FR2518421A1 - Sepn. and/or exchange appts. for treating biological liquids - has permeable membrane sealed with epoxy! and polyurethane compsn. - Google Patents

Abstract

Sepn. and/or exchange appts. for treating biological liquids has a generally selectively permeable membrane inside a housing, the membrane being thermosensitive and at least superficially impregnated with water and/or a hygroscopic cpd. Sealing between the adjacent extremities of the membrane and/or the extremity of the membrane and a part of the housing is effected with an adhesive compsn. comprising at least: an epoxy cpd., a polyurethane cpd. and a crosslinking agent for the epoxy cpd. The appts. is used as haemodialyser, haemofilter, blood oxygenator, blood treatment appts. by plasmapheresis. The adhesive gives good adhesion on surfaces highly impregnated with water and/or a hygroscopic cpd. e.g. glycerine. It crosslinks within 1 1/2 hrs. at below 70, pref. below 55 deg. C. so that the membrane is not damaged. It has excellent chemical and dimensional stability and it does not shrink. It is hemocompatible and non toxic. It is also free from bubbles, has a viscosity of 10-150 poises and, when hardened, a shore D hardness of 30-80, 40-70.

Description

REPOTAGE OF PLASTIFIED, THERMOSENSITIVE MEMBRANES
The present invention relates to separation and / or exchange devices with a generally semi-permeable membrane, for the treatment of biological liquids, in particular of blood, in which new adhesive compositions are used to ensure sealing, on the one hand between the ends of this membrane and on the other hand between the membrane and the compression box.

 It relates more particularly to such devices in which the membranes are impregnated with water and / or a hygroscopic compound such as glycerin and are also thermosensitive.

 These devices are used in particular as hemodialyzers, hemofilters, heat exchangers, blood oxygenators, blood filters and blood treatment apparatus by plasmapheresis.

 The membranes can be used in various forms, flat, tubular, or in the form of hollow fibers. It is generally known to stick or potty their ends in a relatively satisfactory manner, when they are, at least, locally, dry or only wet.

 However, it has been realized on the one hand, that the desired improvement in the ultrafiltration capacities of these membranes and their permeability to substances of higher molecular weight corresponded to increased porosity, and on the other hand, that such membranes generally only retain their remarkable properties if they remain permanently impregnated, for example with water and / or a hygroscopic compound such as glycerin; See, for example, French patent No. 70/32,762 for flat membranes and French patent No. 72/32,285 for hollow fibers. We then come up against the problem of sticking or potting such membranes, which are generally heat-sensitive, while they are heavily impregnated with water and / or glycerin.

Indeed, the constraints required are particularly severe, an adhesive composition having to satisfy simultaneously the following conditions, whatever the shape of the membrane
a) providing and maintaining excellent adhesion to surfaces heavily impregnated with water and / or a hygroscopic compound such as glycerin,
b) have a crosslinking time generally of less than 1 hour 30 minutes and this at a temperature of less than 700 ° C. and preferably less than 550 ° C., so as not to damage the membrane,
c) have excellent chemical and dimensional stability: in particular no shrinkage,
d) be hemocompatible and meet strict criteria of non-toxicity.

In addition, for devices provided with hollow fibers, additional constraints are imposed: the adhesive composition must indeed more
e) have a homogeneous structure: in particular be free of bubbles and preferably be colorless,
f) present during its implementation a relatively low viscosity at room temperature, generally between 10 and 150 poises and preferably between 30 and 100 poises, in order to be able to completely coat each hollow fiber,
g) finally, having, after crosslinking, a shore D hardness of between 30 and 80 and preferably between 40 and 70 d to allow a clean opening of the end of the hollow fibers by slicing, without crushing or chipping.

An object of the present invention is a semi-permeable membrane device, in particular for treating blood, inside which the seals are obtained by virtue of an adhesive composition satisfying all of the conditions set out above;
Another object of the present invention is a simple, reliable and economical method allowing the use of said adhesive composition.
Other items from. the present invention will become apparent from the following description.

