Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Biodegradable polymers based on naturaNy occurring and renewable raw
materials, in particular isosorbitol
The invention relates to biodegradable polycondensates based on
dianhydrohexitols, to their preparation, and also to their use.
Biodegradable polycondensates degrade within a certain period of time in
a biological medium, losing their original mechanical, physical and
chemical properties as a result of breakdown into small fragments, also
termed metabolites when the application is in the physiological sector - in
particular in humans. An example which may be quoted is a biodegradable
surgical suture which initially has the strength to hold together a sutured
wound but then in the course of time is degraded by the body. Of course,
there must be an appropriate relationship here between the rate of
degradation and the healing of the wound.
For the purposes of the present invention, biological media in which
biodegradable polymers may be used are media which occur in the natural
environment, for example water, air or soil, and also human or animal
bodies, and the interior of plants. Biodegradable polymers are frequently
used in forms which serve only a single purpose, for example surgical
sutures which have solely the function of securing the wound for a
particular time, or waste sacks or packaging films, which undergo
biodegradation after use, the degradation products themselves not having
any particular function.
However, it is also possible to admix active substances with the
biodegradable polymers, or as early as during the synthesis of the
polymers to give these a chemical form which allows the polymers
themselves to develop other active functions besides any mechanical
function which they have. For example, it is possible to produce surgical
sutures which, besides their mechanical function, have a disinfecting
action, for example, or develop a certain medicinal action. Waste sacks
may comprise, for example, substances whose odor repels dogs and cats.
Another important factor for biodegradable polymers is that the
degradation products are substantially compatible with the medium in
which they arise. For example, it is clear that biodegradable polymers can
REPLACEMENT SHEET (RULE 26)
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only be used successfully in the medical sector if the fragments (known as
metabolites) produced on biodegradation are nonhazardous.
Finally, there is also great interest in obtaining polycondensates
substantially from starting materials which occur directly in the natural
environment or are obtained from products which occur in the natural
environment, that is to say from what are known as renewable raw
materials. Particular compounds which are possible molecular building
blocks here are those which occur in metabolism in the natural
environment, either in humans, in animals or in plants. They also include
compounds which can be obtained by hydrolysis, oxidation, redu~ion or
elimination of water from products such as carbohydrates. These
compounds also include what are known as dianhydrohexitols, which are
obtained by dehydrating the corresponding hexahydric alcohols,
specifically isosorbitol, a compound which is obtained by dehydrating
sorbitol and is also called 1,4:3,6-dianhydro-D-sorbitol (DAS), 1,4:3,6-
dianhydro-D-mannitol (DAM), a compound which is obtained by
dehydrating mannitol, and 1,4:3,6-dianhydro-L-iditol (DAI).
There is already extensive literature, especially scientific publications,
concerning the preparation of dianhydrohexitols and their use for preparing
poiycondensates. In this connection it should be pointed out that,
especially in German publications, different names are given to one and
the same compound. For example, the terms isosorbide, isomannide and
isoidide are found in addition to 1,4:3,6-dianhydro-D-sorbitol (DAS) etc.
E. Fl~che et al., for example in starch/st~rke 38(1 ), 26-30 (1986) describe
the preparation and properties of isosorbitol. J. Thiem et al., in
starch/st~rke 36 (5) 170-6 (1984) are concerned with the preparation and
controlled polycondensation of anhydroalditol units from starch. Storbeck
et al., in Makromol. Chem. 194, 53-46, 1993, describe the synthesis of
polyesters from DAS, DAM (1,4:3,6-dianhydro-D-mannitol) and DAI
(1,4:3,6-dianhydro-L-iditol). Other literature references which may be
mentioned are Polymer 34 (23) 5003-6 (1993); Journal of Polymer
Science: Part A: Polymer Chemistry 3~, 2813-20 (1995); Journal of Applied
Polymer Science 59, 1199-1202 (1996); Die Angewandte Makromolekulare
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Chemie 199 (No. 3530) 191-205 (1992) and 2~ (No. 3659) 173-196
(1993).
DE-C 1 263 981 describes modified polyesters in which the glycol
component may be composed of up to 20% by weight of isosorbitol, and
which may moreover have branching brought about by polyfunctional
esters of tri- to pentabasic acids. However, these polycondensates are not
biodegradable.
