GB2151921A

GB2151921A - Controlled release form of ketoprofen for oral administration

Info

Publication number: GB2151921A
Application number: GB08431987A
Authority: GB
Inventors: Raymond Bentejac; Michel Veillard
Original assignee: Rhone Poulenc Sante SA
Current assignee: Rhone Poulenc Sante SA
Priority date: 1983-12-21
Filing date: 1984-12-19
Publication date: 1985-07-31
Also published as: FR2556965A1; GB8431987D0; JPH0635383B2; GB2151921B; FR2556965B1; JPS60132915A

Abstract

Sustained release tablets for oral administration of ketoprofen comprise ketoprofen in a hydrophilic matrix covered with a gastro-resistant coating.

Description

SPECIFICATION Controlled release form of ketoprofen for oral administration The present invention relates to compositions for oral administration containing 2-(3-benzoylphenyl)propionic acid, a powerful non-steroidal anti-inflammatory agent known as ketoprofen.

Ketoprofen is absorbed very rapidly from the upper part of the digestive tract. It has a short half-life and is rapidly eliminated.

The usual forms of ketoprofen for oral administration, such as gelatin capsules, which have a rapid rate of dissolution, do not modify the rate of absorption of ketoprofen, and it is necessary, for an effective dosage to take 2 gelatin capsules containing a 50 mg dose 2 to 3 times a day. As a result, the repeated administration is accompanied by peaks of relatively high maximum plasma concentration, which can cause gastric intolerance phenomena.

It is advantageous to be able to dispense to patients a controlled release form of ketoprofen for oral administration which permits gradual release of the ketoprofen, so as to reduce the number of administrations per day, to level out the peaks of maximum concentration, and to maintain a therapeutically effective plasma concentration for at least 12 hours.

It has now been found that tablets can be made which make it possible to control the release of ketoprofen.

According to the present invention, controlled release tablets for oral administration of ketoprofen comprise ketoprofen in a hydrophilic matrix covered with a gastro-resistant coating.

The gastro-resistant coating makes it possible to avoid any direct contact between the irritant active substance and the gastric mucous membrane. Disaggregation of the gastro-resistant coating takes place beyond the stomach by virtue of the pH difference which exists between the gastric liquid and the intestinal liquids. Free of its coating, the hydrophilic matrix can then play its part in regulating the release of the active principle.

The manner in which the hydrophilic matrix functions can be schematically broken down into three stages: 1) Under the effect of the intestinal fluids, a gelled barrier forms on the surface by hydration and gelling of the polymer which makes up the hydrophilic matrix. The few particles of active principle which are near the surface of the tablet dissolve at the same time; this portion constitutes the initial dose.

2) Water penetrates into the tablet and, in return, the active principle diffuses into solution. The water advances concentrically into the tablet and permits hydration of the hydrophilic polymer to give new gelled barriers at increasing depth, which in turn permit release of ketoprofen. The active principle dissolves at the water penetration front and diffuses through the gelled barrier.

3) The hydrogels formed by the gelled barriers are gradually destroyed starting from the surface of the tablet most exposed to the intestinal fluids. Two phenomena compete in the structure breakdown of these hydrogels: the dissolution of the skeleton formed by the active principle in solid form, and the loosening of the polymer network associated with swelling of the polymer.

For this complex system of structure formation breakdown of the viscous barriers to function appropriately, the swelling of the hydrophilic polymer must be capable of creating a gelled barrier on the surface without causing the tablet to disaggregate; there is competition between the gelling effect, which fuses the body of the tablet, and the disintegrating effect, which tends to disperse it. Numerous parameters take part in this competition, among which there may be mentioned the viscosity of the hydrophilic polymer in aqueous solution, its hydration rate, its gelling rate and also its particle size and its concentration in the tablet. It is therefore particularly advantageous to use a hydrophilic polymer whose viscosity in aqueous solution is high but compatible with the formation of the gelled barrier on the surface in a suitable time.

