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FIELD OF THE INVENTION
The present invention relates to a urethral catheter capable of preventing
urinary tract infection and a process for producing the same.
BACKGROUND OF THE INVENTION
In many cases of spinal injury, cerebral hemorrhage and softening of the
brain, after an operation the patient develops symptoms such as dysuria or
urinary incontinence. In such cases, urethral catheterization using a
catheter is adopted in order to secure a smooth urinary passage. This is
done in order to maintain kidney functions or prevent or promote the
leakage of urine. The catheters used in such cases are called urethral
catheters. Such catheters must have sufficient flexibility, elasticity and
innoxious property because of their use. Almost all of them are composed
of a material such as an olefin polymer, diene polymer or silicone polymer
as the base material.
Since catheterization is a remarkably useful curative means for carrying
out rapid urination, it is frequently used in fields other than urology
such as surgery, internal medicine and obstetrics and gynecology. However,
the procedure is defective in that the occurrence of infection is nearly
unavoidable if the urethral catheter is inserted into the urinary tract.
Since the urethral catheter is left in the urinary tract for a long time,
microbes intrude into the urinary tract through the catheter frequently
causing symptoms such as urethritis, cystitis or pyelitis. It has been
reported that performing an opening continuation catheterization which is
frequently used hitherto (a method of collecting urine in a container such
as a glass bottle which is not sterilized), infection occurs within 3 days
in 42 to 80% of the clinical test and the infection is observed in all
cases after the 7th day.
Therefore, with respect to prevention of urinary tract infection, methods
such as washing of the bladder or injection of antiseptics or
disinfectants are utilized. However, such procedures are disadvantageous
because the operation is troublesome and the operation itself becomes a
new source of infection.
Further, chemotherapy such as preventive administration of antibiotics,
etc. has been carried out. However, it is said that chemotherapy is
sometimes even rather harmful due to problems in the administration of
large amounts or, even a small amount of antibiotics depending upon the
kind of antibiotics. The administration frequently causes an ill effect
and a microbe-exchange phenomenon may easily appear if an infection is
caused. Thus, topical utilization is generally more desirable for
antibiotics.
With respect to topical utilization of antibiotics, a method has been
proposed which comprises applying an ointment containing antibiotics to a
urethral catheter and a method which comprises coating the wall of the
catheter with a resin to form a coating layer in which antibiotics are
contained (Japanese Patent Publication 27680/79). However, in these cases,
the catheter cannot be satisfactorily used, because the antibiotics flow
outside the body within a very short time by urine after insertion of the
catheter, whereby the antimicrobial function cannot be observed within a
short time, because the antibiotics are merely adsorbed on the supporting
layer.
Another method involves directly dropping a diluted solution of antibiotics
into the bladder using a so-called three-way catheter. This method is only
utilized in some areas of urology and it cannot be used in other clinical
fields under existing circumstances, because handling is difficult and
troublesome.
Intrusion passages of microbes include: (1) counter-current intrusion
through a space between the urethral catheter and a mucous membrane of the
urinary tract (outside tract passage), (2) intrusion through a bonding
part of the urethral catheter and a conduit (including treatments such as
washing, etc.), and (3) counter-current intrusion in the interior of the
conduit and the urethral catheter from a urine collecting part (inside
tract passage). In case of intrusion by the outside tract passage,
microbes which are usually present in the urethra rapidly intrude upwards
along the wall of the urethral catheter in the early stage of insertion of
the catheter and reach the neck part of the bladder. For such infection,
the antibiotics which are present on the wall of the urethral catheter
exhibit their antimicrobial function, because they can directly touch the
microbes. However, microbes intruding through the inside tract passage,
for example, microbes intruding from a urine collecting means, namely,
microbes dropping or intruding in the urine collecting means, multiply in
the urine collected and reach the bladder with back flow urine or rising
bubbles. In fact, in an experiment under a static state, it has been
ascertained that microbes go backwards in urine in a manner similar to
carp ascending a waterfall. Since antibiotics are present on the wall of
the urethral catheter, they cannot directly touch microbes intruding from
such a passage, and there is the possibility that microbes which are not
affected by the antimicrobial function will remain. Therefore, sufficient
ability to prevent infection has not been obtained. In order to prevent
infection from all intrusion passages, it is necessary for the antibiotics
to be present on the wall of urethral catheter and also be gradually
released from the wall of the catheter to diffuse into urine so that they
contact microbes ascending and wafting in the urine. Therefore, the rate
of which microbes separate from the wall is important. As described above,
when a method which comprises applying antibiotics or an ointment
containing antibiotics to the catheter or a method which comprises coating
the wall of the catheter with a resin containing antibiotics is used, the
antibiotics easily flow outside the body with the flow of urine.
