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Description  |
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BACKGROUND OF THE INVENTION
This invention pertains to an improved process for the preparation of
uniform, spherical beads of up to 5 mm diameter of a crosslinked,
water-insoluble hydrogel by suspension polymerization in a concentrated
aqueous salt solution of 95-30% by weight of a monoolefinic monomer
containing at least 5% of a hydroxy substituted hydrophilic vinyl monomer
with 5-70% by weight of a terminal polyolefinic macromer crosslinking
agent in the presence of water-insoluble, gelatinous, strong water-bonding
inorganic metal hydroxides as suspending agents in the absence of excess
alkali. The hydrogels have a host of pharmaceutical and industrial uses.
The spherical beads exhibit a degree of swelling in water of from 5 to
200%.
Hydrogels have been described since 1956 (U.S. Pat. No. 2,976,576) and
subsequently a large number of patents have been issued describing the
synthesis and use of hydrogels based primarily on 2-hydroxyethyl
methacrylate and, to a lesser extent, on N-vinylpyrrolidone. Typically,
these hydrogels are crosslinked, water-swellable polymers made by
copolymerization of 2-hydroxyethyl methacrylate with a small amount of
ethylene or butylene dimethacrylate. They are used as polymeric, inert
carriers for active substances, which are slowly and controllably released
from these carriers; such active substances may be drugs (U.S. Pat. Nos.
3,574,826; 3,577,512; 3,551,556; 3,520,949; 3,576,760; 3,641,237;
3,660,563); agricultural chemicals (U.S. Pat. No. 3,576,760); or
fragrances (U.S. Pat. Nos. 3,567,118; 3,697,643).
Their uses as antifogging coatings (U.S. Pat. No. 3,488,215), body implants
and bandages have also been described in U.S. Pat. Nos. 3,577,516;
3,695,921, 3,512,183; 3,674,901. The widely used soft contact lens
consists of this material (U.S. Pat. Nos. 3,488,111; 3,660,545).
In the pharmaceutical field the main interest lies in the slow and
controllable release of drugs from such hydrogels. Drug-containing
hydrogel preparations have been described as being in the form of
bandages; subcutaneous implants; buccal devices, intrauterine devices, eye
inserts. They are made by complicated fabrication procedures which usually
involves casting the monomer solution into a suitable mold and
polymerizing in the presence of a free radical generating initiator.
The use of drug loaded hydrogel granules as an oral dose form has also been
suggested (U.S. Pat. No. 3,551,556). It is indeed one of the most useful
applications of this concept in medicine since it allows the delivery into
the bloodstream of an orally taken drug to be spread out over several
hours in a reproducible manner. This eliminates wasteful and potentially
dangerous peak drug concentrations in the blood, while prolonging the time
during which preferred and effective drug levels in the blood are
maintained.
There are two methods, by which hydrogel granules can be prepared. (1) One
method consists of dicing or granulating a hydrogel sheet cast in the
conventional manner and screening out the proper particle size. This
method has several disadvantages: (a) It involves time consuming bulk
polymerization of large amounts of materials in the form of relatively
thin sheets; (b) the final product consists of jagged, rough particles
with large surface area and sharp edges which are not only objectional
from the aesthetic standpoint, but also are ill-suited for the controlled
release of a drug, which depends on a uniform diffusion rate and therefore
on uniform particles with well-defined surface and volume.
(2) The second method of making hydrogel granules, and by far the superior
one, is suspension polymerization. Suspension polymerization consists of
suspending a liquid monomer phase in a nonsolvent medium by stirring and
with the aid of a protective colloid as a stabilizer, and polymerizing the
stirred suspension by conventional means. Polymerization is heat induced
or catalyzed by decomposition of a free radical chemical initiator. This
method yield uniformly spherical beads in a one-step process and is widely
used in the production of polystyrene, poly(vinyl chloride) and
polyacryaltes, and poly(vinyl acetate). A good summary of the present
state of the art is given by E. Farber in the Encyclopedia of Polymer
Science and Technology, Vol. 13, pp 552-571, (1970), Interscience, N.Y.
The relevant teachings therein are incorporated herein by reference. In
case of water-soluble monomers used in the production of hydrogels, such
as 2-hydroxyethyl methacrylate and N-vinylpyrrolidone, the nonsolvent
medium is usually an organic liquid or an aqueous salt solution.
