Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1999-09-16
2001-07-24
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C514S770000, C514S772300, C514S777000, C514S778000, C514S781000, C514S784000, C514S951000
Reexamination Certificate
active
06264983
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to directly compressible ultra-fine acetaminophen (N-acetyl-p-aminophenol or APAP) compositions and to a process for preparing such ultra-fine compressible granulated compositions. The invention also relates to the preparation of tablets from such compositions. The invention also includes such ultra-fine APAP granulations alone or combined with other pro-active ingredients present in low quantity.
BACKGROUND OF THE INVENTION
Generally there are four methods in use in the United States for manufacture of tablets, namely direct compression, dry powder blend, pre-compressed dry powder blend and wet granulation, as explained in U.S. Pat. No. 4,439,453.
In the direct compression method, all the required tabletting ingredients (active and aids) are incorporated into a free flowing granulation which is supplied to the manufacturer of bulk tablets. The granulation requires no pre-processing or blending with additional aids in order to be tabletted. Rather, the free flowing granulation supplied to the tablet manufacturer can be charged directly to a tabletting press.
The direct compression method is a generally preferred method for a number of reasons including economical reasons. The analgesic aspirin is generally tabletted using such a direct compression method since crystalline aspirin is soft and exhibits good plasticity/elasticity when compacted into tablets.
However, because the analgesic acetaminophen has significantly different properties than aspirin, it is generally considered to be non-compressible and not readily amendable to production of directly compressible granulations thereof. Generally, the less desirable wet granulation method of tabletting has been used to tablet acetaminophen. Generally, these wet granulation processes require large amounts of excipients, e.g., from about 25 to about 40% or more by weight of excipients. That is, in contrast to aspirin, the acetaminophen crystals are hard and brittle and are easily fractured. The acetaminophen crystals have essentially no plasticity/elasticity and, therefore, have required the use of unduly large amounts of aids, lubricants and/or excipients in order to be compressible into tablets by the direct compression method.
Therefore, there is a recognized need for a direct tabletting granulated acetaminophen composition that is free flowing and capable of being directly compressible into tablets. A further need is for such a directly compressible acetaminophen granulation composition to provide a high load, for example, at least 80%, or preferably at least 90% or more, of acetaminophen active in the composition. Thus, the amount of excipients required in the compositions should be kept quite low, for example, 20% or less, preferably 10% by weight or less. In addition, the directly compressible acetaminophen composition should readily be free flowing and readily permit dry blending with other active ingredients should that be desired or required. A further need is that the directly compressible acetaminophen composition be such as to provide good flow and compressibility characteristics so as to produce tablets of content uniformity, acceptable hardness and friability, and also provide a fluid bed granulation with a characteristic rough surface morphology and a high surface area suitable for good blending potential with other co-actives.
SUMMARY OF THE INVENTION
This invention provides a directly compressible acetaminophen granulated composition. A directly compressible acetaminophen granulation composition of this invention and capable of being directly compressed into an acetaminophen tablet, comprises from about 80 to about 95 wt % acetaminophen, from about 1 to about 4 wt % essentially water-insoluble tabletcapsule disintegrant, from about 0.5 to about 5.0 wt % polyvinylpyrrolidone (povidone), from about 0.5 to about 5.0 wt % totally pre-gelantinized starch, about 0.25 to about 3.0 wt % of a fluidizing agent, and from about 0.25 to about 3.0 wt % of a lubricant, the weight percents being based on the total weight of the dry components of the granulation composition, the granulation also comprising a moisture content of up to about 1.5 wt % based on the total weight of the dry components of granulation composition.
The invention also comprises a process for producing such directly compressible acetaminophen granulation compositions. The process for the production of the directly compressible acetaminophen granulation compositions comprises: placing, as dry ingredients in a top spray fluid bed granulator, and dry blending with inert fluidization gas acetaminophen powder, the water-insoluble tablet/capsule disintegrant, a minor proportion of the totally pregelatinized starch, and at least a portion, or optionally all, of the fluidizing agent; heating the dry blend with heated pressurized fluidization gas, such as heated air, to fluidize and essentially uniformly heat the dry blend to a temperature in the range of about 25° C. to about 30° C.; when the dry blend has reached the desired temperature, spraying a first binder solution of a major portion of the polyvinylpyrrolidone dissolved in water from an atomizing spray gun of the granulation onto the heated dry blend to commence granulation of the dry powder blend; drying the granulation until the granulated product rises to about 2° C. above the end product temperature; spraying a second aqueous binder solution of the remaining minor portion of the polyvinylpyrrolidone, the remaining major portion of the totally pregelatinized starch, and optionally a lubricant, from an atomizing gun of the granulator onto the granulated product to further granulate and agglomerate the composition, and then drying this further granulated product until a moisture content of 1.5 wt % or less, preferably about 1.0 to 1.5 wt %, is achieved. The dried, directly compressible acetaminophen granulation composition, including APAP alone or in combination with other actives, is unloaded from the fluid bed granulator, and then can, if desired, be blended with other suitable dry ingredients in a suitable blender, to provide the directly compressible acetaminophen compositions of this invention.
The two spray process is necessary to effectively coat and agglomerate the ultra-fine particles to prepare fine particle sized granules having a high surface area and characteristic rough surface myphology suitable for good blending potential, content uniformity, tablet hardness and dissolution.
DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS
In the directly compressible composition of this invention, the ingredients thereof will generally be present in the following amounts expressed as percent by weight:
acetaminophen: 80 to 95%, preferably 87.5 to 92.5%
tablet/capsule disintegrant: 1 to 4%, preferably 1.5 to 3.5%
polyvinylpyrrolidone: 0.5 to 5%, preferably 2.75 to 3.25%
pregelatinized starch: 0.5 to 5%, preferably 2 to 4%
fluidizing agent: 0.25 to 3%, preferably 0.25 to 1.25%
lubricant: 0.25 to 3%, preferably 0.25 to 1.25%.
The acetaminophen particles of the product are such that preferably a maximum of 30 wt % is retained on a 60 U.S. mesh screen, a maximum of 75 wt % is retained on a 100 U.S. mesh screen, a maximum of 95 wt % is retained on a 200 U.S. mesh screen, and a minimum of 80 wt % is retained on a 325 U.S. mesh screen.
The polyvinylpyrrolidone employed for its binding characteristics is preferably a lower molecular weight grade having an average molecular weight (Mw) of about 30,000 or less. As examples of grades of polyvinylpyrrolidone suitable for use in the invention, there can be mentioned povidone K30 or K29/32. Such polyvinylpyrrolidone impart a low viscosity to the binder solutions. A major amount of the polyvinylpyrrolidone is employed in the first binder solution as a particle coating agent, generally from about 80 to about 85 wt % of the total polyvinylpyrrolidone. The remaining minor amount of the polyvinylpyrrolidone, generally about 15 to 20 wt % of the total is employed in the second binder or agglomerating solution with a maj
Ohlandt Greeley Ruggiero & Perle L.L.P.
Rauchfuss, Jr. George W.
Rhodia Inc.
Spear James M.
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