Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2001-12-03
2003-12-09
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S456000, C424S457000, C424S459000, C424S497000, C424S462000, C514S772300, C514S785000
Reexamination Certificate
active
06660296
ABSTRACT:
The present invention relates to novel forms of sustained-release (SR) microgranules containing Diltiazem as active principle.
Diltiazem is a calcium-antagonist benzothiazepine derivative which is useful for the treatment of arterial hypertension. It may be administered in various forms: tablets, injectable solutions or gelatin capsules containing sustained-release granules. The latter have the advantage of allowing the administration to be taken as a single dose required for daily treatment.
Various forms of Diltiazem SR microgranules have been described in the prior art, the most advantageous being that described in patent application EP-A-0,149,920, comprising a core combining Diltiazem with a water-soluble organic acid, in particular fumaric acid. The reason for this is that Diltiazem, or its pharmaceutically acceptable salts, are sparingly soluble at neutral or basic pH, and the presence of a water-soluble organic acid has proven to be particularly important, making it possible to create a buffered acidic microenvironment, promoting both the dilution and the absorption of the Diltiazem in areas of the digestive tract where the pH is too high. It has, nevertheless, been observed that for these SR forms, the solubilization and absorption of Diltiazem were dependent on the absorption of food, and are different when uptake of the microgranules is carried out on an empty stomach or during meals.
Organic-acid-free SR microgranules have been described in patent application EP-A-0,613,370. The core of the microgranules consists here of a neutral grain coated with a succession of layers of a water-soluble polymer, on the one hand, and of Diltiazem on the other hand.
For these various forms, the sustained release of the active principle is ensured by one or more layers coating the core of the microgranules, generally combining two types of film-forming polymer material, one being water-insoluble and the other water-soluble.
The present invention relates to a novel form of SR microgranules containing Diltiazem, or a pharmaceutically acceptable salt thereof, which is free of water-soluble organic acid, making it possible to obtain solubilization and absorption of the active principle which are at least equivalent to those obtained in the presence of an acid. In addition, the present invention relates to a simple novel form of SR microgranules containing Diltiazem, which is easy to prepare.
The microgranules according to the invention comprise a neutral granular support coated with an active layer comprising Diltiazem or a pharmaceutically acceptable salt thereof, a surfactant and a binder, and a layer which ensures sustained release of the active principle (referred to hereinbelow as the SR layer).
More particularly, the microgranules in accordance with the present invention may be of several categories.
The first category is represented by microgranules whose SR layer ensures slow sustained release of the active principle.
The second category is represented by microgranules whose SR layer ensures rapid sustained release of the active principle.
The difference between these two categories of monolayer microgranules lies essentially in the thickness of the coating agent contained in the SR layer. Indeed, the thicker this SR layer is, the slower will be the diffusion of the active principle.
The dissolution profile of each of these two types of microgranule is determined in vitro using water as dissolution medium, and gives the following specifications:
Preferred
Hours
Dissolution
Dissolution
Rapid microgranules:
2 h
0-45%
≦30%
6 h
≧50%
≧65%
Slow microgranules:
12 h
0-60%
≦30%
20 h
≧50%
≧45%
Mixture:
1 h
≦15%
≦15%
6 h
≦55%
25-55%
10 h
30-70%
30-60%
16 h
30-85%
55-85%
22 h
—
≧80%
The present invention also relates to a third category of microgranules resulting from the coating of the SR layer which ensures slow sustained release of the active principle, that is to say of the SR layer of microgranules of the first category above, from another active layer comprising:
Diltiazem or a pharmaceutically acceptable salt thereof as active principle,
a surfactant, and
a binder,
itself coated with an external layer which ensures rapid sustained release of the active principle contained in this active layer.
In other words, these so-called “bilayer” microgranules consist, from the centre to the periphery, of a neutral granular support, of a first active layer, of an SR layer ensuring slow sustained release of the active principle contained in the first active layer, of a second active layer and of an SR layer ensuring rapid sustained release of the active principle contained in the second active layer.
It is understood that for the so-called “bilayer” microgranules, only the specifications described above and corresponding to the slow and mixed microgranules can be applied.
Advantageously, a so-called protective coating or intercalating layer is applied to the microgranule between the SR layer ensuring slow sustained release of the active principle and the second layer of active principle.
Indeed, it has been shown that during application of the second layer of Diltiazem, and/or during dissolution of the microgranules, interactions are established between the Diltiazem and the SR layer located between the two active layers, thereby leading to the modification of sustained release of the Diltiazem contained in the first active layer. This intercalating layer acts as it were as insulation between the two layers concerned, protecting them from each other. Another means of obtaining the same result would consist in using for the SR layer in question a coating agent which does not interact with the Diltiazem.
The neutral granular support consists of any pharmaceutically acceptable neutral granular support, with an average diameter of between 0.4 and 0.9 mm, preferably 0.4 and 0.6 mm. These are preferably grains consisting of sucrose and starch in a weight ratio in the region of 75/25, such as those described under the name “Sugar Spheres” (Handbook of Pharmaceutical Excipients, 2nd Ed., The Pharmaceutical Press, London, 1994).
The hydrochloride is preferably among the pharmaceutically acceptable salts of Diltiazem.
The surfactant may be an anionic, nonionic, cationic or amphoteric surfactant. It is preferably an anionic surfactant. Among the anionic surfactants are alkali metal (C
10
-C
20
)alkyl sulphates, preferably sodium lauryl sulphate, alkali metal (C
10
-C
20
)alkyl sulphonates or alkali metal (C
10
-C
20
)alkyl benzenesulphonates. The term alkali metal is preferably understood to refer to sodium or potassium.
The binder consists of any pharmaceutically acceptable binder which is useful for coating neutral granular supports, in particular pharmaceutically acceptable polymers such as the polyvinylpyrrolidones described under the name povidone (Handbook of Pharmaceutical Excipients, 2nd Ed., The Pharmaceutical Press, London, 1994), or hydroxypropyl methyl celluloses (HPMC), polyethylene glycols (PEG), etc.
The active layer comprising the Diltiazem may also comprise other common additives, such as a plasticizer.
In general, the active principle
eutral granular support weight ratio is in the region of 4/1. The term active principle is understood to refer to Diltiazem or the pharmaceutically acceptable salts thereof.
The active principle/surfactant weight ratio is advantageously between 99/1 and 95/5, preferably about 98/2.
The active principle/binder weight ratio is itself between 99/1 and 90/10, preferably in the region of 97/3.
The monolayer microgranules according to the invention preferably comprise the following components for the support and the active layer, the percentages being given on a weight basis for a total of 100:
neutral granular support
20-25%
active principle
70-75%
surfactant
0.5-5%
binder
0.5-10%
plasticizer
0-5%.
The bilayer microgranules according to the invention preferably comprise the following components for the support and the active layers, the percentages being given on a weight basis
Debregeas Patrice
Leduc Gerard
Oury Pascal
Suplie Pascal
Foley & Lardner
Laboratories des Produits Ethiques Ethypharim
Spear James M.
LandOfFree
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