Polycondensates which have amide functions are described in Trends in
Polymer Science 2(12)425-36 (1994) and Journal of Polymer Science Part
A: Polymer Chemistry 30 2059-62 (1992), for example.
There are therefore numerous known biodegradable polycondensates, but
these have a wide variety of disadvantages. For example, it is often difficult
to establish a sufficiently high molecular weight, and other
polycondensates release excessive amounts of injurious substances on
biodegradation, and others again have limited availability due to high
preparation costs. There is moreover a tack of polycondensates whose
properties can be quite specifically adapted for particular applications.
Although there is already a wide variety of known biodegradable
polycondensates, there is still a need for improved products, for improved
preparation processes and for products which are versatile in use.
It is therefore an object of the invention to provide biodegradable
polycondensates which have good degradation performance, are simple to
produce and can be prepared partially or entirely from renewable raw
materials, and which can be modified straightaway during their synthesis to
make them suitable for a very wide variety of applications.
This object is achieved by means of biodegradable polycondensates as
claimed in patent claim 1. Patent claims 2 to 7 give particularly
advantageous embodiments of the novel polycondensates. These novel
polycondensates may be prepared by processes as claimed in patent
claims 8 to 11. Claims 12 and 13 give particularly advantageous ways of
using the novel polycondensates.
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a)
The dianhydrohexitols used according to the invention, specifically
isosorbitol, isomannitol and isoiditol, may be prepared by processes known
per se, by dehydrating the corresponding hexitols, such as sorbitol,
mannitol, etc. These compounds, e.g. isosorbitol, can be obtained in
relatively large volumes from starch, and are available commercially.
b)
The dibasic organic carboxylic acids used as second component may be
aliphatic, cycloaliphatic or aromatic. Examples which may be mentioned
here are terephthalic acid, adipic acid, furandicarboxylic acid, and also
3,6,9-trioxaundecanedicarboxylic acid, the use of which is preferred. The
dicarboxylic acids may be used as such during the synthesis, but it is also
possible to use appropriate derivatives, such as acid chlorides or esters o~
the carboxylic acids.
c)
Examples which may be mentioned of the polyfunctional organic carboxylic
acids which, besides two carboxylic acid functions, have at least one other
uncapped or capped function, specifically OH and/or COOH, are tartaric
acid, malic acid, hydroxysuccinic acid, citric acid, isocitric acid, aconitic
acid
and the like. In particular, use may also be made of cholic acid or
deoxycholic acid, the biological functions of which make them particular
suitable for incorporation in functional biopolymers.
An additional point which should be mentioned for group c) is that these
carboxylic acids may be used as such, that is to say with the two or more
functions uncapped, i.e. free and accessible for an immediate
condensation reaction, or capped, e.g. etherified or esterified. It is fully
possible here for all three functions of some trifunctional units to be
involved in the polymerization reaction. Partial reactions are also
conceivable in which the reaction of only one functional group leads to
incorporation into the polymer. This is what is known as a polymer end
group function, and the polymerization reaction does not involve the two
other functional groups. The functional groups not taking part in the
polymerization reaction may either remain capped (protected) or have their
capping removed following the preparation of the polymer, in a polymer-
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analogous reaction. This corresponds chemically to the cleavage of what is
known as a protecting group, initially introduced in order to cap the
function.
Besides these three components a), b) and c), other components may be
incorporated into the biodegradable polycondensates, in particular
bifunctional components, such as alpha amino acids, e.g. serine,
glutamine, lysine, giutamic acid, aspartic acid, and cystein, and it is also
possible to make concomitant use of hydroxycarboxylic acids or of
dihydroxy compounds. Incorporation of molecules of this type does not
alter the stoichiometric ratio of the two different functional groups.
Incorporating, for example, 4-hydroxybenzoic acid increases the distances
between monomers of the same type, as required by statistical laws, and
thus has a controlled effect on the physical properties of the polymer in a
manner known to the skilled worker, e.g. on glass transition temperature.
The polycondensation may be carried out by customary processes known
per se, such as those known as one-pot reactions, in which all of the
starting materials are mixed thoroughly at the very outset and are reacted
with or without the use of a catalyst. This reaction may be carried out in the
melt, or else in solution. However, continuous and semicontinuous
processes are also possible.
Very suitable solvents besides dichloromethane, the use of which is
preferred, include dimethylformamide, dimethyl sutfoxide and N
methylpyrrolidone.