Furthermore, the hydrophilic polymer must be compatible with the active substance and pharmaceutically acceptable.

The hydrophilic polymers which are particularly suitable are chosen from cellulose derivatives such as hydroxyethylcellulose, hydroxypropylcellulose or hydroxypropylmethylcellulose. It is particularly advantageous to use hydroxyethylcellulose and more especially Natrosol 250 HHX (registered trademark of the Hercules company).

Hydroxyethylcellulose permits the formation, within the tablet, after immersion in an aqueous phase, a gastric medium or an intestinal medium, of a hydrophilic matrix regulating the release of the ketoprofen.

This polymer, which is compatible with ketoprofen, has the advantage of a gelling rate which is sufficient to prevent disaggregation of the tablet while at the same time forming a crosslinking network suitable for controlled release of the active principle. Hydroxyethylcellulose has a high viscosity in aqueous solution and a fine particle size and it gives a good compressibility to the granules. The gastro-resistant coating has the effect of further delaying the release of the ketoprofen and of preventing any direct contact between the irritant active substance and the gastric mucous membrane. The gastro-resistant coating is preferably cellulose acetophthalate, but other gastro-resistant polymers can be used.

The tablets according to the invention can contain other adjuvants such as diluents (e.g. dicalcium phosphate, starch, lactose and microcrystalline cellulose), binders (e.g. polyvinylpyrrolidone and starch paste), wetting agents, lubricants (e.g. magnesium stearate, polyoxyethylene glycols and colloidal silicas) and colourants.

In general, a tablet according to the invention contains from 10 to 80% by weight of ketoprofen, from 10 to 60% by weight of hydrophilic polymers and from 0.5 to 10% by weight of gastro-resistant coating.

According to a feature of the invention, the new controlled release tablets are made by preparing granules containing the ketoprofen, one or more hydrophilic polymers, and optionally one or more adjuvants, e.g. as described above, compressing the granules to give tablets containing the required quantity of ketoprofen, and covering the tablets by lacquering with a gastro-resistant coating.

Depending on the particular case, the method of preparation of the granules will involve dry granulation, wet granulation or so-called direct compression. The granules are then compressed to give tablets containing the required quantity of ketoprofen. Finally, the tablets are covered with a gastro-resistant coating by lacquering, e.g. with a solution of cellulose acetophthalate.

The controlled-release ketoprofen tablets according to the present invention make it possible to prevent any contact between the particles of ketoprofen and the gastric mucous membrane, to level out the peaks of maximum plasma concentrations which would be obtained with an immediate-release form of ketoprofen, to maintain a plasma concentration which is still detectable after about 24 hours, and to produce a form which is bio-equivalentto ordinary gelatin capsules.

The Examples which follow show how the invention can be put into practice.

Example 1 Granules (5 kg) having the following composition are prepared: ketoprofen ........................................ 40% dicalcium phosphate ........................................ 48% hydroxyethylcellulose ........................................ 10% magnesium stearate ........................................ 2% A mixture of the first three constituents is granulated with water and the granules are then dried at 45 C for 20 hours in a ventilated oven. The dry granules are brought to a uniform size by passage through a sieve of 1 mm mesh size and then lubricated by mixing with the 2% of magnesium stearate.

The granules are compressed using either a reciprocating or a rotary compressor, the unit weight of the tablet being adjusted so that each tablet contains the chosen dose of ketoprofen (i.e. 500 mg for a tablet containing a 200 mg dose of ketoprofen).

The gastro-resistant lacquer is applied by spraying a solution having the following composition: cellulose acetophthalate ........................................ 5% ethyl phthalate ........................................ 1.25% ethyl acetate ........................................ 46.875% denatured ethyl alcohol ........................................ 46.875% onto the tablets rotating in a turbine, at a rate of 500 g per kilogram of tablets, using a compressed air gun.

After the lacquered tablets have dried for 2 hours at 45 C and then for 16 hours at a temperature of the order of 20 C, the quantity of gastro-resistant lacquer corresponds to 3% of the weight of the coated tablets.