Accordingly, within a short period of time, both the wall and the urine do
not contain the antibiotics. Therefore, the ability to prevent infection
is completely eliminated within a very short period after insertion. In
order to prevent infection, it is important to keep the concentration of
antibiotics in the urine at an effective value or more for a long period
of time by controlling the rate of antibiotics released from the wall.
However, urethral catheter having this ability are as yet unknown.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a urethral catheter,
particularly indwelling urethral catheter which can be simply used and
which can prevent infection from all intrusion passages for a long period
of time without becoming a new source of infection itself.
As a result of various studies to attain the above described object, it has
been found that, when an antimicrobial substance is chemically bonded with
the inside wall or the outside wall of a urethral catheter composed of
olefin polymer, diene polymer or silicone polymer as a base material, the
antimicrobial substance is gradually separated from the wall at a desired
rate into urine to diffuse therein without flowing outside the body by
urine within a short period of time, when the urethral catheter is
inserted into the body. Therefore, antimicrobial substances are maintained
at an effective concentration in the urine for a long period of time.
Thus, the present invention has been completed.
The present invention relates to a urethral catheter capable of preventing
urinary tract infection which comprises a urethral catheter comprised of a
material selected from the group consisting of an olefin polymer, a diene
polymer or a silicone polymer as the base material, and an antimicrobial
substance being chemically bonded with the inside and/or outside walls of
the urethral catheter; and a process for producing the urethral catheter
which comprises bonding chemically an antimicrobial substance with the
inside wall and/or the outside wall of the urethral catheter.
DETAILED DESCRIPTION OF THE INVENTION
The term olefin polymer was used in the present invention means polymers
prepared by homopolymerization or copolymerization of hydrocarbons having
one double bond, such as ethylene, propylene, 1-butene, 3-methyl-1-butene,
3,3-dimethyl-1-butene, 1-pentene, 4-methyl-1-pentene, 3-methyl-1-pentene,
1-hexene, 4-methyl-1-hexene, 5-methyl-1-hexene, 1-heptene, 1-octene,
1-decene, 1-hexadecene, 1-octadecene, vinyl cyclopropane, vinyl
cyclohexane, isobutylene, 2-methyl-1-pentene, cyclobutene or norbornene by
a known process.
The term diene polymer as used in the present invention means polymers
prepared by homopolymerization or copolymerization of hydrocarbons having
two double bonds such as butadiene, isoprene, 1,3-pentadiene,
1,5-hexadiene or 1,6-heptadiene by a known process. By way of exception,
cis-1,4-polymer of isoprene which generally exists as natural rubber is
suitably used in the present invention.
Examples of other copolymerizable components include vinyl acetate, methyl
vinyl ether, styrene, vinyl chloride, vinylidene chloride, maleic acid
anhydride, acrylic acid, methacrylic acid, acrylonitrile, methyl
methacrylate, sulfur dioxide, vinylpyridine, chloroprene, ethylene oxide
and formaldehyde.
Examples of the silicone polymer used in the present invention include
dimethyl polysiloxane, methylphenyl polysiloxane, cyanoalkylmethyl
polysiloxane and fluoroalkylmethyl siloxane. Among them, dimethyl
polysiloxane is particularly preferred in view of its high elasticity,
high strength and innoxious property.
