FIELD OF THE INVENTION
The present invention generally relates to polyanhydrides with tuneable properties
and to methods for their preparation.
BACKGROUND OF THE INVENTION
Polyanhydrides have been investigated as carriers for the controlled delivery of
several drugs [1]. Polyanhydrides are desirable as controlled release careers because of
their surface eroding properties.
Even though polyanhydrides are easy and inexpensive to synthesize and scale up,
they exhibit a short shelf-life. They have inherent high reactivity toward water, which
prompts rapid hydrolytic degradation. Due to the high rate of hydrolysis, polyanhydrides
endure surface erosion rather than bulk degradation. They are also prone to
depolymerisation via anhydride interchange during storage. Hence, polyanhydrides need to
be kept at freezing storage conditions that restricting their usage in drug delivery products.
To overcome some of the known deficiencies, alternating polyanhydride
copolymers have been utilized. The class of poly(ester-anhydride)s exhibits better drug
release profile, however, the shelf life of the polymer does not substantially improve.
Polyanhydrides based on £-caprolactone were found to suffer from enhanced hydrolytic
stability with a limited shelf life.
Polyanhydrides are commonly prepared by poly-condensation of dicarboxylic acids
in a large excess of refluxing acetic anhydride. For example, Jaszcz at al., [2] synthesized a
polyanhydride using 1:10 w/v acetic anhydride; Narasimhan et al., [3] synthesized several
polyanhydrides using 1:45 w/v acetic anhydride; I Ming Chu [ 4] polymerized sebacic acid
and other diacids using 1:10 w/v acetic anhydride; and A P Herrera et al., [5] synthesized
poly(azelaic ahydride) by microwave irradiation (5 minutes) using a 1:3 w/v relation of
solid dicarboxilic acid to acetic anhydride. Early reports on polyahydride synthesis used
1:10 w/v diacid to anhydride ratio, in some cases a 1:5 ratio is reported. Thus, it is noted
that in all available methodologies, excess of acetic anhydride of 3 to 10 w/v times have
been used which formed polymers of uncontrolled molecular weights and polydispersity.
One such example is the poly(ester-anhydride) based on the ricinoleic acid and
sebacic acid reported in [6-7] and [10].
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REFERENCES
[1] Adv. Mater., 30 (2018) 1706815
[2] RSC Adv., 2019, 9, 20892
[3] ACS Biomater. Sci. Eng. 2020, 6, 265-276
[ 4] J Polym Res 26, 1 (2019)
[5] J. Physics: Conf. Series 687 (2016) 012049
[6] us 10,774,176
[7] us 2020/0101163
[8] us 4,888,176
[9] J. Polymer Sci. Part a-Poly. Chern. 1987;25(12):3373-3386
[10] Domb et al., 2017, J of Controlled Release, 257, 156-162
SUMMARY OF THE INVENTION
Polyanhydrides are a class of biodegradable polymers characterized by anhydride
bonds that connect repeat units of a polymer backbone chain. Despite the extensive use of
polyanhydrides and the various methodologies that have been utilized for their preparation,
as indicated in the background of the invention, polyanhydrides remain generally prone to
hydrolysis, depolymerization and may therefore be produced along with decomposition
products which make their usability in the field such as the medical fields less attractive.
The inventors of the technology disclosed herein have developed a methodology
for producing polyanhydrides with improved properties to those previously disclosed in
the prior art. The novel methodology of the invention involves a reaction between a
hydroxyl-acid with a dicarboxylic acid or cyclic anhydride to produce in one pot a narrow
disperse polyanhydride at high reproducibility. Unlike the synthesis leading to the
polydisperse polymers of the art, such as [6] or [7] or [10], narrow disperse polymers with
high reproducibility of molecular weight were prepared by avoiding use of polymerized
precursors. By reacting the polymer units directly in the presence of small amounts of an
acetylation agent, and in absence of a solvent, polymerization of the polymer units was
achieved with great repeatability and uniformity. The narrow dispersed polymer was
manufactured once and again with low or no variability in polymer physical properties,
composition molecular weight and purity.
Thus, in a first aspect of the invention there is provided a process for producing a
polyanhydride of a narrow-polydispersity.
Also provided is a process for producing a narrow-polydispersed polyanhydride,
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the process compnsmg melt polycondensation of a dicarboxylic acid and a hydroxylalkanoic
acid in the presence of an amount of acetic anhydride not exceeding a mole
equivalent thereof per each free carboxylic acid group and in absence of a solvent.
As will be detailed further below, the process of the invention does not utilize any
solvent medium to carry out condensation of the material precursors into the
polyanhydride. No solvent, aqueous or orgamc, IS used for the conversion. Thus, the
materials are thermally transformed in the melt (herein "melt polycondensation"). Within
the context of the process disclosed herein, the material precursors used to manufacture the
narrow-dispersed polyanhydrides do not act as solvents and thus are not to be considered
solvents.
