DESCRIPTION
COMPOSITION FOR HARD TISSUE REPAIR
Technical Field
5 [0001] The present invention relates to a composition
for hard tissue repair.
Background Art
[0002] As bone cement for fixation of hard tissues, such
10 as bones and cartilages, to artificial joints, bone filling materials
used for osteoporosis therapy or the like, artificial bone materials,
etc., various compositions for hard tissue repair have been studied
in the past. For example, compositions containing polymethyl
methacrylate, methyl methacrylate and benzoyl peroxide
15 (polymerization initiator), compositions containing (meth) acrylate,
an inorganic filler, such as calcium phosphate, and an organic peroxide,
etc. have been studied (see, for example, patent literature 1).
[0003] Such compositions, however, undergo large-scale
heat generation during curing and have a high risk of doing damage
20 to the affected tissue.
[0004] When a composition for repair is used for hard
tissues such as bones, it is a usual way that the components to form
the composition are mixed in advance in a container or the like to
prepare a composition and then the composition is applied to the surface
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of the affected part, taking into consideration workability,
prevention of infection, etc. However, the state of the composition
after mixing sometimes has influence on the workability during the
application of the composition.
5 [0005] Since acrylic adhesives using an initiator
containing an organoboron compound have low toxicity and low
harmfulness and have high adhesive strength, development of them to
dental applications has been promoted (see, for example, patent
literature 2). However, if other medical applications, such as
10 surgical applications, are intended, further improvement in handling
stability or workability of the composition between mixing of the
components and application to the application area has been sometimes
required.
15 Citation List
Patent Literature
[0006] Patent literature 1: Japanese Patent Laid-Open
Publication No. 224294/1996
Patent literature 2: Japanese Patent Laid-Open Publication No.
20 110913/1997
Summ ary of Invention
Technical Problem
[0007] It is an object of the present invention to provide
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a composition for hard tissue repair, which undergoes small-scale
heat generation during curing and has excellent workability.
Solution to Problem
5 [0008] In order to solve the above problems, the present
inventors have earnestly studied compositions for hard tissue repair.
The hard tissue repair include adhesion between hard
tissues, filling in hard tissues, adhesion between hard tissues and
artificial substances, such as titanium, ceramics and stainless steel,
10 adhesion between hard tissues and other tissues such as soft tissues,
etc. In such repairs, adhesion between teeth and filling materials
(i.e., dental use) is not included.
As a result, the present inventors have found that the above
problems can be solved by a composition comprising specific amounts
15 of a monomer, a (meth) acrylate polymer and a specific polymerization
initiator composition, and they have accomplished the present
invention.
[0009] That is to say, the composition for hard tissue
repair of the present invention comprises 5 to 98. 95 parts by weight
20 of a monomer (A) , 1 to 75 parts by weight of a (meth) acrylate polymer
(B) and 0.05 to 20 parts by weight of a polymerization initiator
composition (C) containing an organoboron compound (c1), with the
proviso that the total amount of the components (A), (B) and (C)
is 100 parts by weight.
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[0010] The polymer (B) is preferably a polymer mixture
which comprises polymer particles (bl) having a weight-average
molecular weight of 30x104 to 60x104 and a specific surface area of
1.5 to 4.5 (m2/g), polymer particles (b2) having a weight-average
5 molecular weight of 5x104 to 20x104 and a specific surface area of
0.51 to 1.2 (m2/g) and polymer particles (b3) having a weight-average
molecular weight of 5x104 to 20x104 and a specific surface area of
0.1 to 0.5 (m2/g), contains the polymer particles (bl) in an amount
of 0 to 98% by weight, and contains the polymer particles (b2) and
10 the polymer particles (b3) in the total amount of not less than 2%
by weight based on the total weight of the polymer particles (bl),
(b2) and (b3), with the proviso that the total amount of the polymer
particles (b1), (b2) and (b3) is 100% by weight.
[0011] It is preferable that the polymerization initiator
15 composition (C) contains an aprotic solvent (c2) having a boiling
point of 30°C to 150°C in an amount of 30 to 80 parts by weight based
on 100 parts by weight of the organoboron compound (cl) . It is also
preferable that the polymerization initiator composition (C) contains
an aprotic solvent (c2') having a boiling point of 50°C to 120°C in
20 an amount of 5 to 40 parts by weight and an alcohol (c3) having a
boiling point of 60°C to 180°C in an amount of 0.2 to 5 parts by weight,
based on 100 parts by weight of the organoboron compound (cl).
[0012] The composition for hard tissue repair preferably
has a viscosity of 0. 4 to 2, 000, 000 cp within 30 seconds after mixing
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of the components (A), (B) and (C).
[0013] The composition for hard tissue repair may further
comprise, for example, a polymerization inhibitor (D), an ultraviolet
light absorber, a flexibilizer and a plasticizer.
5 [0014] It is a preferred embodiment that the content of
the polymerization inhibitor (D) is in the range of 10 to 5000 ppm
based on the monomer (A).
[0015] The polymerization inhibitor (D) is preferably
at least one substance selected from hydroquinone,
10 dibutylhydroquinone, hydroquinone monomethyl ether,
2,6-di-tert-butylphenol, 2,6-di-tert-butyl-p-cresol, catechol,
pyrogallol, benzoquinone, 2-hydroxybenzoquinone, p-methoxyphenol,
t-butylcatechol, butylated hydroxyani sole, butylatedhydroxytoluene
and t-butylhydroquinone.
15 [0016] The composition for hard tissue repair may further
comprise at least one substance selected from:
anti-infectious agents, antibiotics, antibacterial agents,
anti-virus agents, analgesics, compositions of analgesics, anorectic
drugs, antihelmintic drugs, antiarthritic agents, antiasthmatic
20 drugs, anticonvulsants, antidepressants, antidiuretics,
antidiarrheal agents, antihistamine drugs, anti-inflammatory drugs,
antimigraine drugs, antiemetic agents, antineoplastic drugs,
antiparkinsonian agents, antipruritic drugs, antipsychotics,
antipyretic drugs, antispasmodic drugs, anticholinergic agents,
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sympathomimetic agents, cardiovascular drugs, antiarrhythmic drugs,
antihypertensive drugs, diuretics, vasodilators, immunosuppressant
drugs, muscle-relaxant drugs, parasympatholytic drugs, stimulants,
sedative drugs, tranquilizers, cholinergic agents, chemotherapeutic
5 drugs, radio pharmaceuticals, bone inductive drugs, heparin
neutralizer agents of static bladder, procoagulants, hemostatic
agents, xanthine derivatives, hormones, proteins of natural origin
or proteins synthesized by genetic engineering, polysaccharides,
glycoproteins, lipoproteins, oligonucleotides, antibody, antigen,
10 vasopressin, vasopressin analogs, epinephrine, selectin, clot
promoting toxicants, plasminogen activating factor inhibitors,
platelet activators, bone-forming factors, synthetic peptides having
hemostatic action, and
perfumes, such as orange oil, grapefruit oil, lemon oil, lime
15 oil, clove oil, wintergreen oil, peppermint oil, peppermint spirit,
banana distillate, cucumber distillate, honey distillate, rosewater,
menthol, anethole, alkyl salicylate, benzaldehyde, monosodium
glutamate, ethylvanillin, thymol and vanillin.
[0017] A cured product, which is obtained from the
20 composition for hard tissue repair, is given 24 hours after the
preparation of the composition for hard tissue repair and has a
thickness of not less than 0.1 pm, a length of not less than 25 mm
and a width of not less than 2 mm, preferably has a flexural elastic
modulus, as measured under the conditions of a test rate of 2 mm/min,
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of not less than 100 MPa and a tensile strength, as measured under
the conditions of a test rate of 1 mm/min, of not less than 10 MPa.
[0018] The kit for hard tissue repair of the present
invention has members in which the components of the monomer (A),
5 the (meth)acrylate polymer (B) and the polymerization initiator
composition (C) containing an organoboron compound, which are
contained in the above composition for hard tissue repair, are encased
in two or more divided groups in an optional combination,
[0019] The kit for hard tissue repair preferably has
10 constitution in which the monomer (A), the polymer (B) and the
polymerization initiator composition (C) are each independently
encased, and the monomer (A) is first mixed with the polymerization
initiator composition (C) containing an organoboron compound and
subsequently mixed with the polymer (B).
15 [0020] When the kit further contains a polymerization
inhibitor (D) , the kit preferably has members in which the components
of the monomer (A),the (meth) acrylate polymer (B),the polymerization
initiator composition (C) containing an organoboron compound and the
polymerization inhibitor (D), which are contained in the above
20 composition for hard tissue repair, are encased in two or more divided
groups in an optional combination.
[0021] The kit containing the polymerization inhibitor
(D) preferably has constitution in which a mixture of the monomer
(A) and the polymerization inhibitor (D), the polymer (B) and the
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polymerization initiator composition (C) are each independently
encased, and the mixture of the monomer (A) and the polymerization
inhibitor (D) is first mixed with the polymerization initiator
composition (C) containing an organoboron compound and subsequently
5 mixed with the polymer (B).
[0022] The kit may include a jig that is used for applying
a composition for hard tissue repair obtained by mixing the components
(A) , (B) and (C) and the components added when needed to the affected
part.
10 [0023] The jig is, for example, a brush, a fiber ball,
a cloth, a sponge ball or a piece of sponge.
[0024] The kit may further contain an aqueous solution
for pretreatment containing 1 to 15% by weight of citric acid and
1 to 5% by weight of iron(III) chloride.
15
Advantageous Effects of Invention
[0025] The composition for hard tissue repair of the
present invention undergoes small-scale heat generation during curing,
and besides, it has excellent workability.
20
Brief Description of Drawings
[0026] Fig. 1 is a schematic view showing an example of
a process for preparing a sample of a cured product used in the examples
of the present invention.
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Fig. 2 is a schematic view showing an example of a process for
preparing a sample of a cured product used in the examples (compression
strength) of the present invention.
5 Description of Embodiments
[0027] In the composition for hard tissue repair of the
present invention, a monomer (A) is contained. As the monomer (A),
any monomer can be used without specific restriction as long as it
can be polymerized by the later-described polymerization initiator
10 composition (C) . As the monomer (A), any of a monofunctional monomer
and a polyfunctional monomer can be used depending upon the use purpose .
[0028] Examples of the monomers (A) include methacrylates,
acrylates and other vinyl compounds.
[0029] Of these monomers, at least one substance selected
15 from acrylates and methacrylates is preferable from the viewpoint
of relatively low irritation of the human body (acrylates and
methacrylates are sometimes generically referred to as
"(meth) acrylates" hereinafter).
[0030] Of the monomers (A), monomers having an acidic
20 group are preferable from the viewpoint of excellent adhesion to hard
tissues.
[0031] Therefore, use of a combination of a (meth) acrylate
(having no acidic group) and a monomer having an acidic group as the
monomer (A) is also a preferred embodiment.
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[0032] Examples of the monofunctional (meth)acrylates
(having no acidic group) include:
alkyl (meth)acrylates, such as methyl (meth)acrylate, ethyl
(meth)acrylate, propyl (meth)acrylate, butyl (meth)acrylate, hexyl
5 (meth) acrylate, 2-ethylhexyl (meth) acrylate, dodecyl (meth) acrylate,
lauryl (meth)acrylate, cyclohexyl (meth)acrylate, benzyl
(meth)acrylate and isobornyl (meth)acrylate;
hydroxyalkyl esters of (meth)acrylic acid, such as
2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate,
10 3-hydroxypropyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate,
5-hydroxypentyl (meth)acrylate, 6-hydroxyhexyl (meth)acrylate,
1,2-dihydroxypropyl mono(meth)acrylate, 1,3-dihydroxypropyl
mono(meth)acrylate and erythritol mono(meth)acrylate;
polyalkylene glycol mono(meth)acrylates, such as diethylene
15 glycol mono(meth)acrylate, triethylene glycol mono(meth)acrylate,
polyethylene glycol mono(meth)acrylate and polypropylene glycol
mono(meth)acrylate;
(poly)alkylene glycol monoalkyl ether (meth)acrylates, such
as ethylene glycol monomethyl ether (meth)acrylate, ethylene glycol
20 monoethyl ether (meth) acrylate, diethylene glycol monomethyl ether
(meth) acrylate, triethylene glycol monomethyl ether (meth)acrylate,
polyethylene glycol monomethyl ether (meth)acrylate and
polypropylene glycol monoalkyl ether (meth)acrylate;
fluoroalkyl esters of (meth)acrylic acid, such as
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perfluorooctyl (meth)acrylate and hexafluorobutyl (meth)acrylate;
silane compounds having a (meth) acryloxyalkyl group, such as
y-(meth) acryloxypropyltrimethoxysilane and
y-(meth) acryloxypropyltri(trimethylsiloxy)silane; and
5 (meth)acrylates having a heterocyclic ring, such as
tetrahydrofurfuryl (meth)acrylate.
[0033] Examples of the polyfunctional (meth)acrylates
(having no acidic group) include:
poly (meth) acrylates of alkanepolyols, such as ethylene glycol
10 di (meth) acrylate, propylene glycol di (meth) acrylate, butylene glycol
di (meth) acrylate, neopentyl glycol di (meth) acrylate, hexylene glycol
di(meth)acrylate, trimethylolpropane tri(meth)acrylate and
pentaerythritol tetra(meth)acrylate;
polyoxyalkane polyol poly(meth)acrylates, such as diethylene
15 glycol di(meth)acrylate, triethylene glycol di(meth)acrylate,
polyethylene glycol di(meth)acrylate, dipropylene glycol.
di (meth) acrylate, polypropylene glycol di (meth) acrylate, dibutylene
glycol di(meth)acrylate and dipentaerythritol hexa(meth)acrylate;
alicyclic or aromatic di(meth)acrylates represented by the
20 following formula (1):
[0034]
CIH2
1 C
H2
c-C-0-(CH2CH20 ,. R'-(OCH2CH2)n Oi
-
R O ® R ... (1)
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[0035] wherein R is a hydrogen atom or a methyl group, m and
n are numbers of 0 to 10 which may be the same or different, and R1
is any one of the following:
[0036]
5
CH3
I
C D
CH3
[0037] alicyclic or aromatic epoxy di(meth)acrylates
represented by the following formula (2):
[0038]
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CH2 H H H H H H II CH2
11 I I I 3 i C I ( , I I_ I) it
C-C-0- I _C_C-O._R -O-C- -C- O-Ii -O-C-C I
I
O-C-C
11 1
R O H? H H O H H? H O R
H H H (2}
[0039] wherein R is a hydrogen atom or a methyl group, n is a
number of 0 to 10, and R' is any one of the following:
[0040]
--^R
I
-OH -
CH3
5 Q 9
9
[0041] and
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polyfunctional (meth)acrylates having a urethane bond in a
molecule, which are represented by the following formula (3):
[0042]
CIIH2 IIH2
C-C-O-CHZCHZ-O-C-N-RZN-C-O--CHZCHZ O-C-C
R IOO H H IO IO R
5 [0043] wherein R is a hydrogen atom or a methyl group, and R2
is any one of the following:
[0044]
CHg
)M -'D^
9
H3C
CH3
[0045]
10 [0046] Of these (meth)acrylates, preferred
monofunctional (meth)acrylates include:
9
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15
alkyl (meth)acrylates, such as methyl (meth)acrylate and ethyl
(meth)acrylate;
hydroxyalkyl esters of (meth)acrylic acid, such as
2-hydroxyethyl (meth)acrylate, 1,3-dihydroxypropyl
5 mono(meth)acrylate and erythritol mono(meth)acrylate; and
polyethylene glycol mono (meth) acrylates, such as triethylene
glycol monomethyl ether (meth)acrylate and triethylene glycol
mono(meth)acrylate.
