U.S. patent application number 09/392507 was filed with the patent office on 2002-08-29 for reactive systems from polymerizable monomers which comprise peroxides and stabilized alkylboron compounds.
Invention is credited to POKINSKYJ, PETER, RITTER, WOLFGANG, WENZ, ROBERT.
Application Number | 20020120054 09/392507 |
Document ID | / |
Family ID | 7880464 |
Filed Date | 2002-08-29 |
United States Patent
Application |
20020120054 |
Kind Code |
A1 |
RITTER, WOLFGANG ; et
al. |
August 29, 2002 |
REACTIVE SYSTEMS FROM POLYMERIZABLE MONOMERS WHICH COMPRISE
PEROXIDES AND STABILIZED ALKYLBORON COMPOUNDS
Abstract
Reactive systems for polymerizing ethylenically unsaturated
compounds comprising a first component, comprised of ethylenically
unsaturated compounds capable of polymerization, and a second
component of a hardener system comprised of organoboron compounds
which are stabilized with suitable oligomers. An organic peroxide
(perester, hydroperoxide, perether and/or peranhydride) is admixed
with the compounds. These components are mixed to form a polymer.
The reactive system reaches full strength in reduced time with the
use of the organic peroxide and are suitable for joining hard body
materials in human or animal tissue, in particular in the surgical
and/or dental sector, in the production of body-absorbable or
body-resistant adhesives, cements, and/or filling compounds and for
forming synthetic material moldings.
Inventors: |
RITTER, WOLFGANG; (HAAN,
DE) ; WENZ, ROBERT; (WOLLSTADT, DE) ;
POKINSKYJ, PETER; (ROBDORF, DE) |
Correspondence
Address: |
MILLEN, WHITE, ZELANO & BRANIGAN, P.C.
2200 CLARENDON BLVD.
SUITE 1400
ARLINGTON
VA
22201
US
|
Family ID: |
7880464 |
Appl. No.: |
09/392507 |
Filed: |
September 10, 1999 |
Current U.S.
Class: |
524/523 ;
524/522; 524/556; 524/560; 526/134; 526/196; 526/328;
526/328.5 |
Current CPC
Class: |
A61K 6/30 20200101; A61K
6/30 20200101; A61K 6/30 20200101; A61K 6/30 20200101; A61K 6/30
20200101; A61K 6/30 20200101; A61L 24/06 20130101; A61K 6/30
20200101; A61L 24/06 20130101; A61K 6/30 20200101; A61K 6/64
20200101; C08L 33/10 20130101; C08L 67/04 20130101; C08L 33/10
20130101; C08L 33/08 20130101; C08L 67/02 20130101; C08L 63/00
20130101; C08L 63/00 20130101; C08L 33/06 20130101; C08L 67/02
20130101; C08L 33/08 20130101; A61K 6/30 20200101; C08L 67/04
20130101; A61K 6/30 20200101 |
Class at
Publication: |
524/523 ;
526/134; 526/196; 526/328; 526/328.5; 524/522; 524/556;
524/560 |
International
Class: |
C08J 003/00 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 10, 1998 |
DE |
19841342.4 |
Claims
1. Reactive system comprising a first component comprised of
ethylenically unsaturated reactive compounds capable of
polymerization, and a second component of a hardener system
comprised of organoboron compounds which is stabilized with
oligomers, wherein the first component and second component are
mixed for use of the reactive system and wherein an organic
peroxide, selected from the group consisting of peresters,
hydroperoxides, perethers, peranhydrides and combinations thereof,
is admixed with the ethylenically unsaturated reactive
compounds.
2. Reactive system according to claim 1, characterized in that the
ethylenically unsaturated reactive compounds are
oligohydroxycarboxylic acid acrylates or methacrylates.
3. Reactive system according to claim 2, characterized in that the
oligohydroxycarboxylic acid acrylates or methacrylates have been
prepared using monofunctional and/or difunctional alcohols or
carboxylic acids or carboxylic anhydrides.
4. Reactive system according to claim 3, characterized in that
ethylenically unsaturated reactive compounds are composed of
ethylene glycol or glycerol, lactic acid and glycolic acid.
5. Reactive system according to at least one of claims 1 to 4,
characterized in that said organic peroxide is dissolved in the
ethylenically unsaturated reactive compound.
6. Reactive system according to at least one of claims 1 to 5,
characterized in that the organic peroxide has a half-life at
80.degree. C. in the range of from hours to days.
7. Reactive system according to at least one of claims 1 to 6,
characterized in that the content of organic peroxide is between
0.005 and 10% by weight, preferably between 0.1 and 5% by weight
based on the amount of ethylenically unsaturated compounds.
8. Reactive system according to at least one of claims 1 to 7,
characterized in that tert-butyl peroxybenzoate or dibenzoyl
peroxide are used as the organic peroxide.