In U.S. Pat. No. 3,390,050 suspension polymerization of water-soluble
monomers in the presence of large amounts of active ingredients is
described. This process is, however, not suitable for the preparation of
hydrogel beads for an orally administered drug since it is impossible to
purify the polymer without leaching out the drug.
Most references to suspension polymerization of a 2-hydroxyethyl
methacrylate refer to silicone oil or organic media such as mineral oil or
xylene as the insoluble suspending phase (U.S. Pat. Nos. 3,567,118;
3,574,826; 3,575,123; 3,577,518; 3,583,957). These processes give
generally particles with very irregular, imperfect and porous surfaces,
unsuited for uses where diffusion rather than adsorption and desorption is
the working mechanism. Besides these factors, the workup of the polymer on
a technical scale would pose a problem.
Suspension polymerization of 2-hydroxyethyl methacrylate (HEMA) in the
presence of 0.5 to 2% of shortchain cross-linking agents (a composition
conventionally named "Hydron") and using an aqueous salt solution as
medium has been described in U.S. Pat. No. 3,689,634, but there is no
mention of a suspending agent as being a necessary ingredient of the
recipe. However, it can be demonstrated that without such a suspending
agent no useful particles or beads are obtained, only large agglomerations
of polymer.
It is, however, well-known in the prior art that certain water-soluble
polymers, such as polyvinylpyrrolidone and hydroxyethyl cellulose are
excellent suspending agents for suspension polymerization. It is also
known that certain highly insoluble inorganic compounds such as calcium
sulfate, barium sulfate, calcium phosphate, magnesium phosphate, calcium
carbonate and magnesium hydroxide are also useful.
The use of magnesium hydroxide as the suspension stabilizer in the
suspension polymerization of vinyl monomers is disclosed in U.S. Pat. No.
2,801,992, but with the explicit teaching that excess alkali or free
hydroxyl ions must be present. The magnesium hydroxide in the absence of
excess alkali is ineffective as a suspension stabilizer. Indeed, even a
stoichiometric amount of alkali to form magnesium hydroxide is
insufficient to produce an effective stabilizer.
While the presence of excess alkali and free hydroxyl ions (high pH values)
would cause no deleterious side effects with some suspension
polymerization systems, there are many vinyl monomers, such as the acrylic
esters, vinyl acetate and the like, which could undergo undesired base
catalyzed hydrolysis in such systems at high pH values. It is certainly
preferred to polymerize such vinyl monomers under essentially neutral
conditions not within the purview of the teachings of U.S. Pat. No.
2,801,992.
It was found when water-soluble polymers were used as suspending agents
that the hydrogel granules were of irregular shape and with very porous
surfaces. If uniform beads were formed, they were of such small size
(e.g., <0.3 mm diameter) as to be of no practical value for the slow
release of active ingredients. The same was true for the inorganic
suspending agents, except that even more agglomeration occurred. Of all
inorganic compounds only the insoluble gelatinous metal hydroxides gave
smooth beads. In the case of poly(2-hydroxyethyl methacrylate) or "Hydron"
these beads were of unusable small sizes and not uniformly spherical. But
in the presence of macromeric crosslinking agents as described in this
invention, regular, uniformly smooth spherical beads of up to 5 mm
diameter could be obtained.
In the course of these investigations it was now unexpectedly discovered
that it is the simultaneous presence of at least 5% by weight of
2-hydroxyethyl methacrylate (HEMA) or another hydroxy substituted vinyl
monomer and at least 5% by weight of a polyolefinic macromeric
crosslinking agent in the polymerizing mixture, and insoluble gelatinous
metal hydroxides in the absence of excess alkali or free hydroxyl ions in
the suspending aqueous medium which allows the manufacture of uniform
sperical beads with up to 5 mm diameter. The suspending medium is an
aqueous salt solution dissolving HEMA to not over 10%. The particle size
is easily controlled by stirring, slow stirring speeds resulting in large
beads and higher speeds in small beads.
Although the instant process can be modified to make small beads (<0.3 mm)
by high speed stirring, no other known process is known to make uniform
beads of over 0.3 mm other than the present invention. The preferred bead
size for the controlled delivery of oral medications is from 0.6 mm to
about 1.5 mm.
Some of the hydrogel compositions of this invention are the subject of U.S.
Pat. No. 4,192,827.
SUMMARY AND OBJECT OF THE INVENTION
It is an object of the present invention to provide an improved process for
the preparation of uniform, spherical hydrogel beads of up to 5 mm
diameter having a host of pharmaceutical and industrial uses.