The term antimicrobial substance as used in the present invention means
antibiotics, antiseptics and disinfectants. Examples of antibiotics
include erythromycin ethyl succinate, erythromycin ethylcarbonate,
erythromycin glucoheptanoate, erythromycin stearate, erythromycin lauryl
sulfate propionate, erythromycin lactobionate, triacetyl oleandomycin,
oleandomycin phosphate, amikacin sulfate, bekanamycin sulfate,
aminodeoxykanamycin, kanamycin monosulfate, tobramycin, acetyl
kitasamycin, kitasamycin, kitasamycin succinate, kitasamycin tartarate,
chloramphenicol, chloramphenicol alginine succinate, chloramphenicol
sodium succinate, chloramphenicol stearate, chloramphenicol
morpholinoacetate, chloramphenicol palmitate, chloramphenicol
stearoylglycolate, chloramphenicol sulfate morpholinoacetate, colistin
hydrochloride, colistin, colistin sodium methane sulfonate, colistin
sulfate, josamycin, josamycin propionate, dihydrostreptomycin
hydrochloride, dihydrostreptomycin sulfate, compound streptomycin,
streptomycin hydrochloride, streptomycin calcium chloride hydrochloride,
streptomycin sulfate, streptomycin isoniazone sulfate, cephacetrile
sodium, cephazolin sodium, cephapyrin sodium, cephalexin, cephaglycin,
cephalothin sodium, cephaloridine, ceftezol sodium, cephradine,
oxytetracycline hydrochloride, oxytetracycline, oxytetracycline calcium,
chlorotetracycline hydrochloride, chlorotetracycline, tetracycline
hydrochloride, rolitetracycline nitrate, tetracycline L-methylene-lysine,
tetracycline methaphosphate, rolitetracycline, dimethylchlorotetracycline
hydrochloride, dimethylchlorotetracycline, doxycycline hydrochloride,
minocycline hydrochloride, metacycline hydrochloride, actinomycin D,
azalomycin F, amphotericin B, enbiomycin sulfate, enramycin hydrochloride,
aureothricin, capreomycin sulfate, carzinophilin, carbomycin, gramicidin,
gramicidine S hydrochloride, griseofulvin, chromomycin A3, gentamycin
sulfate, cycloserin, sarkomycin, siccanin, dibekacin sulfate,
acetylspiramycin, spiramycin, spectinomycin hydrochloride, daunorubicin
hydrochloride, doxorubicin hydrochloride, trichomycin, nystatin,
neocarzinostatin, novobiocin calcium, novobiocin sodium, viomycin sulfate,
bacitracin, variotin, paromomycin sulfate, pimaricin, pyrrolnitrin,
fusidate sodium, fradiomycin palmitate, fradiomycin sulfate, bleomycin
hydrochloride, bleomycin sulfate, ampicillin, ampicillin sodium,
talampicillin hydrochloride, carbenicillin sodium, carbenicillin indanyl
sodium, carbenicillin phenyl sodium, phenoxymethylpenicillin,
phenoxymethylpenicillin potassium, phenoxymethylpenicillin calcium,
phenoxymethylpenicillin benzathine, penicillin potassium, penicillin
sodium, penicillin procaine, benzylpenicillin potassium, benzylpenicillin
sodium, benzylpenicillin procaine, benzylpenicillin benzathine, compound
penicillin potassium, compound benzylpenicillin potassium, compound
benzylpenicillin sodium, compound benzylpenicillin benzathine, clindamycin
hydrochloride, clindamycin palmitate hydrochloride, lincomycin
hydrochloride, amoxicillin, oxacillin sodium, cloxacillin sodium,
cyclacillin, dicloxacillin sodium, sulbenicillin sodium, pivmecillinam
hydrochloride, phenethicillin potassium, flucloxacillin sodium,
propicillin potassium, hetacillin potassium, methicillin sodium,
pentamycin, polymyxin B sulfate, mitomycin C, maridomycin propionate,
mikamycin, midecamycin, rifampicin, ribostamycin sulfate, pyrrolenitrin,
actinomycin, bleomycin, daunorubicin, doxorubicin and neocarzinostatin.
Aminoglucosides and polymyxins are preferred to use, because they have
strong alkalinity and a high antibiotic action to microbes which cause
urinary tract infection. As the antiseptics and disinfectants, it is
preferred to use dyestuff medical preparations such as acrinol or
acriflavine, etc., furan medical preparations such as nitrofurazone, etc.,
cationic soap medical preparations such as benzalkonium chloride or
benzethonium chloride, etc., cyclohexidine and povidone-iodine.
These antimicrobial substances can be used alone or as a combination of two
or more of them, and they are chemically bonded with the inside wall or
the outside wall of the urethral catheter.
The urethral catheter of the present invention can be prepared by the
following processes.
(A) Ion-exchange groups are chemically introduced into the molecules of the
inside wall and/or the outside wall of the urethral catheter and,
subsequently, the introduced ion-exchange groups are ionically bonded with
an antimicrobial substance.
(B) Functional groups capable of easily converting into ion-exchange groups
by hydrolysis are chemically introduced into the molecules of the inside
wall and/or the outside wall of the urethral catheter and subsequently the
ion-exchange groups obtained by hydrolyzing the introduced functional
groups are ionically bonded with the antimicrobial substance.
(C) The inside wall and/or the outside wall of the urethral catheter is
coated with a compound having ion-exchange groups and subsequently
ion-exchange groups in the coating layer are ionically bonded with the
antimicrobial substance.