The absence of a solvent and the sequential addition of the various precursors,
allows for producing a final product that is well characterized and reproducible to meet
regulatory requirements of the highest standards and which exhibits narrow polydispersity.
The term "narrow polydispersity" or any lingual variation thereof, when made in reference
to a polyanhydride according to the invention, defines a collection of materials having
substantially identical compositions (type of repeating groups and manner of repetition)
and molecular weights. The narrow polydispersity of polyanhydrides of the invention,
defined by the ratio Mw/Mn (wherein Mw is the weight-average molecular weight
and Mn is the number-average molecular weight) is below 2.5 or below 2. Putting it
differently, the narrow disperse or narrow polydisperse polyanhydrides of the invention
have a polydispersity value of no more than 2.5 or 2 (or a value between 2.5 and 1, or
between 2 and 1). As a person of skill would appreciate these values indicate a very small
variation and thus very narrow dispersity, suggesting a polymer that is nearly
monodisperse.
As a person of skill would also appreciate the reported polydispersity values of
polyanhydrides range between 3 and 9, values that suggest high dispersity of molecular
weights. For example, publications [8] and [9] reporting on polyanhydrides of a molecular
weight exceeding 5,000, reported polydispersity values ranging from about 4 to about 9.
Polyanhydrides of the invention also exhibit high reproducibility, namely a
reproducibility in polymer molecular weight that is no more than 30% deviation from
polymer average molecular weight.
The term "in absence of a solvent" herein refers to the property of the process of
the invention as having no or a minute amount of solvent(s) that may be derived from
impurities present with the precursor materials. Such impurities will not exceed 0.001%,
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0.005%, 0.01%, 0.05% or 0.1% (w/w) of the total weight of the reaction materials used.
Processes of the invention do not comprise and exclude steps of using or adding a solvent,
or steps which provide raw materials or intermediate materials dissolved in a solvent.
The process of the invention comprises:
-reacting a dicarboxylic acid (DA) or a cyclic anhydride with an hydroxy-alkanoic
acid (HA) under conditions permitting esterification of the dicarboxylic acid (to obtain a
mono ester of the dicarboxylic acid or a di-ester thereof or a mixture thereof); and
-transforming the esterified dicarboxylic acid (mono or di- or mixture thereof) into
the narrow-polydisperse polyanhydride.
The process of the invention permits for direct condensation in bulk (in the melt),
without a pre-reaction to form a polymer or an oligomer of any of the material precursors
used. In an exemplary process, sebacic acid (SA) (a dicarboxylic acid) was reacted with
ricinoleic acid (RA) (a hydroxyl-alkanoic acid) at a 30:70 w/w ratio to form a mixture of
SA-RA dimers and RA-SA-RA trimers with minimal or noRA or RA-RA ester molecules
in the reaction product. The SA-RA and RA-SA-RA mixture (free of the precursor
molecules and of the RA-RA molecules) is thereafter treated with no more than one molar
equivalent of acetic anhydride per free carboxylic acid group (being typically 2 free
carboxylic acid groups and thus no more than 2 molar equivalents) to acetylate the free
ester and thereafter polymerize the acetylated segments into the narrow-dispersed
polyanhydride having the repeating .

CLAIMS:
1. A process for producing a narrow-polydisperse polyanhydride, the process
comprising melt polycondensation of a dicarboxylic acid and a hydroxy-alkanoic acid in
the presence of an amount of acetic anhydride not exceeding a mole equivalent thereof per
each free carboxylic acid group and in absence of a solvent, wherein the process excludes
formation of poly(dicarboxylic acid).
2. The process according to claim 1, wherein the narrow polydispersity, Mw/Mn, is
below 2.5; wherein Mw is a weight-average molecular weight and Mn is a number-average
molecular weight.
3. The process according to claim 1, the process comprising:
-reacting a dicarboxylic acid (DA) or a cyclic anhydride with a hydroxy-alkanoic
acid (HA) under conditions permitting esterification of the dicarboxylic acid to obtain a
mono ester of the dicarboxylic acid and/or a di-ester thereof or a mixture thereof; and
-transforming the esterified mono or di-ester or the mixture of the dicarboxylic acid
into the narrow-polydisperse polyanhydride.
4. The process according to any one of the preceding claims, wherein the dicarboxylic
acid (DA) is a dicarboxylic acid of a C6-C15alkylene or alkenylene.
5. The process according to any one of the preceding claims, wherein the dicarboxylic
acid is selected from succinic acid, adipic acid, maleic acid, suberic acid, sebacic acid
(SA), decandioic acid, azelaic acid, undecanedioic acid, dodecanedioic acid, brassylic acid
and phthalic acid.
