The tablets can be orally administered in order to provide for the controlled release of 4-ASA. The tablets are comprised of the active substance (4-ASA) which is distributed homogeneously in a hydrophilic matrix covered with a gastro-resistant coating. The gastro-resistant coating of the tablets impedes any direct contact between the active substance and the gastric mucosa thereby making it possible to avoid irritation of the gastric mucosa and to protect the active substance against gastric fluids. The gastro-resistant coating is selected among acrylic derivatives. The hydrophilic matrix, once removed of its coating as soon as it has reached the duodenum, behaves as a controlled release drug which releases regularly the active substance in the small intestine, the ileum, the colon and the ampulla recti. The hydrophilic polymers are selected among cellulose derivatives.

Description

The present invention relates to a new galenic form of amino 4 hydroxy 2 benzoic acid which is a potent non-steroidal anti-inflammatory drug known as 4-ASA. 4-ASA is used to treat ulcerative colitis and the lower forms of Crohn's disease. There is currently a 5-ASA product used for the same therapy (ethylcellulose coated tablet). Different studies have shown the comparable action of 4-ASA and 5-ASA. 5-ASA is an expensive product, difficult to synthesize and chemically unstable. 4-ASA provides an alternative to 5-ASA in the treatment of ulcerative colitis.

We used as a comparison tablet a 5-ASA specialty marketed in France: PENTASA ^R.

The PENTASA ^R tablet contains 1 mm microgranules of 5-ASA coated with an ethylcellulose membrane which are compacted to make the tablet. The microgranules of 5-ASA are released, still theoretically coated with ethylcellulose, in the stomach. They follow the intestinal path with a release profile of the active ingredient pH dependent, so that it begins in the stomach. The release of 5-ASA in vitro at constant temperature (37 ° C) reveals that at pH = 7.5, 90% of 5-ASA diffuses through the semi-permeable membrane over the entire length of the intestinal tract. About 60% of 5-AS A is released in the small intestine, with the remainder being released in the colon.

It is particularly advantageous to be able to have a dosage form which can be administered orally allowing the gradual release of 4-ASA, by prohibiting the release of active ingredient before pH = 5.5, that is to say before having reached the duodenum, which allows protection of the gastric mucosa against the irritant effect of the active ingredient and protection of the active ingredient against degradation in an acid medium.

It has been found, and this is what is the subject of the present invention, that tablets can be produced which make it possible to control the kinetics of release of the active principle. According to the present invention, the tablets consist of the active substance (4 - ASA) distributed homogeneously in a hydrophilic matrix covered with an enteric coating.

The gastro-resistant coating prevents direct contact between the active substance and the gastric mucosa, which makes it possible, on the one hand, to avoid irritation of the gastric mucosa and, on the other hand, to protect the active substance gastric fluids.

The disintegration of the gastro-resistant coating takes place from the duodenum.

As soon as it comes into contact with intestinal fluids, the hydrophilic matrix released from its coating can then behave like a controlled release form. The functioning of the hydrophilic matrix can be schematically broken down into 4 phases:

1. under the effect of intestinal fluids, the particles of active ingredient on the surface of the tablet will dissolve and thus constitute the attack dose,

2. the water penetrates inward causing swelling of the matrix and the formation of the gelled barrier,

3. water dissolves the active substance,

4. the dissolved active substance diffuses out of the form.

For the hydrophilic matrix to function properly, it is necessary that the swelling of the hydrophilic polymer is capable of creating a superficial gelled barrier without causing rapid disintegration of the tablet. Among the important parameters, the viscosity of the hydrophilic polymer in aqueous solution, its molecular weight, its gelling rate as well as its concentration in the tablet can be mentioned.

It is therefore particularly advantageous to use a hydrophilic polymer whose viscosity in aqueous solution is high but compatible with the establishment of the gelled surface barrier in a suitable time. In addition, the hydrophilic polymer must be compatible with the active substance and be pharmaceutically acceptable.