It is a further objective of the present invention to provide uniform,
spherical hydrogel beads comprising a crosslinked polymer prepared by
suspension polymerization in an aqueous salt solution of 95 to 30% by
weight of a hydrophilic monomer (A) which consists of 5-100% of a hydroxy
substituted vinyl monomer; and 5 to 70% by weight of a terminally
substituted polyolefinic macromer crosslinking agent (B) in the presence
of a suspending agent selected from the water-insoluble, gelatinous,
strongly water-bonding, inorganic metal hydroxides and metal hydroxy salts
in the absence of excess alkali.
The instant process involves the combined use of the particular gelatinous
inorganic hydroxides, the monomer crosslinking compound and hydroxy
substituted monomer in order to produce the uniform sperical hydrogel
beads with up to 5 mm diameter. Each of the three ingredients was found,
unexpectedly, to be necessary for the preparation of up to 5 mm large
beads.
DETAILED DESCRIPTION
The instant invention pertains to an improved process for preparing
essentially uniform sperical beads of up to 5 mm diameter of a
crosslinked, water-insoluble hydrogel by suspension polymerization of (A)
95 to 30% by weight of the hydrogel of a water-soluble monoolefinic
monomer or mixture of said water-soluble monomers, and from 0-70 by weight
based on the total monomer of a water-insoluble monoolefinic monomer or
mixture of said water-insoluble monomers, with the proviso that the final
hydrogel does not contain over 60% by weight of said water-insoluble
monomer components, with (B) 5 to 70% by weight of the hydrogel of a
polyolefinic crosslinking agent, with a polymerization initiator in a
concentrated aqueous inorganic salt solution wherein the improvement
comprises
carrying out the suspension polymerization with monoolefinic monomers
containing at least 5% by weight of the total monomers of a hydroxy
substituted hydrophilic vinyl monomer;
employing as the crosslinking agent a polyolefinic macromer having a
molecular weight from about 400 to about 8,000, and
utilizing from 0.01 to 5% by weight, based on the hydrogel, of a suspending
agent selected from the water-insoluble, gelatinous strongly
water-bonding, inorganic metal hydroxides and metal hydroxy salts in the
absence of excess alkali or free hydroxy ions.
The hydrophilic portion of the hydrogel composition is prepared by the
polymerization of a water-soluble monoolefinic monomer or a mixture of
said monomers containing at least 5% of a hydroxy substituted vinyl
monomer and which can contain from 0 to 70%, and preferably at most 50%,
by weight of the total amount of the monomers, of a water-insoluble
monoolefinic monomer or mixture of said water-insoluble monomers.
The process employs as water-soluble, hydroxy substituted monomers
water-soluble derivatives of acrylic and/or methacrylic acid, such as
hydroxyalkyl esters where alkyl is of 2 to 4 carbon atoms, e.g.,
2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl or 2,3-dihydroxypropyl
esters.
Still another group of water soluble hydroxy substituted esters of acrylic
or methacrylic acid are the ethoxylated and poly-ethoxylated hydroxyalkyl
esters, such as esters of alcohols of the formula
HO--C.sub.m H.sub.2m --O--(CH.sub.2 CH.sub.2 --O).sub.n --H
where
m represents 2 to 5 and
n represents 1 to 20
or esters of analogous alcohols, wherein a part of the ethylene oxide units
is replaced by propylene oxide units. Further suitable esters are
3-(dimethylamino)-2-hydroxypropyl esters.
Another class of suitable derivatives of acrylic or methacrylic acid are
their water-soluble amides or imides substituted by lower hydroxyalkyl
groups where alkyl is of 2 to 4 carbon atoms such as
N-(hydroxymethyl)-acrylamide and -methacrylamide,
N-3-(hydroxypropyl)-acrylamide, N-(2-hydroxymethyl)-methacrylamide and
N-[1,1-dimethyl-2-(hydroxymethyl)-3-oxabutyl]-acrylamide; water-soluble
hydrazine derivatives, such as dimethyl-(2-hydroxypropyl)amine
methacrylimide and the corresponding derivatives of acrylic acid.
