Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-05-01
2004-07-13
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S451000, C424S489000, C514S770000, C514S772300, C514S777000, C514S778000, C514S781000, C514S951000, C514S960000, C514S961000
Reexamination Certificate
active
06761905
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a novel granulation process for the preparation of direct tabletting formulations for pharmaceutically-active ingredients, or direct pharmaceutical tabletting aids using pharmaceutical excipients. In particular, this novel granulation process is performed under the condition of low moisture content or low content of a pharmaceutically-acceptable solvent by subjecting a mixture containing one or more diluents and/or active ingredients; a binder; and optionally a disintegrant, to heating in a dosed system under mixing by tumble rotation.
The invention furthermore relates to tablets, capsules, or pellets, which comprise such direct tabletting formulations or tabletting aids, and to processes for producing the tablets, capsules, or pellets comprising the direct tabletting formulations or tabletting aids according to the present invention.
2. Description of the Related Art
The modern tabletting process often involves the compression of direct tabletting aids (excipients), along with active substances, into a tablet under pressure. Direct tabletting aids are required to have not only good flow properties and binding capacity but also a high uptake capacity for active substances, which are generally difficult to compress. This is also true for developing a directly compressible formulation for any pharmaceutically active ingredients. Optimally, the resulting tablets are generally intended to have low friability and high fracture resistance. Some of these requirements are contradictory. For example, high tablet fracture resistance is associated with the presence of many points of contact between the diluent (filler) or pharmaceutically active ingredient and binder inside the tablet, which is usually achieved with the use of diluent and binder in the form of fine particles. However, fine-particle substances in turn have poor flow properties, limiting their suitability for use in high-speed processes. Attempts have been made over the years to improve or modify the diluents (or pharmaceutically active ingredient) and binders so that these contradictory properties are substantially eliminated while retaining the beneficial characteristics.
Direct tabletting aids of this type, which are also referred to as “multipurpose excipients”, are, as a rule, preparations which are produced via specific processes, consist of a plurality of components and are also mentioned as co-processed materials in the literature. For example, a combination of &agr;-lactose monohydrate and powdered cellulose is disclosed for direct tabletting in DE-C 3 506 276. Although this composition has a high binding capacity, it has no disintegration-promoting properties, especially when the compressive forces are relatively high. Another combination of &agr;-lactose monohydrate and polyvinyl pyrrolidone as binder, and crosslinked, insoluble polyvinyl pyrrolidone to promote disintegration, disclosed in DE-A 35 05 433 (U.S. Pat. No. 5,006,345), has excellent flow properties and results, without further addition of a disintegrant, in rapidly disintegrating tablets. However, this direct tabletting aid is less suitable for high-dose active substances whose compressibility is poor, because its uptake capacity for active substances to form tablets with sufficient mechanical stability is limited.
U.S. Pat. No. 5,840,769 described a direct tabletting aid using microcrystalline cellulose (MCC) as diluent, soluble polyvinyl pyrrolidone (PVP) as binder, and crospovidone as disintegrant. It was taught that this product can be prepared by conventional wet granulation methods such as mixer granulation, Shugi granulation, extrusion, perforated plate granulation, or preferably, fluidized bed granulation. Wet Granulation of excipients (diluents or disintegrants) or pharmaceutically active ingredients, using a binder, such as PVP, dissolved in water and/or organic solvents, is a common practice. However despite its widespread usage, wet granulation is a process with certain fundamental drawbacks.
The technique of wet granulation is often employed in the pharmaceutical industry to improve the properties of a tabletting mixture. Wet granulation involves the addition of a binder solution to aggregate smaller particles into larger granules for the improvement of powder flowability. Due to the even distribution of the binder on the surface of the diluent or active ingredient, thereby increasing the points of contact, binding efficiency of the resulting granules is often increased and results in greater tablet strength. Granulation also serves to reduce dust in the tabletting mixture and improve workplace conditions during the automated tabletting processes. Another benefit of wet granulation is that it helps to facilitate the uniform blending of components in a tabletting mixture.
Wet granulation requires a large amount of liquid to be added, which necessitates tanks and handling equipments. Since the liquid used in wet granulation must subsequently be removed, a drying step is also needed, thereby requiring drying equipment and further complicating the manufacturing process, as well as significantly increasing the energy, cost and production time of the overall process. Furthermore, the use of large amounts of volatile organic solvent as granulating fluid may be harmful to the operator as well as the environment Special precaution and equipments are necessary to avoid explosions and protect workers from exposure to these solvents.
Another disadvantage of wet granulation is that, in certain instances, the presence of excessive moisture can negatively affect the ingredients in the tabletting formulation. For example, as discussed in U.S. Pat. No. 6,103,219, it is known that the exposure of microcrystalline cellulose to moisture in the wet granulation process severely reduces the compressibility of this excipient, mainly due to softening of the cellulose fibers. This loss of tabletting strength dictates that a larger amount of the MCC may be needed to obtain an acceptably compressed final product, especially when a high dose of active ingredients is sought The additional amount of MCC required not only adds cost to the preparation, but more importantly, increases the size and bulk of the resulting tablet, making it more difficult to swallow. The loss of compressibility of microcrystalline cellulose caused by wet granulation has long been considered a problem in the art for which there has been no satisfactory solution.
The literature is flooded with various examples for the use of PVP (or other binders) in wet granulation (eg., WO 93/09763; WO 00/06125; U.S. Pat. No. 4,968,509; U.S. Pat. No. 5,200,193; U.S. Pat. No. 5,462,747). By in large, wet granulation with a large amount of aqueous or alcoholic solution to dissolve the binder is still the most popular way to prepare granules for tabletting or to manufacture matrix-forming material for sustained-release dosage forms Considering the drawbacks of wet granulation, it would be desirable to obtain an alternative granulation process which improves the flowability, while retaining or improving other tabletting features, such as tablet hardness, of a direct tabletting formulation or aid, without the extensive use of granulation liquid as employed in wet granulation.
SUMMARY OF THE INVENTION
Thus, the object of the present invention is to develop an alternative granulation process which utilizes considerably less water or solvent than the traditional wet granulation method.
Another object of the present invention is to utilize the granulation process for providing direct tabletting formulations with good flow properties and binding capacity to form tablets of low friability and adequate hardness.
A further object of the present invention is to utilize the granulation process for producing direct tabletting aids which, while having good flow properties and binding capacity to form tablets of low friability and adequate hardness, have a high uptake capacity for active substances whose tablettability is poor.
An addition
Yeh Daniel Hungting
Yeh Ta-Shuong
Morrison & Foerster / LLP
Spear James M.
Wei Ming Pharmaceutical Mfg. Co., Ltd.
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