9. Reactive system according to at least one of claims 1 to 8,
characterized in that said organoboron compounds are selected from
the group consisting of boron compounds having alkyl and/or aryl
radicals and bicyclic organoboron compounds, and are in the form of
mixtures with said oligomers or are in the form of adducts with
unsaturated fats or said oligomers resulting from a hydroboration
reaction.
10. Reactive system according to claim 9, characterized in that
said oligomers are oligoesters of lower hydroxy carboxylic acids
having 2 to 10 C atoms.
11. Reactive system according to claim 9 or 10, characterized in
that 9-borabicyclo [3.3.1] nonane is used as said organoboron
compound.
12. Reactive system according to one of claims 9 to 11,
characterized in that the content of organ boron compound is in the
range from 0.5 to 10% by weight, preferably from 1 to 5% by weight,
based on the hardener component.
13. Reactive system according to claim 11 which is an adhesive
mixture wherein the boron content in said adhesive mixture is in
the range from 0.005 to 0.2% by weight.
14. Reactive system according to claim 1, which is an adhesive
mixture that reaches 50% of its final strength in less than 20
minutes.
15. Reactive system according to claim 1, characterized in that the
strength on bone in blood or blood-Ringer solution in the tensile
test reaches at least 0.3 MPa.
16. A method of using a reactive system according to claim 1 which
comprises joining hard body materials, optionally together with a
synthetic material, metal or both, in human or animal tissue.
17. A method according to claim 16, wherein the reactive system is
used as a reactive adhesive or cement in a surgical or dental
procedure.
18. Reactive system according to claim 1, in the form of a kit
ready for use consisting of two or more separate components,
wherein one separate component comprises said first component and
another separate component comprises said second component.
19. Reactive system according to claim 18, comprising the separate
components, each within a separate chamber of a dual-chamber
syringe with static mixer.
20. Reactive system according to claim 18, wherein the separate
components are within plastic ampoules after production.
21. Reactive system according to claim 20, characterized in that
the plastic ampoules comprise materials with a high diffusion
coefficient for oxygen.
22. Reactive system according to claim 20, characterized in that
said second component is stored in a synthetic material which has a
low diffusion coefficient for oxygen, or is stored in material
which is laminated with metal foils.
23. Reactive system according to claim 18, characterized in that
the separate components are produced and separately packed sterile
and are combined to give an adhesive mixture ready for use.
24. Reactive system according to claim 1, wherein the first
component and second component are reacted to form a polymerized
product.
25. Reactive system according to claim 24, characterized in that
the polymerized product is suitable for constructing a degradable
sheet which prevents unwanted adhesion of organs in operations.
Description
[0001] The present invention describes reactive systems which are
composed of ethylenically unsaturated monomers on the one hand, and
of oxygen-reactive organoboron compounds which are stabilized by
means of carrier materials on the other hand. The monomer component
additionally comprises small amounts of peroxides.
[0002] The novel reactive systems are suitable in principle for
many applications, for example for the industrial or craft sector,
but they have a particular and preferred significance for use in
medicine in human or animal tissue. They are suitable as binders or
adhesives for bonding endogenous hard tissue and for bonding such
tissue to synthetic material and/or metal and/or for in situ
formation of synthetic material moldings in surgical work. They are
used in particular in the area of reactive adhesive and cement
systems for medical and/or dental applications and, in the
last-mentioned area, also as filling materials.
[0003] Polymer-based synthetic materials, and reactive systems
curable by initiation of reaction are becoming increasingly
important both in human medicine and in the veterinary sector.
Reference may be made to surgical and/or dental adhesives, cements,
filling materials and the like which usually set after application
and implantation into the living body and then remain in contact
with the living body.
[0004] The curable adhesives preferably employed in practice
normally consist of the following components:
[0005] one or more free-radical polymerizable, ethylenically
unsaturated monomers which are, where appropriate, mixed with
inhibitors to prevent unwanted premature initiation of
reaction;
[0006] a starter system to initiate polymerization;
[0007] polymers for improving cohesion and adjusting the viscosity
and, where appropriate,
[0008] active fillers for improving the mechanical properties.
[0009] A starter system frequently used to initiate polymerization
in reaction systems comprising ethylenic double bonds consists of
oxygen-reactive organoboron compounds. There is a wide-ranging
literature on this, and therefore the following publications may be
cited as only a small selection: DE 30 41 843, DE 30 41 904, DE 31
43 945, DE 32 01 780, DE 32 04 504 or else DE 32 29 635.
[0010] DE 39 39 164 likewise describes starter systems based on
oxygen-active organoboron compounds which are combined with a
carrier material. The carriers employed are oligoesters of lower
hydroxy carboxylic acids. These carriers improve the stability of
the system towards oxygen. In order for such reactive boron
compounds such as, for example, 9-borabicyclo[3.3.1]nonane (9-BBN)
in fact to be processible and stable on storage, they are
introduced into a matrix of an ester of a polyhydric alcohol, and
of an oligomer of a hydroxy carboxylic acid.