Also useful, in combination with comonomers, are for instance, the
hydroxyalkyl esters of maleic and fumaric acids with alkyl of 2 to 4
carbon atoms, such as di-(2-hydroxyethyl) maleate, and ethoxylated
hydroxyalkyl maleates, hydroxyalkyl monomaleates, such as 2-hydroxyethyl
monomaleate and alkoxylated hydroxyalkyl monomaleate with vinyl ethers,
vinyl esters, styrene or generally any monomer which will easily
copolymerize with maleates or fumarates.
Still other preferred water-soluble monomers are hydroxyalkyl vinyl ethers
with alkyls of 2 to 4 carbon atoms, such as 2-hydroxyethyl vinyl ether,
4-hydroxybutyl vinyl ether, in combination with maleates, fumarates, or
generally all monomers which will easily copolymerize with vinyl ethers.
Especially valuable as hydroxy-substituted, water-soluble monomers are
hydroxyalkyl acrylates and methacrylates, such as 2-hydroxyethyl acrylate,
2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 3-hydroxypropyl
methacrylate and 2,3-dihydroxypropyl methacrylate. Especially preferred
hydroxy substituted vinyl monomers are 2-hydroxyethyl methacrylate and 2-
or 3-hydroxypropyl methacrylate.
Most preferred is 2-hydroxyethyl methacrylate.
Water-soluble comonomers, which do not contain hydroxy groups are: acrylic
and methacrylic acid and alkyl ethers of polyethoxylated hydroxy alkyl
esters thereof, such as esters of alcohols of the formula
HO--C.sub.m H.sub.2m O--(CH.sub.2 CH.sub.2 --O).sub.n CH.sub.3,
where
m=2 to 5 and
n=4 to 20
Dialkyl amino alkyl esters and amides, such as 2-(dimethylamino)ethyl,- or
2-(diethylamino)ethyl acrylate and methacrylate, as well as the
corresponding amides; amides substituted by lower oxa-alkyl or lower
dialkylamino alkyl groups, such as N-(1,1-dimethyl-3-oxa-butyl)
acrylamide; water-soluble hydrazine derivatives, such as trialkylamine
methacrylamide, e.g., triethylamine-methacrylimide and the corresponding
derivatives of acrylic acid. Monoolefinic sulfonic acids and their salts,
such as sodium ethylene sulfonate, sodium styrene sulfonate and
2-acrylamido-2-methylpropanesulfonic acid;
N-[2-(dimethylamino)-ethyl]-acrylamide and -methacrylamide,
N-[3-(dimethylamino)-2-hydroxypropyl]-methacrylamide.
Still another class of water-soluble monomers are the monoolefinic,
monocyclic, azacyclic compounds such as N-vinylpyrrole,
N-vinylsuccinimide, N-vinyl-2-pyrrolidone, 1-vinylimidazole,
1-vinylindole, 2-vinylimidazole, 4(5)-vinylimodazole,
2-vinyl-1-methylimidazole, 5-vinylpyrazoline,
3-methyl-5-isopropenylpyrazole, 5-methylenehydantoin,
3-vinyl-2-oxazolidone, 3-methacrylyl-2-oxazolidone,
3-methacrylyl-5-methyl-2-oxazolidone, 3-vinyl-5-methyl-2-oxazolidone, 2-
and 4-vinylpyridine, 5-vinyl-2-methylpyridine, 2-vinyl-pyridine-1-oxide,
3-isopropenylpyridine, 2- and 4-vinylpiperidine, 2- and 4-vinylquinoline,
2,4-dimethyl-6-vinyl-s-triazine and 4-acrylylmorpholine.
The preferred monomer is N-vinyl-2-pyrrolidone.
Preferred among these monomers which can be used at a level of from 0 to
about 15% by weight of the total monomers are acrylic acid, methacrylic
acid, 2-vinyl pyridine, 4-vinylpyridine, 2-(dimethylamino)ethyl
methacrylate, N-[2-dimethylamino)ethyl] methacrylamide and sodium styrene
sulfonate.
Preferred water-soluble monomers are 2-hydroxyethyl acrylate,
2-hydroxyethyl methacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl
methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate,
2,3-dihydroxypropyl acrylate, 2,3-dihydroxypropyl mathacrylate,
N-vinyl-2-pyrrolidone and N-methylolacrylamide. It is noted that, when
N-vinyl-2-pyrrolidone or any other non-hydroxy bearing water-soluble
monomer is used, a second monomer containing hydroxyl groups must also be
used concomitantly in the instant process.