(D) The inside wall and/or the outside wall of the urethral catheter was
coated with a compound having functional groups capable of easily
converting into ion-exchange groups by hydrolysis and subsequently
ion-exchange groups obtained by hydrolyzing the functional groups in the
coating layer are ionically bonded with the antimicrobial substance.
(E) Two or more compounds are subjected to reacting on the inside wall
and/or the outside wall of the urethral catheter to form a film having an
ion-exchange group on the inside wall and/or the outside wall and,
subsequently, the ion-exchange groups are ionically bonded with the
antimicrobial substance.
(F) Two or more compounds are subjected to reacting on the inside wall
and/or the outside wall of the urethral catheter to form a film having
functional groups capable of easily converting into ion-exchange groups by
hydrolysis and, subsequently, ion-exchange groups obtained by hydrolyzing
the functional groups in the film are ionically bonded with the
antimicrobial substance.
In these processes (A) to (F), the processes (E) and (F) are preferred and
the process (F) is more preferred.
According to these processes, since the antimicrobial substance is held on
the inside wall or the outside wall of the urethral catheter by an ionic
bond, it does not flow out of the body with the urine in a short period of
time like an antimicrobial substance supported by mere physical adsorption
or coating. The ionic bond gradually dissociates and, consequently, the
antimicrobial substance gradually diffuses into the urine keeping the
concentration of the antimicrobial substance in the urine at a minimum
inhibitory concentration (MIC), namely, a minimum concentration necessary
to kill microbes in the urine, for a long period of time. The minimum
inhibitory concentration (MIC) cannot be absolutely specified because it
is determined by the amount of a specific antimicrobial substance to be
needed to kill a specific microbes. However, 0.1 to 15 .mu.g/ml (the
factor of the antimicrobial substance/the volume of urine) is generally
preferred as a MIC in many cases.
Examples of the above described ion exchange groups include an amino group,
carboxyl group and a sulfonic acid group, preferably a carboxyl group.
Examples of the functional groups capable of easily converting into
ion-exchange groups in the present invention include acid anhydride groups
and sulfonic acid chloride group which are easily converted into a
carboxyl group or a sulfonic acid group by reacting with water at a room
temperature or so, preferably acid anhydride groups.
In the above described processes (A) and (B), for example, the following
reactions (i) to (vi) can be adopted as reactions for chemically
introducing ion-exchange groups or functional groups capable of easily
converting into ion-exchange groups into the polymer. Reactions (i) to
(iv) are utilized for olefin polymers, reactions (i) and (v) are utilized
for diene polymers and reaction (vi) is utilized for silicone polymers.
The reaction for introduction may be carried out prior to molding of the
urethral catheter or may be carried out after molding of the urethral
catheter, preferably after molding of the urethral catheter.
(i) A vinyl monomer having reactive functional groups such as acrylic acid,
methacrylic acid or maleic acid anhydride is copolymerized with an olefine
or diene to introduce carboxyl groups or acid anhydride groups (J. De
Merlier and J. Le Bras: Industrial and Engineering Chemistry; Product
Research and Development; Vol. 2, page 22, (1963)), (U.S. Pat. No.
3,177,269 incorporated herein by reference).
(ii) A plasma processing is carried out in the presence of ammonia or a
mixed gas composed of nitrogen and hydrogen to introduce amino groups (J.
R. Hollahan, B. B. Stafford, R. D. Falb and S. T. Payne: Journal of
Polymer Science; Vol. 13, page 807, (1969)).
(iii) A surface treatment is carried out with fuming nitric acid to
introduce sulfonic acid groups (Shin Ogawara: Kobunshi no Kagakuhanno;
Vol. 1, page 12, published by Kagakudojin Co.).
(iv) It is previously activated with ozone and processed with a C.sub.3
O.sub.2 solution to introduce carboxylic acid groups (Shin Ogawara:
Kobunshi no Kagakuhanno; Vol. 1, page 14, published by Kagakudojin Co.).
(v) Nitrile oxide prepared using benzhydroxamil chloride is reacted with
double bond (C.dbd.C) to introduce the carboxyl group (Shin Ogawara:
Kobunshi no Kagakuhanno; Vol. 1, page 22, published by Kagakudojin Co.).