[0011] However, even these systems are not optimal because it has
been found that the storage stability is inversely proportional to
the concentration of the boron compound. It would therefore be
desirable to have starter systems or reactive systems in which the
concentration of organoboron compounds was as low as possible, also
because of the toxicity of the boron compounds, but without this
reduction having a deleterious effect on the polymerization.
[0012] The object was therefore to find improved reactive or
adhesive systems which have a content of organoboron compounds
which is as low as possible, and wherein the criteria such as pot
life, time to reach the final strength, and strength of the
bonding, are likewise optimized.
[0013] It has now been found that the required results can be
achieved by admixing a peroxide to the monomer component in the
reaction system. Peroxides suitable for this purpose are in
principle various structural elements, namely both peresters,
hydroperoxides, perethers and peranhydrides. This is very
surprising since it was absolutely unexpected that such
monomer/peroxide mixtures can be manipulated and are stable on
storage since it is often difficult even to store the monomer
components stably on their own, i.e. to prevent unwanted
polymerization.
[0014] The invention therefore relates to a two-component reactive
system for polymerizing ethylenically unsaturated compounds,
comprising as first component monomers capable of the
polymerization (=reactive component), and as second component a
starter or hardener system composed of organoboron compounds
(=initiator component), which are stabilized with suitable
oligomers, where these components are mixed for the application,
characterized in that an organic peroxide is admixed to the
monomers.
[0015] The invention further relates to the use of the reactive
systems improved according to the invention in the area of joining
hard body materials where appropriate together with synthetic
material and/or metal in human or animal tissue, in particular also
in the area of reactive adhesive or cement systems in the surgical
and/or dental sector.
[0016] In this case, the peroxide is introduced into, that is to
say suspended or dissolved in, the monomer components to be
polymerized. The organic peroxides preferably used are those which
dissolve in the monomer system.
[0017] The peroxide is thus in intimate contact with the reactive
end groups of the substances to be polymerized, whereby the
complete course of the polymerization is speeded up. The initiation
of the polymerization thus takes place on the one hand by the
action of the starter on the ethylenically unsaturated compounds,
and on the other hand additionally due to the peroxide which is
likewise induced to decompose by the starter and acts as
polymerization accelerator.
[0018] However, a great advantage also derives from the fact that
addition of the peroxide to the monomer allows the content of
organoboron compound in the initiator component to be reduced,
which is important in respect of toxicology.
[0019] It is possible in principle to use for this purpose all
organic peroxides, that is to say peresters, hydroperoxides,
perethers and peranhydrides. However, the selection is also
determined by their distribution in the substances to be
polymerized, a solution being preferred to suspensions. In
addition, the peroxides or reaction catalysts which can be admixed
must not be prone to decomposition at room temperatures or below
50.degree. C. The peroxides preferably used have a half-life at
80.degree. C. in the range from hours to days.
[0020] Particularly preferred peroxides have proved to be
tert-butyl peroxybenzoate or di-tert-butyl peroxide.
[0021] The peroxides are admixed in an amount of from 0.005 to 10%
by weight, preferably from 0.1 to 5% by weight, based on the
monomer components.
[0022] The hardener or starter component employed in the reactive
systems according to the invention are boron compounds having alkyl
and/or aryl radicals, or bicyclic organoboron compounds, which are
stabilized or retarded with suitable oligomers. Such a
stabilization can preferably take place by the appropriate organic
boron compounds being in the form of mixtures with oligomers or of
adducts with unsaturated fats or oligomers resulting from a
hydroboration reaction. These starter systems are well known to the
skilled person and are, for example, described in detail in the
documents DE 39 39 164, DE 32 07 263 or DE 32 07 264. This will
therefore be dealt with only briefly below.
[0023] Thus, a preferred way of stabilizing the organoboron
compounds is to prepare physical mixtures of these compounds with
oligomers. One possibility for retardation is to mix the organic
boron compounds homogeneously with an organic oligomer or polymer
which is liquid or solid at room temperature and, where possible,
compatible with the body. Suitable oligomeric or polymeric organic
components in this case are preferably oligoesters, oligoamides
and/or oligoethers which are liquids or spreadable pastes at room
temperature.
[0024] A particularly preferred starter system consists of
oxygen-reactive organoboron compounds in combination with a carrier
material which is in the form of an oligoester of lower hydroxy
carboxylic acids.
[0025] The essential ester-forming constituent of these carrier
materials are thus hydroxy carboxylic acids of the preferred C
number range from about 2 to 10. Particularly important hydroxy
carboxylic acids are glycolic acid and/or, in particular, lactic
acid, which can be used in the form of selected isomers or else as
mixture of isomers. Also suitable are the optionally isomeric
.alpha.- or .beta.-hydroxypropionic acids, .beta.-, .beta.- or
.gamma.-hydroxybutyric acids, o-, m- and/or p-hydroxybenzoic
acid.
[0026] The oligoesters of the said hydroxy carboxylic acids can
also have been prepared using monofunctional and/or polyfunctional
reactants which result in oligoesters terminated with hydroxyl
groups or with carboxyl groups of the lower hydroxy carboxylic
acids being present as carriers.
