GALENIC FORMULATIONS FOR ORAL USE OF RHEIN DERIVATIVES WITH DELAYED RELEASE FOR THERAPEUTICAL USE

Abstract: Several methods are disclosed for the preparation of oral pharmaceutical forms with delayed release of rhein and its derivatives.

Description: The derivatives of rhein, particularly diacetylrhein, are drugs endowed with a relevant antiarthrosic, analgesic and anti-inflammatory activity (Italian Patent No. 1098332). The present invention relates to a number of formulations for oral use with slow release of diacetylrhein and other derivatives of rhein for therapeutical purposes. It is known that the more widespread solid pharmaceutical forms for oral use with delayed release of active ingredients may be prepared by the following schemes: a) comminution of the drug in particles of very small size, and supporting them onto nuclei of inert substances. The microgranules thus obtained are thereafter coated with particular excipients (e.g. fatty substances and natural or synthetic waxes and plastic substances) so as to afford to the microgranules different rates of drug release. b) Absorption of the drug into suitable supports, (e.g. polymers and synthetic resins) so as to obtain insoluble complexes from which the active principle is gradually and slowly eluted under the action of the several biological factors of the gastro-enteric tract, such as pH, enzymatic activities and electrolitic concentration. c) Supporting on an inert matrix capable of slowly swelling within the gastro-enteric duct (for example chemically modified celluloses and polysaccharides) thus permitting the release of the drug in gradual manner by diffusion. d) Mixed technologies among those listed above which permit as well the delayed release of the drug. The present invention relates to the preparation of rhein derivatives and particularly of diacetylrhein derivatives in pharmaceutical formulations which permit a gradual and programmed release of the drug and such as to ensure a pharmacologically active hematic level throughout the period of 24 hours from the administration of the therapeutical dose of the drug. Some examples of formulation of rhein derivatives with slow release of the drug are hereinafter described, which have been controlled by the in vitro release test as well as by determining the hematic levels of the drug after experimental administration to animals. The examples hereinafter reported are not limiting and are described for the only purpose of better illustrate the content of the present invention. EXAMPLE 1 500 g of diacetylrhein with granule size of between 50 and 100 µm are carefully admixed with 150 g of finely powdered saccharose and 150 g of maize starch; the mixture is finely ground and then supported on 1000 g of micronuclei having about 0.4 mm diameter by wetting with a solution containing 37.5 g polyvinylpyrrolidone dissolved in 1 l of water. The granulate is dried in a hot air oven and the dried granulate is sieved to prepare different portions of end granules in each portion, containing granules of narrow size range and charaterized by having an average granules size different from the other portions, is coated in a basin with a 20% polyvinylpyrrolidone and 30% shellac isopropanol solution. The number of applications of the coating solution onto the several portion of the granules is adjusted as a function of the release times as experimentally measured by means of the in vitro test. The granules with different coating degrees are admixed as a function of the related release time measured so as to obtain in the same posologic unit (for example a capsule of hard gelatin) the desired amount of drug (for example 100 mg) and the release of the active principle within the programmed times (for instance 24 hours). EXAMPLE 2 500 g of diacetylrhein are carefully admixed with 10 g of polyvinylpyrrolidone, 50 g of microcrystalline cellulose, 100 g of sodium citrate; the mixture is wet granulated with water and the granulate is dried in a hot air oven. Separately 125 g of soya polysaccharides, 10 g of talc and 150 g of magnesium stearate are admixed and the mixture is wet granulated and dried. The two combined granulates are converted into tablets by means of a pressing machine and resulting tablets are coated by subsequent application of a solution containing 40 g of hydroxypropyl-methyl-cellulose phthalate, 10 g of acetylated monoglyceride and 10 g of titanium dioxide dissolved in 1 l of ethanol. "In vitro" release The capsules obtained according to Examples 1 and 2 are tested by means of an in vitro release test according to the method reported in U.S.P. XXI. Active principle/ /capsules mg 100 Percent of released active principle 1 h 4 h 8 h 18 h 24 h Example No. 1 46.4 63.1 72.7 79.3 88.7 Example No. 3 40.7 46.7 54.7 68.5 80.3 In "vivo" release As an example, the comparison between slow release diacetylrhein prepared according to Example No. 1 and diacethylrhein in a formulation with immediate release, administered to 4 male beagle dogs having an average weight of 10 kg, fasted since about 16 hours before the test, is reported. The diacetylrhein was administered in the two pharmaceutical forms according to a "cross-over" experimental scheme at a dose of 20 ml/kg and with a washout time of a week. The blood sampling was carried out at time 0 (basal) and thereafter 1, 2, 4, 12, 16, 20 and 24 hours following the treatment. In the serum samples the rhein was dosed by means of H.P.L.C.. The data reported in Figure 1 demonstrate that the slow release formulation whilst not essentially modifying the bioavailability (AUC 0-24h ) of diacetylrhein with respect to that of normal formulation, causes on the contrary a favourable change of the profile of the serum levels by extending the time of drug permanence in the hematic flow at therapeutical level up to 24 hours.

Claims: A delayed release pharmaceutical composition containing rhein or a derivative thereof as the active ingredient in the form of a mixture of granules characterized in that said granules are coated with a film of different thickness and are mixed in proportion depending on the scheduled release time, said film consisting of at least one compound selected from polyvinylpyrrolidone, shellac, hydroxy propylmethycellulose and their mixtures. The delayed pharmaceutical composition according to claim 1 wherein the rhein derivative is diacetylrhein or dipropionylrhein. The delayed pharmaceutical composition according to claim 1 wherein said film is in the form of a multiple layer.

Inventors: COPPI, GERMANO, SCEVOLA, MARIO ERCOLE, SPRINGOLO, VANNA
Applicants: PROTER S.P.A.
Application year: 1987
Main classification: A61K31
IPC codes: A61K47, A61K9, A61K31, A61P25, A61P29