Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2001-07-13
2004-08-03
Page, Thurman K. (Department: 1615)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C424S489000
Reexamination Certificate
active
06770368
ABSTRACT:
The subject of the present invention is a composition of granules based on starch and lactose, as well as the process which makes it possible to obtain these granules.
It also concerns the use of such granules in particular as excipient in the pharmaceutical industry or as additive or carrier in the food or chemical industries.
The pharmaceutical industry consumes many tons of starch and lactose. These are in particular used as excipients in dry formulations such as, for example, powders for filling hard capsules, powders to be dissolved, pulverulent nutrient preparations and tablets.
The food industry uses, for its part, this type of excipient in particular in foods and drinks to be dispersed and to be diluted.
As regards the field which is of particular interest for the present invention, namely pharmaceutical or food excipients, such excipients exist in the form of powders obtained by wet granulation of a mixture of lactose and starch, supplemented with binders or surfactants. These powders generally possess unsatisfactory direct tableting capacities.
The most important factors for assessing the direct tableting capacity of a powder are the flow capacity (regular supply to the tableting chamber from the hopper), the resistance to abrasion (or non-friability), and the cohesion after compacting of the particles, which determines the hardness of the tablets. The tablets produced must be sufficiently hard to withstand breaking but at the same time have good disintegration properties when they are in the gastric medium.
Among the excipients most commonly encountered in tableting, there may be mentioned in particular cellulose, starch, lactose and dicalcium phosphate.
Microcrystalline cellulose fulfils all the conditions expected of a direct tableting excipient, but it remains difficult to produce and is relatively costly. It has, in addition, the disadvantage of causing a decrease in the hardness of the tablets following uptake of water during storage. Additionally, it causes an unpleasant sensation in the mouth.
Lactose is a diluent which is widely used in tablet technology. It exists in two main forms: crystallized or spray-dried. Crystallized lactose exists in three different crystalline forms: anhydrous &agr;-lactose (not commercially available), anhydrous &bgr;-lactose (usually referred to as anhydrous lactose) and &agr;-lactose monohydrate. Anhydrous lactose has the disadvantage of being hygroscopic, which causes problems of stability over time. &agr;-lactose monohydrate is stable but its tableting capacity and disintegration time remain inadequate. In order to improve the latter, lactose has been modified by spray drying and compression.
Spray-dried lactose is highly compressible, and the spherical shape of its particles allows good flow properties. It is less stable and its storage period is shorter than that of crystalline lactose. Tablets manufactured from spray-dried lactose develop a yellowish colour during storage which is more intense than that developed by lactose monohydrate.
Compressed lactose is a stable powder which flows well but is less compressible than spray-dried lactose. The tableting properties of lactose remain inadequate but they have been improved by addition of a binding or diluent excipient possessing better tableting capacity, such as a microcrystalline cellulose. These mixtures can be easily tableted by virtue of the addition of a lubricant. Microcrystalline celluloses have, however, the disadvantage of a high price, and of a reduction in the hardness of the tablets formed following moisture uptake.
As for starch, it has, because of the small size of its particles and its low density, the disadvantage of not flowing. The high elasticity of its granules make its tableting capacity inadequate to allow the manufacture of tablets of sufficient hardness. On the other hand, it possesses good disintegrating properties because of its swelling power in water. Starch can also serve as binder and diluent and even as flow-promoting agent.
It has been proposed to combine lactose and starch by wet granulation (BODE-TUNJI M. O., JAIYEOBA K. T., Labo-Pharma—Probl. Tech.—32, No. 340, March 1984, pp 190-192). However, it has been demonstrated that the addition of starch to lactose reduces the mean size of the granules and increases their friability, this effect being compensated for by the addition of a surfactant.
It has also been proposed to granulate lactose and starch using a synthetic polymer as binder (WAN L. C., LIM K. S., S.T.P. Pharma Sciences 1 (5) 285-293, 1991). The compositions obtained have an acceptable flow, but relatively low densities.
Processes for the preparation, by spray-drying, of complex tableting excipients, such as that described in U.S. Pat. No. 5,006,345, comprising lactose, a binder such as polyvinylpyrrolidone or hydroxypropylmethyl-cellulose, and a disintegrating agent such as in particular crosslinked carboxymethylcellulose or carboxymethylated starch, are also known.
A need therefore remains, which has not been satisfied, for a composition of lactose and starch granules possessing reduced friability, efficient flow, good tableting capacity and satisfactory disintegrating properties, while being only slightly hygroscopic.
The aim of the invention is to satisfy this need and the applicant has had the merit of finding, after numerous studies, that this aim can be achieved when granules in accordance with the invention, based on starch and lactose, are used. To obtain such granules, the applicant has observed that, against all expectations, it was advisable to use a granular starch and lactose mixture and to modify its physical characteristics by using an appropriate process such that moderate friability, satisfactory tableting capacity and efficient flow are obtained at the same time, while preserving the disintegrating properties.
The invention thus concerns granules consisting of lactose and starch, characterized in that they exhibit a friability of less than or equal to 80% according to a test A.
This test A consists in subjecting the granules to be tested to mechanical action in an apparatus called a friabilimeter. For this, an apparatus is used which is of the ERWEKA TA trademark manufactured by the company ERWEKA (GERMANY-6056 HEUSENSTAMM) revolving at a uniform rotating speed of 25 revolutions/minute, and equipped with a crushing chamber into which there are introduced 5 identical steel beads having a diameter of 17 mm and a weight of 18.87 g. To carry out this test A, a quantity of 15 g of product having a particle size between 100 and 200 &mgr;m is introduced into the crushing chamber of this friabilimeter and then the apparatus is rotated for 5 minutes.
At the end of the experiment, the proportion by weight represented by the residue retained on a sieve having a mesh width of 100 microns is determined.
The friability value corresponds to the percentage of powder not retained by the sieve defined above. The greater the percentage of powder not retained by the sieve, the greater the friability.
The granules in accordance with the invention exhibit, according to this test A, a moderate friability, that is to say of less than or equal to 80%, and preferably less than or equal to 60%.
The granules in accordance with the invention can also be characterized by a spherical structure when they are observed by scanning electron microscopy. This very specific structure is illustrated by FIGS.
1
,
1
′ and
2
,
2
′ which show the perfect sphericity of the granules obtained.
FIG. 1
shows a scanning electron micrograph of a granule according to the invention having a lactose/starch ratio of 75/25.
FIG. 2
shows a scanning electron micrograph of a granule according to the invention, having a lactose/starch ratio of 85/15. By virtue of this structure, the granules in accordance with the invention have a completely satisfactory flow.
According to one embodiment of the invention, the granules are characterized by a lactose to starch ratio of between 90/10 and 25/75. It is indeed possible to vary at will the proportions of lact
Joynes Robert M.
Page Thurman K.
Roquette Freres
Sturm & Fix LLP
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