[0027] Suitable coreactants are, in particular, monoalcohols and/or
monocarboxylic acids, with corresponding compounds having up to 6 C
atoms being preferred. However, particularly suitable as carrier
material are oligoesters which have been prepared using polyhydric
alcohols or else polyfunctional carboxylic acids. Suitable
polyhydric alcohols are 2- to 4-functional alcohols, in particular
diols or else glycerol. Suitable polyfunctional carboxylic acids
are, in particular, dicarboxylic acids having 2 to 10 C atoms.
[0028] The formation of the oligoesters is a conventional
esterification reaction carried out in a manner known per se in the
presence of suitable catalysts.
[0029] In both variants, the carrier materials or the oligomers are
then mixed with the organoboron compounds, preferably with
exclusion of atmospheric oxygen, possibly with gentle heating where
appropriate.
[0030] Another possibility for a suitable starter system is to
prepare alkylboron compounds which are bound to fatty acid and/or
fatty alcohol esters or other oligomers. These alkylboron compounds
are preferably the products of the reaction of borane and/or an
organoboron compound having at least one B-H linkage with oligomers
or polymers which contain carbon double bonds capable of addition,
or with esters of olefinically unsaturated fatty acids and/or
olefinically unsaturated fatty alcohols. The compounds can be
prepared by subjecting the appropriate starting compounds with
carbon double bonds capable of addition to hydroboration with
diborane or mono- and/or disubstituted boranes.
[0031] Possible and particularly preferred matrix materials are
esters of unsaturated monocarboxylic acids (unsaturated fatty
acids) with polyhydric alcohols. Suitable polyhydric ester-forming
reaction components are, in particular, appropriate compounds with
a functionality of up to 6, preferably from 2 to 4. Thus, in the
preferred embodiment, monocarboxylic acids of the stated C number
range are esterified with polyhydric alcohols--in particular with
dihydric, trihydric or tetrahydric alcohols, as matrix for the
boron-containing substituents.
[0032] It may in this connection be preferred for the
polyfunctional ester component to have a comparatively small number
of carbon atoms, which may be, for example, in the range from 2 to
10, preferably in the range from 2 to 6. Accordingly, particularly
suitable polyfunctional alcohols are the lower glycols such as
ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, the C4
glycols with terminal and/or internal hydroxyl groups and
corresponding C5 and C6 compounds. A particularly preferred alcohol
is glycerol or polyhydric alcohols of the pentaerythritol type.
Conversely, monofunctional fatty alcohols can be esterified with
lower polycarboxylic acids, in particular lower di- or
tricarboxylic acids.
[0033] Generally suitable as boron compounds for the described
variants of the starter component are numerous known alkylborons.
Typical representatives are, for example,
9-borabicyclo[3.3.1]nonane and its derivatives such as
B-methoxy-9-borabicyclo[3.3.1]nonane, diisopino-campheylborane,
dicyclohexylborane, thexylborane (2,3-dimethyl-2-butylborane),
3,5-dimethylborinane or else diisoamylborane.
[0034] Of these compounds, 9-borabicyclo[3.3.1]nonane (9-BBN) is
very particularly preferred for practical reasons.
[0035] A compilation of the possibilities for preparing suitable
boron compounds is to be found in the monograph by Herbert C.
Brown, 1975 "Organic Synthesis via Boranes", published by John
Wiley & Sons.
[0036] The content of organoboron compound in the starter mixture
can be chosen according to the invention to be very much lower than
is the case in the hardener systems disclosed to date. The content
is from 0.5 to 10% by weight, preferably in the range from 1 to 5%
by weight, these data being based on the boron compound. This is a
significant advantage, especially also in view of the toxicity of
many organoboron compounds.
[0037] The boron content in the finished adhesive mixture is
preferably in the range from 0.005 to 0.2% by weight.
[0038] The polymerizable component in the reactive systems
according to the invention are mixtures of one or more free-radical
polymerizable monomers, polymers to improve cohesion and adjust the
viscosity, where appropriate active fillers to improve the
mechanical properties and, where appropriate, stabilizers.
[0039] Polymerizable monomers which have been investigated besides
methyl methacrylate in combination with methacrylic acid (bone
cement) are numerous other systems, some of which have achieved
practical significance, compare in this connection J. M. Antonucci,
Polymer Science and Technology 14, 357 (1981).
[0040] However, particularly suitable monomer components for use
within the scope of this invention are oligomer components like
those described in the documents DE 32 05 504 and 32 29 635. These
are binder systems for surgical purposes, which are characterized
in that the absorbable (meth)acrylate components they comprise are
(meth)acrylic esters which are liquid or solid at room temperature
and have (meth)acrylate residues on polyester oligomer chains from
hydroxy carboxylic acids. These free-radical reactive components
may moreover have one or, preferably, also more than one
(meth)acrylic acid residue on the polyester oligosegment.
