Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2001-01-25
2003-07-15
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S469000
Reexamination Certificate
active
06592897
ABSTRACT:
This is the U.S. national phase of International Application No. PCT/EP99/02386 filed Apr. 8, 1999, the entire disclosure of which is incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to slow-release tablets comprising linear water-insoluble polysaccharides, a process for preparation, and use thereof, in particular for the controlled release of active compounds.
2. Description of Related Technology
In modern pharmaceutical technology, formulations of excipients whose administration form specifically brings an influence to bear on the biodistribution, bioavailability, biocompatibility and absorption are of importance. Moreover, excipients must have good mechanical properties, such as adequate hardness and resistance to tension and stress. Although a few compounds can already be pressed themselves to give compact stable masses (e.g. sucrose or lactose), ingredients—tablet auxiliaries—are also necessary, such as binders, fillers, lubricants and additives. Typical dry binders for increasing stability which are used here are:
calcium phosphates, microcrystalline cellulose (e.g. Avicel®, PH 102®, especially Celsphere), polyvinylpyrrolidones (e.g. Kollidon®, Luviskol VA 64®, Plasdone®), corn, wheat or potato starch, derivatized polysaccharides, so-called gums, (e.g. xanthan gum), cellulose derivatives (e.g. hydroxypropylmethylcellulose: Klucel®) or ethylcellulose (Aqualon®). Moreover, the excipients must disintegrate in the body in an optimum and controlled manner in contact with body fluids. Therefore, so-called disintegrants are often added for disintegration control. Typical compounds for this purpose are corn starch, gelatinized starch and starch modifications. Substances which can also be employed are those which develop a disintegrating power due to water absorption and accompanying swelling. These include crosslinked polyvinylpyrrolidones (Kollidon CL®), carboxymethylcellulose and their calcium salts or galactomannans. With some compounds (e.g. Avicel® and PH 102®), it is possible to achieve both the necessary mechanical stability and to control tablet disintegration.
Specific starches, including amylose, are described as advantageous excipients for tablet formulation (Journal of Pharmaceutical Sciences 55 (1966), 340). However, the Nepol amylose used (A. E. Stanley Manufacturing Co., USA) proves disadvantageous, since the active compounds are not exhaustively released and the excipient has a high water content (10-12%), which is why hydrolytically labile active compounds cannot be formulated. In particular, crosslinked amylose (degree of crosslinkage 15%) is as a superior binding agent described (S.T.P. Pharma Sciences 4 (1994), 329-335 and Journal of Controlled Release 15, (1991) 39-46, Journal of Controlled Release 15, (1991) 3946), which on account of its water absorption capacity acts as a disintegration accelerator. In WO 94/21236, crosslinked amylose (degree of crosslinkage 25%) is used as a binder and disintegrant. A high degree of crosslinkage, however, has a disadvantageous effect on the biological compatibility. The crosslinking agent used is up to 30% by weight of the intolerable epichlorohydrin. Even low crosslinkages in the range of a few percent lead to a rapidly growing slowness to react, so residues of unreacted crosslinker which remain have to be expected.
All starch- and amylose-containing excipients on the market until now use plant sources of origin.
It is disadvantageous here that these biopolymers, like all naturally occurring substances, have considerable variations in composition and structure and therefore the necessary reproducibility and thus constant product quality is not guaranteed, even with respect to controlled release of active compound.
In the case of native starch, the content of amylose and amylopectin varies considerably depending on the origin. For example, starch from potatoes contains about 20% by weight of amylose and about 80% by weight of amylopectin, whereas starch from corn contains about 50% by weight of amylose and about 50% by weight of amylopectin. Additional variance within a plant community results due to soil condition, fertilizer absorption, seasonal climatic differences etc.
Moreover, amylose, a 1,4-linked polyglucan, having a molecular weight of approximately 50,000 to 150,000 daltons, and amylopectin, a highly branched 1,4- and 1,6-linked polyglucan, having a molecular weight of approximately 300,000 to 2,000,000 daltons, have wide molecular weight distributions.
The transitions from highly branched to linear are fluid and vary in the original plant material, so that a sharp delimitation is almost impossible. In particular, excipients which still contain amylopectin cause irregular swelling on account of the branchings, whereby the carrier stability is adversely affected. Amylopectin is therefore usually laboriously removed by means of enzymatic debranching (Journal of Controlled Release 45, (1997) 25-33 and EP 0499 648 B1=U.S. Pat. No. 5,468,286).
Beside these marked disadvantages, the wide molecular weight distribution or mixtures of polymers of different spatial arrangements, native polymers contain further constituents such as low molecular weight compounds, e.g. fats and oils, which can only be separated with difficulty and have a disadvantageous effect in further processing and application (e.g. U.S. Pat. No. 3,490,742). In particular, yield-decreasing working steps have to be carried out, in some cases it not being possible to eliminate impurities completely.
Experiments are also known to optimize biopolymers, i.e. even starch, by genetically modifying the plant of origin. WO 94/03049 describes the preparation and use of high amylose-containing starch from genetically modified corn. Regardless thereof, the disadvantages of nonuniformity and contamination remain.
The reproducibility and quality is substantially dependent on the uniformity and purity. To guarantee products of high quality, these starting substances must be clearly definable and characterizable.
SUMMARY OF THE INVENTION
The present invention has the object, while avoiding the above disadvantages, of making available a slow-release material which can be used as a slow-release tablet in a pharmaceutical composition for the controlled release of active compounds, preferably for oral administration.
The object is achieved by using as the slow-release material water-insoluble linear polysaccharides which are biocompatible, chemically inert, pressure-stable starting materials which make possible the controlled release of active compound without further additives. Preferably, the starting material used is linear water-insoluble poly(1,4-alpha-D-glucan) as such or in the form of spherical microparticles.
DETAILED DESCRIPTION OF THE INVENTION
“Slow-release tablets” in the sense of the present invention are, in particular, tablets, coated tablets, pills, pellets, pressings, small plates, disks and the like, whose formulation requires compression. Likewise to be included are capsules which are filled with the slow-release material.
Slow-release materials are to be regarded in the following as linear water-insoluble polysaccharides.
Linear water-insoluble polysaccharides in the sense of the present invention are polysaccharides, preferably polyglucans, in particular poly(1,4-alpha-D-glucan), which consist of monosaccharides, disaccharides, further oligomers thereof or derivatives.
These are always linked to one another in the same way. Each base unit defined in this way has exactly two linkages, each one to another monomer. Excluded therefrom are the two base units, which form the beginning and end of the polysaccharide. These base units have only one linkage to a further monomer. In the case of three or four linkages (covalent bonds) of a monomer to another group, preferably a further saccharide unit, branching is referred to. At least three glycosidic bonds then leave from each saccharide unit in the polymer backbone.
According to the invention, branchings do not occur or only occur t
Bengs Holger
Böhm Gitte
Grande Jürgen
Schneller Arnold
Schuth Silke
Axiva GmbH
Spear James M.
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