It has now been found, and this is the subject of the present invention in the production of which participated
Mr. Marc ROBERT, a separation and / or exchange device for the treatment of biological liquids, comprising a generally selectively permeable membrane inside a housing, characterized in that, said membrane being thermosensitive and at least superficially impregnated of water and / or of a hygroscopic compound, the sealing between the adjacent ends of said membrane and / or between the end of said membrane and part of said housing is carried out, at least partially, using an adhesive composition comprising at least
- an epoxy compound,
- a polyurethane compound,
a crosslinking agent for said epoxy compound.

 The present invention relates to devices for separation and / or exchange of materials and / or calories of any type known per se and of which a membrane is the essential element. Such devices are used for the treatment of biological fluids, in particular blood.

 By separation device means a device in which the treated fluid is separated by the membrane into at least two of its components: this is the case for example of an ultrafilter for blood. By exchange device is meant a device schematically separated by the membrane into two compartments traversed, one by the treated fluid (blood for example) and the other, generally against the current, by another fluid, by example a dialysis liquid in the case of a hemodialyzer.

 Although the membrane may be impermeable to fluids in the case of a # heat exchanger, it is generally selectively permeable, for example in the case of hemodialysis or hemofiltration. It can also be microporous in the case of oxygenation of the blood or treatment of the blood by plasmapheresis.

 In a manner known per se, the membrane is arranged inside a housing and the various compartments of such a device are arranged on either side of zones of tight seals made either between the ends of the membrane and internal parts of the housing, either between the ends of the membrane itself.

 The present invention applies to devices provided with a membrane of the flat type, the latter being able to be either folded. in accordion around superimposed dividers, or cut into elements- arranged.

between and / or around overlapping dividers. It also applies to devices provided with a flattened tubular type membrane; the latter can be rolled in a spiral, for example around a mandrel to constitute a device of the wound type.

 However, it is particularly advantageous for devices provided with a membrane constituted by a plurality of fine hollow fibers, generally grouped in bundles. Indeed, it is with this type of device that the sealing problems are most difficult to solve and, without the invention being in any way limited to this particular embodiment, it is to simplify the description that 'It will be essentially referred to this type of device thereafter.

 The present inv # ention concerns ~ devices provided with generally heat-sensitive membranes, that is to say which risk being damaged by excessive temperatures, either in intensity or in duration. Thus, the invention is particularly suitable for sticking or potting membranes which must not be subjected to temperatures exceeding 700 ° C. and preferably 550 ° C. during the time of crosslinking, that is to say ~ at plus-equal to 1 hour 30 and preferably 1 hour.

 The present invention relates to devices whose ~ membrane is at least superficially impregnated with water and / or a hygroscopic compound such as glycerin. It is known in fact that, for the treatment of biological liquids, in particular of blood, one is led to use membranes which, in order to offer improved ultrafiltration and permeability rates, and to preserve their mechanical properties and in particular their flexibility initial, may be impregnated, generally at the core and in a homogeneous manner, but sometimes also on the surface only, of materials such as water and / or glycerin, in sufficient quantities.

 Water in particular fills the pores which contribute to giving the membrane its characteristics of ultrafiltration rate and rate of permeability to the impurities to be removed, the molecular weights of which can be included in a predetermined range.

 The level of polymer entering into the composition of the membrane is generally between 15% and 70% and preferably between 20% and 50%. The difference can be constituted in particular by water and / or by a hygroscopic compound.

 The water impregnation rate of the membrane is generally between traces and 80% and preferably between 5% and 55%. The rate of impregnation with the hygroscopic compound of the membrane is generally between traces and 80% and preferably between 10% and 65%.

 To maintain a good seal, it has been found advantageous that in the membrane the ratio of water and hygroscopic compound is stable, so that there is no migration of these constituents, for example exudation of water from the membrane, either as a result of variations in hygrometric conditions, or when applying the adhesive. Thus, with membranes made of acrylonitrile copolymers, the ratio between the respective weights of glycerin and water is advantageously around 70% and 30%.

The present invention is particularly applicable to membranes of homogeneous structure, called symmetrical, that is to say having a uniform microporosity and for example devoid of skin
With membranes made of acrylonitrile copolymers, the polymer content is generally between 20 and 40%, the water impregnation rate is generally between 5 and 20% and the glycerol impregnation rate is generally between 55 % and 65%.