[0047] Preferred polyfunctional (meth)acrylates
10 include:
di (meth) acrylates having an ethylene glycol chain in amolecule,
such as triethylene glycol di (meth) acrylate and polyethylene glycol
di(meth)acrylate;
compounds represented by the following formula (1)-a:
15 [0048]
2
2C-O-(CH2CH2O)m- -cI--
s
-Q--(OCH2CH-z2)„o-r-I"
R O CH3 O R .-- (1) -a
[0049] - wherein R is a hydrogen atom or a methyl group, and m
and n are numbers of 0 to 10 which may be the same or different;
compounds represented by the following formula (2)-a:
20 [0050]
C- o-C-C-C-o
R O H C H
H
CH H H H CH2
C--O - O C- C -C-O-I'-C
CH3 H O H O R
H ... (2) -a
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16
[0051] wherein R is a hydrogen atom or a methyl group;
and
compounds represented by the following formula (3)-a:
[0052]
IIHz
I 1i-
0-CB2CHZ0-^ -^-C
R O 0 H
CH3 ? H3
IIH2
Z-CHZ-C-CHz-cH2 -'C-O-CHZCH2-0-'I
CH3 H H 01 0 R ... (3) -a
[0053] wherein R is a hydrogen atom or a methyl group.
[0054] These (meth)acrylates can be used singly or in
combination of two or more kinds.
[0055] Examples of the monomers having an acidic group
10 include:
monomers having a carboxylic acid group or its anhydride group,
such as (meth)acrylic acid and its anhydride,
1,4-di(meth)acryloxyethylpyromellitic acid,
6-(meth) acryloxyethylnaphthalene-1,2,6-tricarboxylic acid,
15 N-(meth)acryloyl-p-aminobenzoic acid,
N-(meth)acryloyl-o-aminobenzoic acid,
N-(meth)acryloyl-m-aminobenzoic acid,
N-(meth)acryloyl-5-aminosalicylic acid,
N-(meth)acryloyl-4-aminosalicylic acid,
20 4-(meth)acryloxyethyltrimellitic acid and its anhydride,
4-(meth)acryloxyeutyltrimellitic acid and its anhydride,
4-(meth)acryloxyhexyltrimellitic acid and its anhydride,
4-(meth)acryloxydecyltrimellitic acid and its anhydride,
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2- (meth) acryloyloxybenzoic acid, 3- (meth) acryloyloxybenzoic acid,
4-(met7)acryloyloxybenzoic acid, (3-(meth) acryloyloxyethyl
hydrogensuccinate, (3-(meth) acryloyloxyethyl hydrogenmaleate,
(3-(meth) acryloyloxyethyl hydrogenphthalate,
5 11-(meth)acryloyloxy-1,1-undecanedicarboxylic acid, and
p-vinylbenzoic acid;
monomers having a phosphoric acid group, such as
(2-(meth)acryloxyethyl) phosphoric acid,
(2-(meth) acryloxyethylphenyl)phosphoric acid and
10 10-(meth)acryloxydecylphosphoric acid; and
monomers having a sulf onic acid group, such as p-styrenesulfonic
acid and 2-acrylamido-2-methylpropanesulfonic acid.
[0056] Of these monomers having an acidic group,
4-methacryloxyethyltrimellitic acid and its anhydride are
15 preferable.
[0057] These monomers having an acidic group can be used
singly or in combination of two or more kinds. The monomers having
an acidic group can be used as calcium salts. By the use of these
monomers having an acidic group, the composition for hard tissue repair
20 of the present invention tends to have more improved adhesion
properties.
[0058] The monomer having an acidic group is preferably
contained in an amount of 1 to 20 parts by weight, more preferably
1 to 10 parts by weight, still more preferably 1 to 8 parts by weight,
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based on 100 parts by weight of the total amount of the (meth) acrylate
and the monomer having an acidic group contained in the composition
for hard tissue repair of the present invention. If the amount thereof
is out of the above range, an evil influence is sometimes exerted
5 on the adhesive strength to hard tissues or the biocompatibility with
organisms.
[0059] The amount of the monomer (A) is preferably in
the range of 5 to 98.95 parts by weight, more preferably 7."I to 98.5
parts by weight, still more preferably 24 to 84 parts by weight, based
10 on 100 parts by weight of the total amount of the monomer (A), the
later-described polymer (B) and the later-described polymerization
initiator composition (C).
[0060] If the amount of the monomer (A) is less than the
lower limit of the above range, viscosity is increased, and application
15 or injection into bone tissues becomes difficult, that is, operability
tends to be not excellent. If the amount of the monomer (P) exceeds
the upper limit of the above range, adhesive strength and other
properties, such as flexural elastic modulus, tensile strength,
compression strength and flexural strength, tend to become poor.
20 [0061] In the composition for hard tissue repair of the
present invention, at least one polymer (B) selected from acrylate
polymers and methacrylate polymers is further contained (methacrylate
polymers and acrylate polymers are sometimes generically referred
to as "(meth)acrylate polymers" hereinafter).
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[0062] Examples of the (meth) acrylate polymers include:
uncrosslinked polymers, such as polymethyl (meth)acrylate,
polyethyl (meth)acrylate, a methyl (meth)acrylate/ethyl
(meth)acrylate copolymer, a methyl (meth)acrylate/butyl
5 (meth)acrylate copolymer and a methyl (meth)acrylate/styrene
copolymer: and
cross linked polymers, such asa methyl (meth)acrylate/ethylene
glycol di(meth)acrylate copolymer, a methyl
(meth) acrylate/triethylene glycol di (meth) acrylate copolymer and a
10 copolymer of methyl (meth)acrylate and a butadiene-based monomer,
and polymers which have partially formed calcium salts.
[0063] In the (meth)acrylate polymers, organic or
inorganic composites in which metal oxides or metal salts are coated
with the above-mentioned uncrosslinked polymers or crosslinked
15 polymers are also included.
[0064] The weight-average molecular weight of the polymer
is preferably in the range of 1,000 to 1,000,000, more preferably
50,000 to 500,000, still more preferably 100,000 to 500,000. The
above molecular weight is a molecular weight in terms of standard
20 polymethyl methacrylate, as determined by gel permeation
chromatography (GPC).
[0065] Thepolymer (B) maybecomposedofpolymer particles.
When the polymer (B) is composed of polymer particles, they may be
polymer particles of plural kinds.
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[0066] Examples of such polymer particles include polymer
particles (bl) having a weight-average molecular weight of 30xl09
to 60x109 and a specific surface area of 1.5 to 4.5 (m2/g), polymer
particles (b2) having a weight-average molecular weight of 5x109 to
5 20x109 and a specific surface area of 0.51 to 1.2 (m2/g), and polymer
particles (b3) having a weight-average molecular weight of 5x109 to
20x109 and a specific surface area of 0.1 to 0.5 (m2/g).
[0067] The specific surface area of the polymer particles
(b1) is preferably in the range of 1.5 to 4.5 (m2/g), more preferably
10 2.0 to 4.0 (m2/g).
[0068] The specific surface area of the polymer particles
(b2) is preferably in the range of 0.51 to 1.2 (m2/g) , more preferably
0.6 to 1.0 (m2/g).
[0069] The specific surface area of the polymer particles
15 (b3) is preferably in the range of 0. 1 to 0. 5 (m2/g) , more preferably
0.2 to 0.45 (m2/g).
[0070] The volume mean particle diameter of the polymer
particles (bl) is usually in the range of 1 to 50 (pm), preferably
5to40(pm). The volume mean particle diameter of the polymer particles
20 (b2) is usually in the range of 0.1 to 40 (pm), preferably 1 to 20
(pm). The volume mean particle diameter of the polymer particles
(b3) is usually in the range of 1 to 50 (pm) , preferably 5 to 40 (pm) .
[0071] When the polymer (B) is a polymer mixture composed
of the polymer particles (b2) and the polymer particles (b3), and
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if necessary, the polymer particles (bl), the total amount of the
polymer particles (b2) and the polymer particles (b3) is preferably
not less than 2% by weight, more preferably not less than 5% by weight,
based on the total weight of the polymer particles (b1) , the polymer
5 particles (b2) and the polymer particles (b3). The polymer mixture
is sometimes composed of the polymer particles (b2) and the polymer
particles (b3) in the total amount of 100% by weight.
[0072] When the total amount of the polymer particles
(b2) and the polymer particles (b3) is not less than the lower limit
10 of the above range, the polymer (B) is apt to be homogeneously dispersed
in the monomer (A) and is more excellent in solubility in the monomer
(A) Further, in the course of an operation of filling the composition
in bones as bone cement or an operation of adhesion between hard tissues,
between hard tissues and artificial substances, such as titanium and
15 ceramic, or adhesion between hard tissues and other tissues such as
soft tissues, rapid increase of viscosity can be inhibited and a
sufficient operation time can be ensured. Furthermore, when the
later-described X-ray contrast medium is added to the composition
for hard tissue repair of the present invention, precipitation of
20 the X-ray contrast medium does not take place during mixing, and the
X-ray contrast medium can be homogeneously dispersed.
[0073] When the polymer particles (hi) is contained in
the polymer particles, the total amount of the polymer particles (b2)
and the polymer particles (b3) is preferably not more than 99% by
22
weight, more preferably.-not more than 95% by weight, still more
preferably not more than 90% by weight, based on the total weight
of the uolymer particles (b1),, the polymer particles (b2) and the
polymer particles (b3).
5 [00741 When the polymer particles (bi) is contained in
the polymer particles, the content of the polymer articles (bi) is
preferably not more than 98% by weight, more preferably not more than
95% by weight, based on the total weight of the polymer particles
(bl), the polymer particles (b2) and the polymer particles (b3). The
10 content of the polymer ,articles (bi) is preferably not less than
1% by weight, more preferably not less than 5% by weight, still more
preferably not less than 10% by weight, based on the total weight
of the polymer articles (b1), the polymer particles (b2) and the
polymer particles (b3). When the polymer particles (b1) is contained
15 in the above amount in the polymer particles, precipitation of a
contrast medium tends to rarely occur even if the composition of the
present invention contains the contrast medium.
.[0075] The amount of the (meth)acrylate polymer (B) is
preferably in the range of 1 to 75 parts by weight, more preferably
20 1 to 73 parts by weight, still more preferably 15 to 73 parts by weight,
based on 100 parts by weight of the total amount of the monomer (A),
the (meth)acrylate polymer (B) and the later-described polymerization
initiator composition (C).
[0076] If the amount of the (meth)acrylate polymer (B)
is less than the lower limit of the above range, progress of
polymerization becomes difficult, and adhesive strength and other
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23
properties, such as flexural elastic modulus, tensile strength,
compression strength and flexural strength, tend to become poor. If
the amount of the (meth)acrylate polymer (B) exceeds the upper limit
of the above range, viscosity is increased, and application or use
5 for bone tissues becomes difficult, that is, workability tends to
be not excellent.
[0077] When the polymer (B) is a (meth)acrylate polymer
and is a mixture of the polymer particles (bl), (b2) and (b3), the
following embodiment is preferable under the conditions that the total
10 amount of the polymer particles (bl) , (b2) and (b3) is 100% by weight
and the total amount of the polymer particles (b2) and (b3) is not
less than 2% by weight, preferably not less than 5% by weight.
[0078] When the amount of the polymer (B) is not less
than 35 parts by weight but less than 65 parts by weight based on
15 100 parts by weight of the total amount of the monomer (A) , the polymer
(B) and the polymerization initiator composition (C), the amount of
the polymer particles (b1) is preferably in the range of 10% by weight
to 98% by weight, more preferably 20% by weight to 95% by weight,
the amount of the polymer particles (b2) is preferably not more than
20 90% by weight, more preferably not more than 80% by weight, and the
amount of the polymer particles (b3) is preferably not more than 90%
by weight, more preferably not more than 80% by weight.
[0079] The composition for hard tissue repair of the
present invention is characterized by using the later-described
SF-2300
24
organoboron compound (cl) as the initiator composition (C) contained,
and when the organoboron compound is added to a composition containing
a monomer, polymerization reaction begins in a relatively early stage
and proceeds gently. This greatly differs from a case of using a
5 peroxide as a polymerization initiator where a relatively long time
is required for the beginning of polymerization even if the
polymerization initiator is added, and if the polymerization reaction
once begins, the reaction proceeds rapidly and is completed in a
relatively short time. In order to prepare a composition that is
10 preferably used for hard tissues, etc., therefore, it is important
to use such a polymer (B) of the present invention in such an amount
as described above based on the monomer (A) . By the use of such a
polymer (B), not only can workability be ensured over a long time
but also fluidity and application properties that are preferable in
15 use for hard tissues, etc. can be ensured.
[0080] The polymerization initiator composition (C)
contained in the composition for hard tissue repair of the present
invention contains an oragnoboron compound (c1) as an essential
component, and can contain an aprotic solvent (c2) and an alcohol
20 (c3), when needed. The organoboron compound (cl) has a feature that
the polymerization rate is increased when a small amount of oxygen
or water is present, and since the polymerization initiator composition
(C) containing the organoboron compound (cl) is contained in the
composition of the present invention, a part of the composition
SF-2300
25
penetrates into a hard tissue to initiate polymerization at the contact
interface when the composition comes into contact with an organism
having moisture content as in an operation of filling in the hard
tissue or application thereto. Hence, leakage of the monomer (A)
5 and the composition is little. Further, even after the whole
composition is cured in the organism, a residue of the monomer (A)
tends to be smaller as compared with a composition using a peroxide
as a polymerization initiator. Accordingly, the composition of the
present invention is favorably used for organisms.
10 [0081] Examples of the organoboron compounds (cl) include
trialkylboron, alkoxyalkylboron, dialkylborane and partially
oxidized trialkylboron.
[0082] Examples of the trialkylborons include
trialkylborons having an alkyl group of 2 to 8 carbon atoms, such
15 as triethylboron, tripropylboron, triisopropylboron, tributylboron,
tri-sec-butylboron, triisobutylboron, tripentylboron,
trihexylboron, triheptylboron, trioctylboron, tricyclopentylboron
and tricyclohexylboron. The alkyl group maybe any of a straight-chain
alkyl group, a branched alkyl group and a cycloalkyl group, and three
20 alkyl groups contained in the trialkylboron may be the same or
different.
[0083] The alkoxyalkylboron is, for example,
monoalkoxydialkylboron or dialkoxymonoalkylboron. Specifically,
the alkoxyalkylboron is, for example, monoalkoxydialkylboron such
SF-2300
26
as butoxybutylboron. The alkyl group of the alkoxyallcylboron may
be the same as or different from the alkyl part of the alkoxy group.
[0084] Examples of the dialkylboranes include
dicyclohexylborane and diisoamylborane. Two alkyl groups of the
5 dialkylborane maybe the same or different. Two alkyl groups contained
in the dialkylborane may be bonded to form a monocyclic structure
or a bicyclo structure. Examples of such compounds include
9-borabicyclo[3.3.1]nonane.