[0041] Adhesive systems based on such reactive components are
distinguished by a large number of outstanding properties. In
particular, they result in cured synthetic materials which can be
absorbed by the living body.
[0042] The polyester oligosegment is in a preferred embodiment
formed from monohydroxy monocarboxylic acids which do not exceed a
C number of about 20 in the molecule and, in particular, of about
10. Lower hydroxy carboxylic acids having 2 to 6 C atoms may be
particularly important in this connection. Particularly suitable
hydroxy carboxylic acids for forming this central piece of the
(meth)acrylate compounds are glycolic acid, the isomeric lactic
acids, the optionally isomeric .alpha.- or .beta.-hydroxypropionic
acids, .alpha.-, .beta.- or .gamma.-hydroxybutyric acids, o-, m-
and/or p-hydroxybenzoic acid. It is moreover possible to use either
particular isomers of the said acids or else any mixture.
[0043] The polyester oligomers are moreover preferably prepared
using monofunctional and/or, preferably, polyfunctional reactants.
Particularly suitable coreactants are monoalcohols and
monocarboxylic acids. Polyfunctional coreactants for preparing the
polyester oligomers are polyfunctional alcohols, in particular 2-to
4-hydric alcohols, or corresponding polycarboxylic acids and their
functional reactive derivatives. Lower polyfunctional alcohols such
as ethylene glycol, propanediol, in particular 1,2-propanediol,
glycerol and the like may have particular importance in this
connection.
[0044] In all the cases described there is formation of modified
ester oligomers which can easily be converted in a manner known per
se into the (meth)acrylate compounds to be used according to the
invention.
[0045] In a very particularly preferred embodiment of the
invention, the monomer component employed is a product which is
preferably composed of ethylene glycol or glycerol, lactic acid and
glycolic acid, with particular preference for the product of
ethylene glycol and lactic acid with an average degree of
polymerization of less than 10.
[0046] Further particularly preferred adhesive systems according to
the invention are those which are completely composed--that is to
say monomer component and oligomers to stabilize the boron
compound--of building blocks such as polyethylene glycol and lactic
acid or glycolic acid.
[0047] The polymers produced from the reactive components may be
degradation resistant or degradable in the body. The same applies
to any preformed polymers also used. The starter systems in which
oligomeric or polymeric carriers are also used may also optionally
be designed to be degradation resistant or absorbable in the body
and can be combined in an appropriate manner with the complete
system.
[0048] If systems which are degradable in the body are employed,
hydroxy carboxylic acid residues, in particular corresponding
residues of glycolic acid and/or lactic acid, are essential
building blocks of the molecules both in the ethylenically
unsaturated monomer component and in the polymer components which
are to be used where appropriate.
[0049] In many cases it may be preferable or necessary to add
further auxiliaries such as fillers, for example silica flour or
the like. Finally, coloring with suitable dyes or pigments may be
preferable.
[0050] The mixing ratios of the starter system to the reactive
component are in the normal range. For example, the starter systems
can be used in amounts of about 0.5 to 30% by weight-based on the
material to be polymerized. However, it may be mentioned once again
in this connection that the content of organoboron compound within
the starter system is considerably lower according to the invention
than in the prior art.
[0051] The two-component reactive systems described herein are used
for joining--that is to say for bonding--hard body materials, for:
example bones, together, but also to exogenous materials such as
synthetic material and/or metal, in human or animal tissue. The use
as adhesives or cement systems in the surgical and/or dental sector
is moreover preferred.
[0052] It is furthermore possible for the reactive systems of the
type described to be used for in situ production of individually
formed moldings, in particular in connection with the bonding of
endogenous hard tissue, where appropriate, together with synthetic
material and/or metal.
[0053] The components of the reactive system, that is to say the
monomer components and the hardener or starter components, are,
after they have been produced--if necessary with exclusion of
air--, preferably each packed sterile, preferably being dispensed
into plastic ampoules. The components are mixed to give the system
ready for reaction only immediately before use.
[0054] The monomer components are stored in ampoules, preferably in
materials with a high diffusion coefficient for oxygen, a low
density polyethylene being particularly suitable.
[0055] On the other hand, the starter component is likewise
preferably stored in a plastic material which has a low diffusion
coefficient for oxygen, or in a material which is laminated with
metal foils.
[0056] The individual components are preferably subjected to
sterilization by filtration before dispensing into containers. It
may furthermore be advantageous to surface-sterilize the closed
ampoules with hydrogen peroxide plasma.
[0057] The invention also relates to a two-component reactive
system as described above, which is characterized in that it is in
the form of a kit ready for use consisting of two or more separate
components, one component of which comprises the monomers and
another component of which comprises the hardener component.
[0058] The mixing of the individual components can preferably take
place using mixing systems known per se from (medical) technology,
such as, for example, systems for mixing bone cements, reactive
adhesives or impression compounds.
