Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-05-22
2004-04-06
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S466000, C424S470000, C424S439000, C424S441000, C424S442000, C424S489000
Reexamination Certificate
active
06716453
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to improvements in composition formulation technology, more particularly improvements in the formulation of compressible compositions including one or more active ingredients that are combined with inactive excipients such as binders and/or hardening agents to enable the production of a final compressed form such as a tablet, pellet, bead or the like.
BACKGROUND OF THE INVENTION
The compressed tablet is one of the oldest and most popular unit forms for oral dosage of medicinal substances. As a result of the introduction of new carriers and compression vehicles, tablets are replacing many forms of pills, powders and capsules. Accordingly, tablets presently represent the largest production volume of all pharmaceuticals and nutritional supplements.
The reasons for the widespread use of tablets are apparent, since tablets facilitate: (1) administration of medication in an accurate dose; (2) fast and accurate dispensing with less chance of error and contamination: (3) ease of administration: (4) administration in a form in which the time and area of contact between the active ingredient and the taste buds are reduced, thus obviating the physiological problems associated with the oral administration of drugs that possess a bitter taste and, in the case of coated tablets, with drugs that possess a disagreeable odor; (5) release of drugs at specific locations in the gastro-intestinal tract to prevent degradation of drugs sensitive to the low pH environment in the stomach, prevent release of drugs that irritate the gastric mucosa in the stomach, and facilitate local action or preferential absorption at specific sites in the tract: (6) enhanced stability by effecting a marked reduction in the surface of the drug exposed to the environment; (7) rapid production; and (8) economy and ease in storage, packaging and shipping.
The preparation of a solid compressed form containing one or more active ingredients (such as drugs or nutrients such as vitamins) requires that the materials to be compressed into the form possess certain physical characteristics that lend themselves to such processing. Among other things, the material to be compressed must be free flowing, must be lubricated, and, importantly, must possess sufficient cohesiveness to insure that the solid dosage form remains intact after compression.
A tablet is formed typically 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. The 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 insure 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 since the compressed material must be readily ejected from the punch faces.
Since most drugs and nutritional supplements have none or only some of these properties, methods of tablet formulating have been developed to impart these desirable characteristics to the material(s) which is to be compressed into a solid dosage form. Typically, excipients, which impart good flow and compression characteristics to the material as a whole, are added to the active material that is to be compressed. Such properties are typically 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.
There are three general methods of preparing the materials to be included in the solid dosage form prior to compression: (1) dry granulation; (2) wet granulation; and (3) direct compression.
Dry granulation procedures may be utilized where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted. The method includes mixing the ingredients with a lubricant, if required, slugging the ingredients, dry screening, lubricating and finally compressing the ingredients.
The wet granulation procedure includes mixing the powders to be incorporated into the dosage form 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 or fluid-bed drying. One disadvantage of the wet granulating technique is that it has been known to reduce the compressibility of some pharmaceutical ingredients including microcrystalline cellulose.
Direct compression is a relatively quick process wherein the powdered materials included in the solid dosage form are compressed directly without modifying their physical nature. Usually, the active ingredient, direct compression vehicle and other ancillary substances, such as a glidant to improve the rate of flow of the tablet granulation and lubricant to prevent adhesion of the tablet material to the surface of the dies and punches of the tablet press, are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.
Direct compression is usually limited to those situations where the drug or active ingredient has a requisite crystalline structure and the physical characteristics required for formation of an acceptable tablet. However, only a very limited number of substances possess enough cohesive strength and flowability to allow direct compression without previous granulation. A limited number of crystalline materials, such as potassium bromide and potassium chloride, can be compressed without preliminary treatment. Also, drugs such as aspirin and phenolphthalein can be directly compressed after blending with suitable tableting excipients.
It has been estimated that about 20 percent of the materials used for tableting in the pharmaceutical field may be compressed directly. In order to use this method to a greater extent, many more materials are modified either by treating the material in some special way during early stages of preparation, or by adding a direct compression vehicle, i.e., a dry binder or excipient material which will mix with the active ingredient to provide a flowable powder and form an easily compressible carrier.
There are currently several available binders or excipients that can be used as direct compression vehicles. They include spray-dried lactose; anhydrous lactose: microcrystalline cellulose; dicalcium phosphate dihydrate, unmilled; spray-congealed mannitol; ungelatinized starch (e.g., cornstarch), and partially or fully pregelatinized starch.
Microcrystalline cellulose, processed 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 tradename Emcocel® from Edward Mendell Co., Inc. and as Avicel® from FMC Corp. Compared to other directly compressible excipients, microcrystalline cellulose is generally considered to exhibit superior compressibility and disintegration properties as long as it is not wet granulated prior to compression.
Many types of partially or fully pregelatinized starches are commercially available for use in direct compression tablet formulations. Pregelatinized cornstarch provides tablets with hardness properties in the range of 1 to 4 Kp. Present demands, however, require hardness levels in the range of 10-14 Kp and higher, an expectation which many starches modified by prior art methods simply can not meet. While the use of starch in tableting formulations is still common practice, problems of uniformity between modified batches and a demand for tablets of greater hardness resulted in its departure from the status of a preferr
Glover Duane
Harden Jerome W.
Redding, Jr. Bruce K.
Spear James M.
Synnestvedt & Lechner LLP
Tran S.
Verion Inc.
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