(vi) It is allowed to react with a silane coupling agent such as
n-.beta.-(aminoethyl)-.gamma.-aminopropyl trimethoxy silane or
n-.beta.-(aminoethyl)-.gamma.-aminopropyl methyldimethoxy silane, etc. to
introduce amino groups. This reaction is carried out, for example, by
processing with a 10 wt% solution of .gamma.-aminopropyltriethoxy silane
in chloroform at a room temperature for 24 hours or so.
Examples of compounds used for coating in the above described processes (C)
and (D) include the following compounds: Polycarboxylic acids such as
polyacrylic acid, polymethacrylic acid, polymaleic acid, poly-(maleic acid
monoester), polyaspartic acid, polyglutamic acid, alginic acid or pectinic
acid, polycarboxylic acid anhydrides such as polymaleic anhydride,
polymethacrylic anhydride or polyacrylic acid anhydride, polyamines and
polyammonium ions such as polyethylene imine, polyvinylamine, polylysine,
poly-(dialkylaminoethyl methacrylate), poly-(dialkylaminomethyl styrene),
poly-(vinylpyridine), poly-(2-methacryloxyethyl trialkyl ammonium ion),
poly-(vinylbenzyl trialkyl ammonium ion),
poly-(N,N-dialkyl-3,5-methylenepiperidinium ion),
poly-(vinyl-N-alkylpyridinium ion) or poly-(dialkyloctamethylene ammonium
ion), and polysulfonates such as poly-(vinyl sulfonate) or poly-(styrene
sulfonate).
Linear copolymers, crosslinked copolymers, graft copolymers and block
copolymers containing the monomers as constituents of the above
exemplified polymers can also be used in and are included within the scope
of the present invention. A suitable molecular weight for these polymeric
materials will depend on the mechanical strength desired for the coating,
but generally is more than about 500, preferably more than 10,000.
In the above described processes (C) and (D), the above described compound
for coating is used by dissolving in a suitable solvent or the compound
per se is used when it is liquid itself, and it is applied by a known
method such as a dip coating method, a spray coating method or a brush
coating method, etc. In carrying out the coating, the compound for coating
may be used alone or may be used as a mixture of two or more of them.
Formation of a plurality of coating layers is carried out, for example, as
follows. More specifically, when it is necessary to bond a large amount of
an antimicrobial substance having only anion-exchange groups to a urethral
catheter into which only carboxyl groups are introduced in an insufficient
amount, a compound having amino groups in a large amount, such as
polyethylene imine, is previously applied to form a coating layer and a
compound having carboxylic acid anhydride groups in an excess amount, such
as maleic anhydride copolymer, is applied to the resulted coating layer.
Then, the reactive functional groups are ionized to obtain cation-exchange
groups, by which ionic bonds are formed between the cation-exchange groups
and the anion-exchange groups in the antimicrobial substance. Further, if
necessary, it is desirable to provide an adhesive layer or admix an
adhesive with the compound for coating according to the kind of compound
for coating or raw material for the urethral catheter.
As the solvent used for coating, any material may be used if it dissolves
the compound for coating and does not erode the base material of the
urethral catheter. However, the present invention have found it useful for
carrying out effective coating to use a solvent which swells the base
material of the urethral catheter at coating but does not damage the
strength and dimensional stability of the base material after evaporation
of the solvent (for example, solvent mixture composed of tetrahydrofuran
and water for natural rubber).
The reaction of two or more compounds in the above described processes (E)
and (F) can be carried out, for example, by the following processes (1) to
(10).
(1) A process which comprises reacting (A) a compound having amino groups
with (B) a polyfunctional compound having a plurality of groups selected
from an aldehyde group, an isocyanate group, a thioisocyanate group, an
epoxy group, a carboxyl group and a sulfonic acid group under a condition
of an excess amount of the compound having amino groups (A).
(2) A process which comprises reacting (A) a compound having amino groups
with (B) a polyfunctional compound having a plurality of carboxyl group
under a condition of an excess amount of the polyfunctional compound
having a plurality of carboxyl group (B).
(3) A process which comprises reacting (A) a compound having amino groups
with (B) a polyfunctional compound having a plurality of sulfonic acid
chloride group under a condition of an excess amount of the polyfunctional
compound having a plurality of sulfonic acid chloride group (B) and
thereafter hydrolyzing the sulfonic acid chloride groups.
(4) A process which comprises reacting (A) a compound having hydroxyl
groups with (B) a polyfunctional compound having a plurality of isocyanate
groups and thereafter hydrolyzing the isocyanate groups.
(5) A process which comprises reacting (A) a compound having hydroxyl
groups with (B) a polyfunctional compound having a plurality of acid
chloride groups and thereafter hydrolyzing the acid chloride groups.