[0085] The partially oxidized trialkylboron is a
10 partially oxidized product of the above trialkylboron. As the
partially oxidized trialkylboron, partially oxidized tributylboron
is preferable. As the partially oxidized trialkylboron, partially
oxidized trialkylboron obtained by the addition of oxygen in an amount
of preferably 0.3 to 0.9 mol, more preferably 0.4 to 0.6 mol, based
15 on 1 mot of the trialkylboron can be used.
[0086] Of the above organoboron compounds, tributylboron
or partially oxidized tributylboron is preferable, and partially
oxidized tributylboron is more preferable. When tributylboron or
partially oxidized tributylboron is used as the organoboron compound
20 (cl), not only is the operability of the composition improved but
also the composition tends to have proper reactivity to organisms
having moisture content. When tributylboron or partially oxidized
tributylboron is used as the organoboron compound (cl), further, the
reaction is initiated and proceeds even in a place of high moisture
SF-2300
27
content such as an organism, so that the monomer rarely remains on
the interface between the adhesive and the organism. Therefore, the
injurious properties to the organism are extremely little. Such
organoboron compounds (cl) can be used singly or in combination of
5 two or more kinds.
[0087] In the polymerization initiator composition (C),
an aprotic solvent (c2) may be further contained. Since the aprotic
solvent is contained in the polymerization initiator composition (C)
as above and the organoboron compound is diluted, exothermic properties
10 of the organoboron compound (cl) having ignition properties become
gentler to suppress ignition properties, and hence, handling of the
composition during transportation, storage and mixing is facilitated.
In the case where an extremely large amount of the composition of
the present invention is used, rapid generation of heat can be inhibited
15 because of proper lowering of the exothermic properties, and
consequently, damage of an organism that is in contact with the
composition of the present invention tends to be decreased. The
boiling point of the aprotic solvent (c2) at 1 atm is usually in the
range of 30°C to 150°C, preferably 50°C to 120°C. If the boiling
20 point is lower than the lower limit of the above range, the aprotic
solvent is evaporated or scattered from the polymerization initiator
composition during transportation or storage, and the ignition
suppressing effect of the organoboron compound (cl) tends to be lowered.
If the boiling point exceeds the upper limit of the above range, a
SF-2300
28
residue of the aprotic solvent in a cured product formed from the
composition for hard tissue repair of the present invention is
increased, and consequently, adhesion strength of the cured product
to the affected part and other properties, such as flexural elastic
5 modulus, tensile strength, compression strength and flexural strength,
tend to become poor.
[0088] As the aprotic solvent (c2), a solvent that does
not have a group containing active hydrogen, said group being reactive
to the organoboron compound (cl) , such as hydroxyl group or mercapto
10 group, and is capable of forming a homogeneous solution together with
the organoboron compound (cl) is preferable.
[0089] Examples of the aprotic solvents (c2) include:
hydrocarbons, such as pentane, hexane, cyclohexane, heptane,
benzene and toluene;
15 halogenated hydrocarbons, such as fluorobenzene,
1,1-dichloroethane, 1,2-dichloroethane and so-called floes;
ethers, such as diethyl ether, diisopropyl ether, ethylene
glycol dimethyl ether and tetrahydrofuran;
ketones, such as acetone, methyl ethyl ketone and diethyl ketone;
20 and
esters, such as methyl acetate, ethyl acetate and isopropyl
acetate.
[0090] Of these, saturated aliphatic hydrocarbons, such
as pentane, hexane and heptane, ethers and esters are preferable,
SF-2300
29
and hexane, diisopropyl ether and ethyl acetate are more preferable.
[0091] These aprotic solvents (c2) can be used singly
or in combination of two or more kinds.
[0092] The content of'the aprotic solvent (c2) in the
5 polymerization initiator composition (C) is preferably in the range
of 30 to 80 parts byweight based on 100 parts byweight of the organoboron
compound (c1).
[0093] If the content of the aprotic solvent (c2) is less
than the lower limit of the above range, satisfactory dilution effect
10 is not obtained, and the effect to suppress generation of heat or
ignition tends to be insufficient. On the other hand, if the content
of the aprotic solvent (c2) exceeds the upper limit of the above range,
polymerization initiation ability of the polymerization initiator
composition (C) tends to be lowered.
15 [0094] In the polymerization initiator composition (C),
an alcohol (c3) may be further contained in addition to the aprotic
solvent (c2) . By adding a small amount of the alcohol (c3) to the
polymerization initiator composition (C), the reaction by the
oragnoboron compound (cl) is made still gentler without lowering the
20 polymerization activity, and even if the composition is brought into
contact with paper or the like in air, burning or ignition tends to
be suppressed.
JU
[0095] The boiling point of the alcohol (c3) at 1 atm
is usually in the range of 60°C to 180°C, preferably 60°C to 120°C.
If the boiling point is lower than the lower limit of the above range,
the alcohol. is evaporated or scattered from the
5 polymerization initiator composition during transportation or
storage, and the ignition suppressing effect of the organoboron
compound (cl) tends to be lowered. If the boiling point exceeds the
upper limit of the above range, the curing time of the composition
of the present invention tends to become longer, and adhesion strength
10 of the cured product to the affected part and other properties, such
as flexural elastic modulus, tensile strength, compression strength
and flexural strength, tend to become poor.
[0096] Examples of the alcohols (c3) include methanol,
ethanol, n-propanol and its isomers, n-butanol and its isomers,
15 n-pentanol and its isomers, n-hexanol and its isomers, and n-heptanol
and its isomers.
[0097] Of these alcohols (c3) , alcohols of 4 or less carbon
atoms, namely, methanol, ethanol, n-propanol and its isomers, and
n-butanol and its isomers are preferable, and ethanol and n-propanol
20 are more preferable.
[0098] These alcohols (c3) can be used singly or in
combination of two or more kinds.
[0099] The content of the alcohol (c3) in the
polymerization initiator composition (C) is usually in the range of
0.2 to 5 parts by weight, preferably 0.3 to 4.5 parts by weight, more
preferably 0.5 to 4 parts by weight, based on 100 parts by weight
SF-2300
31
of the organoboron compound (cl).
[0100] If the content of the alcohol (c3) is less than
the lower limit of the above range, satisfactory dilution effect is
not obtained, and the effect to suppress generation of heat or ignition
5 tends to be insufficient. On the other hand, if the content of the
alcohol (c3) exceeds the upper limit of the above range, polymerization
initiation ability of the polymerization initiator composition (C)
tends to become lower than needed.
[0101] When the alcohol (c3) and the aprotic solvent (c2)
10 are used in combination, the content of the aprotic solvent (c2) in
the polymerization initiator composition (C) is preferably in the
range of 5 to 40 parts by weight, more preferably 10 to 30 parts by
weight, still more preferably 10 to 25 parts by weight, based on 100
parts by weight of the organoboron compound (cl).
15 [0102] If the content of the aprotic solvent (c2) is less
than the lower limit of the above range based on 100 parts by weight
of the organoboron compound (cl), the effect to suppress generation
of heat or ignition tends to be insufficient. On the other hand,
if the content of the aprotic solvent (c2) exceeds the upper limit
20 of the above range based on 100 parts by weight of the organoboron
compound (c1), polymerization initiation ability of the
polymerization initiator composition (C) tends to be lowered.
[0103] The amount of the polymerization initiator
composition (C) is usually in the range of 0.05 to 20 parts by weight,
SF-2300
32
preferably 0.5 to 10 parts by weight, more preferably 1 to 3 parts
by weight, based on 100 parts by weight of the total amount of the
monomer (A), the polymer (B) and the polymerization initiator
composition (C).
5 [0104] If the amount of the polymerization initiator
composition (C) is less than the lower limit of the above range, progress
of polymerization is difficult, and the curing time tends to be
prolonged. If the amount of the polymerization initiator composition
(C) exceeds the upper limit of the above range, there is a possibility
10 of lowering viscosity because of dilution or a possibility of exerting
evil influence on safety. Moreover, it is presumed that rapid
polymerization proceeds to forma polymerization product immediately.
[0105] In the composition for hard tissue repair, other
components may be further contained when needed, as long as they do
15 not exert evil influence on the performance of a hard tissue repair
agent.
[0106] As one of the other components, a polymerization
inhibitor (D) can be mentioned. Examples of the polymerization
inhibitors (D) include hydroquinone compounds, such as hydroquinone
20 and dibutylhydroquinone, hydroquinone monomethyl ether, phenols,
such as 2,6-di-tert-butylphenol and 2,6-di-tert-butyl-p-cresol,
catechol, pyrogallol, benzoquinone, 2-hydroxybenzoquinone,
p-methoxyphenol, t-butylcatechol, butylated hydroxyanisole,
butylated hydroxytoluene and t-butylhydroquinone. Of these, a
SF-2300
33
mixture of hydroquinone monomethyl ether and
2,6-di-tert-butyl-p-cresol is preferably used.
[0107] Of these polymerization inhibitors (D),
hydroquinone monomethyl ether is sometimes preferable from the
5 viewpoint of good stability of the hydroquinone monomethyl ether
itself.
[0108] The above polymerization inhibitors (D) can be
used singly or in combination of two or more kinds.
[0109] When the polymerization inhibitor (D) is added,
10 the amount thereof is preferably in the range of 10 to 5000 ppm, more
preferably 50 to 1000 ppm, still more preferably 50 to 500 ppm, based
on the whole amount of the composition for hard tissue repair.
[0110] It is also preferable to add the polymerization
inhibitor (D) in an amount of 10 to 5000 ppm based on the monomer
15 (A).
[0111] By preparing such a composition, for example, when
the composition is applied to a part, such as the affected part (hard
tissue containing moisture such as body fluid) in the surgical
operation, the composition becomes more excellent in ensuring
20 application properties and a proper curing time and can be more stably
handled than before. Moreover, the composition is excellent in
workability.
[0112] Although the amount of the polymerization
inhibitor (D) is as described above, the polymerization inhibitor
SF-2300
34
(D) is more preferably added in an amount of 50 to 1000 ppm, still
more preferably 50 to 500 ppm, based on the monomer (A) . By preparing
such a composition, for example, the composition can be not only handled
stably during application but also cured efficiently after application.
5 If the content of the polymerization inhibitor (D) is less than the
lower limit of the above range, curing takes place immediately after
mixing of the monomer (A), the polymer (B) and the polymerization
initiator composition (C), and hence, application tends to become
difficult. On the other hand, if the content of the polymerization
10 inhibitor (D) exceeds the upper limit of the above range,
polymerization initiation ability of the polymerization initiator
composition (C) is lowered, and the curing time becomes longer than
needed. Hence, medical use of the composition tends to become
difficult.
15 [0113] As one of the other components, an ultraviolet
light absorber can be further mentioned. Examples of the ultraviolet
light absorbers includes
benzotriazole compounds, such as
2-(2'-hydroxy-5'-methylphenyl)benzotriazole,
20 2-(3',5'-di-tert-butyl-2'-hydroxyphenyl)benzotriazole,
2-(5'-tert-butyl-2'-hydroxyphenyl)benzotriazole,
2-(2'-hydroxy-5'-(1,1,3,3-tetramethylbutyl)phenyl)benzotriazole,
2-(3',5'-di-tert-butyl-2'-hydroxyphenyl)-5-chlorobenzotriazole,
2-(3'-tert-butyl-2'-hydroxy-5'-methylphenyl)-5-chlorobenzotriazo
SF-2300
35
le, 2-(3'-sec-butyl-5'-tert-butyl-2'-hydroxyphenyl)benzotriazole,
2-(2'-riydroxy-4'-octoxyphenyl)benzotriazole,
2-(3',5'-di-tert-amyl-2'-hydroxyphenyl)benzotriazole,
2-(3',5'-bis(a,(x-dimethylbenzyl)-2'-hydroxyphenyl)benzotriazole,
5 2-(3'-tert-butyl-2'-hydroxy-5'-(2-octyloxycarbonylethyl)phenyl)-
5--chlorobenzotriazole,
2-(3'-tert-butyl-5'-[2-(2-ethylhexyloxy)carbonylethyl]-2'-hydrox
yphenyl)-5-chlorobenzotriazole,
2-(3'-tert-butyl-2'-hydroxy-5'-(2-methoxycarbonylethyl)phenyl)-5
10 -chlorobenzotriazole,
2-(3'-tert-butyl-2'-hydroxy-5'-(2-methoxycarbonylethyl)phenyl)be
nzotriazole,
2-(3'-tert-butyl-2'-hydroxy-5'-(2-o(7tyloxycarbonylethyl)phenyl)b
enzotriazole,
15 2-(3'-tert-butyl-5'-[2-(2-ethylhexyloxy)carbonylethyl]-2'-hydrox
yphenyl)benzotriazole,
2- (3'-dodecyl-2' -hydroxy-5'-methylphenyl) benzotriazole, a mixture
of
2-(3'-tert-butyl-2'-hydroxy-5'-(2-isooctyloxycarbonylethyl)pheny
20 1)benzotriazole and
2,2'-methylene-bis[4-(1,1,3,3-tetramethylbutyl)-6-benzotriazol-2
-ylphenol], an ester interchange reaction product of
2-[3'-tert-butyl-5'-(2-methoxycarbonylethyl)-2'-hydroxyphenyl]be
nzotriazole with polyethylene glycol 300, and [[R-CH2CH2-000CH2]3]2-
SF-2300
36
(wherein R is
3'-terL-butyl-4'-hydroxy-5'-2H-benzotriazol-2-ylphenyl);
benzophenone compounds, such as 2,4-dihydroxybenzophenone,
2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-octoxybenzophenone,
5 2-hydroxy-4-decyloxybenzophenone,
2-hydroxy-4-dodecyloxybenzophenone,
2-hydroxy-4-benzyloxybenzophenone,
2,2',4,4'-tetrahydroxybenzophenone, and
2,2'-dihydroxy-4,4'-dimethoxybenzophenone;
10 4-tert-butylphenyl salicylate, phenyl salicylate, octylphenyl
salicylate, dibenzoylresorcinol,
bis(4-terrt-butylbenzoyl)resorcinol, benzoylresorcinol,
2,4-di-tert-butylphenyl 3,5-di-tert-butyl-4-hyderoxybenzoate,
hexadecyl 3,5-di-tert-butyl-4-hyderoxybenzoate, octadecyl
15 3,5-di-tert-butyl-4-hyderoxybenzoate,
2-methyl-4,6-di-tert-butylphenyl benzoate, and
