Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Ion exchange resin
Reexamination Certificate
2001-05-14
2003-02-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Ion exchange resin
C424S070210, C424S070190, C424S070220, C424S070270
Reexamination Certificate
active
06524569
ABSTRACT:
The present invention relates to polyion complexes, that is intimate blends of overall cationic polymers and overall anionic polymers, at least one of which said polymers has pendant zwitterionic groups to provide improved biocompatibility.
Physical gels are three-dimensional, disordered networks formed by associative forces that initiate noncovalent crosslinks. Mechanisms of interaction are numerous, including hydrogen bonding, hydrophobic interactions, crystalline segment formation and ionic association amongst others (Tanaka & Edwards,
Macromolecules,
25, 1516, 1992). In contrast to chemical gels that have defined point crosslinks, physical gels have so-called junctions zones where linear segments of the polymer chain form ordered structures. The nature and number of these zones determine the differences between gels.
It is well known in the literature that there are water-soluble polymers that contain complexing groups, whether neutral or charged, that can form gels by ionic association. This is most commonly achieved by the presence of sufficient inorganic metal salts under the appropriate conditions. The bonding chemistry between the metal ions is specific, each forming a gel with different polymers under specific conditions of pH, ionic strength and concentration of the polymer.
Another method of obtaining a gel by complexation of relevance to this invention, is by the formation of an interpolymer complex. As its name suggests, this is a process by which two distinct polymer entities interact to form a complex. If complexation is achieved by the interaction of oppositely charged ionic groups within the two polymers, the system is termed a polyion or polyelectrolyte complex (Michaels,
Indust
. &
Eng. Chemistry,
57, 32, 1965). If the interaction is between a strongly acidic polyanion and a strongly basic polycation, coulombic forces at the polyion sites results in the release of a microanion and microcation (the counterions of the original polyelectrolytes), which are then free to diffuse into the body of the solvent. The reaction will propagate rapidly from site to site, releasing the microions providing the entropy increase upon their liberation is not outweighed by the entropy decrease upon collapse and condensation of the polyion pair.
The polyion complexes have the potential to be solubilised in ternary solvent systems consisting of water, a water-soluble organic solvent like acetone and a strongly ionised simple electrolyte such as NaBr. This allows fabrication into many forms including fibres, films and coatings. This, together with their reported inherent non-thrombogenic nature, has made these materials interesting as biomaterials (Ratner & Hoffman, ACS Symposium Series 71 ed. J. D. Andrade, ACS, Washington D.C., 1976, p1).
The use of polyion complexes in medical applications has been suggested for many years. Indeed, Michaels made reference to the use of such complex solutions for potting or encapsulating aneurysms, commenting that the materials were reasonably well tolerated by the tissue. Ioplex 101 (a complex poly(triethyl-(3 & 4)-vinylphenylammonium bromide) and poly(sodium vinyl benzenesulphonate)) has been examined intensively for biomedical usage (Vogel et al.
J.Macromol. Sci., Chem.,
4. 675, 1970; Marshall et al.,
J. Biomed Mater. Res.,
4, 357, 1970; Bruck et al.,
Ann. N.Y Acad. Sci.,
283, 332, 1977). Analogues of this system have been studied to determine the effect of charge and structure on the complex and their behaviour towards blood platelets (Kataoka et al.,
Makromol. Chem.,
179. 1121, 1978 & 181 1363, 1980) and have been used as encapsulating agents in the development of artificial liver support systems (Kataoka et al.,
Jinko Zoki
(
Artificial Organs
), 8, 296, 1979).
Nakabayashi et al. have previously described the use of polyion complexes of polymers having zwitterionic pendant groups for the selective adhesion of platelets (
J. Biomed Mater. Res.,
28(11), 1347, 1994 by Ishihara et al. Adv. Biomat. Biomed. Eng.
Drug Delivery Syst. (1995) 227-228 by Ishihara, K. et al., and Japanese Patent JP-A-7-238124). Their invention claims specifically the use of a ternary polymer system consisting of 2-methacroyoyloxyethyl phosphorylcholine (MPC), butyl methacrylate (BMA) and sulfur propyl methacrylate (SPM) or trimethyl ammonium propyl methacrylate (TPM). Further to this, they define the compositions in which the MPC:BMA molar ratio is between 2:98-50:50, and the ratio of these two components to the ionic monomer (SPM or TPM) is between 98:2-80:20. These systems seem to have been designed to produce coatings with weak ionic interactions that have favourable properties in terms of platelet binding and activation. The anionic and cationic polymers are water insoluble, alcohol soluble. The polyion complexes described in these references are tested as coatings on glass beads and one of the products is said to be under test for use to encapsulate activated charcoal used for an artificial liver support system. Coatings of the PIC's are produced by mixing preformed solutions at 10% solids concentrations of the terpolymers each in ethanol, dipping the substrate to be coated in the solution and allowing the alcohol to evaporate from the film of coating composition.
JP-A-08-165491 (1996) describes complexes formed of a polymer having an overall cationic charge and which further includes pendant hydrophobic groups and pendant carboxybetaine groups, with an anionic surfactant such as a-olefin sulphonates and fatty acid soaps. The complexes are flexible solids and are for use with detergent components.
JP-A-10-245325 (1998) describes hair setting compositions comprising a cationic polymer having pendant hydrophobic groups, and a polymer having pendant carboxybetaine groups and pendant hydrophobic groups.
According to the invention there is provided a new method in which a solution of an anionic polymer having an overall anionic charge and a cationic polymer having an overall cationic charge together in a solvent system comprising a first solvent and an inorganic salt, in solution, is gelled by contact with water, whereby the ions of the inorganic salts become dissociated from the polymer and extracted from the gel formed by electrostatic attraction between polymer bound cationic groups and polymer bound anionic groups, and is characterised in that at least one of the cationic and anionic polymers comprises zwitterionic groups.
The method of the invention thus involves a transformation of the polymer from being in a mobile solution or suspension form to being a gel. The method generally involves collapsing of the gel, that is the gel has a lower volume than the starting volume of the solution in the solvent system.
In the method, the solvent system generally comprises an organic solvent. Preferably the organic solvent is water-miscible. Most preferably the solvent system comprises at least two solvents, in which the second solvent is water.
Examples of suitable organic solvents for use in the solvent systems are alcohols, ethers, esters and, most preferably, ketones. Most preferably the solvent is a ketone such as acetone.
For a solvent system comprising two solvents, these are generally used in a ratio in the range 5:1 to 1:5. Preferably the range of organic solvent water is in the range 2:1 to 1:5, preferably 1:1 to 1:4.
The inorganic salts should be soluble in the solvent system. Where the solvent system contains water, therefore, the salt should be water-soluble, for instance at a concentration of at least 10% by weight. Preferably the salt is soluble in a concentration of at least 20% by weight.
Preferably the salt comprises a single, preferably monovalent metal salt. Di- or higher valent metal salts may cause premature coagulation or gelation. Likewise the anion of the salt is preferably a sinly charged anion, preferably of a strong acid, most preferably other than an oxyanion although some oxyanions may be useful. Preferably the anion is a halide. The salt is preferably a halide of an alkali metal. The alli metal is lithium, potassium, or,
Court Jane Louise
Lewis Andrew Lennard
Stratford Peter William
Biocompatibles UK Limited
Fubara Blessing
Page Thurman K.
Sughrue & Mion, PLLC
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