Example 2 The procedure of Example 1 is followed, but the unit weight of the tablets is adjusted to 250 mg to give a tablet containing a 100 mg dose of ketoprofen.

Example 3 The procedure of Example 1 is followed, but the unit weight of the tablets is adjusted to 375 mg to give a tablet containing a 150 mg dose of ketoprofen.

The efficacy of the tablets of the present invention has been demonstrated in vitro and in vivo.

In vitro, the dissolution rate of a controlled-release tablet containing a 200 mg dose of ketoprofen is compared with the dissolution rate of an immediate-release form containing a 200 mg dose of ketoprofen, according to the USP technique using a rotating basket with changing of the medium. The results are collated in Table 1.

TABLE I Dissolution Sampling Percentage of ketoprofen dissolved Medium time Immediate- Controlled release form release form 30 minutes 75% pH = 1 60 minutes 97% 2 hours 100% 1% 1 hour - 15% 3 hours - 27% pH = 7.4 5 hours - 37% 21 hours - 90% In vivo, the rate of release can be monitored by measuring the plasma concentrations (in Fg/cc) after a single oral administration, to a healthy man, of a controlled-release tablet containing a 200 mg dose of ketoprofen and of an immediate-release form containing the same 200 mg dose. The results are collated in Table II, which gives the averages obtained for 10 subjects treated.

TABLE II Controlled-release form Immediate-release form Time Average Standard Time Average Standard (hours) plasma deviation (hours) plasma deviation concentration concentration 0.75 11.31 7.63 1.00 0.00 0.02 1.00 14.62 6.72 1.25 13.73 5.55 1.50 12.41 3.98 1.75 12.92 3.97 2.00 0.57 0.91 2.00 11.16 3.93 2.50 9.42 4.12 3.00 1.96 1.76 3.00 6.96 3.39 3.50 2.40 1.48 4.00 2.34 1.06 4.00 4.06 1.61 4.50 2.39 0.98 5.00 2.44 0.55 5.00 2.40 0.74 5.50 2.51 0.57 6.00 2.62 0.85 6.50 2.61 0.87 7.00 2.65 1.00 7.00 0.93 0.33 7.50 2.54 0.99 8.00 2.41 0.94 9.00 2.56 1.03 9.00 0.38 0.07 13.00 2.25 0.98 13.00 0.15 0.13 17.00 1.40 0.47 20.00 0.87 0.31 24.00 0.64 0.52 24.00 0.04 0.06

Claims

1. A controlled release tablet for oral administration of ketoprofen, comprising ketoprofen in a hydrophilic matrix covered with a gastro-resistant coating.

2. A tablet according to claim 1, wherein the hydrophilic matrix is a cellulose derivative.

3. Atablet according to claim 2, wherein the cellulose derivative is hydroxyethylcellulose, hydroxypropy Icellulose or hydroxypropylmethylcellulose.

4. A tablet according to any of claims 1 to 3, wherein the gastro-resistant coating is cellulose acetophthalate.

5. A tablet according to any of claims 1 to 4, which also contains an adjuvant.

6. A tablet according to any of claims 1 to 5, which contains from 10 to 80% by weight of ketoprofen, from 10 to 60% by weight of the hydrophilic matrix and from 0.5 to 10% by weight of the gastro-resistant coating.

7. A tablet according to claim 1 substantially as hereinbefore described in Example 1,2 or 3.

8. A process for the preparation of a tablet according to any of claims 1 to 6, which comprises preparing granules containing the ketoprofen, one or more hydrophilic polymers, and optionally one or more adjuvants, compressing the granules to give a tablet containing the required quantity of ketoprofen, and covering the tablet by lacquering with a gastro-resistant coating.

9. A controlled release tablet for oral administration of ketoprofen, comprising ketoprofen in a hydrophilic matrix covered with a gastro-resistant coating when prepared by the process claimed in claim 8.