 As hygroscopic compound, other than glycerine, it is possible to use, for example and in a nonlimiting manner: urea and non-toxic products in the following classes: glycols, polyoxyethylene glycols, alcohols, polyols, glycerides, glycol ethers, dextrans, xanthans (water-soluble polymers) and generally heavy solvents in water.

 Given the multiple efforts that have so far been unsuccessful in finding an adhesive composition which satisfies all of the conditions set out above for membranes which have been in existence for several years; also taking into account the negative results obtained so far with silicone elastomers, epoxy resins; polyurethanes associated or not with epoxy groups, even when they were reputed to be not very sensitive to water, it was completely unexpected to find adhesive compositions which finally make it possible to obtain satisfaction.

The adhesive compositions which are suitable for the particular application envisaged according to the present invention comprise at least
- an epoxy compound, #
- a polyurethane compound,
- a crosslinking agent for the epoxy compound.

 It has been found that the combination of these three elements is necessary to obtain an adhesive composition which satisfies the conditions set out above.

 The essential function of the epoxy compound, generally an epoxy resin, is to ensure good adhesion of the adhesive to a wet and glycerine support. The essential function of the polyurethane compound is to provide the adhesive with the flexibility necessary for # crosslinking of the epoxy resin. It can also act as a constituent of the crosslinking agent.

 The adhesive is generally manufactured only just before its implementation and it is much simpler and therefore preferable for this to have to mix only two components.

 It is thus advantageously possible to obtain a first component by premixing the polyurethane compound and a crosslinking agent of the epoxy resin to which it is possible, if necessary, to add other constituents such as diluents, plasticizers or accelerators for crosslinking the epoxy resin. The stability of such a mixture generally makes it possible to ensure. its storage and transport.

 During the application of the adhesive, it suffices to mix the second component constituted by the epoxy resin with the preliminary mixture thus obtained, under the conditions which will be specified below.

 Epoxy compounds contain one and usually more than one epoxy group per molecule. They may consist of glycidyl ethers of polyols, such as glycerin, hydrogenated diphenylolpropane, or of polyphenols such as resorcinol, diphenylolpropane or phenol-aldehyde condensates. It is also possible to use the glycidyl esters of polycarboxylic acids such as hexahyurophthalic acid or dimerized fatty acids.

 However, liquid epoxy resins based on epichlorohydrin and diphenoloipropane are preferred, in particular with a molecular weight of 340 to 450.

 If necessary, the viscosity of the mixtures can be lowered and thus facilitate their use using monofunctional epoxy compounds.

 It is thus possible, for example, to use aliphatic and aromatic glycidyl ethers such as butyl and glycidyl oxide, phenyl and glycidyl oxide, or glycidyl esters such as glycidyl acrylate or alternatively epoxides such as styrene.

 For the same purpose, it is also possible and if necessary, in combination, to use reactive diluents such as agents with an amino group of low reactivity and low viscosity, and / or to add non-reactive diluents such as phthalates, for example dioctylphthalate. However, we are limited in this way because the presence of plasticizers generally reduces the adhesion of the adhesive.

 The polyurethane compound advantageously consists of a prepolymerized blocked polyurethane which no longer has free isocyanate groups, in order to avoid any gassing in the presence of moisture, in particular in contact with the membrane, gassing which would be liable to form bubbles.

 These polyurethane compounds preferably carry amine groups in the terminal position; they are obtained by reacting isocyanate pre-adducts with ketimines or enamines containing hydroxyl groups.

 The isocyanate pre-adducts are themselves obtained by reaction of linear or branched polyalkylene ether-polyols, preferably propylene polyoxides, for example polypropylene glycol, with di- or polyisocyanates.

 Among the di- or polyisocyanates, it is preferred to use # aliphatic or cycloaliphatic diisocyanates #, such as hexamethylene diisocyanate and isophorone diisocyanate.

