Drug – bio-affecting and body treating compositions – Solid synthetic organic polymer as designated organic active... – Polymer from ethylenic monomers only
Reexamination Certificate
2001-05-14
2003-05-13
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Solid synthetic organic polymer as designated organic active...
Polymer from ethylenic monomers only
C424S078080, C424S400000, C514S772200, C514S772300
Reexamination Certificate
active
06562330
ABSTRACT:
The present invention relates to the use of a polymer in a method of treatment in which it is introduced into a body cavity under conditions whereby insoluble polymer is deposited in the body cavity. In the invention polymer having pendant zwitterionic groups is used, whereby biocompatibility is optimised.
The current chosen method for the treatment of aneurysms involves the packing of the aneurysm with platinum coils. Some work has been performed on the coating of these coils to provide a surface with increase thrombogenicity and render it biologically active by enabling the release of cellular growth factors and the like (German Patent DE-A-19647280). Others have concentrated on the use of polymer systems for embolising aneurysms, often simply by precipitating the polymer from a solution in a biocompatible solvent (WO-A-9745131). Specifically, a Japanese Group has had some success using a liquid composition containing a hardening polymer (cellulose acetate), with an X-ray contrast agent in a solvent such as DMSO. The polymer is caused to precipitate in-situ within the aneurysm when contacted with blood (JP-A-06-107549
, J. Neurosurg.,
83(3), 531, 1995). Another approach has been to directly polymerise monomers in-situ, an example of which is a iron-acrylic compound which polymerises rapidly and is non-toxic (
J.Neurosurg.,
47(2), 137, 1977). Yet another approach described in U.S. Pat. No. 5,749,894 is to introduce a coil and a polymeric composition which is melted by incident radiation and re-solidified in situ in the aneurysm. Examples of polymers are polyalkenes, poly(meth)acrylates, polyesters, polyamides and polysaccharides.
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 a.,
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, K. 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 sulfopropyl 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 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.
In the present invention there is provided a new use of a charged polymer in a method of manufacture of a composition for use in the method of treatment of a human or animal by therapy or diagnosis in which the charged polymer containing composition is introduced into a body cavity and is contacted with a separate composition comprising a polyvalently charged counterion whereby the polymer is rendered insoluble in the body cavity, and is characterised in that the charged polymer has zwitterionic pendant groups.
The present invention also includes the method of treatment itself.
In the present invention, the insoluble polymer is deposited as a gel in the body cavity. The polymer should be insoluble in situ, so that it remains in situ over a period of time, for instance at least several hours, days or weeks. A gel comprises a matrix of polymer and solvent distributed throughout the matrix. Preferably the solvent in the gel is aqueous and substantially free of organic solvent.
The gel depot may be used as a vehicle for delivery to the body cavity of therapeutically active agents, or diagnostic agents such as contrast agents. Contrast agents may, for instance, be introduced to allow medical practitioners to visualise the position of the insoluble polymer, which itself may be providing a therapeutic benefit, or diagnostic utility in a patient. According to a preferred aspect of the invention therefore the insoluble polymer is, in the body cavity, combined with a therapeutically active or imaging agent.
The gelled polymer may be a coating, or encapsulating agent, on particulate or non particulate solid material which is opaque to electromagnetic radiation (possibly radio frequency). The opaque material may, for instance, be an imaging agent such as described in U.S. Pat. No. 5,667,767 such as tantalum, tantalum oxide and barium sulphate, or as described in U.S. Pat. No. 5,695,480 including gold, tungsten and platinum. The opaque agent may be particulate or may be a solid material having a discrete physical shape, for instance being 1 mm or larger in size such as a metallic coil, filament, wire, mesh or tube. For instance coils as described in U.S. Pat. Nos. 4,994,069, 5,122,136, 5,226,911 or U.S. Pat. No. 5,702,361 may be included.
The present invention is particularly useful for embolising blood vessels, or for packing aneurysms. The polymer is thus used in methods analogous to those described in the prior art discussion above. The invention may also be used as a therapeutic or cosmetic filler, for instance for use following tumour excision, for enhancing lips or breasts, for improving muscle control, for instance sphincter muscles to control incontinence, for endoluminal gel paving, for the treatment of patent ductus arteriosus, or for replacement or supplement of synovial fluid.
The charged polymer is prior to insolubilisation, soluble, in the composition in which it is introduced into the body cavity. That composition is preferably aqueous. The polymer is thus preferably water-soluble. The counterion is also preferably soluble in the separate composition in which it is introduced into the body cavity. It is most convenient for the separate composition to be aqueous, so that it is preferred for the counterion to be introduced in a water-soluble form, in solution in an aqueous composition.
The two compositions may be mixed in the body cavity or immediately before being introduced into the body cavity. Preferably they are introduced using a catheter designed for the purpose, which has separate lumens for each composition and means for allowing contact and mixing of the compositions immediately before delivery of the insoluble, usually gel form, polymer from the catheter into the desired location in a body cavity.
The counterion may be inorganic or organic. It may be a di- or tri-valently charged soluble ion, for instance a metal cation, or a multivalent oxyanion. Calcium ions are suitable multivalent cations.
Preferably in the invention, the counterion is a polyelectrolyte. The counterionic charges of the two polymers attract one another when the polymers are intimately mixed, thereby insolubilising (gelling) the blend. This blend is consequently a polyion (or polyelectrolyte) complex. At least one of the polymers forming
Court Jane Louise
Lewis Andrew Lennard
Stratford Peter William
Biocompatibles Limited
Fubara Blessing
Page Thurman K.
Sughrue & Mion, PLLC
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