It is appropriate for the reaction to be carried out by reacting equal molar
amounts of OH and COOH groups. However, it is possible to deviate from
the stoichiometric ratio, but the deviation from the stoichiometric ratio is
preferably not more than 5 mol%.
Balancing of the stoichiometry of the different functional groups with
respect to one another is generally advantageous. In the ideal case, diol
components and dicarboxylic acid components, for example, are present in
an equimolar ratio. For particular applications, e.g. if retarded or
accelerated biodegradation is required, it may be appropriate to deviate
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from this ideal condition, and therefore it is also possible to pn3pare
crosslinked polymers (gels) by methods known to the skilled worker.
The dianhydrohexitols, e.g. isosorbide, which are used according to the
invention to build up the polycondensates react as glycols with the COOH
groups of the carboxylic acids used. The molar amounts of these
compounds used are preferably such that at least 50 percent, preferably at
least 70 percent, of the COOH groups of the acids can react with the OH
groups of the dianhydrohexitols.
The properties of the novel polycondensates may particularly
advantageously be modified by incorporating other units, and it is therefore
possible to prepare tailored polycondensates for specific applications. An
example which may be mentioned here is the corxomitant use of amino
acids and hydroxycarboxylic acids, e.g. hydroxybutyric acid, 4-
hydroxybenzoic acid, 2-hydroxy-6-naphthoic acid, 4-aminobenzoic acid,
glycolic acid, 4-hydroxybiphenyl-4-carboxylic acid, lithochdic acid, or 4-
hydroxycinnamic acid.
The novel polycondensates have very good biodegradability. Although
there is no desire to lay down a theory here, it is bkely that the
improvement in biodegradability over other biodegradable poaycondensates
is brought about by the incorporation of the units with the at least three
functions, i.e. by the polyfunctional carboxylic acid which have one or more
additional OH or COOH functions, e.g. malic acid.
It is also possible to exert a further favorable effect on biodegradability by
making concomitant use of condensable starting materials which have
heteroatoms. 3,6,9-Trioxaundecanedicarboxylic acid espeaally shouki be
mentioned here. It is also advantageous for there to be some concomitant
incorporation of compounds which have amino functions.
For the purposes of the present invention, a biodegradable potycondensate
is one which, when placed in an appropriate medium, is degraded over the
course of time into relatively small cleavage products which are preferably
nonhazardous to the environment, humans, animals and plants. For the
purposes of the present invention, the concept of biodegradability includes
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concepts such as bioerodability, enzymatic cleavability, compostability,
biodegradability, hydrolyzabil'rty, digestability, edibility etc.
The incorporation of compounds having more than two functional groups in
the biodegradable polymers described here according to the invention
makes these polymers especially suitable for use as functional
biodegradable polymers.
The novel polymers may be processed in the melt, but may also be
processed using appropriate solvents. They can be processed to give any
conceivable type of molding, such as bags, films, tablets, capsules, fibers,
hollow fibers, powders and the like.
They may be used in particular where controlled release of active
substances is involved. The active substance here may have been
incorporated into the polycondensate, and in this case is released during
biodegradation in the medium itself and can then develop its action.
According to the invention it is also possible for the polycondensates to be
used to produce articles, such as capsules, which encompass an active
substance which is then either released after a certain time when the
capsule has been dissolved or leached out from the capsule by the
medium over the course of time.
However, it is also possible for the polycondensate to be used as a matrix,
in this case the active ingredient is uniformly dispersed in the polymer, e.g.
in the melt or else in a solution, so that degradation of the polycondensate
is accompanied by release of the active substance.
The polycondensates may be used in a very wide variety of sectors. For
example, they may be used in agriculture for the controlled release of
fertilizers or of herbicides, pesticides or the like. Another application
sector
is the pharmaceutical sector, where the polycondensates can be used as
tablets, for example. In the medical sector, the polycondensates may also
be used subcutaneously, e.g. in an appropriate form, for example in the
form of microparticles or of extrudates.
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The preparation process is very flexible and controllable, and it is therefore
even possible to produce different molecular weights, or else
polycondensates with a tailored property profile.