3,5-di-tert-butyl-4-hydroxybenzyl benzoate;
hindered amine compounds, such as
bis(2,2,6,6-tetramethylpiperidyl)sebacate,
20 bis(2,2,6,6-tetramethylpiperidyl)succinate,
bis(1,2,2,6,6-pentamethylpiperidyl)sebacate,
bis(1,2,2,6,6-pentamethylpiperidyl)
n-butyl-3,5-di-tert-butyl-4-hydroxybenzylmalonate, a condensation
product of 1-hydroxyethyl-2, 2, 6, 6-tetramethyl-4-hydroxypiperidine
SF-2300
37
and succinic acid, a condensation product of
N,N'-bls(2,2,6,6-tetramethyl-4-piperidyl)hexamethylenediamine and
4-tert-octylamino-2,6-dichloro-1,3,5-s-triazine,
tris(2,2,6,6-tetramethyl-4-piperidyl)nitrilotriacetate,
5 tetrakis(2,2,6,6-tetramethyl-4-piperidyl)-1,2,3,4-butanetetraoat
e, 1,1'-(1,2-ethanediyl)bis(3,3,5,5-tetramethylpiperazinone),
4-benzoyl-2,2,6,6-tetramethylpiperidine,
4-stearyloxy-2,2,6,6-tetramethylpiperidine,
bis(1,2,2,6,6-pentamethyl-4-piperidyl)-2-n-butyl-2-(2-hydroxy-3,
10 5-di-tert-butylbenzyl)malonate,
3-n-octyl-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-d
ions, bis(1-octyloxy-2,2,6,6-tetramethylpiperidyl)sebacate,
bis(1-octyloxy-2,2,6,6-tetramethylpiperidyl)succinate, a
condensation product of
15 N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)hexamethylenediamine and
4-morpholino-2, 6-dichloro-1, 3, 5-triazine, a condensation product of
2-chloro-4,6-di-(4-n-butylamino-2,2,6,6-tetramethylpiperidyl)-1,
3, 5-triazine and 1,2-bis (3-aminopropylamino) ethane, a condensation
product of
20 2-chloro-4,6-di-(4-n-butylamino-1,2,2,6,6-pentamethylpiperidyl)-
1,3,5-triazine and 1,2-bis(3-aminopropylamino)ethane,
8-acetyl-3-dodecyl-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]dec
ane-2,4-dione,
3-dodecyl-l-(2,2,6,6-tetramethyl-4-piperidyl)pyrrolidine-2,5-dio
SF-2300
38
ne, and
3-dodecyl-l-(1,2,2,6,6-pentamethyl-4-piperidyl)pyrrolidine-2,5-d
Tone;
oxalamide compounds, such as 4,4'-dioctyloxyoxanilide,
5 2,2'-diethoxyoxanilide,
2,2'-dioctyloxy-5,5'-di-tert-butyloxanilide,
2,2'-didodecyloxy-5,5'-di-tert-butyloxanilide,
2-ethoxy-2'-ethyloxanilide,
N,N'-bis(3-dimethylaminopropyl)oxalamide, a mixture of
10 2-ethoxy-5-tert-butyl-2'-ethyloxanilide and
2-ethoxy-2'-ethyl-5,4'-di-tert-butyloxanilide, a mixture of
o-methoxy- and p-methoxy-di-substituted oxanilides, and a mixture
of o-ethoxy- and p-ethoxy-di-substituted oxanilides;
2-(2-hydroxyphenyl)-1,3,5-triazine compounds, such as
15 2,4,6-tris(2-hydroxy-4-octyloxyphenyl)-1,3,5-triazine,
2-(2-hydroxy-4-octyloxyphenyl)-4,6-bis(2,4-dimethylphenyi)-1,3,5
-triazine,
2-(2,4-dihydroxyphenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazi
ne,
20 2,4-bis(2-hydroxy-4-propyloxyphenyl)-6-(2,4-dimethylphenyl)-1,3,
5-triazine,
2-(2-hydroxy-4-octyloxyphenyl)-4,6-bis(4-methylphenyl)-1,3,5-tri
azine,
2-(2-hydroxy-4-dodecyloxyphenyl)-4,6-bis(2,4-dimethylphenyl)-1,3
SF-2300
39
5-triazine,
2-[2-hydroxy-4-(2-hydroxy-3-butyloxypropyloxy)phenyl]-4,6-bis(2,
4-dimethylphenyl)-1,3,5-triazine,
2-[2-hydroxy-4-(2-hydroxy-3-octyloxypropyloxy)phenyl]-4,6-bis(2,
5 4-dimethylphenyl)-1,3,5-triazine, and
2-[4-dodecyl/tridecyloxy-(2-hydroxypropyl)oxy-2-hydroxyphenyl]-4
,6-bis(2,4-dimethylphenyl)-1,3,5-triazine; and
phosphite compounds or phosphonite compounds, such as triphenyl
phosphite, diphenylalkyl phosphite, phenyldialkyl phosphite,
10 tris(nonylphenylphosphite), trilauryl phosphite, trioctadecyl
phosphite, distearyl pentaerythrytyl diphosphite,
tris(2,4-di-tert-butylphenyl)phosphite, diisodecyl
pentaerythrityl diphosphite,
bis(2,4-di-tert-butylphenyl)pentaerythrityl diphosphite,
15 bis (2, 6-di-tert-butyl-4-methylphenyl) pentaerythrityl diphosphite,
bisisodecyloxypentaerythrityl diphosphite,
bis (2, 4-di-tert-butyl-6-methylphenyl) pentaerythrityl diphosphite,
bis(2,4,6-tri-tert-butylphenyl)pentaerythrityl diphosphite,
tristearyl sorbityl triphosphite,
20 tetrakis (2, 4-di-tert-butylphenyl) -4, 4' -biphenylene diphosphonite,
6-isooctyloxy-2,4,8,10-tetra-tert-butyl-12H-dibenzo[d.g]-1,3,2-d
ioxaphosphocine,
6-fluoro-2,4,8,10-tetra-tert-butyl-l2-methyldibenzo[d,g]-1,3,2-d
ioxaphosphocine, bis(2,4-di-tert-butyl-6-methylphenyl)methyl
SF-2300
40
phosphite, and bis(2,4-di-tert-butyl-6-methylphenyl)ethyl
phosphite.
[0114] As the ultraviolet light absorber, a benzotriazole
compound is preferable.
5 [0115] When the ultraviolet light absorber is added, the
amount thereof is preferably in the range of 10 to 1,000 ppm, more
preferably 100 to 800 ppm, based on the monomer (A) By adding the
ultraviolet light absorber as above, coloring of a liquid containing
a monomer is suppressed, and storage stability of the monomer itself
10 tends to be enhanced.
[0116] As examples of the other components, a flexibilizer
and a plasticizer can be further mentioned.
[0117] Examples of the flexibilizers include rubbers,
such as natural rubbers and synthetic rubbers, and elastomers, such
15 as thermoplastic elastomers. By the use of such a flexibilizer,
flexibility of the composition for hard tissue repair can be enhanced.
[0118] Examples of the synthetic rubbers include EPT
(ethylene/propylene/terpolymer). Examples of the thermoplastic
elastomers include styrene-based elastomers, vinyl chloride-based
20 elastomers, olefin-based elastomers, polyester-based elastomers,
polyamide-based elastomers, and urethane-based elastomers.
[0119] The molecular weight of the elastomer is usually
in the range of 1, 000 to 1, 000, 000, preferably 2, 000 to 500, 000. The
glass transition point (Tg) of the elastomer is usually not higher
SF-2300
41
than 20°C, preferably not higher than 0°C.
[0120] Examples of the plasticizers include
hydroxycarboxylic acid esters, such as citrate esters, isocitrate
esters, tartrate esters, malate esters, lactate esters, glycerate
5 esters and glycolate esters; trimethyl trimellitate, diethylene
glycol dibenzoate, diethyl malonate, triethyl o-acetylcitrate,
benzyl butyl phthalate, dipropylene glycol dibenzoate, diethyl
adipate, tributyl o-acetylcitrate, dimethyl sebacate, and alkylene
glycol diester.
10 [0121] Although the amount of the flexibilizer and the
plasticizer is properly selected according to the types of the
materials, they are used so that they may be usually contained in
an amount of 0 to 30% by weight, preferably 0 to 20% by weight, more
preferably 0 to 10% by weight, in the whole composition for hard tissue
15 repair.
[0122] As one of the other components, a preservative
can be further mentioned.
[0123] Examples of the preservatives include:
methylparaben, methylparaben sodium, ethylparaben,
20 propylparaben, propylbaraben sodium, butylparaben;
cresol, chlorocresol;
resorcinol, 4-n-hexylresorcinol,
3a,4,7,7a-tetrahydro-2-((trichloromethyl)thio)-1H-isoindole-1,3(
2H)dione;
SF-2300
42
benzalkonium chloride, benzalkonium sodium chloride,
benzethonium chloride;
benzoic acid, benzyl alcohol, cetylpyridinium chloride,
chlorobutanol, dehydroacetic acid, o-phenylphenol, phenol,
5 phenylethyl alcohol, potassium benzoate, potassium sorbate, sodium
benzoate, sodium dehydroacetate, sodium propionate, sorbic acid,
thimerosal, thymol, phenylmercuric compounds, such as phenylmercuric
borate, phenylmercuric nitrate and phenylmercuric acetate, and
formaldehyde.
10 [0124] As examples of the other components, there can
be further mentioned anti-infectious agents, antibiotics,
antibacterial agents, anti-virus agents, analgesics, compositions
of analgesics, anorectic drugs, antihelmintic drugs, antiarthritic
agents, antiasthmatic drugs, anticonvulsants, antidepressants,
15 antidiuretics, antidiarrheal agents, antihistamine drugs,
anti-inflammatory drugs, antimigraine drugs, antiemetic agents,
antineoplastic drugs, antiparkinsonian agents, antipruritic drugs,
antipsychotics, antipyretic drugs, antispasmodic drugs,
ant ichol inergic agents, sympathomimetic agents, cardiovascular drugs,
20 antiarrhythmic drugs, antihypertensive drugs, diuretics,
vasodilators, immunosuppressant drugs, muscle-relaxant drugs,
parasympatholytic drugs, stimulants, sedative drugs, tranquilizers,
cholinergic agents, chemotherapeutic drugs, radio pharmaceuticals,
bone inductive drugs, heparin neutralizer agents of static bladder,
SF-2300
43
procoagulants, hemostatic agents, xanthine derivatives, hormones,
proteins of natural origin or proteins synthesized by genetic
engineering, polysaccharides, glycoproteins, lipoproteins,
oligonucleotides, antibody, antigen, vasopressin, vasopressin
5 analogs, epinephrine, selectin, clot promoting toxicants,
plasminogen activating factor inhibitors, platelet activators,
bone-formingf actors, and synthetic peptides having hemostatic action.
Since these components are contained, the composition of the present
invention can be used also for the drug delivery system or the purpose
10 of regenerative medicine.
[0125] Examples of the antibacterial agents include:
element iodine, solid polyvinylpyrrolidone iodine,
polyvinylpyrrolidone iodine;
phenol compounds, such as tribromophenol, trichlorophenol,
15 tetrachlorophenol, nitrophenol, 3-methyl-4-chlorophenol,
3,5-dimethyl-4-chlorophenol, phenoxyethanol, dichlorophene,
o-phenylphenol, m-phenylphenol, p-phenylphenol,
2-benzyl-4-chlorophenol, 2,4-dichloro-3,5-dimethylphenol,
4-chlorothymol, chlorophene, triclosan, fenticlor, phenol,
20 2-methylphenol, 3-methylphenol, 4-methylphenol, 4-ethylphenol,
2,4-dimethylphenol, 2,5-dimethylphenol, 3,4-dimethylphenol,
2,6-dimethylphenol, 4-n-proylphenol, 4-n-butylphenol,
4-n-aminophenol, 4-tert-amylphenol, 4-n-hexylphenol,
4-n-heptylphenol, monoalkylhalophenol, polyalkylhalophenol,
SF-2300
44
aromatic halophenol, and ammonium salts, alkali metal salts and
alkaline earth metal salts of these substances;
silver nitrate, hexachlorophene, merbromin, tetracycline HC1,
tetracycline hydrate and erythromycin.
5 [0126] In the composition for hard tissue repair,
bone-forming factor, etc. may be contained for the purpose of
accelerating tissue reparation and the like.
[0127] As examples of the other components, there can
be further mentioned perfumes, such as orange oil, grapefruit oil,
10 lemon oil, lime oil, clove oil, wintergreen oil, peppermint oil,
peppermint spirit, banana distillate, cucumber distillate, honey
distillate, rose water, menthol, anethole, alkyl salicylate,
benzaldehyde, monosodium glutamate, ethylvanillin, thymol and
vanillin.
15 [0128] Furthermore, an inorganic filler, an organic
filler, an organic composite filler, a filler colorant, etc. may be
contained as the other components to impart X-ray contrast property
and to enhance properties such as adhesive strength and compression
strength.
20 [0129] Examples of the inorganic fillers include:
metal oxide powders, such as zirconium oxide, bismuth oxide,
titanium oxide, zinc oxide and aluminum oxide particles;
metal salt powders, such as bismuth carbonate, zirconium
phosphate and barium sulfate;
SF-2300
45
glass fillers, such as silica glass, aluminum-containing glass,
barium-containing glass, strontium-containing glass and zirconium
silicate glass;
fillers having silver sustained-release property;
5 fillers having calcium sustained-release property; and
fillers having fluorine sustained-release property.
[0130] From the viewpoint of formation of strong bonding
between an inorganic filler and the monomer (A) after curing, it is
preferable to use an inorganic filler having been subjected to surface
10 treatment such as silane treatment or polymer coating.
[0131] These inorganic fillers can be used singly or in
combination of two or more kinds.
[0132] As one of the other components, an X-ray contrast
medium can be mentioned. Examples of the X-ray contrast media include
15 zirconium oxide, barium sulf ate, bismuth carbonate, calcium tungstate,
ytterbium and an iodine compound. Of these X-ray contrast media,
zirconium oxide is preferable from the viewpoint that zirconium oxide
has actual results of use for hard tissues, particularly as bone cement,
and it exhibits higher X-ray contrast property and higher
20 dispersibility as compared with barium sulfate that also has actual
results of use.
[0133] Although the amount of the X-ray contrast medium
is properly selected according to the use purpose, etc. , it is usually
in the range of 10 to 70 parts by weight, preferably 15 to 65 parts
SF-2300
46
by weight, based on 100 parts by weight of the whole weight of the
composition for hard tissue repair excluding the X-ray contrast medium.
[0134] The composition for hard tissue repair of the
present invention is excellent in operability as a hard tissue repair
5 agent, that is, application properties and injection properties.
[0135] In the present invention, the monomer (A), the
(meth) acrylate polymer (B), the polymerization initiator composition
(C) and the components to be contained when needed are previously
mixed to prepare a composition for hard tissue repair, and the
10 composition can be used by applying it to the affected part. The
temperature of heat generated by the composition prepared as above
is usually not higher than 70°C, and the risk of doing damage to the
affected tissue becomes lower.
[0136] When these components are mixed, the order of mixing
15 is not specifically restricted, but it is preferable that the monomer
(A) is first mixed with the polymerization initiator composition (C)
and subsequently mixed with the polymer (B) , from the viewpoint that
the stability of the resulting composition for hard tissue repair
is more excellent.
20 [0137] When the composition for hard tissue repair of
the present invention contains the polymerization inhibitor ()) , it
is preferable that a mixture of the monomer (A) and the polymerization
inhibitor (D) is first mixed with the polymerization initiator
composition (C) and subsequently mixed with the polymer (B), from
SF-2300
47
the viewpoint that the stability of the resulting composition is more
excellent.
[0138] A cured product, which is obtained from the
composition for hard tissue repair, is given 24 hours after the
5 preparation of the composition and has a thickness of not less than
0.1 pm, a length of not less than 25 mm and a width of not less than
2 mm, preferably has a flexural elastic modulus, as measured under
the conditions of a test rate of 2 mm/min, of not less than 100 MPa,
and preferably has a tensile strength, as measured under the conditions
10 of a test rate of 1 mm/min, of not less than 10 MPa, and preferably
has a flexural strength, as measured under the conditions of a test
rate of 2 mm/min, of not less than 10 MPa.