Suitable hydrophobic comonomers, which may be incorporated into the
reaction mixture, are for example, water-insoluble olefinic monomers, such
as alkyl acrylates or methacrylates in which alkyl has 1 to 18 carbon
atoms, e.g., methyl and ethyl methacrylate or acrylate; vinyl esters
derived from alkane-carboxylic acids having 2 to 7 carbon atoms, e.g.,
vinyl acetate and vinyl propionate, or vinyl benzoate; acrylonitrile;
styrene; and vinyl alkyl ethers in which the alkyl portion of the ether
chain has 1 to 5 carbon atoms, e.g., methyl, ethyl, propyl, butyl or amyl
vinyl ether.
Preferred embodiments are the alkyl acrylates or metacrylates where alkyl
is 1 to 18 carbon atoms.
Other preferred embodiments are the vinyl alkyl ethers wherein alkyl is
from 1 to 5 carbon atoms.
Still other preferred water-insoluble monomers are acrylonitrile and
styrene.
The terminal polyolefinic macromer crosslinking agent (B) olefinic moieties
are preferably provided by acyl groups of lower
.alpha.,.beta.-mono-unsaturated aliphatic monocarboxylic or dicarboxylic
acids or by vinyloxy moieties. These vinyl moieties are linked by a
macromolecular chain containing repeating ester, amide or urethane, but
particularly ether linkages. The molecular weight of the chain may vary
from about 400 to about 8,000, preferable between about 600 and 5,000 and,
especially, between about 1,500 and 3,000. Thus, the macromer preferably
corresponds to the formula
##STR1##
wherein a is 1 or 2; R.sub.1 is a polycondensate chain having a molecular
weight from about 200 to about 8,000 which contains hydrocarbon residues
connected via ether, ester, amide or urea linkages or is a polysiloxane of
molecular weight between 400 and 8,000; R.sub.2 is hydrogen, methyl or
--CH.sub.2 COOR.sub.4 ;
R.sub.4 is hydrogen or alkyl of 1 to 10 carbon atoms; R.sub.3 is hydrogen
or --COOR.sub.4 with the proviso that at least one of R.sub.2 and R.sub.3
is hydrogen; X is an oxygen atom, --COO-- or --CONR.sub.5 --;
R.sub.5 is hydrogen or alkyl of 1 to 5 carbon atoms; Y is a direct bond or
the radical --R.sub.6 --Z.sub.1 --CONH--R.sub.7 --NHCO--Z.sub.2 ;
R.sub.6 is linked to X and represents branched or linear alkylene of 1 to 7
carbon atoms; Z.sub.1 is an oxygen atom or --NR.sub.5 --; Z.sub.2 is
Z.sub.1 or a sulfur atom; and R.sub.7 is the diradical of an aliphatic,
alicyclic or aromatic diisocyanate with the proviso that in case X is
oxygen, Y is different from a direct bond and R.sub.2 and R.sub.3 are
hydrogen.
Preferably a is 1.
In the compounds of formula B.sub.1 and B.sub.2, R.sub.1 is in particular a
polyethylene oxide chain, a polypropylene oxide chain or a
polytetramethylene oxide chain, or a chain consisting of a polyethylene
oxide-polypropylene oxide block copolymer, but it can also represent a
chain derived from dicarboxylic acids, diols, diamines or diisocyanates
etc., by well known methods of poly-condensation. R.sub.1 can also be a
polysiloxane containing chain. The terminal radicals of the compounds of
formula B.sub.1 are according to the definitions of R.sub.2 and R.sub.3
and if X represents --COO-- or CONR.sub.5 --, the acyl radicals of acrylic
or methacrylic acid or the monoacyl radicals of maleic, fumaric or
itaconic acid, or of monoalkyl esters of these acids with straight or
branched chain alkanols of 1 to 10 carbon atoms, such as methanol,
ethanol, butanol, diisobutyl alcohol or decanol, or if X represents
oxygen, the vinyloxy radical of vinyl ethers. Compounds of the formula
B.sub.1 with Y being a direct bond are diesters of macromolecular diols,
wherein two hydroxy groups are attached to the polycondensate chain
R.sub.1 in opposite terminal or almost terminal positions, with
.alpha.,.beta.-unsaturated acids. Such diesters can be prepared from said
macromolecular diol by well-known acylation methods using reactive
functional derivatives or suitable acids, e.g., acid chlorides of acrylic
or methacrylic acid, or of monoalkyl esters of maleic, fumaric or itaconic
acid, or the anhydride of maleic or itaconic acid. Compounds of formula
B.sub.1 with amide group X are diamides obtained from macromolecular
diamines by well-known acylation reactions using, e.g., the acid chlorides
or anhydrides mentioned above. The macromolecular diamines are prepared,
e.g., by reacting corresponding macromolecular diols with twice the molar
amount of an alkylenimine, e.g., propylenimine.