The invention is further described by the examples below:
Example 1
3.18 g (21.76 mmol) of L-isosorbitol, 2.472 g (10.88 mmol) of dichloro-2,3-
o-isopropylidene L-tartrate, 2.209 g (10.88 mmol) of terephthalic dichloride,
50 ml of dried dichloromethane and 3.6 ml (44.60 mmol) of pyridine are
mixed and refluxed for 3 days, with stirring. During this process a white
precipitate forms. The polycondensate is then precipitated in cyclohexane,
and after drying it is dissolved in tetrahydrofuran (TH~/acetone and
precipitated in water, filtered off with suction and dried in vacuo.
White powder; yield 3.9 g corresponding to 64% of theory.
Elemental anal % C % H
sis:
calc. 56.3 4.9
found 56.8 5.3
Rotation determined in solution in dichloromethane
a = +82.4°
D
Molecular weight 6,700 (MW) (after previous calibration of a gel permeation
chromatography (GPC) system using polystyrene standard).
25 Example 2
3.046 g (20.8 mmol) of L-isosorbide, 1.15 g (6.28 mmol) of adipic
dichloride, 3.31 g (14.57 mmol) of dichloro-2,3-o-isopropylidene L-tartrate,
70 ml of dried dichloromethane and 3.3 ml (41.72 mmol) of pyridine are
mixed, and then the procedure continues as in example 1.
White powder, yield 3.8 g corresponding to 639'0 of theory.
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Elemental sis:~ C ~ H
ana
talc. 53.1 5.6
found 58.4 5.5
Rotation determined in solution in dichloromethane: a25 = + 78.6°
D
Molecular weight 6,400 Dalton (Mw), polydispersity (M",/M") = 2.9 (after
previous calibration of a gel permeation chromatography (GPC) system
using polystyrene standard).
Example 3
3.193 g (21.85 mmol) of L-isosorbide, 1.489 g (6.55 mmol) of dichloro-2,3-
o-isopropylidene L-tartrate, 2.952 g (15.30 mmol) of furandicarboxylic
dichloride, 70 ml of dried dichloromethane and 3.5 ml (44.5 mmol) of
pyridine are mixed, and then the procedure continues as in example 1.
White powder, yield 4.9 g corresponding to 83% of theory.
20
Elemental anal % C % H
sis:
calc. 42.3 4.3
found 42.9 4.5
Rotation determined in solution in dichloromethane: a25 --35.3°
D
Molecular weight 8,200 Dalton (Mw) (after previous calibration of a gel
permeation chromatography (GPC) system using polystyrene standard).
Example 4
The biodegradability of the polymers was studied using a modified Sturm
test. The test was carried out to OECD Guideline 301 B (1992; Sturm test).
The test serves to determine the biodegradability of organic substances by
aerobic microorganisms in an aqueous test medium. The organic test
substance is the sole source of carbon in the experiment and is therefore
the supplier of energy for the microorganisms. The degradation of the
organic substances to be studied here is determined indirectly via
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measurement of the amount of carbon dioxide evolved. Each test lasts for
28 days. Sodium benzoate serves as an internal standard.
The detailed test conditions are: a supernatant used from activated sludge
from the Frankfurt Niederrad sewage-treatment plant (10 ml per 1 I of test
mixture); brown glass bottles of 5 I capacity; magnetic stirrer, room
temperature, C02 determined via barium carbonate formation in aqueous
Ba(OH)2 solution and back-titration of the excess of alkali.
TIME BLIND SODIUM SODIUM POLY-L-LACTIC ACID
(DAYS) MIXTURE BENZOATE BENZOATE DEGREE OF
C02 (mg) COZ (mg) DEGREE OF DEGRADATION (%)
DEGRADATION COMPARATIVE
EXAMPLE
1 0.7 1.6 1 2
4 , 2.4 24.3 34 8
7 3.6 40.7 58 18
11 4.6 50.7 72 38
14 5.3 55.6 78 53
18 6.7 59.3 g 1
21 8.4 61.9 83 71
25 10.7 65.4 85 79
28 14.8 69.6 85 82
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TIME SODIUM POLYMER POLYMER POLYMER
(DAYS) BENZOATE EXAMPLE 1 EXAMPLE 2 EXAMPLE 3
DEGREE OF DEGREE OF DEGREE OF DEGREE OF
DEGRADATIO DEGRADATlO DEGRADATIO DEGRADATIO
N % N % N % N
1 2
4 34 2 14 g
7 58 2~ 29 26
11 72 51 58 45
14 78 66 75 6
18 81 79 79 74
21 83 83 83 78
25 85 86 85 82
28 g5 89 8 85