The hydrophilic polymers which are particularly suitable are chosen from cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, carboxymethylcellulose, acrylic derivatives such as Carbopol ^R 934 P.

Among the various hydrophilic polymers, it is possible to use more particularly hydroxypropylmethylcellulose, or Methocel K 100 (Corlorcon), the latter being able to be used in direct compression.

Talc will be used for its lubricating properties (non-stick). Magnesium stearate is a compression lubricant (anti-friction). The aerosil will play the role of flow regulator, facilitating the good flow of the grain in the matrix, pledge of a good regularity of the weight of the tablet.

A formula is developed with a small amount of excipients because the active ingredient already occupies a large volume (a diluent is therefore not necessary). Current therapeutic habits show that patients are treated with several 500 mg tablets per day (generally 4 to 6 tablets per day). Initially, the tablets will be produced by direct compression.

The formula of the tablet obtained is as follows: 4 -AS A 500 mg HPMC K 100 100 mg (20%) Talc 5 mg (1%) Mg stearate 2.5 mg (0.5%)

According to the methods of the Pharmacopoeia, the powder undergoes flow and compaction tests; the tablets undergo tests for friability, dissolution, average weight and hardness.

The powder has a major drawback: the flow is very irregular, so the powder lacks fluidity. On the other hand, the tablets undergo a weight loss during the friability test greater than 1%, which is not acceptable for tablets manufactured for coating. Dissolution tests clearly show that we are in the presence of a matrix.

In a second step, modifications are made:

* aerosil is used to improve flow

* the tablets are produced by dry granulation and no longer by direct compression. It is the only possible way, the active ingredient being very sensitive to humidity and heat. The following example, given without limitation, shows the practice of the invention.

The tablet formula is as follows: 4-ASA 79.9%

HPMC K 100 16.0%

Talc 0.8%

0.4% Mg stearate

+ 1.0% Aerosil 1.9% for one tablet 100.0%

Diagram of compression by dry granulation:

ACTIVE INGREDIENT

+ Hydrophilic polymer + Mg stearate

Mixture + Talc + Aerosil

POWDER MIX

Compression

BRIQUETTES

Crushing - sieving

GRAIN

Mixture + Mg Stearate

LUBRICATED GRAIN

Compression

TABLETS

This formula is satisfactory after the packing and flow tests carried out on the powder, and after the hardness, friability, dissolution and average weight tests carried out on the tablets.

The tablet releases 96% of the active ingredient in 4 hours with dissolution at pH = 7.5. After 5 hours, 100% of the active ingredient is released.

The irritant nature of 4-ASA towards the gastric mucosa, common to all salicylates, leads to choosing an enteric coating which will protect the active principle and the gastric mucosa, and will give the tablet a more pleasant appearance. This coating also allows the protection of the active principle against gastric juice. For the coating of the 4-ASA matrices, a polymer which can be used in an organic medium will be used, in order to avoid the problems posed by humidity (hydrophilic matrix, hydrolysis of the active principle) and the heat-drying of the aqueous dispersions. . Among the gastro-resistant polymers usable in organic medium, the acrylic derivatives correspond best to the requirements of the tablet of 4- ASA- The range of Eudragit ^R (Rôhn - Pharma) allows a large choice of pH of dissolution, modular according to the quantities of Eudragit ^R L and Eudragit ^R S associated. Eudragit ^R S100 is an anionic polymer synthesized from ethyl esters composed of methacrylic acid and methyl ester of methacrylic acid, it is insoluble in acids and pure water. It is enteric-soluble from pH = 7. It is a white powder, very fine and fluid, with a slightly aromatic odor. The solvents are preferably isopropanol, acetone and ethanol as well as mixtures in equal parts acetone / isopropanol or isopropanol / methylene chloride or else a 60/40 ethanol / water mixture.