 For the preparation of the pre-adducts, the polyalkylene ether polyols and the diisocyanates are mixed in amounts corresponding to an NCO / OH ratio of 1.5 to 2.5: 1 and preferably 2: 1.

 After addition of a suitable catalyst, for example dibutyltin dilaurate in proportions of 0.1%, the mixture is heated for a few hours at a temperature of 50 to 1000 ° C. until the isocyanate content determined by analysis coincides practically with the calculated value.

 The ketimines or enamines carrying hydroxyl groups and suitable for use according to the invention are obtained by known means. The isocyanate pre-adducts are mixed with the enamines or ketimines carrying hydroxyl groups, when cold, in an NCO / CHi ratio of i: 1 and the mixture is stirred until the infrared spectrum no longer contains the line of the groups. NCO.

 Polyether-urethanes bearing amino terminal groups can give storage stable mixtures with usual low molecular weight amino hardeners bearing at least two hydrogen bonds of reactive amines. The addition of these hardeners causes a significant decrease in the viscosity of the polyether-urethanes and an increase in the reactivity when reacting with epoxy resins.

 The number of amino hardeners with functionalities and viscosities. different that can be used allows great flexibility of use.

 Among these amine hardeners of the usual type, there may be mentioned aliphatic amines, for example # polyethylene polyamines and polypropylene polyamines, inter alia diethylene triamine and dipropylene triamine; cycloaliphatic diamines; heterocyclic amines such as piperazine; long chain polyether amines; aromatic amines; poly amidoamines derived from natural or synthetic fatty acids and polyamines; amino adducts; phenol-aldehydamine condensates.

 For the preparation of one-component mixtures with epoxy resins, it is also possible to combine amine-releasing compounds, for example ketimines or enamines, with polyether-urethanes carrying terminal groups ketimines or enamines.

The amino hardeners can be combined in a manner known per se with viscosity regulators, accelerators such as tertiary amines, triphenyl phosphite, alkylphenols, or with rapid hardeners such as bases.
MANNICH. Epoxy resins can be cured hot or cold using these hardeners or mixtures of hardeners.

According to the present invention, the implementation of the adhesive is generally carried out by successively carrying out the following main operations
- if necessary, pre-heating one or more of the
adhesive components, to obtain viscosity
sufficiently low,
- mixing of the components to obtain the desired adhesive,
- introduction of the adhesive in the fluid state into the zone to
potting, in contact with the membrane to be sealed,
- crosslinking and molding of the adhesive,
- possible cutting, deburring or slicing of the adhesive
molded in contact with the membrane.

EXAMPLE
For the manufacture of a hemodialyzer, there is a bundle of 8000 hollow fibers with an external diameter of 350 #, of the type described in French patent No. 72 / 32,285, the composition of which by weight is as follows
copolymers of acrylonitrile and
sodium methallylsulfonate 29 S
glycerin 59%
water 12%
To seal these hollow fibers tightly at their ends, an adhesive consisting of the following two components is used.
The first component is a liquid epoxy resin consisting of diglycidic ether of bisphenol A and bisphenol F, viscosity between 65 and 90 poises at # 250 C, density at 200 C 1.17 g / cm3 This resin offers a value epoxy of between 0.52 and 0.55 and an epoxy equivalent weight of 182 to 192.

The second component consists of the prior mixing of: a) an amino polyurethane of low reactivity consisting of a mixture
2- 2- 4- tri-dimethylaminomethyl phenol and polyetherurethane
obtained from polypropylene glycol and isophorone
diisocyanate, viscosity at 250 C around 200 poises and density
3
at 200 C: 1.02 g / cm3.-It offers an amine index of around 70 and
an equivalent H / amine weight of approximately 890.

b) as an accelerator, a modified polyamine hardener, consisting of
a mixture of m-xylylenediamine and bisphenol A, with high
reactivity, viscosity around 4 poises at around 250 C and density
1.01 g / cm3. It offers an amine index of around 392 and a
active H equivalent of 76.

