Pharmaceutical superdisintegrant

Details Pharmaceutical superdisintegrant Pharmaceutical superdisintegrant

2000-12-06

2003-12-09

Hartley, Michael G. (Department: 1616)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S494000, C424S493000, C424S464000, C424S465000

Reexamination Certificate

active

06660303

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to enhanced high functionality excipients in the class of superdisintegrants. Superdisintegrants are typically incorporated into pharmaceutical solid dosage forms (such as tablets including one or more active ingredients) in order to provide improved disintegration of the dosage form. Preferably, other properties, including but not limited to, compressibility, material flow, content uniformity, processing steps, and/or tablet size are maintained or improved.
In order to prepare a solid dosage form containing one or more active ingredients (such as drugs), it is necessary that the material to be compressed into the dosage form possess certain physical characteristics which lend themselves to processing in such a manner. Among other things, the material to be compressed must be free-flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to ensure that the solid dosage form remains intact after compression.
For example, tablets are formed by pressure being applied to the material to be tableted on a tablet press. A tablet press includes a lower punch which fits into a die from the bottom and a upper punch having a corresponding shape and dimension which enters the die cavity from the top after the tableting material fills the die cavity. A tablet is formed by pressure applied on the lower and upper punches. The ability of the material to flow freely into the die is important in order to ensure that there is a uniform filling of the die and a continuous movement of the material from the source of the material, e.g. a feeder hopper. The lubricity of the material is crucial in the preparation of the solid dosage forms because the compressed material must be readily ejected from the punch faces.
As most drugs have none, or only some, of these properties, methods of tablet formulation have been developed which impart these desirable characteristics to the one or more materials compressed into the solid dosage form. Typically, the material(s) to be compressed into a solid dosage form include one or more excipients which impart the free-flowing, lubrication, and cohesive properties to the drug or drugs being formulated into the dosage form.
Lubricants are typically added to avoid the material(s) being tableted from sticking to the punches. Commonly used lubricants include magnesium stearate and calcium stearate. Such lubricants are commonly included in the final tableted product in amounts of less than 1% by weight.
In addition to lubricants, solid dosage forms often contain diluents. Diluents are frequently added in order to increase the bulk weight of the material to be tableted in order to make the tablet a practical size for compression. This is often necessary where the dose of the drug is relatively small.
Another commonly used class of excipients in solid dosage forms are binders. Binders are agents which impart cohesive qualities to the powdered material(s). Commonly used binders include starch, and sugars such as sucrose, glucose, dextrose, and lactose.
There are three general methods of preparing the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) direct compression; and (3) wet granulation. Dry granulation procedures may be utilized when one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method includes mixing the ingredients, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients. In direct compression, the powdered material(s) to be included in the solid dosage form is compressed directly without modifying the physical nature of the material itself. The wet granulation procedure includes mixing the powders to be incorporated into the dosage form in, e.g., a twin shell blender or double-cone blender and thereafter adding solutions of a binding agent to the mixed powders to obtain a granulation. Thereafter, the damp mass is screened, e.g., in a 6- or 8-mesh screen and then dried, e.g., via tray drying, the use of a fluid-bed dryer, spray-dryer, radio-frequency dryer, microwave, vacuum, or infra-red dryer.
A limitation in the use of the direct compression method is that the drug or active ingredient must have the requisite crystalline structure and physical characteristics required for formation of a pharmaceutically acceptable tablet. It is well known in the art, however, that one or more excipients can be included to make the direct compression method applicable to drugs or active ingredients which do not possess the requisite physical properties. For solid dosage forms wherein the drug itself is to be administered in a relatively high dose (e.g., the drug itself comprises a substantial portion of the total tablet weight), it is necessary that the drug(s) itself have sufficient physical characteristics (e.g., cohesiveness) for the ingredients to be directly compressed.
Typically, when making direct compression formulations, excipients which impart good flow and compression characteristics to the material as a whole are added to the formulation which is to be compressed. These desirable properties are commonly imparted to these excipients via a pre-processing step such as wet granulation, slugging, spray drying, spheronization, or crystallization. Useful direct compression excipients include processed forms of cellulose, sugars, and dicalcium phosphate dihydrate, among others. A processed cellulose, microcrystalline cellulose, has been utilized extensively in the pharmaceutical industry as a direct compression vehicle for solid dosage forms. Microcrystalline cellulose is commercially available under the trade name EMCOCEL® from Edward Mendell Co., Inc. and as Avicel® from FMC Corp. When compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties.
Another limitation in the use of direct compression as a method of tablet manufacture is the size of the tablet. If the amount of active ingredient is high, a pharmaceutical formulator may choose to wet granulate the active ingredient with other excipients to attain an acceptably sized tablet with the desired compact strength. This is because the amount of filler/binder or excipients usually needed in wet granulation is less than that required for direct compression because the process of wet granulation contributes to some extent toward the desired physical properties of a tablet. Thus, despite the advantages of direct compression (such as reduced processing times and costs), wet granulation is widely used in the industry in the preparation of solid dosage forms. Many of those skilled in the art prefer wet granulation as compared to direct compression because this method has a greater probability of overcoming any problems associated with the physical characteristics of the various ingredients in the formulation, thereby providing a material which has the requisite flow and cohesive characteristics necessary to obtain an acceptable solid dosage form.
Due to the popularity of microcrystalline cellulose, pharmaceutical formulators have deemed it desirable to include this excipient in a formulation which is wet granulated prior to tableting. Unfortunately, currently-available microcrystalline cellulose does not hold to the typical principle that the amount of filler/binder needed in wet granulation is less than that in direct compression. It is known that the exposure of the microcrystalline cellulose to moisture in the wet granulation process severely reduces the compressibility of this excipient. The loss of compressibility of microcrystalline cellulose is particularly problematic when the formulation dictates that the final product will be relatively large in the environment of use. For example, if a pharmaceutical formulator desires to prepare a solid oral dosage form of a high dose drug, and the use of the wet granulation technique is deemed necessary, the loss of compressibility of the micro

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