Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-03-14
2003-08-19
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S489000
Reexamination Certificate
active
06607750
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to directly compressible acetaminophen (N-acetyl-p-aminophenol or APAP) compositions and to a process for preparing such compositions. The invention also relates to the preparation of tablets from such compositions. The invention also includes such acetaminophen granulations alone or combined with other co-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 acceptable content uniformity, 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
In a first aspect, the present invention is directed to an acetaminophen composition capable of being directly compressed, without addition of other components, into a compressed dosage form, said composition comprising, based on the total weight of the dry components of the composition, from greater than 90 to about 98 percent by weight acetaminophen and further comprising a fluidizing agent, a binder compound, a disintegrant and a lubricant, said composition comprising free flowing granules, at least a portion of said granules each comprising at least one acetaminophen-rich core, said acetaminophen-rich core comprising acetaminophen and fluidizing agent and having an outer surface, and a binder-rich region supported on at least a portion of the outer surface of the acetaminophen-rich core, said binder-rich region comprising binder compound, wherein, based on the dry weight of the components of the respective acetaminophen-rich core and binder-rich region, the acetaminophen-rich core comprises a relatively higher amount of acetaminophen than the binder-rich region and the binder-rich region comprises a relatively higher amount of binder than the acetaminophen-rich core.
In another aspect, the present invention is directed to an acetaminophen composition capable of being directly compressed, without addition of other components, into a compressed dosage form, said composition comprising, based on the total weight of the dry components of the composition, from greater than 80 percent by weight to about 98 percent by weight acetaminophen and further comprising a fluidizing agent, a binder compound, a disintegrant and a lubricant, said composition comprising free flowing granules, said granules exhibiting a surface area of greater than 0.8 square meters per gram.
In another aspect, the present invention is directed to an acetaminophen composition capable of being directly compressed, without addition of other components, into a compressed dosage form, said composition comprising from 90 to about 98 percent by weight acetaminophen and further comprising a fluidizing agent, a binder compound, a disintegrant and a lubricant, said composition comprising free flowing granules wherein at least a portion of said granules are made by atomizing a binder solution onto a fluidized bed of particles of the acetaminophen and fluidizing agent.
In another aspect, the present invention is directed to an acetaminophen composition capable of being directly compressed, without addition of other components, into a compressed dosage form, said composition comprising, based on the total weight of the dry components of the composition, from greater than 95 to about 98 percent by weight acetaminophen and further comprising, a combined amount of from about 2 to less than 5 percent by weight, a binder compound, a disintegrant and a lubricant.
In another aspect, the present invention is directed to an acetaminophen-containing compressed dosage form, comprising from greater than 90 percent by weight to 98 percent by weight acetaminophen and exhibiting a initial dissolution of greater than 80% according to US Pharmacopeia test method number 711, as applied to acetaminophen.
DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS
In a preferred embodiment, the acetaminophen composition of the present invention comprises, based on the total weight of the dry components of the composition, from 80 to 98 percent by weight (wt %), more preferably from 91 to 98 wt % and even more preferably from 94 to 97 wt %, acetaminophen, from 0.05 to 5 wt %, more preferably from 0.1 to 3.5 wt %, and even more preferably from 0.5 to 3 wt % disintegrant, from 0.05 to 5 wt %, more preferably from 0.5 to 3.25 wt % and even more preferably from 1 to 3 wt %, binder compound, from 0 to 5 wt %, more preferably from 0 to 4 wt % and even more preferably from 0 to 2 wt %, pregelatinized starch, from 0 to 3 wt %, more preferably from 0.1 to 1.25 wt % and even more preferably from 0.2 to 1 wt %, fluidizing agent and from 0.05 to 3 wt %, more preferably from 0.1 to 2 wt % and even more preferably from 0.1 to 1 wt %, lubricant.
In a first preferred embodiment, the acetaminophen composition of the present invention comprises, based on the total weight of the dry components of the composition, from about 80 to about 95 wt %, more preferably from 87.5 to 92.5 wt %, acetaminophen, from about 1 to about 4 wt %, more from preferably 1.5 to 3.5 wt %, disintegrant, from about 0.5 to about 5.0 wt %, more preferably from 2.75 to 3.25 wt %, polyvinylpyrrolidone, from about 0.5 to about 5.0 wt %, more preferably from 2 to 4 wt %, totally pregelatinized starch, from about 0.25 to about 3.0 wt %, more preferably from 0.25 to 1.25%, fluidizing
Camarco Wayne
Upadhyay Ajay Hasmukhlal
Rhodia Inc.
Spear James M.
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