[0059] The mixing is preferably carried out by a two-component
syringe. An example which may be mentioned is the dual chamber
syringe known to the skilled person, with fitted static mixer. It
is also possible with these mixing systems simply to adjust and
vary the mixing ratio of the components. This ensures accurate
dosage and rapid mixing even with unfavourable monomer/hardener
ratios. Also suitable are, for example, mixing systems supplied by
MIXPAC Systems AG.
[0060] The addition according to the invention of a peroxide to the
monomer components results in a system which is easily manipulated
and has a low boron content. The reactive system is further
distinguished by a convenient pot life, a rapid rate of hardening
and an improved final strength.
[0061] The adhesives according to the invention are particularly
distinguished by reaching 50% of their final strength within less
than 20 minutes after mixing the components.
[0062] The strength of these adhesive systems can be determined,
for example, by bonding iron sheets which have been sandblasted and
degreased within the pot life, and measuring the strength in a
tensile shear test.
[0063] When hard tissue is bonded in medicine, the strength
achieved additionally depends greatly on the pretreatment of the
bone material and the storage conditions of the joint parts. For
use inside the body, strength measurements on degreased, dry bone
tissue have little validity. It appears more relevant to bond moist
and greasy bones which have not been pretreated, and to measure the
strength on the resulting specimens after storage in (blood) Ringer
solution. Under these simulated in vivo conditions, conventional
methacrylate adhesives and bone cements achieved tensile strengths
of about 60 N cm.sup.-2 on bone material (cf. in this connection G.
Giebel et al., Biomed. Techn. 26, (1981) 170).
[0064] The adhesives according to the invention are thus also
characterized in that the strength on bone reaches at least 0.3 MPa
in the tensile test in blood or (blood) Ringer solution.
[0065] The invention also relates to reaction systems as described
above, which are characterized in that they are essentially
composed of the building blocks polyethylene glycol and lactic acid
or glycolic acid. Systems of this type are particularly suitable
for constructing a degradable sheet which prevents unwanted
adhesion of organs in operations.
[0066] It is assumed that a skilled person is able even without
further statements to utilize the above description in the widest
scope. The preferred embodiments are therefore to be regarded
merely as a descriptive and by no means in any way limiting
disclosure.
[0067] The complete disclosure in all applications and publications
mentioned hereinbefore and hereinafter, including DE 19841342.4
filed Sep. 10, 1998 is included in this application by
reference.
[0068] The following examples are intended to illustrate the
invention in detail.
EXAMPLES
[0069] I) Oligohydroxycarboxylic Acids with Hydroxyl End Groups
[0070] Preparation from Lactide and Ethylene Glycol
[0071] L-lactide S and ethylene glycol are introduced into a
stainless steel stirring apparatus and phosphoric acid is added.
The mixture is heated under nitrogen to 100.degree. C. over the
course of 1 h, kept at this temperature for 15 min and then heated
further to 130.degree. C. over the course of 30 min. This
temperature is maintained for 5 h, and then the product is
discharged hot.
[0072] The composition and the oligomer properties are to be found
in Table 1 (Example 1).
1TABLE 1 Oligohydroxycarboxylic acids with hydroxyl end groups from
lactide and ethylene glycol Precursors Ethylene Calculated
L-lactide S glycol Phosphoric Acid molecular weight Example mol mol
acid value G/mol Characteristics 1 2 1 4.2 mg/g 7 350 clear
viscous, pale yellow
[0073] II) Oligohydroxycarboxylic Acids with Polymerizable End
Groups
[0074] a) from Oligohydroxycarboxylic Acids with Terminal Hydroxyl
Groups and Methacrylic Acid
[0075] The oligohydroxycarboxylic acid with hydroxyl end groups
from Example 1 and 1.75 equivalent of methacrylic acid per hydroxyl
group are introduced into a three-neck flask with stirrer and water
trap. At the same time, 2000 ppm of D,L-tocopherol and 0.2
equivalent of methanesulphonic acid are added. The mixture is
evacuated to 900 mbar with rapid stirring and passing through of
air, and heated to 105.degree. C. After reducing the pressure
further to 500 mbar, the water formed in the reaction is removed in
the water trap. After a reaction time of 3.5 h, the pressure is
lowered to 100 mbar. The reaction is terminated as soon as 85 to
90% of the water expected in the reaction has formed. The reaction
product is adjusted to 100.degree. C., and calcium hydroxide is
added to neutralize. After addition of Celite, the mixture is
stirred at 105.degree. C., 500 mbar with an air throughput of 300 1
for 1 h. The resulting suspension is filtered hot and the resulting
filtrate is introduced into a PE bottle.
[0076] b) from Oligohydroxycarboxylic Acids with Terminal Hydroxyl
Groups and Methacryloyl Chloride
[0077] The oligohydroxycarboxylic acid with hydroxyl end groups
from Example 1 is dissolved in methyl tert-butyl ether in a
three-neck flask. Then 2 equivalents per hydroxyl group of
anhydrous potassium carbonate are suspended therein, and a solution
of 0.9 equivalent per hydroxyl group of methacryloyl chloride in
methyl tert-butyl ether is added dropwise over the course of 30
min. The reaction solution is stirred at room temp. for 24 h and
left to stand without stirring for 48 h. The colorless precipitate
is filtered off and washed twice with methyl tert-butyl ether. The
combined organic filtrates are washed with water and dried over
magnesium sulphate. The desiccant is filtered off and then washed
twice more with methyl tert-butyl ether. After addition of 500 ppm
of Ionol (2,6-di-tert-butyl-4-methylphenol), the solvent is slowly
removed over the course of 24 h under reduced pressure. The
resulting product is stored in a PE bottle.