(6) A process which comprises reacting (A) a compound having acid anhydride
groups with (B) a polyfunctional compound having a plurality of amino
groups under a condition of an excess amount of the polyfunctional
compound having a plurality of amino groups (B).
(7) A process which comprises reacting (A) a compound having acid anhydride
groups with (B) a polyfunctional compound having a plurality of amino
groups.
(8) A process which comprises reacting (A) a compound having acid anhydride
groups with (B) a polyfunctional compound having a plurality of amino
groups under a condition of an excess amount of the compound having acid
anhydride groups (A), and thereafter hydrolyzing the acid anhydride
groups.
(9) A process which comprises reacting (A) a compound having acid anhydride
groups with (B) a polyfunctional compound having a plurality of hydroxyl
groups.
(10) A process which comprises reacting (A) a compound having acid
anhydride groups with (B) a polyfunctional compound having a plurality of
hydroxyl groups under a condition of an excess amount of the compound
having acid anhydride groups (A), and thereafter hydrolyzing the acid
anhydride groups.
Examples of the compounds having amino groups used in the above described
processes (1), (2) and (3) include the following compounds:
Polyvinylamine, polylysine, poly(dialkylaminoethyl methacrylate),
poly-(dialkylaminomethylstyrene), polyamine synthesized from amine and
alkylene dihalide or epichlorohydrin (Encyclopedia of Poly Science and
Technology, Vol. 10, page 10) and alkyleneimine polymers obtained by ring
opening polymerization of ethyleneimine or propyleneimine, etc.
(Encyclopedia of Polymer Science and Technology; Vol. 1, page 734). Among
the above described compounds, polyethyleneimine is particularly preferred
because it is cheap and has a number of amino groups.
Examples of the compounds having hydroxyl groups used for the above
described reactions (4) and (5) include esterified derivatives of
cellulose such as acetyl cellulose, cellulose propionate, cellulose
butylate, nitrocellulose, cellulose acetate, cellulose phosphate or
cellulose dithiocarboxylate, etc., etherified derivatives of cellulose
such as methyl cellulose, ethyl cellulose, benzyl cellulose, trimethyl
cellulose, cyanoethyl cellulose aminoethyl cellulose or oxyethyl
cellulose, etc., polyvinyl alcohol, copolymers of polyvinyl alcohol and
ethylene, propylene, vinyl chloride, allyl alcohol or N-vinyl pyrrolidone,
etc., polyvinyl alcohol ether derivatives such as methyl, ethyl, propyl,
butyl, octyl, dodecyl or phenyl ether of polyvinyl alcohol, polyvinyl
alcohol acetal derivatives such as formal, ethylal, butyral or
aminoacetal, etc. of polyvinyl alcohol, polyvinyl alcohol ester
derivatives such as acetate, formate, butyrate, caproate, laurate,
stearate or benzoate, etc. of polyvinyl alcohol, polyether polyol such as
polyethylene glycol, polypropylene glycol, polytetramethylene glycol or
polyethylene-polypropylene glycol, etc., polyesters having hydroxyl groups
on both ends prepared by condensing dicarboxylic acid such as succinic
acid, glutaric acid, adipic acid, sebacic acid, isophthalic acid, phthalic
acid or terephthalic acid, etc. with glycol such as ethylene glycol,
propylene glycol or butylene glycol, etc., and natural high molecular
substances such as starch, gelatine or dextran.
Examples of the compounds having acid anhydride groups used for the above
described reactions (6), (7), (8), (9) and (10) include polycarboxylic
acid anhydrides such as, polymaleic acid anhydride, polyitaconic acid
anhydride, polyacrylic acid anhydride or polymethacrylic acid anhydride,
etc., preferably polymaleic acid anhydride, and copolymers comprising the
above described polycarboxylic acid anhydride as a constitutional unit.
For example, it is possible to use copolymers of maleic acid anhydride and
aliphatic vinyl ether such as maleic acid anhydride-butanediol divinyl
ether copolymer, maleic acid anhydride-ethyl vinyl ether copolymer, or
maleic acid anhydride-methyl vinyl ether copolymer, etc., copolymers of
maleic acid anhydride and olefin monomer such as maleic acid
anhydride-ethylene copolymer or maleic acid anhydride-propylene copolymer,
etc., copolymers of maleic acid anhydride and aromatic vinyl monomer such
as maleic acid anhydride-styrene copolymer, etc., and copolymers of maleic
acid anhydride and aliphatic vinyl ester such as maleic acid
anhydride-vinyl acetate copolymer, etc.
