Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1993-04-16
1995-12-19
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424490, 424497, 424467, A61K 914
Patent
active
054766672
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a method (melt granulation) for producing pellets which contain a therapeutically active substance. The pellets produced have a spherical configuration. The invention is applicable primarily to high-dosage substances, i.e. compounds which shall be ingested per os in dosages of about 300-500 mg when administered to humans.
Pellets (e.g. spheres) intended for the administration of drugs per os are normally smaller than 2.5 mm (diameter) and larger than 0.3 mm, and are preferably in the range of 0.3-2.0 mm.
Melt granulation is a known process and involves mechanically working a particulate substance mixed with a binder which has a melting point of 40.degree.-70.degree. C., such as to form granules (pellets). During the process of manufacture, the binding agent melts and adheres to to the surface of the particulate substance, said particles therewith adhering together and building up to a granule form (pellets). Melt granulation will preferably result in matrix-type spherical pellets of low porosity. See, for instance, Drug. Dev. Ind. Pharm. 16 (1990), pages 1249-77. Melt granulation has been applied to the production of sustain release pellets, see U.S. Pat. Nos. 4,013,784; 4,132,753; and 4,935,246.
The most important pellet manufacturing methods are: solution that contains an active substances, binder and water. The amount of active substance used is normally </=30% (w/w) of the ultimate pellets. The method is primarily intended for active substances which are administered in dosages of 20-30 mg. The pellets obtained are spherical in shape when the particles used are spherical. appropriate plastifying binder (e.g. 10-50% microcrystalline cellulose or methyl cellulose), followed by rounding the extrudate on a rotating disc. The amount of active substance present in pellets produced in accordance with this method is at maximum about 50% (w/w). This method produces primarily pellets of an elongated configuration. suitable polymers. The geometric shape of the pellets obtained is determined by the geometric shape of the crystals. See for instance U.S. Pat. No. 4,957,746 or the corresponding EP publication 168,360.
When it is desired to release active substances in defined regions of the gastrointestinal tract, prepared pellets have been coated with a protective layer, for example a gastric-juice resistant film (enteric-coated), or have been placed in capsules that possess appropriate release properties.
None of these earlier known pelletizing methods have been found satisfactory for use with therapeutically active cohesive substances which are intended to be administered in high dosages and when quick release of the active substance from the administered pellet is desired subsequent to the pellets having reached their intended location in the gastrointestinal tract. The pellets produced have normally been excessively. small and/or have exhibited marked agglomeration tendencies. The pellets produced in accordance with the earlier known methods have also been too porous to enable the pellets to be converted to tablet form--more compact pellets have been desirable. There has been found the need for new methods of producing pellets, particularly pellets which contain water-soluble, therapeutically active substances of high dosage type.
The present invention provides one such method, which can also be applied to other therapeutically active substances. The inventive melt-granulating method (pelletizing) enables the production of a novel drug composition for active substances of high dosage type. This novel composition constitutes one aspect of the invention.
The inventive method for pelletizing a therapeutically active substance is characterized by: C., preferably from 40.degree. C. to 70.degree. C., while supplying energy in an amount such that the binder will melt and the mixture will granulate to form spherical pellets, wherein the quantity ratio between active substance and binder is selected so that the spheroids formed will be overwetted; optionally with the inclusion of inter
REFERENCES:
patent: 4013784 (1977-03-01), Speiser
patent: 4129666 (1978-12-01), Wizerkaniuk
patent: 4132753 (1979-01-01), Blichare et al.
patent: 4572833 (1986-02-01), Pedersen et al.
patent: 4935246 (1990-06-01), Ahrens
patent: 4957746 (1990-09-01), Valducci
patent: 5147655 (1992-09-01), Ibsen
Drug Development And Industrial Pharmacy vol. 16, No. 8, 1990 T. Schaefer et al: "Melt granulation in a laboratory scale high shear mexer", pp. 1249-1277.
Holm Per
Kristensen Arne
Benston, Jr. William E.
Kabi Pharmacia AB
Page Thurman K.
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