Eudragit ^R L100-55 is an anionic polymer synthesized from ethyl esters of acrylic acid and methacrylic acid. It is insoluble in acid and pure water. It is enteric soluble from pH = 5.5. It is a white powder, quite fine, fluid, with a slightly aromatic odor. The solvents are preferably isopropanol, methanol, ethanol and acetone as well as the solvent mixtures: acetone / isopropanol in the proportion 60/40 and isopropanol / water in the proportion 60/40.

Diethyl phthalate is a plasticizer whose role is to increase the flexibility of the macromolecules and allow the formation of a flexible film having good mechanical strength.

Talc is used as a non-stick to prevent sticking.

After various tests (disintegration, swelling and dissolution) and studies of the behavior of the tablets in an acid and alkaline medium, it is Eudragit ^R L100 - 55 which appears to be the polymer best suited to the desired goal. One of the coating formulas for 1000 g of uncoated tablet is as follows: Isopropanol 132.75 g

Acetone 88.92 g

Eudragit ^R L100- 55 12.82 g Diethyl phthalate 1.20 g

Talc 2.82 g

Sedisperse ^R 2.30 g

Tests have shown that satisfactory formulas are obtained when the tablets contain: - from 40 to 90%, and preferably from 60 to 80%, by weight of 4-ASA,

- from 10 to 40%, and preferably from 15 to 25%, by weight of hydrophilic polymer,

- from 0.5 to 5%, and preferably from 1% to 2.5% by weight, of gastro-resistant coating.

A formula retained for the 4-ASA controlled release tablet is as follows:

4 -AS A 500 mg HPMC K 100 100 mg Talc 5 mg Mg Stearate 2.5 mg

+ 6.2 mg

Aerosil 12.15 mg

Eudragit ^R L100-55 8.03 mg percentage of varnish

Diethyl phthalate 0.75 mg corresponding to 1.9%

Talc 1.77 mg of the mass of the product

Sedisperse ^R 1.44 mg tablet

The speed of dissolution of such a controlled release tablet dosed at 500 mg of 4-ASA according to the USP technique with a rotating basket with change of medium gives the following results (Table 1):

TABLE 1

PERCENTAGE OF 4-ASA DISSOLVED

MIDDLE TIME matrix matrix DISSOLUTION SAMPLING hydrophilic hydrophilic uncoated coated

pH = 1 30 minutes 0 0

60 minutes 0 0

2 hours <2% 0

0:30 a.m. 23% 0

1 h 32% 0

1 h 30 46% 0

2 h 54% 0

2:30 a.m. 62% 1%

3 h 75% 4%

PH = 7.5

4 h 96% 11%

± 1

5 h 100% 19%

6 h - 30%

7 a.m. - 42%

8 a.m. - 51%

12:00 p.m. - 81%

4 p.m. - 95%

Claims

1. Tablets administered orally for the controlled release of 4-ASA characterized in that they consist of 4-ASA in a hydrophilic matrix covered with a gastro-resistant coating.

2. Tablets according to claim 1, characterized in that the hydrophilic matrix is chosen from cellulose derivatives.

3. Tablets according to claim 2, characterized in that the cellulose derivatives are chosen from hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl¬ methylcellulose, methylcellulose and carboxymethylcellulose.

4. Tablets according to claim 1, characterized in that the gastro-resistant coating is chosen from acrylic derivatives.

5. Tablets according to claim 4, characterized in that the acrylic derivatives are chosen from anionic polymers synthesized from ethyl esters of acrylic acid and methacrylic acid.

6. Tablets according to claim 1, characterized in that they also contain adjuvants.

7. Tablets according to claim 1, characterized in that they contain: from 40 to 90%, and preferably from 60 to 80%, by weight of 4-ASA, from 10 to 40%, and preferably from 15 to 25%, by weight of hydrophilic polymer, - from 0.5 to 5%, and preferably from 1% to 2.5% by weight, of enteric coating.

8. A method of preparing tablets according to claim 1, characterized in that a granule containing 4-ASA, one or more hydrophilic polymers and one or more adjuvants is prepared which is compressed to obtain tablets containing the quantity required of 4-ASA, and which is covered with an enteric coating.