[0139] The flexural elastic modulus of the above cured
product may be preferably not less than 100 MPa, more preferably not
15 less than 150 MPa, still more preferably not less than 200 MPa.
[0140] When the composition for hard tissue repair
contains an X-ray contrast medium, a cured product, which is obtained
from the composition for hard tissue repair, is given 24 hours after
the preparation of the composition and has a thickness of 0.5 mm,
20 a length of 25 mm and a width of 2 mm, preferably has a flexural elastic
modulus, as measured under the conditions of a test rate of 2 non/min,
of not less than 1800 MPa, more preferably not less than 2000 MPa,
still more preferably not less than 2200 MPa, and preferably has a
flexural strength, as measured under the conditions of a test rate
SF-2300
48
of 2 mm/min, of not less than 50 MPa.
[0141] Further, a cured product, which is obtained from
the composition for hard tissue repair and is given 24 hours after
the preparation of the composition, preferably has a shear strength
5 of not less than 10 MPa (test rate. 2 mm/min). Furthermore, this
cured product preferably has a compression strength of not less than
10 MPa (test rate: 2 mm/min). When the composition for hard tissue
repair contains an X-ray contrast medium, a cured product, which is
obtained from the composition for hard tissue repair, is given 24
10 hours after the preparation of the composition and has a thickness
of 5 mm, a length of 10 mm and a width of 10 mm, preferably has a
compression strength, as measured under the conditions of a test rate
of 2 mm/min, of not less than 70 MPa, more preferably not less than
75 MPa.
15 [0142] The composition for hard tissue repair is excellent
in adhesion between hard tissues, filling in hard tissues, adhesion
between hard tissues and artificial substances, such as titanium,
ceramics and stainless steel, adhesion between hard tissues and other
tissues such as soft tissues, etc., excluding dental applications.
20 [0143] A film, which is obtained from the composition
for hard tissue repair of the present invention, is given 24 hours
after the preparation of the composition and has a thickness of not
less than 1 pm (preferably not more than 1 cm), a length of not less
than 25 mm and a width of not less than 2 mm, may preferably have
SF-2300
49
a tensile elongation, as measured under the conditions of a test rate
of 1 mm/min, of not less than 30%, more preferably not less than 40%,
still more preferably not less than 50%.
[0144] When the composition for hard tissue repair
5 contains an X-ray contrast medium, a cured product, which is obtained
from the composition for hard tissue repair, is given 24 hours after
the preparation of the composition and has a thickness of 0.5 mm,
a length of 25 mm and a width of 2 mm, preferably has a tensile strength,
as measured under the conditions of a test rate of 1 mm/min, of not
10 less than 30 MPa, more preferably not less than 31 MPa.
[0145] Accordingly, the composition of the present
invention is favorable for hard tissue repair.
[0146] The composition for hard tissue repair of the
present invention preferably has a viscosity of 0.4 to 2,000,000 cp
15 within 30 seconds after mixing of the components (A), (B) and (C)
and the components to be contained when needed.
[0147] Since the viscosity is in the above range, the
composition is excellent in operability, that is, for example,
application of the composition in the hard tissue repair is easily
20 made, or injection of the composition to fill it in bone tissue is
easily made.
[0148] From the viewpoints of operability and fluidity,
the viscosity is preferably in the range of 0.4 to 500,000 cp, more
preferably 1 to 500,000 cp.
SF-2300
50
[0149] The composition for hard tissue repair of the
present invention preferably has a viscosity of 1 to 2,000,000 cp,
more preferably 10 to 2,000,000 cp, 60 seconds after mixing of the
components (A), (B) and (C) and the components to be contained when
5 needed.
[0150] Further, the composition for hard tissue repair
of the present invention preferably has a viscosity of 10 to 80, 000, 000
cp, more preferably 50 to 50,000,000 cp, still more preferably 100
to 20,000,000 cp, 540 seconds after mixing of the components (A),
10 (B) and (C) and the components to be contained when needed.
[0151] Since the viscosity is in the above range, the
composition is excellent in operability, that is, for example,
application of the composition in the hard tissue repair is easily
made, or transfusion of the composition into a cement gun to fill
15 it in bone tissue or injection of the composition into bone is easily
made.
[0152] Prior to or during curing of the composition for
hard tissue repair of the present invention, the composition may be
irradiated with electromagnetic waves, such as visible light, ionizing
20 radiation (e.g., y-rays) or electron rays, to perform sterilization.
Irradiation with visible light is sometimes desirable because the
visible light does not greatly change the curing conditions.
Sterilization may be carried out by treatment with gas, such as dry
heat, steam, ethylene oxide (EO) or hydrogen peroxide, filtration,
SF-2300
51
treatment with liquid, autoclave sterilization, or the like.
[0153] Prior to application of the composition for hard
tissue repair of the present invention to the affected part, the surface
of the affected part may be disinfected with a disinfectant such as
5 alcohol.
[0154] Prior to application of the composition for hard
tissue repair of the present invention to the affected part,
pretreatment may be further carried out for the purpose of improving
adhesion totheaffectedpart. The pretreatment liquid is, forexample,
10 an aqueous solution containing 1 to 15% by weight of citric acid and
1 to 5% by weight of iron(III) chloride.
[0155] If there is a fear that the form or the performance
of the composition for hard tissue repair of the present invention
varies over a long time, thereby impairing the effect of the present
15 invention, it is possible that all the components, which consist of
the monomer (A), the (meth)acrylate polymer (B), the polymerization
initiator composition (C) and the components to be contained when
needed and are used for hard tissue repair, are stored in the form
of a kit for hard tissue repair having two or more members in which
20 the above components are encased independently or in groups divided
in an optional combination, and prior to use, the components are mixed
to form the composition for hard tissue repair. The members for
encasing the components therein are, for example, sealable resin
containers having gas barrier properties in order to prevent
SF-2300
52
evaporation or scattering of the monomer (A) and the polymerization
initiator composition (C), or glass syringes. The members for
encasing the polymer (B) therein are, for example, resin containers
having good sealing properties in order to prevent moisture absorption,
5 or glass containers. As for the quantity to be encased, there is
a case where the quantity that is used up one time is encased or a
case where the quantity that is used plural times is encased.
[0156] Examples of manners to store the components include
a manner in which the components are divided into three groups
10 consisting of a mixture of the component (A) and the components to
be contained when needed, a mixture of the component (B) and the
components to be contained when needed, and a mixture of the component
(C) and the components to be contained when needed, followed by storing
them; a manner in which the components are divided into two groups
15 consisting of a mixture of the component (A), the component (B) and
the components to be contained when needed, and the component (C),
followed by storing them; a manner in which the components are divided
into two groups consisting of a mixture of the component (A) and the
component (B), and a mixture of the component (C) and the components
20 to be contained when needed, followed by storing them; a manner in
which the components are divided into two groups consisting of amixture
of the component (A), the component (B) and a part of the components
to be contained when needed, and a mixture of the component (C) and
a residue of the components to be contained when needed, followed
SF-2300
53
by storing them; a manner in which the components are divided into
two groups consisting of a mixture of the component (A) and the
components to be contained when needed, and a mixture of the component
(B) and the component (C) , followed by storing them; a manner in which
5 the components are divided into two groups consisting of the component
(A), and a mixture of the component (B), the component (C) and the
components to be contained when needed, followed by storing them;
and a manner in which the components are divided into two groups
consisting of a mixture of the component (A) and a part of the components
10 to be contained when needed, and a mixture of the component (B), the
component (C) and a residue of the components to be contained when
needed, followed by storing them.
[0157] When the polymerization inhibitor (D) is contained,
examples of manners to store the components include a manner in which
15 the components are divided into three groups consisting of a mixture
of the component (A) and the components to be contained when needed,
a mixture of the component (B) and the components to be contained
when needed, and a mixture of the component (C) and the components
to be contained when needed, followed by storing them; a manner in
20 which the components are divided into two groups consisting of amixture
of the component (A), the component (B), the component (D) and the
components to be contained when needed, and the component (C) , followed
by storing them; a manner in which the components are divided into
two groups consisting of a mixture of the component (A) , the component
SF-2300
54
(B) and the component (D), and a mixture of the component (C) and
the components to be contained when needed, followed by storing them;
a manner in which the components are divided into two groups consisting
of a mixture of the component (A), the component (B), the component
5 (D) and a part of the components to be contained when needed, and
a mixture of the component (C) and a residue of the components to
be contained when needed, followed by storing them; a manner in which
the components are divided into two groups consisting of a mixture
of the component (A), the component (D) and the components to be
10 contained when needed, and a mixture of the component (B) and the
component (C), followed by storing them; a manner in which the
components are divided into two groups consisting of a mixture of
the component (A) and the component (D) , and a mixture of the component
(B) , the component (C) and the components to be contained when needed,
15 followed by storing them; and a manner in which the components are
divided into two groups consisting of a mixture of the component (A) ,
the component (D) and a part of the components to be contained when
needed, and a mixture of the component (B), the component (C) and
a residue of the components to be contained when needed, followed
20 by storing them.
[0158] When a mixture of a monomer having an acidic group
and a monomer having no acidic group is used as the monomer (A) , the
components may be stored in such a manner that the monomer having
an acidic group is not in contact with the polymerization initiator
SF-2300
55
composition, in addition to the above manners. Examples of such
manners include a manner in which the components are divided into
two groups consisting of a mixture of the monomer having an acidic
group, the component (B) and the components to be contained when needed,
5 and a mixture of the monomer having no acidic group and the component
(C), followed by storing them; a manner in which the components are
divided into two groups consisting of a mixture of the monomer having
an acidic group and the component (B), and a mixture of the monomer
having no acidic group, the component (C) and the components to be
10 contained when needed, followed by storing them; a manner in which
the components are divided into two groups consisting of a mixture
of the monomer having an acidic group and the components to be contained
when needed, and a mixture of the monomer having no acidic group,
the component (B) and the component (C), followed by storing them;
15 and a manner in which the components are divided into two groups
consisting of the monomer having an acidic group, and a mixture of
the monomer having no acidic group, the component (B), the component
(C) and the components to be contained when needed, followed by storing
them.
20 [0159] The components divided into two groups are placed
in separate members, e.g., containers such as syringes, then the
members are encased in a kit for hard tissue repair, and the kit can
be provided as an article.
[0160] The constitution of the kit for hard tissue repair
SF-2300
56
is not specifically restricted as long as there is no fear that the
former the performance is changed by the storage to impair the effect
of the present invention, but the kit preferably has constitution
in which the monomer (A), the polymer (B) and the polymerization
5 initiator composition (C) are each independently encased, and the
monomer (A) is first mixed with the polymerization initiator
composition (C) containing an organoboron compound and subsequently
mixed with the polymer (B). By virtue of such constitution, a
composition for hard tissue repair having more stable performance
10 tends to be obtained.
[0161] Examples of the kits for hard tissue repair include:
a kit having members (e.g., containers, syringes) in which
the monomer (A), the polymer (B) and the polymerization initiator
composition (C) are each independently encased and having a member
15 (e.g., mixing container, mixing dish) for taking out the encased
components from the members and mixing them; and
a kit having one container which has three or more chambers
separated by partitions, in said chambers the monomer (A), the polymer
(B) and the polymerization initiator composition (C) being each
20 independently encased, and having a stirring unit for mixing the
monomer (A) and the polymerization initiator composition (C) with
the polymer (B), said components (A) and (C) having passed through
a bypass formed in a syringe owing to rapture of the partitions or
shifting of the partitions.
SF-2300
57
[0162] When the kit contains the polymerization inhibitor
(D), the kit preferably has constitution in which a mixture containing
the monomer (A) and the polymerization inhibitor (D), the polymer
(B) and the polymerization initiator composition (C) are each
5 independently encased, and the mixture containing the monomer (A)
and the polymerization inhibitor (D) is first mixed with the
polymerization initiator composition (C) containing an organoboron
compound and subsequently mixed with the polymer (B) . By virtue of
such constitution, a composition having more stable performance tends
10 to be obtained.
[0163] Examples of such kits include:
a kit having members (e.g., containers, syringes) in which
a mixture containing the monomer (A) and the polymerization inhibitor
(D) , the polymer (B) and the polymerization initiator composition
15 (C) are each independently encased and having a member (e.g., mixing
container, mixing dish) for taking out the encased components from
the members and mixing them; and
a kit having one container which has three or more chambers
separated by partitions, in said chambers a mixture containing the
20 monomer (A) and the polymerization inhibitor (D), the polymer (B)
and the polymerization initiator composition (C) being each
independently encased, and having a stirring unit for mixing the
mixture containing the monomer (A) and the polymerization inhibitor
(D) and the polymerization initiator composition (C) with the polymer
SF-2300
58
(B) , said mixture and said component (C) having passed through a bypass
formed in a syringe owing to rapture of the partitions or shifting
of the partitions.
[01641 The kit having one container wherein the components
5 are encased in the separated three or more chambers requires less
labor as compared with a means wherein the composition of the present
invention is divided, placed in two or more members, typically
containers, and mixed immediately before use. Moreover, this kit
uses no mixing container or the like and can be economically used
10 by taking a necessary amount of the composition out of the container
and bringing it into contact with a jig such as sponge.
[0165] It is also possible that a jig that is used for
applying the composition for hard tissue repair to the affected part,
e.g., hard tissue such as bone or cartilage, soft tissue, or an
15 artificial substance such as titanium, ceramic or stainless steel
is allowed to contain apart or the whole of the polymerization "initiator
composition (C) in advance, and the jig is brought into contact with
the monomer (A) or a mixture containing the monomer (A) and the
polymerization inhibitor (D), the polymer (B) and the components to
20 be contained when needed to prepare the composition for hard tissue
repair of the present invention in situ, followed by applying it to
the affected part.
[0166] Examples of the jigs for applying the composition
to the affected part include a brush, a fiber ball, a cloth, a sponge
SF-2300
ball and a piece of sponge.
59
[0167] In the kit for hard tissue repair or the like,
the aforesaid disinfectant liquid such as alcohol, the aforesaid
pretreatment solution for improving adhesion properties, etc. may
5 be included.
[0168] When the components of the composition are stored
in the kit or the like, they may be subjected to sterilization treatment
with electromagnetic waves such as visible light preferably under
the conditions that the components are not modified (e.g., monomer
10 is not cured).
[0169] The composition for hard tissue repair of the
present invention can be used as bond cement that is used for adhesion
between hard tissues, filling in hard tissues, adhesion between hard
tissues and artificial substances, such as titanium, ceramics and
15 stainless steel, adhesion between hard tissues and other tissues such
as soft tissues, fixation of hard tissues, such as bone and cartilage,
to artificial joints, etc., or can be used as a filling material into
bone defectives, a bone substitute material, an artificial bone or
the like.
20
Examples
[0170] The present invention is further described with
reference to the following examples, but it should be construed that
the present invention is in no way limited to those examples.
SF-2300
60
Examples IA to 10A, Comparative Examples IA and 2A
Reagents
In the examples, the following compounds and composition were
used as the monomer (A), the polymer (B) and the polymerization
5 initiator composition (C).
