Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-01-31
2002-04-30
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S499000, C424S501000, C424S494000, C424S495000, C424S497000
Reexamination Certificate
active
06379706
ABSTRACT:
The invention concerns pharmaceutical forms of administration that are in the form of pellets which contain at least one rounding agent required to produce extrusion pellets which acts as a retardant or disintegration-retarding agent which is suitable for delaying the release time of active substances, wherein the release of the active substance from the pellet (pellet A) is not less than that of a corresponding reference core pellet (pellet B) which does not contain this rounding agent as a pharmaceutical auxiliary substance. The release rate of these rapidly disintegrating pellets is at least about 90% within a time period of 30 minutes. In addition the present invention also concerns processes for the production these pellets.
Pellets are usually used for modified release drug forms. They have considerable advantages compared to conventional pharmaceuticals with a modified release of the active substance such as e.g. the avoidance of dose-dumping and local intolerances, minimized intra- and interindividual variations, independent of stomach emptying times, mixing of various retarded pellets, mixing of pellets with different (optionally incompatible) active substances and improvement of bioavailability.
The following principles are often used to produce pellets with a modified release of the active substance: a) modification of the active substance release with the aid of coatings or b) matrix systems.
Coatings that are resistant to gastric juice are stable in the acidic environment of the stomach and slowly dissolve by salt formation in a weakly acidic or basic range. Since, however, pellets are substantially independent of the stomach emptying rhythms, gastric juice-resistant coatings only lead to a short-term delay of the release of active substance.
Coatings are also used which are insoluble in the gastro-intestinal tract and release the dissolved active substance by means of diffusion through the coat. In this case the release rate can for example be set by means of the diffusion coefficients, the film thickness, the concentration gradient, the osmotic pressure and the use of pore formers. However, in the case of poorly soluble active substances the amount of liquid diffusing through the coat into the core is not sufficient to dissolve the active substance so that only a part of the total dose is released.
In order to circumvent these disadvantages time-controlled systems have been developed in recent years in which the envelope bursts after a certain delay time. The release profile can be adjusted by mixing pellet collectives with various coatings. These systems are distinguished by being independent of intraindividual and interindividual variations, they release the complete dose of active substance and are suitable for readily soluble as well as for poorly soluble pharmaceutical substances.
Milosovich (U.S. Pat. No. 3,247,066) developed a drug form with controlled release of the active substance based on small pellets which contain a colloid that swells in water and are coated with an indigestible envelope. Digestive fluid passes into the core containing disintegrant by means of diffusion which then swells and bursts the core.
A further variant of this multilayered so-called time controlled explosion system (abbreviated: TCES) (cf. EP 0 210 540 B1) in which a layer directly under the envelope which contains disintegrant causes the coating to burst.
Bayer AG (patent DD 297 767) developed a pellet formulation with a time controlled release that was produced by rotor granulation. With the aid of a release-controlling double layer composed of an external indigestible lacquer layer and an inner coat which controls the migration of the water towards the core, moisture reaches the core containing disintegrant which then bursts the envelope.
However, the formulations produced in U.S. Pat. No. 3,247,066, in EP 0 210 540 B1 and DD 297 767 were not produced by means of extrusion and rounding so that it was not possible to obtain pellets with a narrow particle-size distribution.
Double-coated granulates are known from EP 0 421 921 B1 which are obtained by extrusion of the wet granulate mass and which are moulded into spherical pellets with a diameter of 0.3 to 1.5 mm. However, these are pellets which achieve a time controlled release by a gastric juice-resistant but intestinal juice-soluble film and not by a burst mechanism.
Although an advantage of extrusion processes over rotor granulation is that a narrow distribution of particle sizes can be achieved, a fundamental disadvantage of extrusion pellets is that it is not possible to dispense with certain pharmaceutical additives such as microcrystalline cellulose for their production since they give the extrudate the required plastic-rigid properties required for rounding. In this case such additives in most cases also act as retarding agents i.e. they lead to a delayed (retarded) release of the active substance. This retardation which is often an inevitable consequence is not desirable in all cases. Retarding agents (in particular microcrystalline cellulose), can form a matrix system which prevents the disintegration of the pellets so that overall pellets with retarding properties with regard to the release of the active substance are obtained. Furthermore the additives used as rounding agents also acts as disintegration retarding agents i.e. they prevent the rapid decay of the pellets into smaller particles. Especially in the case of poorly soluble medicinal substances these effects cause a considerable delay in the release of the active substance and a retardation of the drug release. Hence active substances that have a strongly pH-dependent solubility profile and which are poorly soluble especially in the basic intestinal juice are characterized by the formation of a dense matrix system with microcrystalline cellulose. In such cases the release profile cannot be varied as desired by means of the composition and the thickness of the coating since the leaching of the drug from the matrix and the rate of disintegration of the pellets play an important role in the release properties.
Therefore the object of the invention was to provide such pellets that rapidly disintegrate and release the active substance in as short a time as possible from the core pellets although the pellets contain rounding aids which among others act as retarding agents and/or as disintegrating retarding agent.
It was surprisingly found that pellet cores which contain a) a rounding agent acting as a retarding agent or as a disintegration-retarding agent b) a tablet disintegrant (also referred to as intensive disintegrant in the following) and c) at least one auxiliary substance selected from the group comprising surfactants and binding agents and d) optionally fillers or combinations of these auxiliary substances, disintegrate well. Furthermore the corresponding active substances are rapidly released from the core pellets and essentially without delay compared to a pellet which does not have this rounding agent or retarding agent. This applies particularly to poorly soluble active substances. In particular the core pellets contain an intensive disintegrant, a surfactant and a binding agent in addition to the rounding agent. It is also possible to use a binding agent e.g. polyvinylpyrrolidone (PVP) instead of the surfactant. In a preferred variant a PVP is additionally added to the pellet core in addition to the surfactant.
A further advantage of the pellets according to the invention is that they have a narrow particle size distribution: At least 90% of the particles have a diameter of about 0.6-1.2 mm. Moreover the pellets also disintegrate relatively rapidly when they contain active substances which have a strong pH-dependent solubility profile. The pellets usually have a diameter between 0.5-2 mm, depending on the perforated disk used for the extrusion.
The rapidly disintegrating pellets according to the invention (also referred to as core pellet A in the following) have a release rate of the active substance which is not delayed despite the presence of
Gabel Rolf-Dieter
Lee Geoffrey
Opitz Michaela
Von Burën Hendrik
Arent Fox Kintner & Plotkin & Kahn, PLLC
Ghali Isis
Page Thurman K.
Roche Diagnostics GmbH
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