A CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITION FOR THE ORAL USE CONTAINING NON STEROIDAL ANTI-INFLAMMATORY DRUGS

Abstract: A pharmaceutical composition for the controlled release of non steroidal anti-inflammatory drugs, which gives effective plasmatic levels of drug during 12-24 hours. Said controlled-release composition includes: a) 3 or 4 dosage units (cores) containing 1/3 or 1/4 respectively of the drug total dose, said single dosage units consisting in tablets which can disgregate and/or in tablets which cannot disgregate, including the active ingredient as well as hydrophilic polymeric materials which can gradually release the active ingredients; and b) hard gelatin capsules containing 3 or 4 release units.

Description: A CONTROLLED-RELEASE PHARMACEUTICAL COMPOSITION FOR THE ORAL USE CONTAINING NON STEROIDAL ANTI-INFLAMMATORY DRUGS The present invention relates to pharmaceutical compositions for the controlled release of non steroidal anti-inflammatory drugs. The use of antirheumatic medicaments generally in- volves long-term treatments with 3-4 daily administrations, thus implying a poor compliance of the posology by the patient, besides a remarkable variability in the drug hematic levels. This problem can be overcome by controlled- or su- stained-release pharmaceutical formulations which allow to reduce the number of daily administrations, there¬ fore obtaining a more strict compliance of the posology by the patient. This kind of formulations can be classified in : - single-unit dosage forms - multiple-unit dosage forms. Single-unit dosage forms are generally easier and safer to be prepared, but sometimes they can suffer from the drawbacks of lacking release of the active in- gredient, or a "burst effect" due to a too fast release of the active ingredient. Multiple-dosage forms (generally chronoids or pel¬ lets) provide an improvement in bioavailability of the active ingredient and lower incidence of side-effects (such as gastrolesivity) . The present invention relates to a pharmaceutical composition for the controlled-release of non steroidal anti-inflammatory drugs which assures safety and repro- ducibility of the preparation, a precise control of drug plasmatic levels after the administration, a com¬ plete bioavailability and an extremely reduced incidence of side-effects. Said pharmaceutical composition is characterized in that the drug total dosage can be divided into 2,3 or 4 sub-units, consisting each of a small size tablet, which sub-units can be placed in a hard gelatin cap- sule. Sub-units can either be identical as far as the release characteristics are concerned, or they can be different from each other, depending on the desired du¬ ration of the therapeutical effect. Particularly, since symptomatology of the rheuma¬ tic disease can show exacerbations also depending on circadian rhythms, it sometimes is preferable to make use of dosage forms which can give rise to an initial high plasmatic concentration, followed by a slower re- lease of the drug, thereby lasting for a long time (for example overnight) . In any case, the dosage form of the invention has the following advantages : - Easiness of preparation : the preparation of the single dosage sub-units (small size tablets or coated tablets) involves no difficulties, since it is based on a well-established preparation technique. - Easiness of distribution : distribution of the 2, 3 or 4 dosage units in hard gelatin capsules can be carried out using well-established and reliable processes. - Control of the release : the formulation and composition of the single units determines the release characteristics. - Plasmatic levels and bioavailability : the con- trolled-release form administered to healthy volunteers gave rise to active plasmatic levels during a 12-24 hour period, with a complete bioavailability. Variability of the plasmatic level values turned out to be extremely reduced. - Side-effects: no healthy volunteer participating to the tests showed side-effects. Said advantages are obtained, according to *.he in¬ vention, by means of a tuning of the release characte¬ ristics of the sub-units, according to methods known to those skilled in the art. For example, 1 or 2 sub-units can give rise to a quick release of the active ingredient, whereas the re¬ maining 1, 2 or 3 sub-units can consist of hydrophilic matrices (based on hydrophilic polymeric materials and/or hydrogels) which can release gradually the active ingredient. Examples of said hydrophilic matrices include cellulose derivatives such as hydroxypropylmethyl cellulose, hydroxypropyl cellulose, sodium carboxy ethyl cellulose or polyvinyl alcohols of different molecular weights. Said alcohols or polymeric substances are present in the sub-units at percentages ranging from 5 to 80%, depending on the desired release characteristics. Of course, the capsule can also contain 2, 3 or 4 identical sub-units (of either the quick-release type or the sustained-release one) depending on the desired therapeutical effect. Examples- of non steroidal anti-inflammatory drugs which can advantageously be used as active ingredients in the compositions of the invention include arylacetic acids such as diclofenac, alclofenac, acemethacin, in- do ethacin; arylpropionic acids, such as ketoprofen, ibuprofen, naproxen, flurbiprofen, suprofen; salicylic derivatives, such as diflunisal; benzothiazine deriva¬ tives such as piroxicam, isoxicam, sudoxicam and the like. Ketoprofen is particularly preferred, in form of 4 50 mg