[0171] Monomer (A): 4-META/MMA, methyl methacrylate
solution of 4-methacryloxyethyltrimellitic anhydride (weight ratio:
about 5%)
Polymer (B): mixture of three kinds of the following PMMA
10 (polymethyl methacrylates) (bl) to (b3) and pigment
The weight ratios of these components are as follows:
in 100 parts by weight of the total amount of the three kinds of PMMA
and the pigment, (b1) is contained in an amount of 20.03 parts by
weight, (b2) is contained in an amount of 62.5 parts by weight, (b3)
15 is contained in an amount of 12.5 parts by weight, and the pigment
is contained in the residual amount.
Molecular weights and properties of the PMMA (bl) to (b3) are
as follows.
(b1) weight-average molecular weight: 450,000, volume mean
20 particle diameter: 26.7 pm, specific surface area: 2.913 m2/g
(b2) weight-average molecular weight: 140,000, volume mean
particle diameter: 8.2 pm, specific surface area: 0.827 m2/g
(b3) weight-average molecular weight: 140,000, volume mean
particle diameter: 24.6 pm, specific surface area: 0.371 m2/g
SF-2300
61
The volume mean particle diameter of PMMA (refractive index.
v)
1.49) was measured in the following manner. As a dispersion medium,
special grade reagent methanol (refractive index: 1.33, available
from Wako Pure Chemical Industries, Ltd.) was used. The PMMA was
5 dispersed in the dispersion medium by an ultrasonic homogenizer
integrated in the apparatus for 5 minutes (output: 25 W), and the
measurement was carried out under the concentration conditions of
the proper range of the apparatus Loading Index at a circulation rate
of 50% (100%: 65 ml/sec) by the use of Microtrac MT3300EXII (particle
10 size distributionmeter manufactured byMicrotracInc.). The specific
surface area is a value determined by nitrogen gas adsorption at the
liquid nitrogen temperature (77 K) using Autosorb 3 (manufactured
by Quantachrome Instruments) , and is a value measured by BET method.
[0172] Polymerization initiator composition (C)e TBB A
15 type, namely, partially oxidized tributylboron: 80 parts by weight,
hexane: 19 parts by weight, ethanol: 1 part by weight
Evaluation of viscosity
In a sample tube, the polymer (B) was weighed in accordance
with a blending ratio described in Examples 1A to 6A and Comparative
20 Example 1A of the following Table 1. In the sample tube in which
thepolymer (B) hadbeenweighed, themonomer (A) and the polymerization
initiator composition (C) , which had been mixed together in a different
SF-2300
61
The volume mean particle diameter of PMMA (refractive index:
1.49) was measured in the following manner. As a dispersion medium,
special grade reagent methanol (refractive index: 1.33, available
from Wako Pure Chemical Industries, Ltd.) was used. The PMMA was
5 dispersed in the dispersion medium by an ultrasonic homogenizer
integrated in the apparatus for 5 minutes (output: 25 W), and the
measurement was carried out under the concentration conditions of
the proper range of the apparatus Loading Index at a circulation rate
of 50% (100%: 65 ml/sec) by the use of Microtrac MT3300EXII (particle
10 sizedistributionmeter manufactured byMicrotracInc.). The specific
surface area is a value determined by nitrogen gas adsorption at the
liquid nitrogen temperature (77 K) using Autosorb 3 (manufactured
by Quantachrome Instruments), and is a value measured by BET method.
[0172] Polymerization initiator composition (C) : TBB A
15 type, namely, partially oxidized tributylboron: 80 parts by weight,
hexane: 19 parts by weight, ethanol: 1 part by weight
Evaluation of viscosity
Ina sample tube, the polymer (B) was weighed in accordance
with a blending ratio described in Examples 1A to 6A and Comparative
20 Example 1A of the following Table 1. In the sample tube in which
thepolymer (B) hadbeenweighed, themonomer (A) and the polymerization
initiator composition (C) , which had been mixed together in a different
sample tube in accordance with a blending ratio described in Examples
1 to 6 and Comparative Example 1 of the following Table 1 similarly
62
sample tube in accordance with-a blending ratio described in Examples
2A to GA and Comparative Example IA of the following Table 1 similarly
to the abov , were injected, and they were mixed together at 25°C
to prepare an adhesive composition of the present invention. Within
5 30 seconds after the preparation, viscosity of the composition was
measured. The viscosity at the time of preparation was not less than
0.4 cp, and it was confirmed that the viscosity increased with time.
The viscosity was measured by aft E type viscometer (manufactured by
Tokyo Keiki Inc., EHP type) at 25°C. The evaluation results are set
10 forth in Table 1.
[0173] Evaluation of application properties
In a syringe having a cap at the luer part, the polymer (B)
was weighed in accordance with a blending ratio described in Examples
1A to 6A and Comparative Example lA of the following Table 1. In
15 this syringe, the monomer (A) and the polymerization initiator
composition (C), which had been mixed together in a sample tube in
accordance with a blending ratio described in Examples lA to 6A and
Comparative Example IA of the following Table 1 similarly to the above,
were injected, and they were mixed together at 25°C. Thereafter,
20 the cap of the syringe was removed, then a nozzle having a width of
1 cm and a thickness of 1 mm was fitted, and 1 ml of the composition
mixed was applied by 4 cm onto a polyethylene sheet. The application
properties were evaluated based on the 5-grade evaluation of 1 to
5. That is to say, a case where the width of the applied composition
was not less than 1 cm but less than 1.2 cm was evaluated to be 5;
a case where the width of the applied composition was not less than
SF-2300
63
1.2 cm but less than 1,4 cm was evaluated to be 4; a case where the
width of the applied composition was not less than 1.4 cm but less
than 1. 6 cm was evaluated to be 3; a case where the width of the applied
composition was not less than 1.6 cm was evaluated to be 2; and a
5 case where application was impossible was evaluated to be 1. The
evaluation results are set forth in Table 1.
[0174] Evaluation of extrusion from container
In a syringe whose discharge opening had been closed with a
cap, the polymer (B) was weighed in accordance with a blending ratio
10 described in Examples 1A to 6A and Comparative Example lA of the
following Table 1. In the syringe in which the polymer (B) had been
placed, the monomer (A) and the polymerization initiator composition
(C), which had been mixed together in a sample tube in accordance
with a blending ratio described in Examples 1A to 6A and Comparative
15 Example l of the following Table 1 similarly to the above, were inj ected,
and they were mixed together at 25°C. Thereafter, the cap of the
syringe in which the three components of (A), (B) and (C) had been
placed was removed, then a needle of 11G was fitted, and 1 ml of the
composition mixed was extruded onto a polyethylene sheet. The
20 extrusion was evaluated based on the 3-grade evaluation of 1 to 3.
That is to say, a case where the whole amount of the composition was
extruded within 20 seconds at a pressure of 50 kPa was evaluated to
be 3; a case where the whole amount of the composition was extruded
in not shorter than 20 seconds but shorter than 60 seconds was evaluated
SF-2300
64
to be 2; and a case where the whole amount of the composition was
not extruded even in not shorter than 60 seconds was evaluated to
be 1. The evaluation results are set forth in Table 1.
[0175]
5 Table 1
Adhesive composition Viscosity 30 Application Extrusion
(part(s) by weight) seconds after properties from
mixing (cp) container
Ex. 1A Monomer (A): 1680mg 0.5 2 3
(87.2)
Polymer (B): 192.7mg
(10.0)
Polymerization
initiator composition
(C): 54mg (2.8)
Ex. 2A Monomer (A): 1680mg 1 4 3
(82.4)
Polymer (B): 192.7mg
(15.0)
Polymerization
initiator composition
(C): 54mg (2.6)
Ex. 3A Monomer (A): 1680mg 24 4 3
(77.5)
Polymer (B): 433.5mg
(20.0)
Polymerization
initiator composition
(C): 54mg (2.5)
Ex. 4A Monomer (A): 1680mg 40 5 3
(67.8)
Polymer (B): 743.1mg
(30.0)
Polymerization
initiator composition
_ (C): 54mg (2.2)
Ex. 5A Monomer (A) : 1680mg 164 5 3
(58.1)
Polymer (B): 1156mg
(40.0)
Polymerization
initiator composition
(C): 54mg (1.9)
Ex. 6A Monomer (A): 1680mg 2560 5 3
(48.4)
Polymer (B): 1734mg
(50.0)
Polymerization
initiator composition
(C): 54mg (1.6)
Comp. Ex. 1A Monomer (A): 1680mg immeasurable 1 1
(19.4)
SF-2300
65
Polymer (B): 6939mg
(80.0)
Polymerization
initiator composition
(C): 54mg (0.6)
[0176] Evaluation of flexural elastic modulus, tensile strength
and flexural strength
In a 5 ml sample tube, the polymer (B) was weighed in accordance
5 with a blending ratio described in Examples 7A to 9A of the following
Table 2. In the sample tube in which the polymer (B) had been weighed,
a mixed liquid of the monomer solution (A) and the polymerization
initiator composition (C), which had been prepared in a different
1 ml sample tube in accordance with a blending ratio described in
10 Examples 7A to 9A of the following Table 2 similarly to the above,
was introduced, and they were mixed together at 25 °C for about 5 seconds
using a glass bar so that the mixture might become homogeneous.
[0177] The resulting composition was injected into a
syringe and immediately filled in a frame to prepare a cured product
15 sample in accordance with the following procedure, as illustrated
in Fig.- 1. On a glass plate, a sheet of PE Lumirror (trade mark)
and a fluororesin frame having a thickness of 0.5 mm (internal size
of frame: 25 mm (length) x 2= (width)) were superposed in this order.
In this frame, the composition for hard tissue repair prepared was
20 filled. The filling work was carefully carried out so that bubbles
should not be formed. After the filling was completed, a sheet of
PE Lumirror (trade mark) and a glass plate were further superposed
SF-2300
66
thereon in this order, and the four corners of the outermost two glass
plates were fixed with clips. Thereafter, they were allowed to stand
for 24 hours at 25°C (room temperature), and then the cured product
was taken out of the frame. When the resulting cured product had
5 irregularities on the surfaces, the surfaces were abraded with a
waterproof abrasive paper #600 to remove irregularities, whereby a
cured product was prepared. The resulting cured product had a size
of a length of 25 mm, a width of 2 mm and a thickness of 0.5 mm.
[0178] Flexural elastic modulus (test rate: 2 mm/min),
10 tensile strength (test rate: 1 mm/min) and flexural strength (test
rate: 2 mm/min) of the cured product were determined 24 hours after
the preparation by EzTest/CE manufactured by Shimadzu Corporation.
The values are each a mean of values obtained by measurements of four
times. The evaluation results are set forth in Table 2.
15 Evaluation of compression strength
In a 5 ml sample tube, the polymer (B) was weighed in accordance
with a blending ratio described in Examples 7A to 9A of the following
Table 2. In the sample tube in which the polymer (B) had been weighed,
a mixed liquid of the monomer solution (A) and the polymerization
20 initiator composition (C), which had been prepared in a different
1 ml sample tube in accordance with a blending ratio described in
Examples 7A to 9A of the following Table 2 similarly to the above,
was introduced, and they were mixed together at 25 °C for about 5 seconds
using a glass bar so that the mixture might become homogeneous.
SF-2300
67
[0179] From the resulting composition, a cured product
having 4 size of 4.0 mm x 4.0 mm x 3.0 mm and a curd product of 6
mm (diameter) x 8 mm (length) were prepared. 24 hours after the
preparation, compression strength (test rate: 2 m/min) was measured
5 by an Autograph (DSS500 manufactured by Shimadzu Corporation) . The
results are set forth in Table 2.
[0180]
Table 2
Adhesive composition Flexural Tensile Compression Flexural
(part(s) by weight) elastic strength strength strength
modulus (MPa) (MPa) (MPa)
(MPa)
Ex. 7A Monomer (A): 586mg 420 30 55 50
(66.6)
Polymer (B): 262mg
(29.7)
Polymerization
initiator composition
(C): 33mg (3.7)
Ex. 8A Monomer (A): 586mg 540 26 60 60
(51.2)
Polymer (B): 525mg
(45.9)
Polymerization
initiator composition
(C): 33mg (2.9)
Ex. 9A Monomer (A): 586mg 1500 50 63 67
(32.6)
Polymer (B): 1180mg
(65.6)
Polymerization
initiator composition
-(C): 33mg (1.8)
10 [0181] Exothermic properties
In a 30 ml sample tube, the polymer (B) and barium sulfate
(available from Wako Pure Chemical Industries, Ltd.) were weighed
68
in accordance with a blending ratio described in Example 10A. Then,
in a 10 ml sample tube, the monomer solution (A) and the polymerization
initiator composition (C) were weighed in accordance with a blending
ratio described in Example 10A similarly to the above, and they were
5 mixed together. The mixture was introduced into the sample tube in
which the polymer (B) had been weighed, and they were mixed together
at 25°C for 1 minute using a glass bar so that the mixture might become
homogeneous. Thereafter, the mixture was placed in a cylindrical
container having a diameter of 30 mm and a height of 15 mm, and a
10 thermometer was inserted into the central part of the mixture tomeasure
the temperature.
[01.82] An example of a case where benzoyl peroxide
(available from Wako Pure Chemical Industries, Ltd.) was used as a
polymerization initiator is shown as Comparative Example 2A. That
15 is to say, in a 100 ml beaker, the polymer (B), barium sulfate and
benzoyl peroxide were weighed in accordance with a blending ratio
described in Comparative Example 2A. In this beaker, the monomer
solution (A) was weighed and introduced, and they were mixed together
at 25°C for 1 minute using a glass bar so that the mixture might become
20 homogeneous. Thereafter, the mixture was placed in a cylindrical
container having a diameter of 30 mm and a height of 15 mm, and a
thermometer was inserted into the central part of the mixture tomeasure
the temperature.
[0183] The results are set forth in Table 3. As for the
composition prepared from the monomer (A), the polymer (B) and the
polymerization initiator comptoisoni ,( Ct)he temperature begun to
SF-2300
69
slowly rise immediately after mixing, and the highest temperature
was relatively low. On the other hand, in the case of using benzoyl
peroxide as a polymerization initiator, a relatively long time was
required before the temperature rise, and after the temperature rise
5 begun once, the temperature rapidly rose in a short time. Moreover,
the highest temperature was higher than that of the composition
prepared from the monomer (A) , the polymer (B) and the polymerization
initiator composition (C).
[0184]
10 Table 3
Adhesive composition
(part(s) by weight)
Temperature
Ex. 10A Monomer (A): 20g (27.7) The temperature gently rose for 5 minutes and
Polymer (B): 48g (66.4) 30 seconds after mixing to reach 30°C,
Polymerization thereafter relatively rapidly rose to reach the
initiator composition highest temperature of 60°C in 7 minutes and
(C): 0.9g (1.2) 30 seconds after mixing and then slowly lowered.
Barium sulfate: 3.4g
(4.7)
Comp. Monomer (A): 20g (30.6) The temperature hardly rose for 6 minutes after
Ex. 2A Polymer (B): 40g (61.2) mixing, then gently rose to reach 30°C in 9
Polymerization minutes after mixing, thereafter rapidly rose
initiator composition to reach the highest temperature of 85°C in 9
(C): 0.4g (0.6) minutes and 30 seconds after mixing and then
Barium sulfate: 5.0g slowly lowered.