In the polyfunctional compounds used for the above described processes (1)
to (10), examples of polyfunctional compounds having aldehyde groups
include glutaraldehyde, terephthalaldehyde, isophthalaldehyde and
dialdehyde starch. Examples of the polyfunctional compounds having
isocyanate groups include hexamethylene diisocyanate, toluene
diisocyanate, xylene diisocyanate, phenylene diisocyanate and isocyanate
derivatives of aniline-formaldehyde resin. An example of a polyfunctional
compound having thioisocyanate groups is hexamethylene thioisocyanate.
Examples of polyfunctional compounds having carboxyl groups include
polycarboxylic acids such as alginic acid, pectinic acid or carboxymethyl
cellulose, etc., homopolymers and copolymers of methacrylic acid, acrylic
acid, maleic acid, itaconic acid, aspartic acid or glutamic acid, etc.,
alkyl esters of the above described acids such as methyl, ethyl propyl,
butyl, amyl, hexyl, octyl or dodecyl ester, haloalkyl esters thereof such
as chloromethyl, 2-chloroethyl or 2-bromoethyl ester, ether group
containing esters thereof such as 2-ethoxyethyl, 2-butoxyethyl,
2-(2-ethoxymethoxy)ethyl or phenoxyethyl ester, basic nitrogen containing
esters thereof such as 2-aminoethyl, 2-N,N'-dimethylaminoethyl or
2-N,N'-dipropylaminoethyl ester, mono- and diesters thereof such as
ethylene glycol, diethylene glycol or triethylene glycol mono- or diester,
etc. Examples of polyfunctional compounds having sulfonic acid chloride
groups include sulfonic acid chlorides of polyethylene and polypropylene,
etc.
Examples of polyfunctional compounds having acid chloride groups include
polyacid chlorides such as adipoyl chloride, isophthaloyl chloride,
terephthaloyl chloride or cyanuric chloride, etc.
Examples of polyfunctional compounds having amino groups include all of the
above described compounds having amino groups used for the process (3). In
addition, examples of low molecular polyamines include ethylenediamine,
trimethylenediamine, 1,2-diaminopropane, 2-diaminopropane,
tetramethylenediamine, 1,3-diaminobutane, 2,3-diaminobutane,
pentamethylenediamine, 2,4-diaminopentane, hexamethylenediamine,
octamethylenediamine, nonamethylenediamine, decamethylenediamine,
undecamethylenediamine, dodecamethylenediamine, tridecamethylenediamine,
octadecamethylenediamine, N,N-dimethylethylenediamine,
N,N-diethyltrimethylenediamine, N,N-dimethyltrimethylenediamine,
N,N-dibutyltrimethylenediamine, N,N,N'-triethylethylenediamine,
N-methyltrimethylenediamine, N,N-dimethyl-p-phenylenediamine,
N,N-dimethylhexamethylenediamine, diethylenetriamine,
triethylenetetramine, tetraethylenepentamine, heptaethyleneoctamine,
nonaethylenedecamine, 1,3-bis-(2'-aminoethylamino)propane,
bis-(3-aminopropyl)amine, 1,3-bis-(3'-aminopropylamino)propane,
1,2,3-triaminopropane, tris-(2-aminoethyl)amine,
tetra-(aminomethyl)methane, methyliminobispropylamine,
methyliminobisethylamine, ethyliminobisethylamine,
N-aminopropyl-2-morpholine, N-aminopropyl-2-pipecoline,
N-(2-hydroxyethyl)trimethylenediamine, xylylenediamine, phenylenediamine,
piperazine, N-methylpiperazine, N-(2-aminoethyl)ethanolamine,
N-aminoethylpiperazine, N,N,N',N'-tetramethylethylenediamine and
N,N,N',N'-tetramethyltetramethylenediamine, etc.
Examples of polyfunctional compounds having a plurality of hydroxyl group
used for the above described processes (9) and (10) include all of the
exemplified compounds having hydroxyl groups used for the processes (4)
and (5). In addition, examples of low molecular polyols include ethylene
glycol, propylene glycol, butylene glycol, diethylene glycol,
cyclohexanediol, pentaerythritol, glycerin and 1,1,1-trimethylolpropane,
etc.