sub-units, one of which being immediately relea¬ sed, whereas the other ones are gradually released during time, thus assuring effective plasmatic levels for 12-24 hours. A preparation as well as the "_in vitro" release characteristics and the plasmatic levels obtained after administration to healthy volunteers are reported by way of examples. EXAMPLE 1 Controlled-release pharmaceutical formulation con¬ taining 200 mg ketoprofen, consisting in a capsule in¬ cluding 4 dosage units, each containing 50 mg ketopro¬ fen and being designed for a controlled-release of the active ingredient. Dosage units were prepared as fol¬ lows : a) Preparation of sub-units (single units) The following material were used to prepare 1.000.00 cores : ketoprofen 50.00 kg hydroxypropylmethyl cellulose (Methocel K4M) R -(Colorcon) 37.50 kg mannitol 20.00 kg polyvinylpyrrolidone 7.500 kg colloidal silica 0.25 kg magnesium stearate 0.5 kg The active ingredient is mixed with hydroxypropyl- methyl cellulose and mannitol in a suitable mixing- kneading apparatus. The homogeneous mixture is wet with a 5% polyvinylpyrrolidone alcoholic solution, then kneaded, the resulting homogeneous humid mass is forced through a 400 micron screen and dried in an air- circulation oven. The dried granulate is added with magnesium stearate and colloidal silica, then it is compressed into tablets, according to the conventional technique, with 7 mm d. convex punches to obtain 3.0- 3.2 mm height tablets. Said tablets have hardness = 7 (Monsanto scale) and do not disgregate. b) Film coating A pharmaceutical composition (for example, a single tablet) with improved organoleptic characteri¬ stics and with uniform diffusion into the dissolution medium after the capsule disintegration, giving no aggregation, can be obtained by means of a typical film coating operation, for example, using an aqueous suspension having the following composition: Hydroxypropyl methyl cellulose g 4.01 (Methocel 606; Shinetzu, Tokyo) Talc g 0.30 Titanium dioxide g 0.20 Polyethylene glycol 6000 g 0.40 c) Packaging 4 Sub-units prepared as described in a) are placed into a transparent capsule Capsugel CONI-SNAP SϋPRO A type 0. "In vitro" release characteristics They were evaluated using the apparatus according to XXII (paddle) operating at 100 rpm, in 1000 ml of simulated intestinal fluid at pH 7.5 (according to XXII) at 37 C C. The "in_ vitro" release kinetic had the following profile : "In vitro" release characteristics The controlled-release formulation was administered to a healthy volunteer, recording the plasmatic concentration of the active ingredient at fixed time intervals. The results were as follows : EXAMPLE 2 Controlled-release pharmaceutical formulation con¬ taining 200 mg ketoprofen, consisting in a capsule in¬ cluding 4 dosage units, each containing 50 mg ketopro¬ fen and being designed for a controlled-release of the active ingredient. Dosage units were prepared as fol¬ lows : a) Preparation of sub-units (single units) The following materials were used to prepare 1.000.000 cores : ketoprofen 50.00 kg maize starch 40.00 kg methyl cellulose 0.65 kg polyvinylpyrrolidone 10.00 kg colloidal silica 0.25 kg magnesium stearate 0.5 kg The active ingredient is mixed with maize starch in a suitable mixing-kneading apparatus. The homogene¬ ous mixture is wet with a 2% methyl cellulose alcoholic solution, then kneaded, the resulting homogenous humid mass being forced through a 400 micron screen and dried in air-circulation oven. The dried granulate is added with cross-linked polyvinylpyrrolidone, Mg stearate and colloidal silica and it is compressed, according to the known technique, with 7 mm d. convex punches, to obtain 3.0-3.2 mm height tablets. The tablets have hardness = 3 (Monsanto scale) and do not disgregate. Packaging: One core prepared as described above and 3 cores prepared as reported in Example 1 are placed into a transparent capsule Capsugel CONI-SNAP SUPRO A type. "In vitro" release characteristics: They were evaluated using the apparatus according to XXII (paddle) operating at 100 rpm, in 1000 ml of simulated intestinal fluid at pH 7.5 (according to U.S.P. XXI) at 37°C.

Claims: CLAIMS 1. A pharmaceutical composition for the controlled release of non steroidal anti-inflammatory drugs, including: a) dosage units containing 1/3 or 1/4 of the drug total dose, which consist in tablets whose release cha¬ racteristics can be the same of different from each other; b) hard gelatin capsules containing 3 or 4 of said dosage units. 2. A pharmaceutical composition according to claim 1, in which tablets constituting the dosage sub-units con¬ tain hydrophilic polymeric materials which can cause a delay in the release of the active ingredient. 3. A pharmaceutical composition according to claim 2 , in which hydrophilic polymeric materials are selected from cellulose derivatives or polyvinyl alcohols having different molecular weights. 4. A pharmaceutical composition according to claim 2 or 3, characterized in that the polymeric materials are present in each sub-unit at a percentage from 5 to 80%. 5. A pharmaceutical composition according to any one of the preceding claims, containing ketoprofen as the active ingredient. 6. A pharmaceutical composition according to claim 5, in which the ketoprofen total dose is 200 mg, divided in four 50 mg sub-units with differentiate release of the active ingredient.

Inventors: CONTE UBALDO, CONTE, UBALDO
Applicants: FARCON AG
Application year: 1991
Main classification: A61K9
IPC codes: A61K9