The macromolecular bis-maleamic acids obtained by the above reaction when
maleic acid anhydride is used as the acylating agent for macromolecular
diamines can be further heated or reacted with dehydrating agents to yield
the macromolecular bis maleimido compounds of formula B.sub.2. In these
compounds, R.sub.1 thus may be, e.g., one of the macromolecular
polycondensate chains named as moieties of compounds of the formula
B.sub.1.
According to the definition of formula B.sub.1, y can further be a divalent
radical --R.sub.6 --Z.sub.1 --CONH--R.sub.7 --NH--CO--Z.sub.1 --. Therein
R.sub.6 is, e.g., methylene, propylene, trimethylene, tetramethylene,
pentamethylene, neopentylene (2,2-dimethyltrimethylene),
2-hydroxytrimethylene, 1,1-dimethyl-2-(1-oxo-ethyl)trimethylene or
1-(di-methylaminomethyl)ethylene and particular ethylene. The divalent
radical R.sub.7 is derived from an organic diisocyanate and is an
aliphatic radical such as alkylene, e.g., ethylene, tetramethylene,
hexamethylene, 2,2,4-trimethylhexamethylene, 2,4,4-trimethylhexamethylene;
fumaroyldiethylene or 1-carboxypentamethylene; a cycloaliphatic radical,
e.g., 1,4-cyclohexylene or 2-methyl-1,4-cyclohexylene; and aromatic
radical, such as m-phenylene, p-phenylene, 2-methyl-m-phenylene, 1,2-,
1,3-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,7-naphthylene, 4-chloro-1,2- and
4-chloro-1,8-naphthylene, 1-methyl-2,4-, 1-methyl-2,7-, 4-methyl-1,2-,
6-methyl-1,3-, and 7-methyl-1,3-naphthylene, 1,8-dinitro-2,7-naphthylene,
4,4'-biphenylene, 3,3'-dichloro-4,4' -biphenylene,
3,3'-dimethoxy-4,4'-biphenylylene, 2,2'-dimethyl- and
3,3'-dimethyl-4,4'-biphenylylene,
2,2'-dichloro-5,5'-dimethoxy-4,4'-biphenylene, methylenedi-p-phenylene,
methylenebis-(3-chlorophenylene), ethylenedi-p-phenylene or
oxydi-p-phenylene. If in structure B.sub.1, Y is no direct bond, R.sub.6
is always connected to X.
Thus, compounds of the formula B.sub.1, in which Y is said divalent
radical, are, if X represents oxygen, bis-vinyl ethers or, if X represents
--COO-- or
##STR2##
bis-acrylates, bis-methacrylates, bis-maleates, bis fumarates and
bis-itaconates.
R.sub.1 is in particular derived from macromeric diols and diamines of 200
to 8000 molecular weight (MW).
Useful macromeric diols are polyethylene oxide diols of 500 to 3000 MW,
polypropylene oxide diols of 500 to 300 MW, poly-n-butylene oxide diols of
500 to 3000 MW; poly(-block-ethylene oxide-co-propylene oxide) diols of
500 to 3000 MW, wherein the percentage of ethylene oxide units can vary
from 10 to 90%; polyester diols of 500 to 3000 MW obtained by the known
methods of polycondensation from diols and diacids, for instance, from
propylene glycol, ethylene glycol, butanediol or 3-thia-pentane diol and
adipic acid, terephthalic acid, phthalic acid or maleic acid, and which
may also contain macromeric diols of the polyether type mentioned above.
More generally, any diol of MW 500 to 3000 is useful, which can be obtained
by polycondensation of diols, diamines, diisocyanates, or diacids and thus
contain ester, urea, urethane or amide linkage groups.
Similarly useful are diamines of 500 to 4000 MW, especially the
bis-aminopropyl ethers of the above-mentioned diols, especially the
bis-3-aminopropyl ethers of polyethylene oxide and polypropylene oxide
diols.
A preferred embodiment of the instant process employs a macromer (B)
wherein R.sub.1 is a poly(ethylene oxide), poly(propylene oxide) or
poly(tetramethylene oxide) chain with a molecular weight of about 600 to
about 4,000.