(7.6)
[0185] Evaluation of adhesive strength
Onto a cortical bone surface of the canine femur, an acrylic
resin bar having a diameter of 5 mm was fixed at right angles using
15 a composition obtained by mixing the components in accordance with
a blending ratio described in Example 10A, and they were immersed
in water at 37°C for 24 hours, followed by carrying out a peel test
SF-2300
70
of the acrylic resin bar from the bone using an Autograph (DSS500
manufactured by Shimadzu Corporation). As a result, the adhesive
strength was 10 MPa.
5 Examples 1B to 13B, Comparative Examples 1B to 13B
In the following examples and comparative examples, the same
monomer (A) and the same polymerization initiator composition (C)
as in the above examples were used. As the polymer (B), a mixture
obtained by mixing the aforesaid polymers (bl), (b2) and (b3) in a
10 blending ratio described in the following Tables 4 to 11 was used.
As the X-ray contrast medium, zirconium oxide available from Daiichi
Kigenso Kagaku Kogyo Co., Ltd. was used. Mixing of the polymers (b1) ,
(b2) and (b3) with zirconium oxide was carried out by a Turbula shaker
(T2C type manufactured by Willy A. Bachofen AG) for 30 minutes at
15 23±1°C.
[0186] Evaluation of homogeneous dispersibility
In a polypropylene container having an inner diameter of 2.5
cm and a-depth of 1 cm, the polymer (B) and zirconium oxide were weighed
in accordance with a blending ratio of Examples 1B to 13B and Comparative
20 Examples 1B to 13B described in the following Tables 4 to 11. In
this plastic container, the monomer (A) and the polymerization
initiator composition (C), which had been mixed together in a 10 ml
glass sample tube in accordance with a blending ratio of Examples
lB to 13B and Comparative Examples 1B to 13B described in the following
SF-2300
71
Tables 4 to 11 similarly to the above, were injected, and they were
mixed together by a polypropylene spatula at 25°C for 20 seconds.
Thereafter, the state of the mixture in the container was confirmed
by visual observation. The evaluation was carried out in the following
5 manner. A case where a powder of the polymer (B) could not be blended
was evaluated to be 0; a case where undissolved lumps of powder were
observed was evaluated to be 1; a case where the mixture had no fluidity
and was in the clay-like dissolved state was evaluated to be 2; and
a case where the mixture had fluidity and was in the dissolved state
10 was evaluated to be 3. The evaluation results are set forth in Table
7. In the case of 0, any test sample could not be prepared, and therefore,
other evaluations were not carried out. The evaluation results are
set forth in Tables 4 to 11.
[0187] Homogeneous dispersibility of X-ray contrast medium
15 In a polypropylene container having an inner diameter of 2.5
cm and a depth of 1 cm, the polymer (B) and zirconium oxide were weighed
in accordance with a blending ratio of Examples 1B to 13B and Comparative
Examples lB to 13B described in the following Tables 4 to 11 similarly
to the above. In this plastic container, the monomer (A) and the
20 polymerization initiator composition (C), which had been mixed
together in a 10 ml glass sample tube in accordance with a blending
ratio of Examples 1B to 13B and Comparative Examples 1B to 13B described
in the following Tables 4 to 11 similarly to the above, were injected,
and they were mixed together by a polypropylene spatula at 25°C for
SF-2300
72
20 seconds. The state of the mixture in the container was confirmed
by visual observation through mixing by spatula and pipetting. The
evaluation was carried out in the following manner. A case where
precipitation of the X-ray contrast medium in the polymer (B) was
5 observed was evaluated to be 0; a case where precipitation of the
X-ray contrast medium was observed but the precipitation came to be
unobserved during the stirring of 20 seconds by the spatula was
evaluated to be 1; and a case where precipitation of the X-ray contrast
medium was not observed from the stirring stage was evaluated to be
10 2. The evaluation results are set forth in Tables 4 to 11.
[0188] Evaluation of initial viscosity
In a polypropylene container having an inner diameter of 2.5
cm and a depth of 1 cm, the polymer (B) and zirconium oxide were weighed
in accordance with a blending ratio of Examples 1B to l3B andComparative
15 Examples 1B to 13B described in the following Tables 4 to 11. In
this plastic container, the monomer (A) and the polymerization
initiator composition (C), which had been mixed together in a 10 ml
glass sample tube in accordance with a blending ratio of Examples
1B to 13B and Comparative Examples 1B to 13B described in the following
20 Tables 4 to 11 similarly to the above, were injected, and they were
mixed together by a polypropylene spatula at 25°C for 20 seconds.
60 seconds after mixing, the viscosity was measured at 25°C by the
use of a rheometer (manufactured by HAAKE, RS150). It was confirmed
that the viscosity increased with time. The evaluation results are
SF-2300
73
set forth in Tables 4 to 11.
Evaluation of operability
In a polypropylene container having an inner diameter of 2.5
cm and a depth of 1 cm, the polymer (B) and zirconium oxide were weighed
5 in accordance with a blending ratio of Examples 1B to 13B and Comparative
Examples 1B to 13B described in the following Tables 4 to 11. In
this plastic container, the monomer (A) and the polymerization
initiator composition (C), which had been mixed together in a 10 ml
glass sample tube in accordance with a blending ratio of Examples
10 18 to 13B and Comparative Examples 1B to 13B described in the following
Tables 4 to 11 similarly to the above, were injected, and they were
mixed together by a polypropylene spatula at 25°C for 20 seconds.
540 seconds after mixing, the viscosity was measured at 25°C by the
use of a rheometer (manufactured by HAAKE, RS150). It was confirmed
15 that the viscosity increased with time. The evaluation was carried
out in the following manner. A case where the viscosity was not less
than 80000x103 cP was evaluated to be 0; a case where the viscosity
was in the range of 80000x103 cP to 50000x103 cP was evaluated to be
1; a case where the viscosity was in the range of 50000x103 cP to
20 20000x103 cP was evaluated to be 2; and a case where the viscosity
was not more than 20000x103 cP was evaluated to be 3. The evaluation
results are set forth in Tables 4 to 11.
[0189] Evaluation of mechanical properties
(1) Flexural elastic modulus, flexural strength and tensile strength
SF-2300
74
In a polypropylene container having an inner diameter of 2.5
cm and a depth of 1 cm, the polymer (B) and zirconium oxide were weighed
in accordance with a blending ratio of Example 1B, Example 2B, Example
8B, Comparative Example 1B, Comparative Example 2B, Comparative
5 Example 4B, and Comparative Examples 6B to 9B described in the following
Tables 4 to 11. In this plastic container, the monomer (A) and the
polymerization initiator composition (C), which had been mixed
together in a 10 ml glass sample tube in accordance with a blending
ratio of the above examples and comparative examples described in
10 the following Tables 4 to 11 similarly to the above, were injected,
and they were mixed together by a polypropylene spatula at 25°C for
20 seconds. The resulting mixture was immediately filled in a frame
to prepare a cured product sample in accordance with the following
procedure, as illustrated in Fig. 1. On a glass plate, a sheet of
15 PE Lumirror (trade mark) and a fluororesin frame having a thickness
of 0.5 mm (internal size of frame: 25 mm (length) x 2 mm (width))
were superposed in this order. In this frame, the composition for
hard tissue repair prepared was filled. The fillingworkwascarefully
carried out so that bubbles should not be formed. After the filling
20 was completed, a sheet of PE Lumirror (trade mark) and a glass plate
were further superposed thereon in this order, and the four corners
of the outermost two glass plates were fixed with clips. Thereafter,
they were allowed to stand for 24 hours at 25°C (room temperature),
and then the cured product was taken out of the frame. When the
SF-2300
75
resulting cured product had irregularities on the surfaces, the
surfaces were abraded with a waterproof abrasive paper #600 to remove
irregularities, whereby a cured product was prepared. The resulting
cured product had a size of a length of 25 mm, a width of 2 mm and
5 a thickness of 0.5 mm.
[0190] 24 hours after the preparation, flexural elastic
modulus (test rate: 2 mm/min) , flexural strength (test rate: 2 mm/min)
and tensile strength (test rate: 1 mm/min) of the cured product were
determined by an Autograph (EZ-S manufacturedby Shimadzu Corporation).
10 The values are each a mean of values obtained by measurements of four
times. The evaluation results are set forth in Tables 4 to 11.
[0191] The evaluation was carried out in the following
manner. A case where the flexural elastic modulus was not less than
1800 MPa, the flexural strength was not less than 50 MPa, and the
15 tensile strength was not less than 30 MPa was regarded as pass. A
case where the X-ray contrast medium was not homogeneously dispersed
and any specimen of a homogenous cured product was not obtained was
regarded as immeasurable. The evaluation results are set forth in
Tables 4 to 11.
20 (2) Evaluation of compression strength
In a polypropylene container having an inner diameter of 2.5
cm and a depth of 1 cm, the polymer (B) and zirconium oxide were weighed
76
in accordance with a blending ratio of Example 2B, Example 82,
Comparative Example 1B, ComparativeExample 2B and Comparative Example
6B descttibed in the following Tables 4 to 11.
In this plastic container, the monomer (A) and the polymerization
initiator composition (C), which had been mixed together in a 10 ml
glass sample tube in accordance with a-blending ratio of the above
examples and comparative examples described in the following Tables
4 to 11 similarly: to the above, were injected-, and they were mixed
together by a polypropylene spatula at 25°C for 20 seconds., On a
10 glass plate, a sheet of PE Lumirror (trade mark) and a silicon resin
frame having a thickness of 5 mm (internal size of frame: 10 mm (length)
x 10 mm (width) ) were superposed in this order as illustrated in Fig.
2. In this frame, the composition for hard tissue repair prepared
was filled. The filling workwas carefully carried out so that bubbles
15 should not be formed. After the filling was completed, a sheet of
PE Lumirror (trade mark) and a glass plate were further superposed.
thereon in this order, and a weight of 200 g was placed on the top.
Thereafter, they were allowed to stand for 24 hours at 25°C (room
to --...atu-re), then the cured product was taken out of the frame, and
20 thus, a cured product was prepared. When. the resulting cured product
had irregularities on the surfaces, the surfaces were abraded with
a.waterproof abrasive paper #600 to remove irregularities. 24 hours
after the preparation, compression strength of the cured product was
measured by a precision universal testing machine
(2100 type manufactured by Intesco Co., Ltd.) at a
test rate of 2 mm/min and at 23±1°C. - The evaluation was carried out
in the following manner-. A case where. the compression strength was
SF-2300
77
not less than 70 MPa was regarded as pass. A case where no yield
point was observed was regarded as immeasurable. The evaluation
results are set forth in Tables 4 to 11.
[0192] Overall evaluation
5 A case where the homogeneous dispersibility was not less than
2, the homogeneous dispersibility of the X-ray contrast medium was
not less than 1, the initial viscosity, i. e. , viscosity after 60 seconds,
was in the range of 10 to 2,000,000 cP, the operability was 3, and
the mechanical properties were regarded as pass was evaluated to be
10 AA; a case where the solubility was not less than 1, the homogeneity
of dissolution was not less than 1, the viscosity after 60 seconds
was in the range of 10 to 2, 000, 000 cP, the operability was not less
than 2, and the mechanical properties were regarded as pass was
evaluated to be A; a case where the solubility was not less than 1,
15 the homogeneity of dissolution was not less than 1, the viscosity
after 60 seconds was in the range of 10 to 2, 000, 000 cP, the operability
was not less than 1, and the mechanical properties were regarded as
pass was evaluated to be B; a case where the solubility was 0, or
a case where the homogeneity of dissolution was 0, or a case where
20 the viscosity after 60 seconds was out of the range of 10 to 2, 000, 000
cP, or a case where the operability was 0, or a case where the mechanical
properties were regarded as failure was evaluated to be C. The
evaluation results are set forth in Tables 4 to 11.
SF-2300
[0193]
Table 4
78
Coposition for Stirrability Stirring Initial Operability Mechanical properties (MPa) Overall
hard tissue repair homogeneity viscosity Evaluation viscosity Flexural Flexural Tensile Compression evaluation
(part (s) byweight) (x103 cP) (xl03 cP) elastic modulus strength strength strength
Ex. Monomer (A): 56Omg 3 1 150 3 5000 AA
lB (58.4)
Polymer (B):
363.5 mg (37.9)
(bl): 87.5%
(b2): 0%
(b3): 12.5%
Polymerization
initiator
composition (C):
35mg (3.7)
Zirconium oxide:
363.5m7
Ex. Monomer (A): 560mg 3 2 2.8 3 280 pass pass pass pass AA
2B (53.8) 2660 59 45 114
Polymer (B):
446.5mg (42.9)
(bl): 25.0%
(b2): 62.5%
(b3): 12.5%
Polymerization
initiator
ocrposition (C) :
35mg (3.3)
Zirconium oxide:
446. Smg
SF-2300
Table 4 (continued)
79
Ex. Monomer (A): 560mg 3 2 58 3 5500 AA
3B (53.8)
Polymer (B) :
446.5mg (42.9)
(bl): 75.0%
(b2): 25.0%
(b3): 0%
Polymerization
initiator
carrposition (Q:
35mg (3.3)
Zirconium oxide:
446.5mg
Ex. Monomer (A) : 560mg 3 2 444 3 14800 AA
4B (53.8)
Polymer (B):
446.5 mg (42.9)
(bl): 87.5%
(b2) : 0%
(b3): 12.5%
Polymerization
initiator
composition (C):
35mg (3.4)
Zirconium oxide:
446.5mg
Notes: (bl)+(b2)+(b3) = 100% "%" of (bl) to (b3) means "% by weight". The same shall apply in Table
5 to 11.
