Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-03-12
2003-06-03
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S465000, C424S489000, C514S777000, C514S778000
Reexamination Certificate
active
06572887
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of using compressible polysaccharides having a tap density of less than 0.4 g/ml as a filler/binder for tablets prepared by direct compression, excipient blends including said polysaccharides, a method of tableting an active ingredient therein from the excipient blends and the tablets produced therefrom. More particularly, this invention relates to the use of low-density starches as binders for tablets prepared by direct compression, excipient blends, and methods of tableting an active ingredient therein from such starches. Further, this invention describes a starch-based excipient composition having a tap density of less than 0.4 g/ml, which has excellent moisture resistance.
BACKGROUND OF THE INVENTION
Direct compression is a process by which a powder blend of an active ingredient, such as a drug, and a suitable excipient and/or filler, which is capable of flowing uniformly into a die cavity, are compressed directly into an acceptable tablet. The advantages of direct compression include limiting exposure of the active material to moisture and/or heat, and long-term physical and chemical stability. Direct compression requires only two steps, mixing the dry ingredients and compressing the mixture into a tablet, and hence it is the most preferred and economical method of tableting.
The direct compression process has a number of limitations dependent upon the compactibility, particle size, crystallinity, polymorphism, flowability and density of the excipient as well as the active ingredient. In particular, tablets containing a high dose of an active ingredient which has poor compactibility ordinarily cannot be prepared by direct compression because filler/binders have a limited dilution potential. Thus, one of the most important properties of a filler/binder is high compactability which ensures that the compacted mass will remain bonded after the release of the compaction pressure.
It is common to use a combination of two or more filler/binders in order to obtain a mixture with adequate compactibility, stability, and cost. Only a few excipients can be compressed directly into tablets without physical modification.
Typical direct compression excipients or filler/binders include microcrystalline cellulose, specialty compressible sugars, modified calcium salts, lactose, starches, and dextrose. Of these, microcrystalline cellulose (“MCC”) is often the binder of choice. However, MCC has inherent flow problems and is very expensive. Other fillers/binders include physically modified calcium phosphate (di- or tribasic) and specialty compressible sugars, but each filler/binder has its limitations. The calcium salts do not allow for the preparation of tablets with a high level of active ingredient, tend to undesirably alter behavior during prolonged storage and generally require the use of disintegrants. The use of sugars (usually sucrose) present a darkening problem, tend to change tablet crushability with age, and have chemical incompatibility with some drugs. Lactose has limited binding properties and undesirably darkens in the presence of amino substituted drugs. Specialty mannitol and sorbitol compounds have properties similar to sugars, but have limited application, and are used primarily to provide chewable tablets.
Starches and their derivatives have been used as excipients in drug products functioning as disintegrants, diluents and binders. Bolhuis, Gerard K. and Chowhan, Zak T., “Materials for Direct Compression” in
Pharmaceutical Powder Compaction Technology,
Alderborn, 9 & Nystrom Editors, Vol. 71, Chapter 14, 419-500, Marcer Decker, N.Y. In particular, U.S. Pat. Nos. 3,622,677 and 4,072,535 issued to R. W. Short et al. Report that physically modified, partially gelatinized, and pregelatinized starches are useful as binder-disintegrants for direct compression tableting. The modification, which is carried out by passing the starch through closely spaced steel rollers with or without the use of supplemental thermal energy, disrupts and fractures at least some of the granules and results in a mixture of birefringent and non-birefringent granules and fragments, as well as completely solubilized starch (typically about 10-20%). The compacted mass is ground and classified into desired particle size fractions. The resulting starch has limited direct compression binding ability, and the use of an auxiliary binder is often required.
U.S. Pat. No. 4,384,005 issued May 17, 1983 to D. R. McSweeney et al., describes the use of certain hydrolyzed starches as “melting point elevators” in a hybrid wet granulation-direct compression tableting process for preparing nonfriable, rapidly water-dispersable tablets for sweetened or unsweetened beverage tablets. The inclusion of a melting point elevator raises the melting point of the mixture so that the tablets made therefrom do not soften, melt or form a hard core during drying and compression.
Solubilized fractionated starches described in U.S. Pat. No. 3,490,742 issued Jan. 20, 1970 to G. K. Nichols, such as non-granular amylose, are also reportedly useful as binder-disintegrants in direct compression tableting processes. The amylose fraction is non-granular because the starch from which it is derived is totally solubilized in order to free the amylose. This material is prepared by gelatinizing the starch. Then high molecular weight (long chain) amylose is fractioned from the gelatinized starch in water at elevated temperatures. In order to function as a binder, such a starch must contain at least 50% of the native (e.g., long chain) amylose which was present in the starch.
U.S. Pat. No. 4,551,177 issued Nov. 5, 1985 to Trubiano, et al. discloses a compressible starch, useful as a binder for tablets prepared by direct compression. This starch consists of a free-flowing compressible powder derived from a cold-water-insoluble, granular starch. The granular starch is prepared by treatment with an acid, alkali, and/or alpha-amylase enzyme at a temperature below the gelatinization temperature which results in weakened granules having less dense interiors and disrupted surfaces. Likewise, U.S. Pat. No. 5,468,286 issued Nov. 21, 1995 to C. W. Chiu et al. describes enzymatically debranched starches which are also useful as direct compression binders. Both products are substantially crystalline, have relatively high densities and have low dilution potential compared to other binders used in the industry.
Low-density polymers, including polysaccharides, are known to be useful in the preparation of cosmetic or pharmaceutical compositions. Such compositions are disclosed in European Patent App. No. 659,403 wherein a low-bulk density polysaccharide is used as a carrier for an adsorbed oil or oil soluble substance. In addition, U.S. Pat. No. 4,232,052 issued Nov. 4, 1980 to B. H. Nappen describes a combination of a low-bulk density starch and a grinding agent which forms a carrier suitable for adsorbing high fat foodstuffs. These carriers may be incorporated as adjuvants in processed foodstuffs, tablets, or powders.
Unlike other starches used in direct compression binding, it has been discovered that the low-density polysaccharides of the present invention have unexpectedly excellent compaction properties resulting in tablet crushing strengths comparable to or better than binders currently preferred in the pharmaceutical industry. Thus, the low-density polysaccharides of the current invention advantageously provide binder/filler utility as tablet excipients in direct compression applications.
REFERENCES:
patent: 3490742 (1970-01-01), Nichols et al.
patent: 3622677 (1971-11-01), Short
patent: 4232052 (1980-11-01), Nappen
patent: 4383111 (1983-05-01), Takeo et al.
patent: 4384005 (1983-05-01), McSweeney
patent: 4551177 (1985-11-01), Trubiano et al.
patent: 5135757 (1992-08-01), Baichwal et al.
patent: 5468286 (1995-11-01), Wai-Chiu et al.
patent: 5939091 (1999-08-01), Eoga et al.
patent: 6130321 (2000-10-01), Johnson et al.
patent: 0 659 403 (1994-11-01), None
patent: 00/19982 (2000-04-01), None
Enabosi Amos E.
Rege Pankaj
Shah Himanshu
Weisser Eric M.
Whaley Judith K.
Kaiser Karen G.
National Starch and Chemical Investment Holding Corporation
Spear James M.
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