Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-11-12
2002-09-17
Gitomer, Ralph (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S183000, C514S345000, C424S282100
Reexamination Certificate
active
06451772
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to biopolymer salts having low levels of endotoxin and to biopolymer compositions thereof. The biopolymer salts of this invention are particularly useful as parenteral implants. The invention also relates to methods of purifying biopolymer salts, such as alginates and biogums, to prepare the novel biopolymer salts having low endotoxin content.
2. Background of the Invention
Materials which are to be used parenterally in the body must be essentially free of pyrogens, which are materials that induce fever by triggering an immune response. Introduction of pyrogenic materials into the body can produce a reaction severe enough to produce shock or even death. An important pyrogenic material is the lipopolysaccharide endotoxin which exist as a component of the cell walls of gram negative bacteria. These endotoxins are released in large quantities when the gram negative cells undergo lysis. Materials which come into contact with water having high gram negative bacterial counts can be expected to contain significant quantities of lipopolysaccharide endotoxin. Although this does not pose a problem for compositions that are administered orally, it is unacceptable for parenterally administered compositions.
Lipopolysaccharide endotoxin is not a living material and cannot be deactivated by common sterilization techniques such as autoclaving. While gamma irradiation and dry heat sterilization techniques do destroy endotoxin, these techniques also may destroy or damage many other compounds in the composition. Therefore, many sterile products can contain significant levels of endotoxin unless the endotoxin is specifically removed or deactivated.
In addition, because the lipopolysaccharide originates from gram negative bacteria, non sterile material that was originally endotoxin free can become contaminated with endotoxin as the organisms multiply. Endotoxin free products also can become contaminated after contacting surfaces containing endotoxin; these are primarily surfaces that have contacted water. Thus a composition which is to be administered parenterally must be free of endotoxin and must also be sterile to avoid regeneration of lipopolysaccharide endotoxin.
Biopolymer products such as alginic acid and its salts, gellan gum, and xanthan gum are known for use in a number of pharmaceutical applications, including for example, in sustained release pharmaceuticals that are orally ingested. However, these prior biopolymer products have had an endotoxin level that is not suitable for parenteral administration. For parenteral use, the endotoxin level of biopolymer salts should be less than about 100 endotoxin units per gram of biopolymer, and preferably less than 50 endotoxin units per gram of biopolymer salt. It would be highly desirable to provide biopolymer salts having an endotoxin content sufficiently low such that the biopolymer salts are suitable for parenteral administration.
SUMMARY OF THE INVENTION
The present invention is directed towards biopolymer salts that are suitable for parenteral use. In particular, this invention relates to biopolymer salts, such as alginates or biogums, having water-soluble polysaccharides that are biologically-produced and having an endotoxin content less than about 100 endotoxin units per gram. The invention is also directed to alginate or biogum compositions comprising the biopolymer salt of this invention and a pharmaceutically acceptable solvent.
Another embodiment of this invention relates to methods for preparing the biopolymer salts and compositions thereof that are suitable for parenteral use. In particular, one method comprises the steps of (i) contacting an aqueous solution of a biopolymer salt with a hydrophobic material to adsorb endotoxin on said material; and (ii) precipitating a biopolymer salt having an endotoxin content less than about 100 endotoxin units per gram from the solution by mixing a water miscible organic solvent with the solution. In yet another embodiment of the method of this invention, the step of precipitating may be replaced by the step of extracting endotoxin from the aqueous solution with a water immiscible organic solvent. These methods advantageously provide biopolymer salts and biopolymer compositions that have an endotoxin content of less than 100 endotoxin units per gram. These methods can be applied to a wide variety of biopolymer salts comprising water-soluble polysaccharides, including not only the alginates and biogums mentioned above, but also chitosan, chitan, carrageenan, agar, welan gum, S-657 gum, rhamsan gum, carboxymethylcellulose, and chemical substitutions of carboxymethylcellulose, among others. The novel biopolymer salts and compositions thereof are highly suitable for use as parenteral implants. They may also be used, for example, to supplement natural lubricating fluids, to coat catheters, to thicken parenteral injections, to provide tissue bulking, and for cell encapsulation techniques.
DETAILED DESCRIPTION OF THE INVENTION
Endotoxin levels typically are measured using the Limulus Amoebocyte Lysate (LAL) test method. There are several variations of this test method in common use (e.g., Gel-Clot Endpoint, Chromogenic LAL, Kinetic-Chromogenic LAL) which produce a visual or color response in proportion to the amount of endotoxin present. Endotoxin levels are measured in endotoxin units (eu).
The biopolymer salts and biopolymer compositions of the present invention have endotoxin levels of less than about 100 eu per gram of biopolymer salt on a dry basis. Preferably, the biopolymer salts and biopolymer compositions of the present invention have endotoxin levels less than about 50 eu per gram, and more preferably, less than about 20 eu per gram.
The biopolymer salts of this invention are water-soluble polysaccharides that are either exuded by, or are extracted from, living organisms. Alginates are salts of alginic acid, which is a copolymer composed of D-mannuronic acid and L-guluronic acid units. These units typically exist as blocks of polymannuronic acid, blocks of polyguluronic acid or blocks of alternating mannuronic and guluronic acid units. The arrangement and relative amounts of mannuronic and guluronic acid are determined primarily by the source from which the alginate is manufactured. For example, most commercial alginate salts are produced by extraction from brown seaweeds. Alginate produced from
Macrocystis pyrifera
has a mannuronic to guluronic unit ratio (M/G ratio) of about 1.56:1 while alginate produced from
Laminaria hyperborea
has an M/G ratio of about 0.45. Monovalent salts (sodium or potassium salts) of alginate are typically water soluble while divalent salts (calcium, barium), polyvalent salts (iron, aluminum, etc.) and alginic acid form water insoluble gels or solids. Alginates are commercially available from ISP Alginates (San Diego, Calif.).
Biogums are salts of complex organic acids and are produced by fermentation of microrganisms. Gellan gum refers to the extracellular polysaccharide obtained from microorganisms of the species
Sphingomonas elodea
, in a suitable nutrient medium. Similarly, xanthan gum is a hydrophilic polysaccharide which is obtained by fermentation of microorganisms of the genus Xanthomonas, in a suitable nutrient medium. Gellan gum and xanthan gum are useful viscosifying agents. Gellan gum is also useful as a gelling agent. Depending on the biogum, monovalent salts (sodium or potassium salts) typically, but not necessarily, will render the biogum water soluble while divalent salts (magnesium, calcium, barium) and polyvalent salts (iron, aluminum, etc.) in the biogum may, but not necessarily, form water insoluble gels or solids.
The biopolymer employed in this invention is an alginate or biogum. The alginate is a salt of alginic acid, whereas the biogum is a salt of a complex organic acid, typically with a long polymer chain that increases viscosity.
Most preferably, with regards to alginates, the salt is sodium alginate. The alginate will typically have a ratio of mannuronic
Bousman William S.
Colegrove George T.
Garcia Monica A.
Holahan, III John L.
Raczkowski Robert
Banner & Witcoff , Ltd.
Gitomer Ralph
Khare Devesh
Monsanto Company
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