Mixes are carried out at the rate of 100 g of epoxy resin per 113 g of amino polyurethane and -30 g of modified polyamine hardener.
At the same time, the bundle of hollow fibers is cut to the desired length. This bundle is placed in a polycarbonate shell, of generally cylindrical shape which will constitute an element of the final compression of a hemodialyzer. A temporary stopper intended to contain the potting adhesive is attached to each end of the shell. Each plug is connected to a mixer containing the adhesive resulting from the mixture of the two components. These are previously heated to 500 ° C. and then simultaneously introduced into said mixer.

 The assembly is mounted on a centrifuge device rotating at 500 revolutions / minute. Under the combined action of gravity and the centrifugal effect, the adhesive, maintained at a temperature of 400 C corresponding to a viscosity of 35 poises, flows towards the ends of the bundle of hollow fibers, seeping between hollow fibers, up to temporary stoppers. One hour later, the crosslinking of the epoxy resin is substantially complete, the centrifugal device is stopped and the caps are removed to slice, using a microtome, the end of the tubular sealing plates thus obtained and open the end of the hollow fibers. The plugs are then replaced by permanent caps carrying the orifices for the entry and exit of the blood respectively.

 In the final state, the adhesive forms smooth, perfectly waterproof plates, free of bubbles, having a slight yellow coloring, of shore hardness 50 D, non-toxic and hemocompatible.

Claims (12)

10) Separation and / or exchange device for treatment  biological fluids, usually with a membrane  selectively. permeable inside a housing, characterized in  what, said membrane being thermosensitive and at least  superficially impregnated with water and / or a hygroscopic compound,  the seal between the adjacent ends of said membrane  and / or between the end of said membrane and part of said  housing is carried out, at least partially, using a  adhesive composition comprising at least  - an epoxy compound,  - a polyurethane compound,  a crosslinking agent for said epoxy compound. 20) Device according to claim 1, characterized in that  said adhesive composition is implemented from two  constituents only, said epoxy compound, generally a  epoxy resin, on the one hand, the polyurethane compound and  crosslinking of said epoxy resin on the other hand, the latter  after being 'previously mixed. 30) Device according to any one of claims  above, characterized in that said epoxy compound is a '  11 liquid state, based on epichlorohydrin and diphenylolpropane. 40) Device according to any one of claims  above, characterized in that said polyurethane compound is  a prepolymerized blocked polyurethane which no longer has groups  free isocyanates. 50) Device according to claim 4, characterized in that  said polyurethane compound is included in the composition of said  crosslinking of the epoxy resin. 60) Device according to any one of claims  above, characterized in that said polyurethane compound  bears amino groups in the terminal position and is obtained by  reaction of isocyanate pre-adducts with ketimines or  enamines containing hydroxyl groups. 70) Device according to any one of claims  previous, characterized in that the crosslinking agent of the  epoxy resin consists of a stable mixture of  polyether-urethane carrying amino terminal groups and at  at least one low molecular weight amino hardener carrying at least  2 hydrogen bonds of reactive amines. 80) Device according to any one of claims  above, characterized in that said membrane consists  by a plurality of hollow fibers. 90) Device according to any one of claims  previous, characterized in that the water impregnation rate  of the membrane, at least at the place of contact with said  adhesive, is between traces and 80%. 100) Device according to any one of claims  previous, characterized in that the impregnation rate in  hygroscopic membrane compound, at least where  contact with said adhesive, is between traces and 80%. 110) Device according to any one of claims  above, characterized in that said membrane is  thermosensitive. 120) Device according to any one of claims  above, characterized in that said membrane is in  acrylonitrile copolymers.  130) Device according to any one of claims  previous, characterized in that it is used as  hemodialyzer, hemofilter, blood oxygenator, blood pressure device  blood treatment by plasmapheresis, blood filter and / or  heat exchanger for blood; 14) Method for implementing said adhesive for  manufacture of the device according to any one of  previous claims, which consists of:  - a) if necessary - pre-heat at least one of the  adhesive components,  b) mixing said components to obtain the adhesive  wish,  - c) introduce the adhesive in the fluid state into the zone to  potting; in contact with the membrane to be sealed,  - d) crosslinking the epoxy resin and molding the adhesive,  - d) cut, deburr or possibly slice the adhesive  molded in contact with the membrane.