Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1998-03-18
2002-10-15
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S439000, C424S465000, C424S470000, C424S488000, C514S772000
Reexamination Certificate
active
06465009
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to the field of pharmaceuticals, compressed tablet formulations and methods of manufacturing tablets.
BACKGROUND OF THE INVENTION
Pharmaceutically active agents are commonly formulated as solid tablets for oral administration due to reasons of stability, economy, simplicity and convenience of dosing. However, many patients cannot or will not accept tablet administration. Infants, children, individuals suffering from certain injuries or illnesses, and many elderly and disabled individuals cannot swallow or chew sufficiently to effectively administer a pharmaceutically active agent by means of a solid tablet. An effective means for oral administration of pharmaceutically active agents to these individuals would be highly beneficial. While liquid formulations can address this need in some cases, the technical complexities of liquid formulations and difficulties in patient compliance and ease of administration make liquid formulations a less than optimal approach. Thus, there is a great need to develop solid oral tablets which can be administered to this patient population. In these individuals, if a solid tablet is used to administer a pharmaceutically active agent, the ability of that preparation to rapidly disintegrate upon contact with the mucous membrane, such as the buccal cavity or sublingual area of the mouth, and deliver a therapeutically effective dose of the drug would be a major advantage. Furthermore, in many circumstances, it is important to have a fast disintegrating tablet so that the pharmaceutically active ingredient is absorbed as rapidly as possible.
However, manufacture of a tablet that is capable of such rapid disintegration typically results in a product which is too soft or friable to withstand packaging, shipping, and handling by the patient. Most attempts at producing a tablet capable of rapid disintegration in a body cavity, yet hard enough to not break up during packaging, shipping, and handling, have resulted in manufacturing processes that are complex and expensive.
Furthermore, many tablet manufacturing processes use organic solvents, thereby leaving unwanted and undesirable organic solvent residues in the final tablet formulation.
Thus, there exists a need for compressed tablets which are sufficiently hard to be packaged and handled by patients yet able to rapidly disintegrate in an aqueous environment similar to that found in a body cavity (e.g., oral cavity) and which does not require the additional ingestion of fluids for the purposes of swallowing a solid tablet. It would further be advantageous if such tablets could be made relatively economically, without the use of organic solvents. The present invention fulfills these and other needs.
SUMMARY OF THE INVENTION
This invention advantageously provides for tablets that are uniform in formulation and economical to produce. The formulation and method of manufacture of these compressed tablets surprisingly results in a tablet that is hard, and resistant to breakage during handling. Though the tablets are advantageously hard, they also rapidly disintegrate when they are contacted by body fluid or other aqueous medium. The tablets described here also have a greatly improved tactile effect making the tablets significantly more palatable to the consumer than other so-called rapidly dissolving tablets.
The invention provides a physiologically acceptable tablet comprising a compressed tablet formulation free of organic solvent residue that rapidly disintegrates when placed in a body cavity, that comprises at least one water soluble non-saccharide polymer, and that has a hardness factor of between about 0.5 kilopounds to about 12.0 kilopounds. The compressed tablet can have a hardness factor of over 6 kilopounds.
In various embodiments, the non-saccharide, water soluble polymer can be polyvinylpyrrolidone (PVP), polyethylene glycol, sodium alginate, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or hydroxyethyl cellulose. The non-saccharide, water soluble polymer can be between about 0.5% to about 20% of the dry weight of the tablet.
The PVP can be N-vinyl pyrrolidone, 3-methyl N-vinylpyrrolidone, N-vinyl amide pyrrolidone, N-vinyl acetate pyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, and acrylamide- vinylpyrrolidone co-polymer. The PVP can have a molecular weight (MW) of less than about three million daltons, can have a MW of less than about fifty thousand daltons, or can have a MW of about thirty thousand daltons. The PVP can be about 5% of the dry weight of the tablet.
In one embodiment, the tablet of the invention is a formulation that further comprises a saccharide of low moldability. The low moldable saccharide can be mannitol, lactose, glucose, sucrose, lactitol, or a mixture thereof. The saccharide of low moldability can be between about 25% to about 99% of the weight of the tablet.
The formulation can also comprise a saccharide of high moldability, with the proviso that the formulation does not contain starch. The saccharide of high moldability can be maltose, maltitol, sorbitol, or a mixture thereof. The saccharide of high moldability can be about 0.5% to about 20% of the tablet.
The invention also provides a tablet further comprising a pharmaceutically active ingredient. The formulation of the invention can further comprise at least one additive agent selected from the group consisting of a disintegrant, a flavorant, an artificial sweetener, a perfume, and a colorant.
In various embodiments, the tablet of the invention dissolves in about 1 to about 40 seconds in an aqueous solution, the tablet dissolves in the oral cavity and the aqueous solution is saliva. The pharmaceutical tablet of the invention is suitable for delivery to a body cavity, such as, for example, the oral, buccal, sublingual, vaginal, nasal, rectal (anal), or urethral cavity.
The invention provides a process for producing a pharmaceutical tablet, comprising the following steps: (a) granulating a formulation comprising at least one non-saccharide, water soluble polymer and at least one active ingredient together, wherein no organic solvents are included in the formulation; (b) compressing the product of the granulation into a tablet form; (c) humidifying the tablet by exposing the product of step (b) to an aerated environment at least about 50% to 100% relative humidity; and (d) drying the tablet, wherein the hardness of the tablet is at least about 6 kilopounds. In various embodiments, the water soluble polymer comprises a PVP; the PVP can have a MW of less than about three million daltons, can have a MW of less than about fifty thousand daltons, or can have a MW of about thirty thousand daltons; the PVP can be about 5% of the dry weight of the formulation. The PVP of the process can be selected from the group consisting of N-vinyl pyrrolidone, 3-methyl N-vinylpyrrolidone, N-vinyl amide pyrrolidone, N-vinyl acetate pyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, and acrylamide- vinylpyrrolidone co-polymer.
The process can include the addition of at least one lubricant and at least one filler to the tablet. In various embodiments, the lubricant can be in the range of about 0.5% to about 1.0% of the dry weight of the formulation, the lubricant in the formulation can be magnesium stearate or calcium stearate, the filler in the formulation can be in the range of about 80% to about 98% of the dry weight of the formulation, the filler in the formulation can be in the range of about 95% of the dry weight of the formulation, or the filler in the formulation can be mannitol.
In alternative embodiments of this process, in step (a) the temperature during granulation can range from about 10° C. to about 70°; in step (b) the compression can be by press molding; in step (b) the compression can produce a tablet with a hardness of about 0.3 to about 6.0 kilopounds; in step (c) the humidification can be between about 50% and about 100% relative humidity; in step (c) the humidification can be about 85% relative humidity; in step (c) the temperature can be at about 25° C.; in
Chu James Shunnan
Fix Joseph A.
He Min Michael
Liu Fang-yu
Nyshadham Janaki Ram
Channavajjala Latshmi
Page Thurman K.
Townsend and Townsend / and Crew LLP
Yamanouchi Pharmaceutical Co. Ltd.
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