In order to produce the urethral catheter according to process (E) or (F)
of the present invention, it is necessary to form a film on the inside or
outside wall of the catheter by reacting the component (A) with the
component (B) as described in the processes (1) to (10) on the inside wall
or the outside wall. For this purpose, a solution prepared by mixing the
component (A) and the component (B) using water or an organic solvent as a
medium is brought into contact with the inside wall or the outside wall of
the catheter and the catheter is then heated. Blending of both components
can be carried out by any method, for example, a method which comprises
blending a solution of the component (A) with a solution of the component
(B) or a method which comprises adding a solvent to a mixture of component
(A) and component (B). In order to enhance the blending effect to shorten
the blending time, it is desired, if necessary, to heat or stir the
mixture. Examples of organic solvents which can be used include ketones
such as acetone or methyl ethyl ketone, etc., aldehydes such as
benzaldehyde, formaldehyde or dimethylformaldehyde, etc., ethers such as
tetrahydrofuran, etc., esters such as methyl acetate or ethyl acetate,
etc., and alcohols such as methanol, ethanol, propanol, isopropanol or
butanol, etc. However, it is necessary to select a solvent which does not
react with the component (A) or the component (B) to be used. Ketones and
alcohols are preferably used. These organic solvents may be used alone or
may be used as a mixture of them as occasion demands. There are advantages
to using the solvents as a mixture. For example, the mixture can be
expected to carry out uniform dissolution or blending of component (A) and
component (B) and to increase the adhesive strength of the film to the
wall of the catheter. In order to bring the resulting solution into
contact with the inside wall or the outside wall of the catheter, for
example, the catheter is dipped into the solution, or the solution is
sprayed on the catheter, or the solution is circulated into the catheter,
or the solution is applied to the catheter by means of, for example, a
doctor blade or a brush, etc. These methods can be suitably selected.
After the solution is brought into contact with the catheter, the solvent
is removed by drying. The catheter is then heated at, preferably,
30.degree. to 180.degree. C. and more preferably 50.degree. to 160.degree.
C. for, preferably, 5 minutes to 48 hours and more preferably 10 minutes
to 24 hours to react the component (A) with the component (B). This causes
the film to be formed on the inside wall or the outside wall of the
catheter.
In this process, if necessary, it is possible to bond the film composed of
a reaction product of the component (A) and the component (B) to the
catheter using an adhesive based on the type of components (A) and (B)
used or the base material of the urethreal catheter, etc. In order to
carry out adhesion, it is possible to adopt a process which comprises
providing previously an adhesive layer on the inside wall or the outside
wall of the catheter and carrying out the reaction of both components on
the surface of the adhesive layer. Another process comprises adding
previously an adhesive to the mixture of both components. The process
which comprises providing the adhesive layer can be carried out according
to the process for forming the above described film. In this case, it is
possible to adopt a process which comprises using two or more adhesives as
a mixture or by lamination and a process which comprises using two or more
organic solvents. By utilizing such processes, firm adhesion of the wall
of the catheter to the film can be obtained in many cases.
In order to bond the antimicrobial substance by an ionic bond in the above
described processes (A) to (F), a process can be used which comprises
spraying the solution with an antimicrobial substance. Another process
comprises circulating the solution of the antimicrobial substance through
the interior of the urethral catheter. The simplest process comprises
dipping the urethral catheter in the solution of the antimicrobial
substance. Generally, in order to carry out formation of the ionic bond
effectively, it is preferred to carry out the processing at -10.degree. to
60.degree. C., preferably 0.degree. to 50.degree. C., for several seconds
to 72 hours, preferably 5 minutes to 48 hours. However, there are
instances where the processing time is made longer according to the kind
of the antimicrobial substance used and the form of the catheter used. In
this case, the processing time is preferably about 2 to 10 days. Further,
it is preferred to control the pH of the solution of the antimicrobial at
a suitable range. For example, effective formation of the ionic bond is
accomplished by carrying out the process while keeping the solution of
antimicrobial substance at an alkaline state when using an antimicrobial
substance having anion-exchange groups and at an acid state when using an
antimicrobial substance having cation-exchange groups. This treatment is
carried out by continuously adding dropwise acid or alkali during the
progress of ionic bond reaction.
The catheters prepared by the above described processes (A) to (F) are very
capable of preventing infection regardless of the process for production
thereof. Urethral catheters prepared by the processes (E) and (F) have
particularly ideal characteristics with respect to preventing urinary
tract infection. Namely, the urethral catheter remains in the body for 3
to 5 days in many cases, and sometimes 2 weeks or so and seldom 5 weeks or
so. The urethral cath | | |
