This invention relates to biocompatible and hemocompatible polymeric adsorbents having a basically hydrophobic porous interior and a hydrophilic outer covering, and methods of preparing these adsorbing materials. Polymeric adsorbents with an inverted sequence of the two layers, namely, a polar hydrophilic core and a hydrophobic shell, can be also prepared in accordance with the same general scheme of radical polymerization in a dispersed two phase system.
Porous hydrophobic natural and polymeric materials, in particular, activated carbon and macroporous polystyrene resins, are widely used in manifold adsorption technologies. If not for the low hemocompatibility, they also would present materials of choice for purifying blood or other physiological fluids from many endogenic and exogenic toxic organic compounds. It is exactly because of the high adsorption activity of the surface of the above adsorbent particles, that the hydrophobic materials activate the blood complement system, cause deposition of platelets and, finally, lead to clot formation. Therefore, in hemoperfusion procedures, only surface modified particles of the adsorbents can be employed. Modification means formation of a surface layer or coating with a substancialy reduced adsorption activity, in particular, formation of a hydrophilic and hemocompatible shell, without affecting significantly the basically hydrophobic nature of the pores in the core of the particle.
Traditionally, the coating procedure is carried out as a special chemical procedure that is different both in its chemical nature and reactors involved, as well as reaction conditions.
Thus, best known example of an efficient hydrophobic adsorbent is Amberlite XAD-4 manufactured by Rohm and Haas Company (U.S.). These materials are produced by suspension polymerization of divinylbenzene or copolymerization of the latter with styrene in the presence of a diluent which is miscible with the monomers, but causes precipitation of the polymer formed during the polymerization. Due to the micro phase separation in the polymeric bead under formation, the space occupied by the diluent gives rise to macro pores of the final material, whereas the precipitated polymeric phase represents rigid walls of the pores. Typical values of surface area of the macroporous adsorbents are less than 300-500 sq.m/g, typical pore diameters amount to several hundreds to several thousands angstrom. To make this kind of adsorbing materials biocompatible, Korshak et al (U.S. Pat. No. 4,140,652) suggest adsorption of albumin on the surface of the beads, followed by polycondensation of the adsorbed protein with aldehydes (preferably, formaldehyde) or other bifunctional crosslinking agents for proteins. Similarly, Abe in U.S. Pat. No. 4,202,775 adsorbs total plasma proteins on the surface of porous polymeric materials and then cross-links the adsorbed protein layerwith a suitable cross-linking agent. The hydrophobic basic material is thus provided with a hydrophilic and biocompatible shell.
A thin hydrophilic layer is formed on the surface of porous hypercrosslinked polystyrene materials by chemical transformations of the surface exposed residual chloromethyl groups into hydrophilic functional groups (Davankov et al., U.S. Pat. No. 5,773,384). In another set of chemical reactions, Davankov et al. U.S. Pat. No. 6,114,466 suggest chemical transformation of surface exposed pendant vinyl groups of a divinylbenzene-rich copolymer into a series of other, hydrophilic functional groups. Among these reactions, radical grafting of water soluble monomers by treating the porous polymer in an aqueous or aqueous-organic solution of these monomers and radical initiators was suggested.
It is an object of present invention to provide a method of producing a biocompatible hydrophobic polymeric porous material, which is a further improvement of the existing methods.
In keeping with these objects and with others which will become apparent hereinafter, one feature of present invention resides, briefly stated in a method of producing beaded polymeric porous adsorbents having a hydrophobic porous core part and a hydrophilic shell part with lilophilic property of one of said parts and hydrophilic property of another of said parts, comprising the steps of preparing an organic phase composed of water insoluble monounsaturated and polyunsaturated comonomers and a porogen; preparing an aqueous phase composed of a mixture of water soluble monounsaturated and polyunsaturated comonomers; forming a dispersion of the organic phase and the aqueous phase in a single vessel; and creating conditions for first polymerizing said organic phase and formation of said hydrophobic porous core and thereafter polymerizing said aqueous phase and formation of said hydrophilic the shell part which coats said core part.
In accordance with another feature of the present invention a beaded polymeric porous adsorbent material is proposed having a hydrophobic porous core part and a hydrophilic shell part arranged around said core part wherein said beaded polymeric adsorbent is produced by preparing an organic phase composed of water insoluble monounsaturated and polyunsaturated comonomers and water immiscible organic solvents as porogens; preparing an aqueous phase composed of a mixture of water soluble monounsaturated and polyunsaturated comonomers; forming a dispersion of the organic phase and the aqueous phase in a single vessel; and creating conditions for first polymerizing of said organic phase and formation of said hydrophobic porous core part and thereafter polymerizing said aqueous phase and formation of said hydrophilic porous shell part which coats said core part.