[0078] The composition of the mixtures and the properties of the
polymerizable oligomers are listed in Table 2 (Examples 2-3).
2TABLE 2 Oligohydroxycarboxylic acids with polymerizable end groups
Precursor from Yield Example Method Example % Characteristics 2 a)
1 >90 homogeneous, low viscosity, yellow 3 b) 1 80 homogeneous,
low viscosity, pale yellow
[0079] c) from Lactide S and Hydroxylated Methacrylic Esters
[0080] The methacrylic acid derivative, L-lactide S, magnesium
oxide and Ionol are weighed into a reaction flask and, while
stirring and introducing air, heated to 100.degree. C. over the
course of 30 min. The temperature is maintained at this for 30 min
and then raised to 180.degree. C. over the course of 1 h and
maintained for 3 h. After cooling to room temperature, the catalyst
is filtered off.
[0081] The composition and the oligomer properties are shown in
Table 3 (Examples 4-7). The methacrylic acid derivatives used were
hydroxyethyl methacrylate (A) and glycerol dimethacrylate (B).
3TABLE 3 Methacrylic acid derivatives esterified with
oligohydroxycarboxylic acids Precursors Methacrylic acid Calculated
L-lactide S derivative Magnesium molecular weight Example mol
Type/mol oxide g/mol Characteristics 4 2 A/1 40 mg/g 418 clear,
viscous 5 3 A/1 40 mg/g 562 clear, highly viscous 6 4 A/1 40 mg/g
707 clear, highly viscous 7 3 B/1 40 mg/g 516 clear, highly
viscous
[0082] III Initiator Component
[0083] 100 g of the oligohydroxycarboxylic acid with hydroxyl end
groups from Example 1 are introduced into a round-bottom flask with
distillation apparatus and degassed at 75.degree. C. with stirring
for 2 h. Then a borane solution is added dropwise over the course
of 30 min. After gas evolution ceases, the solvent is distilled
off, initially under 10 mbar and for complete removal under 0.1
mbar.
[0084] The compositions of the mixtures are listed in Table 4
(Examples 8-11)
4TABLE 4 Initiator component Borane solution Example ml Type
Characteristics 8 16.4 9-BBN, 0.5 M homogeneous, in THF viscous,
colourless 9 49.2 9-BBN, 0.5 M homogeneous, in THF viscous,
colourless 10 131.2 9-BBN, 0.5 M homogeneous, in THF viscous, pale
yellow 11 25 BM-9-BBN, 1 M homogeneous, in n-hexane viscous,
colourless 9-BBN= 9-borabicyclo [3.3.1] nonane BM-9-BBN=
B-methoxy-9-borabicyclo [3.3.1] nonane
[0085] IV Reactive Component A
[0086] The oligohydroxycarboxylic acids with polymerizable end
groups prepared in Example 2 and 3 are adjusted to a content of 5%
by dropwise addition of freshly distilled methacrylic acid with
stirring. The amounts of peroxide described in Table 5 are then
mixed into these monomers. The compositions of the mixtures are
listed in the Table 5 (Examples 12-16).
5TABLE 5 Reactive component A Peroxide Example mg Type
Characteristics 12 100 TBPB homogeneous, viscous, pale yellow 13
1000 TBPB homogeneous, viscous, pale yellow 14 2000 TBPB
homogeneous, viscous, pale yellow 15 1000 DTBP homogeneous,
viscous, pale yellow 16 2000 DTBP homogeneous, viscous, pale yellow
DTBP= di-tert-butyl peroxide TBPB= tert-butyl pexoxybenzoate
[0087] The following attempts to prepare mixtures with peroxide did
not result in homogeneous mixtures. (Table 6, Example 17-19)
6TABLE 6 Mixing experiments Peroxide Example mg Type 17 100 BP No
mixing 18 2000 LP No mixing 19 1000 TBHP Mixing problems: H.sub.2O
content of the peroxide BP= dibenzoyl peroxide LP= dilauroyl
peroxide TBHP= tert-butyl hydroperoxide
[0088] V Reactive Component B
[0089] The methacrylic acid derivative esterified with
oligohydroxycarboxylic acids as prepared in Example 4 and 5 are
converted into the reactive components by dropwise addition of
triethylene glycol dimethacrylate (A), glycerol dimethacrylate (B)
or the methacrylic acid derivative (C) prepared in Example 7 with
stirring, and then mixing in organic peroxy compounds.
[0090] The compositions of the mixtures are listed in Table 7
(Examples 20-26).