SF-2300
[0194]
Table 5
80
Canposition for Stirrability Stirring Initial Operability Mechanical properties (MPa) Overall
hard tissue repair homogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Compression evaluation
(part(s) by (x103 oP) (x103 cP) elastic strength strength strength
weight) modulus
Ex. Monrmr (A) : 560mg 3 2 50 3 7900 AA
5B (48.8)
Polymer (B):
552.5 mg (48.1)
(bl): 50.0%
(b2): 0%
(b3): 50.0%
Polymerization
initiator
composition (C):
35mg (3.1)
Zirconium oxide:
552.5mg
Ex. Monomer (A) : 560m3 3 2 140 3 13000 AA
6B (48.8)
Polymer (B):
552.5mg (48.1)
(bl): 62.5%
(b2): 0%
(b3): 37.5%
Polymerization
initiator
composition (C):
35mg (3.1)
Zirconium oxide:
552.5mg
SF-2300
Table 5 (continued)
81
Ex. Monomer (A): 560mg 3 2 500 2 24200 A
7B (48.8)
Polymer (B):
552.5mg (48.1)
(bl) 75.0%
(b2): 0%
(b3): 25.0%
Polymerization
initiator
carposition (c):
35mg (3.1)
Zirconium oxide:
552.5mg
Ex. Monomer (A) 560mg 3 2 76 2 33000 pass pass pass pass A
8B (43.4) 3130 66 48 121
Polymer (B):
694 mg (53.8)
(bl): 25.0%
(b2): 62.5%
(b3): 12.5%
Polymerization
initiator
canposition (c):
35m3 (2.8)
Zirconium oxide:
694mg
SF-2300
[0195]
Table 6
82
Composition for Stirrability Stirring initial Operability Mechanical properties (MPa) Overall '..
hard tissue repair homogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Compression evaluation
(part(s) by (x103 cP) (x103 cP) elastic strength strength strength
weight) modulus
IS. Monomer (A) : 560mg 3 2 29 3 7100 AA
9B (43.4)
Polymer (B):
694 mg (53.8)
(bl): 25.0%
(b2): 0%
(b3): 75.0%
Polymerization
initiator
composition (C):
35mg (2.8)
Zirconium oxide:
694ng
Ex. Monomer (A): 560ngg 3 2 267 1 52000 B
10B (43.4)
Polymer (B):
694mg (53.8)
(bl): 37.5%
(b2): 62.5%
(b3): 0%
Polymerization
initiator
composition (C):
35mg (2.8)
Zirconium oxide:
694m1
SF-2300
Table 6 (continued)
83
Ex. Monomer (A): 560.9 3 2 110 3 8400 AA
11B (43.4)
Polymer (B) :
694mg (53.8)
(bl): 37.5%
(b2) 0%
(b3): 62.5%
Polymerization
initiator
cunposition (C) :
35mg (2.8)
Zirconiian oxide:
694mg
SF-2300
[0196]
Table 7
84
Carposition for Stirrability Stirring Initial Operability Mechanical properties (MPa) Overall
hard tissue repair hanogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Carpression evaluation
(part(s) by (x103 cP) (x103 cP) elastic modulus strength strength strength
weight)
Ex. Monomer (A) : 560mg 3 2 179 2 47800 A
12B (43.4)
Polymer (B):
694 mg (53.8)
(b1): 50.0%
(b2): 0%
(b3): 50.0%
Polymerization
initiator
composition (C):
35mg (2.8)
Zirconium oxide:
694mg
Ex. Monaner (A): 56Cug 3 2 270 1 69680 B
13B (37.6)
Polymer (B):
892.5[[g (60.0)
(bl): 25.0%
(b2): 0%
(b3): 75.0%
Polymerization
initiator
composition (C) :
35mg (2.4)
Zirconium oxide:
892.5mg
SF-2300
[0197]
Table 8
85
Composition for Stirrability Stirring Initial operability Mechanical properties (MPa) Overall
hard tissue repair homogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Ccarpression evaluation
(part(s) by weight) (x103 cP) (x103 cP) elastic strength strength strength
modulus
Cam. Monamer (A): 560mg 3 0 failure failure pass pass C
Ex iB (77.5) 1780 42 37 85
Polymer (B):
127.5 mg (17.6)
(bl): 100%
(b2): 0%
(b3): 0%
Polymerization
initiator
composition (C):
35mg (4.9)
Zirconium oxide:
127.5mg
Corp. Monomer (A): 560m 3 0 1.7 3 64 pass pass pass immeasurable C
Ex. 2B (70.6) 2200 51 41
Polymer (B) :
198.5mg (25.0)
(bl): 100%
(b2): 0%
(b3): 0%
Polymerization
initiator
composition (C):
35ng (4.4)
Zirconium oxide:
198.5mg
SF-2300
Table 8 (continued)
86
Corp. Monomer (A): 560mg 3 0 0.06 3 10 C
Ex. 33 (62.7)
Polymer (B):
297.5mg (33.3)
(bl) 0%
(b2) 100%
(b3): 0%
Polymerization
initiator
composition (C) :
35mg (4.0)
Zirconium oxide:
297.5mg
Coup. Monomer (A): 560mg 3 0 0.4 3 36 pass pass pass C
Ex 4B (62 . 7) 2670 60 45
Polymer (B):
297.5mg (33.3)
(bl): 25.0%
(b2): 62.5%
(b3): 12.5%
Polymerization
initiator
cotpcsition (C):
35mg (4.0)
Zirconium oxide:
297.5ng
SF-2300
[0198]
Table 9
87
Composition for Stirrability Stirring Initial Operability mechanical properties (MPa) Overall
hard tissue repair homogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Cczrpression evaluation
(part (s) by weight) (x103 cP) (x103 cP) elastic strength strength strength
modulus
Cam. Monomer (A): 560mg 3 0 11 3 2400 C
Ex. 5B (62.7)
Polymer (B):
297.5 mg (33.3)
(bl): 100%
(b2): 0%
(b3): 0%
Polymerization
initiator
cagoosition (C):
35mg (4.0)
Zirconium oxide:
297.5mg
Corp. Moncxner (A): 560mg 3 2 700 0 81000 pass pass pass pass C
Ex. 6B (53.8) 2710 64 57 110
Polymer (B):
446.5mg (42.9)
(bl): 100%
(b2): 0% '.
(b3): 0% '.
Polymerization
initiator
composition (c):
35mg (3.3)
Zirconium oxide:
446.5ng
SF-2300
Table 9 (continued)
88
Coup. Monomer (A): 560mg 3 0 70 0 106500 pass pass pass C
Ex.7B (43.4) 5480 93 41
Polymer (B):
694mg (53.8)
(hl): 0%
(b2): 100%
(b3): 0%
Polymerization
initiator
composition (Q:
35mg (2.8)
Zirconium oxide:
694mg
Corp. monomer (A): 560mg 3 0 1.5 3 110 pass pass immeasurable C
Ex.8B (43.4) 8683 103
Polymer (B):
694ing (53.8)
(bl): 0%
(b2): 0%
(b3): 100%
Polymerization
initiator
conposition (c):
35mg (2.8)
Zirconium oxide:
694mg
SF-2300
[0199]
Table 10
89
Composition for Stirrability Stirring Initial Operability mechanical properties (MPa) Overall
hard tissue repair homogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Compression evaluation
(part (s) by weight) (x103 cP) ('CO3 cP) elastic strength strength strength
modulus
Carp. Monaner (A): 560mg 2 2 4000 0 859300 pass pass pass C
Ex. 9B (43.4) 3330 78 110
Polymer (B):
694 mg (53.8)
(bl): 100%
(b2): 0%
(b3): 0%
Polymerization
initiator
composition. (C):
35mg (2.8)
Zirconium oxide:
694mg
Carp. Monarer (A): 560mg 3 2 31 0 99320 C
Ex. LOB (37.6)
Polymer (B):
892.Srrg (60.0)
(bl) : 0%
(b2): 100%
(b3): 0%
Polymerization
initiator
carposition (C):
35mg (2.4)
Zirconium oxide:
892.5mg
SF-2300
Table 10 (continued)
90
Cam. Monomer (A): 560mg 0 C
Ex. 11B (31.4)
Polymer (B) : 1190mg
(66.7)
(bl) : 0% ',.
(b2): 100%
(b3) : 0%
Polymerization
initiator
coposition (C):
35mg (1.9)
Zirconium oxide:
1190mg
SF-2300
[0200]
Table 11
91
Camposition for Stirrability Stirring Initial Operability Mechanical properties (MPa) Overall
hard tissue repair homogeneity viscosity Evaluation Viscosity Flexural Flexural Tensile Capression evaluation
(part(s) by weight) (x103 cP) (x103 cP) elastic strength strength strength
modulus
Comp. Monomer (A) : 560iag 0 C
Ex. 12B (31.4)
Polymer (B):
1190 mg (66.7)
(bl): 0%
(b2): 0%
(b3): 100%
Polymerization
initiator
caposition (C):
35mg (1.9)
Zirconium oxide:
1190mg
Corp. Monomer (A): 560mg 0 C
Ex. 13B (31.4)
Polymer (B) : 1190mg
(66.7)
(b1): 100%
(b2): 0%
(b3): 0%
Polymerization
initiator
ccnposition (C):
35mg (1.9)
Zirconium oxide:
1190mg
SF-2300
Reference Signs List
92
(0201] 11: glass plate, 12: Lumirror (trade mark), 13:
fluororesin frame (the central white part indicates a space of 25
mm (length) x 2 mm (width) , and this part is filled with a mixed liquid
5 of the monomer solution (A), the polymer (B) and the polymerization
initiator composition (C).)
21: glass plate, 22: Lumirror (trade mark), 23: silicon resin
frame (the central white part indicates a space of 10 mm (length)
x 10 mm (width) x 5 mm (thickness), and this part is filled with a
10 mixed liquid of the monomer solution (A), the polymer (B) and the
polymerization initiator composition (C),)
SF-2300
93

CLAIMS
1. A composition for hard tissue repair, comprising 5 to
98.95 parts by weight of a monomer (A), 1 to 75 parts by weight of
5 a (meth)acrylate polymer (B) and 0.05 to 20 parts by weight of a
polymerization initiator composition (C) containing an organoboron
compound (c1) , with the proviso that the total amount of the components
(A), (B) and (C) is 100 parts by weight.
10 2. The composition for hard tissue repair as claimed in claim
1, wherein the polymer (B) is a polymer mixture which comprises polymer
particles (bl) having a weight-average molecular weight of 30x104
to 60x104 and a specific surface area of 1.5 to 4.5 (m2/g), polymer
particles (b2) having a weight-average molecular weight of 5x104 to
15 20x104 and a specific surface area of 0.51 to 1.2 (m2/g) and polymer
particles (b3) having a weight-average molecular weight of 5x104 to
20x104 and a specific surface area of 0.1 to 0.5 (m2/g), contains the
polymer particles (bl) in an amount of 0 to 98% by weight, and contains
the polymer particles (b2) and the polymer particles (b3) in the total
20 amount of not less than 2% by weight based on the total weight of
the polymer particles (bl), (b2) and (b3), with the proviso that the
total amount of the polymer particles (bi), (b2) and (b3) is 100%
by weight.
SF-2300
94
3. The composition for hard tissue repair as claimed in claim
1 or 2, wherein the polymerization initiator composition (C) contains
an aprotic solvent (c2) having a boiling point of 30°C to 150°C in
an amount of 30 to 80 parts by weight based on 100 parts by weight
5 of the organoboron compound (cl).
4. The composition for hard tissue repair as claimed in claim
1 or 2, wherein the polymerization initiator composition (C) contains
an aprotic solvent (c2') having a boiling point of 50°C to 120°C in
10 an amount of 5 to 40 parts by weight and an alcohol (c3) having a
boiling point of 60°C to 180°C in an amount of 0.2 to 5 parts by weight,
based on 100 parts by weight of the organoboron compound (cl).
5. The composition for hard tissue repair as claimed in any
15 one of claims 1 to 4, which has a viscosity of 0.4 to 2,000,000 cp
within 30 seconds after mixing of the components (A), (B) and (C).
6-. The composition for hard tissue repair as claimed in any
one of claims 1 to 5, which further comprises a polymerization inhibitor
20 (D) .
7. The composition for hard tissue repair as claimed in claim
6, wherein the content of the polymerization inhibitor (D) is in the
range of 10 to 5000 ppm based on the monomer (A).
SF-2300
95
8. The composition for hard tissue repair as claimed in claim
6 or 7, wherein the polymerization inhibitor (D) is at least one
substance selected from hydroquinone, dibutylhydroquinone,
5 hydroquinone monomethyl ether, 2,6-di-tert-butylphenol,
2,6-di-tert-butyl-p-cresol, catechol, pyrogallol, benzoquinone,
2-hydroxybenzoquinone, p-methoxyphenol, t-butylcatechol, butylated
hydroxyanisole, butylated hydroxytoluene and t-butylhydroquinone.
10 9. The composition for hard tissue repair as claimed in any
one of claims 1 to 8, which further comprises an ultraviolet light
absorber.
10. The composition for hard tissue repair as claimed in any
15 one of claims 1 to 9, which further comprises at least one substance
selected from a flexibilizer and a plasticizer.
11. The composition for hard tissue repair as claimed in any
one of claims 1 to 10, which further comprises at least one substance
20 selected from:
anti-infectious agents, antibiotics, antibacterial agents,
anti-virus agents, analgesics, compositions of analgesics, anorectic
drugs, antihelmintic drugs, antiarthritic agents, antiasthmatic
drugs, anticonvulsants, antidepressants, antidiuretics,
SF-2300
96
antidiarrheal agents, antihistamine drugs, anti-inflammatory drugs,
antimigraine drugs, antiemetic agents, antineoplastic drugs,
antiparkinsonian agents, antipruritic drugs, antipsychotics,
antipyretic drugs, antispasmodic drugs, anticholinergic agents,
5 sympathomimetic agents, cardiovascular drugs, antiarrhythmic drugs,
antihypertensive drugs, diuretics, vasodilators, immunosuppressant
drugs, muscle-relaxant drugs, parasympatholytic drugs, stimulants,
sedative drugs, tranquilizers, cholinergic agents, chemotherapeutic
drugs, radio pharmaceuticals, bone inductive drugs, heparin
10 neutralizer agents of static bladder, procoagulants, hemostatic
agents, xanthine derivatives, hormones, proteins of natural origin
or proteins synthesized by genetic engineering, polysaccharides,
glycoproteins, lipoproteins, oligonucleotides, antibody, antigen,
vasopressin, vasopressin analogs, epinephrine, selectin, clot
15 promoting toxicants, plasminogen activating factor inhibitors,
platelet activators, bone-forming factors, synthetic peptides having
hemostatic action, and
perfumes, such as orange oil, grapefruit oil, lemon oil, lime
oil, clove oil, wintergreen oil, peppermint oil, peppermint spirit,
20 banana distillate, cucumber distillate, honey distillate, rose water,
menthol, anethole, alkyl salicylate, benzaldehyde, monosodium
glutamate, ethylvanillin, thymol and vanillin.
12. A kit for hard tissue repair, having members in which
SF-2300
97
the components of the monomer (A), the (meth)acrylate polymer (B)
and the polymerization initiator composition (C) containing an
organoboron compound, which are contained in the composition for hard
tissue repair as claimed in claim 1, are encased in two or more divided
5 groups in an optional combination.
13. The kit for hard tissue repair as claimed in claim 12,
which has constitution in which the monomer (A) , the polymer (B) and
the polymerization initiator composition (C) are each independently
10 encased, and the monomer (A) is first mixed with the polymerization
initiator composition (C) containing an organoboron compound and
subsequently mixed with the polymer (B).
14. A kit for hard tissue repair, having members in which
15 the components of the monomer (A), the (meth) acrylate polymer (B),
the polymerization initiator composition (C) containing an
organoboron compound and the polymerization inhibitor (D), which are
contained in the composition for hard tissue repair as claimed in
claim 6, are encased in two or more divided groups in an optional
20 combination.
15. The kit for hard tissue repair as claimed in claim 14,
which has constitution in which a mixture of the monomer (A) and the
polymerization inhibitor (D), the polymer (B) and the polymerization
SF-2300
98
initiator composition (C) are each independently encased, and the
mixture of the monomer (A) and the polymerization inhibitor (D) is
first mixed with the polymerization initiator composition (C)
containing an organoboron compound and subsequently mixed with the
5 polymer (B).
16. The kit for hard tissue repair as claimed in any one of
claims 12 to 15, which includes a jig that is used for applying a
composition for hard tissue repair obtained by mixing components
10 containing the components (A) , (B) and (C) , or a composition for hard
tissue repair obtained by mixing components containing the components
(A),, (B), (C) and (D) to the affected part.
17. The kit for hard tissue repair as claimed in claim 16,
15 wherein the jig is at least one. jig selected from a brush, a fiber
ball, a cloth, a sponge ball and a piece of sponge.
18 The kit for hard tissue repair as claimed in any one of
claims 12 to 17, which further contains an aqueous solution for
20 pretreatment containing 1 to 15% by weight of citric acid and 1 to
5% by weight of iron(III) chloride.