Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Processes of preparing a desired or intentional composition...
Reexamination Certificate
2001-01-19
2003-07-22
Seidleck, James J. (Department: 1711)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Processes of preparing a desired or intentional composition...
C524S035000, C524S038000
Reexamination Certificate
active
06596791
ABSTRACT:
INTRODUCTION
Oxidised cellulose and its derivatives have been widely used in medicine and pharmacy since the first preparation by Chait and Kenyon [Shorygin P P., Chait E. V.: Zh. obshch. chim. 7, 188 (1937); Yackel E. C., Kenyon W. O.: J Am. Chem. Soc. 64, 121 (1942)].
Other types of haemostatics and antifibrinolytics have been introduced, however, oxidised cellulose especially in the highly pure form of a polyanhydroglucuronic acid and their copolymers (PAGA), and notably salts thereof, is used in various medicinal applications as a completely resorbable semi-synthetic polymer with minimum adverse effects in the organism. This is true for both the basic substance prepared according to GB 709684; U.S. Pat. No. 4,100,341, or salts thereof prepared according to more recent patents, such as.: CS AO 242920; EP 0659440A1 and PCT IE 98/00004.
It is known that after application of oxidised cellulose to stop surface bleeding a rigid scab is formed, especially on movable parts of the body, such as knees, fingers or ankles. This may be a disadvantage because it can crack and lead to renewed bleeding. Using a haemostat according to PCT IE 98/00004 this disadvantage can be partially overcome by altering the technological conditions of the manufacture (such as increasing the amount of crosslinks) which brings about increased accumulation of the body fluids in the substance and thereby the flexibility of the wound cover is optimised.
Within the last two decades, during investigations of various types of polysaccharides, it was established that during their biodegradation in the living organism certain functions of various types of cells are influenced. [Berger J., Nemec J., Sedlmayer P., Vortel V.: Report on Toxicological Investigation of a New Drug Preparation “Mikrocel”, Internal report, Research Institute for Pharmacy and Biochemistry, Praha, branch Pardubice-Rosice and Labem, 1984; Burchard W.: Polysacharide, Eigenschaften und Nutzung, Springer-Verlag, Berlin, Heidelberg, New York, Tokyo, p. 144 (1985); U.S. Pat. No. 5,166,137]. Depending on the type of bond in the main glycosydic chain, on the value of the degree of polymerisation, on the presence of various functional groups, and the degree of ionisation thereof, on the type of structural units, and the type of salt or a complex salt thereof, these polysaccharides affect the immune system of the organism. It seems for instance that glucanes bonded by an 1,3 &bgr; bond have immunomodulative properties while 1,4 &bgr; bonded glucanes suppress tumorous growth. There are however exceptions to these rules. An important factor underlying these properties is the presence of the glucuronic acid in the chain.
It is known that a large proportion of bonds between individual substances occurring in living organisms is of a non-covalent nature, such as hydrogen bonds, van der Waals forces, or bonds of an ionic character especially with biopolymers. These bonds create so-called intermolecular polymeric complexes (IMC) such as for example, heparin-peptides. In general these complexes represent a new class of macromolecular substances formed by association of individual polymer chains into macromolecules through secondary bonding interactions. According to the nature of the interactions these complexes can be subdivided into polyelectrolyte complexes, hydrogen bonded complexes, stereo complexes and charge transfer complexes. These types of complexes have a number of common properties, notably an organised supermolecular structure and the ability to create other higher supermolecular entities. The characteristic feature is their ability to undergo restructuring depending on the conditions prevailing in their environment. Further they are capable of undergoing interpolymer substitution reactions and it is especially due to this latter ability that the IMCs in their behaviour come close to imitating biochemical processes occurring in living organisms.
The invention in particular involves the use of polyanhydroglucuronic acids and salts thereof. The term polyanhydroglucuronic acid and salts there of as used herein also includes copolymers thereof, especially with anhydroglucose. This is hereinafter referred to as PAGA.
Co-pending patent application PCT IE98/00004 describes particular polyanhydroglucuronic acids and salts thereof and a method of preparing such compounds. In particular therefore, the term polyanhydroglucuronic acids and salts thereof includes the acids and salts referred to in this co-pending application.
STATEMENTS OF INVENTION
According to the invention there is provided a biocompatible intermolecular polymer complex of:
an anionic component comprising a linear or branched polysaccharide chain wherein at least 5% of the basic structural units are glucuronic acid; and
a non protein cationic component comprising a linear or branched natural, semi-synthetic or synthetic oligomer or polymer.
In a preferred embodiment of the invention the cationic component contains nitrogen that either carries a positive charge or wherein the positive charge is induced by contact with the polysaccharidic anionic component.
In one case the cationic component is selected from derivatives of acrylamide, methacrylamide and copolymers thereof. Preferably the cationic component is selected from polyacrylamide, copolymer of hydroxyethylmethacrylate and hydroxypropylmetacrylamide, copolymers of acrylamide, butylacrylate, maleinanhydride and/or methylmetacrylate.
In another case the cationic component is a cationised natural polysaccharide. Preferably the polysaccharide is a starch, cellulose or gum. The gum may be guargumhydroxypropyltriammonium chloride.
In another case the cationic component is a synthetic or semi-synthetic polyamino acid. Preferably the cationic component is polylysin, polyarginin, or &agr;,&bgr;-poly-[N-(2-hydroxyethyl)-DL-aspartamide].
In a further embodiment the cationic component is a synthetic anti-fibrinolytic. The anti-fibrinolytic may be a hexadimethrindibromide (polybren).
In a still further embodiment the cationic component is a natural or semi-synthetic peptide. Preferably the peptide is a protamine, gelatine, fibrinopeptide, or derivatives thereof.
In a further case the cationic component is an aminoglucane or derivatives thereof. Preferably the aminoglucane is fractionated chitin or its de-acetylated derivative chitosan. The aminoglucane may be of microbial origin or is isolated from the shells of arthropods such as crabs.
In a preferred embodiment of the invention the anionic component is polyanhydroglucuronic acid and/or biocompatible salts thereof.
In this case preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain from 8 to 30 percent by weight of carboxyl groups, at least 80 percent by weight of these groups being of the uronic type, at most 5 percent by weight of carbonyl groups, and at most 0.5 percent by weight of bound nitrogen. Preferably the polyanhydroglucuronic acid and salts thereof contain in their polymeric chain at most 0.2 percent by weight of bound nitrogen.
In a preferred embodiment the molecular mass of the polymeric chain of the anionic component is from 1×10
3
to 3×10
5
Daltons, ideally, the molecular mass of the polymeric chain of the anionic component ranges from 5×10
3
to 1.5×10
5
Daltons.
Most preferably the content of carboxyl groups is in the range of from 12 to 26 percent by weight, at least 95 percent of these groups being of the uronic type.
In a preferred embodiment of the invention the anionic component contains at most 1 percent by weight of carbonyl groups.
The carbonyl groups are preferably intra- and intermolecular 2,6 and 3,6 hemiacetals, 2,4-hemialdals and C2-C3 aldehydes.
The cationic component may be gelatine.
Alternatively the cationic component is chitosan.
The invention also provides a pharmaceutical or cosmetic composition including at least one biocompatible complex of the invention.
Preferably the composition includes at least one biocompatible biologically active substance.
The composition
Briestensky Jiri
Kiss Frantisek
Santar Ivan
Alpenstock Holdings Limited
Jacobson & Holman PLLC
Rajguru U. K.
Seidleck James J.
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