7TABLE 7 Reactive component B Precursor from Admixture Peroxide
Example Example Type/% by wt. % by wt. Characteristics 20 4 -- 1%
homogeneous, viscous 21 4 A/10% homogeneous, viscous 22 4 A/10% 2%
homogeneous, viscous 23 5 A/20% 2% homogeneous, viscous 24 5 A/40%
2% homogeneous, viscous 25 5 B/20% 4% homogeneous, viscous 26 5
C/50% 4% homogeneous, viscous
[0091] VI Tensile Shear Tests on Bonded Iron Sheets and Spongiosa
Cubes
[0092] a) The prepared macromers were used to bond iron sheets
sandblasted and degreased on one side (in analogy to DIN 53 281/53
283). The samples have pot lives between two and ten seconds and
are tested for their shear strength after having been joined for 6
h at room temperature.
[0093] b) Spongiosa cubes were bonded in the same way. The samples
are tested for their shear strength after an adhesion time of 5 h
at 37.degree. C. in phosphate buffer.
[0094] 1. Apparatus:
[0095] Instron type 4502 tester, consisting of testing frame with
traverse, two clamps to receive the iron sheets used, and 10 kN
sensor. Software: Instron Series IX, program 03, testing rate: 2
mm/min.
[0096] 2. Specimens:
[0097] a) Steel sheet 25.times.100.times.1.5 mm, sandblasted on one
side
[0098] b) spongiosa cube 2.times.2.times.2 cm, thawed overnight in
buffer pH=7.4 at 37.degree. C., storage in horse serum at
37.degree. C. for 5 min before bonding.
[0099] 3. Sample preparation:
[0100] a) The steel sheets must be degreased before bonding. This
takes place by twice treating the parts in dichloromethane in an
ultrasonic bath for 15 minutes and then wiping off adherent metal
particles with an acetone-impregnated tissue.
[0101] 4. Bonding:
[0102] a) Using an apparatus, two steel plates are joined together
so that they overlap by 1 cm (bonding area 250 mm.sup.2). One steel
plate is fixed on the apparatus and, after removing the air from
the mixing needle, the adhesive is applied, the second steel plate
is placed on top, and the bonding area is loaded with a weight of 5
kg for 5 min. The bonded steel plates are removed from the
apparatus and stored at room temperature until measured in the
Instron.
[0103] b) The spongiosa cubes removed from the horse serum are
dried using a disposable wipe and, after removing air from the
mixing needle, adhesive is applied to the spongiosa cube, the
second spongiosa cube is put on top, and the two cubes are fixed in
a vice for 2 min. The pair of cubes, which is now bonded, is then
removed from the apparatus and stored in phosphate buffer at
37.degree. C. until measured.
[0104] 5. Standards:
[0105] DIN 53283 testing of metal adhesives, determination of the
strength of overlapping bonds. (Tensile shear test)
[0106] The composition of the mixtures and the shear strengths
achieved are listed in Table 8 (Examples 27-54).
8TABLE 8 Shear strengths for the bonding of iron sheets with
monomer adhesives based on oligohydroxycarboxylic acids with
polymerizable end groups, and methacrylic acid derivatives
esterified with oligohydroxycarboxylic acids Initiator component
Macromer Final strength [N mm.sup.-2] Example Example Example
Mixing ratio Sheet Spongiosa 27 10 --* 1:10 8.79 0.15-0.21 28 10 12
1:10 highly exothermic 29 10 13 1:10 highly exothermic 30 10 14
1:10 highly exothermic 31 10 15 1:10 11.32 0.10-0.28 32 10 16 1:10
11.08 0.37 33 10 --* 1:4 3.43 0.15 34 8 --* 1:10 4.41 35 8 13 1:10
11.58 0.19 36 8 14 1:10 10.88 0.15 37 8 15 1:10 8.79 0.18 38 8 16
1:10 7.88 0.15 39 8 13 1:4 11.40 40 9 --* 1:10 4.85 41 9 13 1:10
10.88 0.34 42 9 14 1:10 10.75 0.37 43 9 15 1:10 7.52 44 9 16 1:10
8.54 45 9 --* 1:4 4.03 46 11 14 1:10 10.89 47 10 20 1:10 7.06 48 10
21 1:10 6.96 49 10 22 1:10 7.90 0.16 50 10 23 1:10 7.79 51 10 24
1:10 8.48 52 10 21 1:4 5.33 53 10 25 1:10 4.98 0.26 54 10 26 1:10
5.33 0.37 *95% of examples 2 or 3 + 5% of methacrylic acid as
described on page 23
[0107] From the foregoing description, one skilled in the art can
easily ascertain the essential characteristics of this invention
and, without departing from the spirit and scope thereof, can make
various changes and modifications of the invention to adapt it to
various usages and conditions.
[0108] The preceding examples can be repeated with similar success
by substituting the generically or specifically described reactants
and/or operating conditions of this invention for those used in the
preceding examples.
* * * * *