Another preferred embodiment of the process employs a macromer (B) wherein
R.sub.1 is a chain obtained by the condensation reaction of an aliphatic,
alicyclic or aromatic dicarboxylic acid or diisocyanate with an aliphatic
diol or diamine.
A particularly preferred embodiment of the instant process uses as the
macromer (B) a reaction product of a polyalkylene ether glycol,
particularly poly(tetramethylene oxide) glycol with a molecular weight of
about 600 to about 4,000, first terminated with tolylene-2,4-diisocyanate
or isophorone diisocyanate, and then endcapped with a hydroxyalkyl
acrylate or methacrylate where alkyl is of 2 to 4 carbon atoms.
Especially useful are the macromers (B) where the poly(tetramethylene
oxide) glycol has a molecular weight of about 1,500 to about 3,000 and the
hydroxyalkyl methacrylate is 2-hydroxyethyl methacrylate.
Other preferred macromers (B.sub.1) are those wherein R.sub.1 can also be
derived from a polysiloxane containing diol, triol, or dithiol, with a
molecular weight of 400 to 8,000. These di- or polyfunctional
polysiloxanes can be of two different structures:
##STR3##
wherein R.sub.8 is a branched or linear alkylene of 1 to 7 carbon atoms or
##STR4##
n is 1 to 20, R.sub.9 is hydrogen or methyl, x is 3 to 120 and y is 2 to
3.
These polysiloxane macromers are preferably endcapped with isophorone
diisocyanate or tolylene-2,4-diisocyanate followed by reaction with excess
2-hydroxyethyl methacrylate, 2-hydroxyethyl acrylate or 2-hydroxypropyl
acrylate and are described in greater detail in U.S. Pat. No. 4,136,250.
Compounds of the formula B.sub.1, wherein Y is --R.sub.6 Z.sub.1
CONHR.sub.7 --NH--CO--Z.sub.2 -- are obtained in a 2-step reaction by
first reacting macromolecular diols or diamines, i.e., compounds which
contain two hydroxy or amino groups attached to the polycondensate chain,
R.sub.1, in opposite terminal or almost terminal positions, with at least
twice the molar amount of an aliphatic, cycloaliphatic or aromatic
diisocyanate consisting of two isocyanate groups attached to the radical
R.sub.7, and, second, reacting the macromolecular diisocyanates so
obtained with a compound of the formula
##STR5##
wherein R.sub.2, R.sub.3, X, R.sub.6 and Z.sub.1 have the meaning defined
for (B.sub.1) above.
If X represents oxygen, (C) is vinyl ether containing the active hydrogen,
for instance an hydroxyalkyl vinyl ether or an aminoalkyl vinyl ether; if
X represents --COO-- or
##STR6##
(C) is an acrylate, methacrylate, maleate, fumarate, itaconate or the
corresponding amide, containing an active hydrogen in the alkyl group. The
macromolecular diol or diamine is preferably used in a small excess, i.e.,
the ratio of isocyano groups to hydroxy or amino groups during the first
step of the macromer synthesis should be at least 1:1, but is preferably
at least 1:1.05. If the compound of formula C used during the second step
of the macromer synthesis, is identical with the hydrophilic monomer
comprising (A), then a large excess of this compound can be used, so that
the resulting solution of macromer B.sub.1 dissolved or dispersed in
Compound C can be used directly for the preparation of the final hydrogel.
The synthesis of the macromer, B, is suitably carried out at a temperature
in the range of from about room temperature to approximately 100.degree.
C. Preferably, the temperature employed is within the range of about
30.degree.-60.degree. C. The conversion of the isocyanato group is
followed by infrared spectroscopy or by titration.
Preferred diisocyanates for preparing the macromer are
tolylene-2,4-diisocyanate and isophorone diisocyanate.
Poly(tetramethylene oxide) glycol chain terminated with
tolylene-2,4-diisocyanate is commercially available as "Adiprene" from
DuPont.
Tolylene-2,4-diisocyanate and isophorone diisocyanate are available
commercially.
Another method for preparing the macromer is by reacting a
hydroxyl-terminated prepolymer, e.g., polybutylene or polypropylene oxide,
with acryloyl chloride, methacryloyl chloride or maleic anhydride and thus
forming a macromer without connecting urethane linkages as, for example, a
macromer of the formula B.sub | | |