6. The process according to claim 1, wherein the dicarboxylic acid IS a cyclic
anhydride of the dicarboxylic acid.
7. The process according to claim 6, wherein the dicarboxylic acid is selected from
succinic acid, maleic acid and phthalic acid.
8. The process according to any one of the preceding claims, wherein the hydroxyalkanoic
acid (HA) is an alkane or alkene substituted with a carboxylic acid group and a
hydroxyl group, wherein the carboxylic acid is an end of chain group and the hydroxyl
group is positioned along the carbon chain.
9. The process according to claim 8, wherein the hydroxy-alkanoic acid has an
alkanoic chain comprising between 2 and 15 carbon atoms.
10. The process according to any one of the preceding claims, wherein the hydroxylalkanoic
acid is selected from ricinoleic acid (RA), hydroxystearic acid (HSA),
hydroxyoctanoic acid, hydroxydecanoic acids, hydroxydodecanoic acid, lactic acid,
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glycolic acid, and hyroxycaproic acid.
11. The process according to any one of the preceding claims, wherein the
polyanhydride is formed of a dicarboxylic acid selected from succinic acid, adipic acid,
maleic acid, suberic acid, sebacic acid (SA), decandioic acid, azelaic acid, undecanedioic
acid, dodecanedioic acid, brassylic acid and phthalic acid and a hydroxy-alkanoic acid
selected from ricinoleic acid (RA), hydroxystearic acid (HSA), hydroxyoctanoic acid,
hydroxydecanoic acids, hydroxydodecanoic acid, lactic acid, glycolic acid, and
hyroxycaproic acid.
12. The process according to any one of the preceding claims, wherein the dicarboxylic
acid is SA.
13. The process according to any one of the preceding claims, wherein the hydroxylalkanoic
acid is RA.
14. The process according to claim 1, wherein the dicarboxylic acid is RA and the
hydroxyl-alkanoic acid is SA.
15. The process according to any one of claims 1 to 14, wherein weight ratio of
dicarboxylic acid : hydroxyl-alkanoic acid is in favor of the hydroxyl-alkanoic acid.
16. The process according to any one of claims 1 to 14, wherein the ratio is 1:1 to 1:2.
17. The process according to claim 3, wherein the reacting of the dicarboxylic acid
(DA) or the cyclic anhydride with the hydroxy-alkanoic acid (HA) to obtain the mixture of
the mono ester of the dicarboxylic acid and/or a di-ester thereof is carried out by heating a
mixture of the DA and the HA at a temperature above 80°C.
18. The process according to claim 17, wherein the temperature is between 80 and 200,
between 100 and 190, between 100 and 180, between 100 and 170, between 100 and 160,
between 100 and 150, between 100 and 140, between 100 and 130, or between 100 and
120 °C.
19. The process according to claim 17, wherein the mono and di-esters are methyl
esters.
20. The process according to claim 19, wherein the methyl esters are obtained in the
presence of acetic anhydride.
21. The process according to claim 20, wherein the acetic anhydride is present in an
amount not greater than one molar equivalent of acetic anhydride per free carboxylic acid
group.
22. The process according to claim 21, wherein the amount is 2, 1.9, 1.8, 1.7, 1.6, 1.5,
1.4 or 1.3 molar equivalents.
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23. The process according to claim 3, wherein the transforming of the esterified mono
or di-ester or the mixture of the dicarboxylic acid into the narrow-polydisperse
polyanhydride is achieved by polymerization.
24. The process according to claim 23, wherein the polymerization is achievable in
vaccuo and heating.
25. The process according to claim 24, wherein the heating compnses heating the
esterified dimer-trimer mixture to a temperature between 100 and 200, between 100 and
190, between 100 and 180, between 130 and 170, between 130 and 160, between 130 and
150, or between 130 and 140°C.
26. The process according to claim 25, wherein the temperature is between 120 and
170 or between 130 and 160°C.
27. The process according to any one of the preceding claims, wherein the process
compnses:
-reacting the dicarboxylic acid (DA) or the cyclic anhydride with the hydroxylalkanoic
acid (HA) at a temperature between 80 and 200°C to obtain a mixture of a mono
ester (DA-HA) and a diester (HA-DA-HA) of the dicarboxylic acid; and
-reacting the mixture with acetic anhydride permitting polymerization of the mono
ester and diester into the polyanhydride.
28. The process according to any one of the preceding claims, the process comprises:
-reacting the dicarboxylic acid (DA) or the cyclic anhydride with the hydroxylalkanoic
acid (HA) at a temperature between 80 and 200°C to obtain a mixture of a mono
ester (DA-HA) and a diester (HA-DA-HA) of the dicarboxylic acid; and
-reacting the mixture with acetic anhydride to acetylate the mixture of the
monoester and diester; and
-thermally treating the acetylated mixture under conditions permitting
polymerization into the polyanhydride.