In accordance with the present invention, the components of the organic phase produce the core part of the final adsorbent, while the components of the aqueous phase produce the shell in the same reaction vessel. This can be done in the form of two successive polymerization reactions, first in the organic phase which forms the core part and then in the aqueous phase which forms the shell part and coats the core part. In some situations, a simultaneous radical copolymerization process or so-called xe2x80x9cone-step processxe2x80x9d can be performed.
If the organic phase is dispersed in the aqueous phase, then the dispersed organic phase produces the hydrophobic porous core part of the final adsorbent, while the water dissolved monomers produce the hydrophilic shell.
The novel features which are considered as characteristic for the present invention are set forth in particular in the appended claims.
In accordance with the present invention biocompatible and hemocompatible polymeric adsorbents having a basically hydrophobic porous interior and a hydrophilic outer covering, are prepared in a xe2x80x9cone-potxe2x80x9d or xe2x80x9cone-stepxe2x80x9d.
The inventive method includes preparing an organic phase composed of water insoluble monounsaturated and polyunsaturated comonomers and a porogen; preparing an aqueous phase composed of a mixture of water soluble monounsaturated and polyunsaturated comonomers; forming a dispersion of the organic phase and the aqueous phase in a single vessel; and creating conditions for first polymerizing of said organic phase and formation of said hydrophobic porous core part and thereafter polymerizing of said aqueous phase and formation of said hydrophilic porous shell part which coats said core part.
In accordance with the invention the two procedures of formation of the polymeric adsorbent bead and coating of the latter are combined into a simple procedure carried out simultaneously or as a sequence of two steps in one single reactor.
In the inventive method polymerization must start within the dispersed phase. Otherwise, the spherical shape of the particles will be destroyed or distorted. The crosslinking density of the core must be higher than that of the shell. Otherwise, the mechanical stability of the shell is endangered.
To meet the first requirement, the radical polymerization initiator is initially added to the dispersed phase, not the dispersion medium. The second radical initiator is added to the dispersion medium only after the major part of the comonomers in the dispersed phase converts into polymeric material. In some cases, no second radical initiator is needed, at all. This is because many growing polymer chains with their chain-end radicals show up at the phase interface and can initiate the polymerization in the dispersion medium. Moreover, the first radical initiator, like benzoyl peroxide, generates radicals relatively slowly. This initiator is only partially consumed during the formation of beads even after several hours of polymerization. This initiator easily moves toward the surface of the bead and activates there the surface exposed pendant vinyl groups of the divinylbenzene moiety of the bead, thus initiating the graft: polymerization of the water soluble monomers.
The dispersed organic phase contains water immisible organic solvents, porogens. Thermodynamically good solvents for the growing polymer chains favor formation of microporous copolymers, "THgr"-solvents favor formation of predominantly mesoporous structure (pore diameters 2.0 to 20.0 nm), whereas non-solvents result in the formation of conventional macroporous beads. All three kinds of the above porogens can be used in the above described simultaneous or step-wise procedures of preparation of the core-shell type adsorbing material.
There is a principal difference between the conventional separate-step coating of the beads and the here described one-step or one-pot procedure. The principal difference is the presence of the porogen within the porous beads that form in the dispersed phase. For this reason, the grafting of the polymeric chains from the dispersion medium can only proceed on the outer surface of the bead, whereas in the case of previously used protocols, all larger pores of the pre-formed polymer appear accessible to the monomers to be grafted. Therefore, the materials prepared in the conventional separate and the here suggested combined version of grafting polymerization are basically different. The difference mainly results in the full hydrophobicity of macro pores in the product of the combined polymerization conducted in accordance with the present invention. Contrary, when receiving the coating in a conventional separate grafting polymerization step, the macropores of the adsorbent get coated as well.
Finally, it turned to be possible to realize the same one-step and one-pot procedures with inverted xe2x80x9cwater-in-oilxe2x80x9d suspensions. Aqueous solution that contains water soluble comonomers and crosslinking agent, when dispersed in an organic media, can receive during the polymerization in the dispersed droplets a hydrophobic coating, by grafting hydrophobic comonomers, for example, styrene from the organic dispersion medium.