U.S. patent application number 14/150430 was filed with the patent office on 2014-10-02 for polymer hydrogels and methods of preparation thereof.
This patent application is currently assigned to GELESIS LLC. The applicant listed for this patent is GELESIS LLC. Invention is credited to Luigi Ambrosio, Christian Demitri, Luigi Nicolais, Alessandro Sannino.
Application Number | 20140296507 14/150430 |
Document ID | / |
Family ID | 39312966 |
Filed Date | 2014-10-02 |
United States Patent
Application |
20140296507 |
Kind Code |
A1 |
Sannino; Alessandro ; et
al. |
October 2, 2014 |
Polymer Hydrogels and Methods of Preparation Thereof
Abstract
The invention relates to a method for the preparation of a
polymer hydrogel, comprising cross-linking a precursor comprising a
hydrophilic polymer optionally in combination with a second
hydrophilic polymer, using a polycarboxylic acid as the
cross-linking agent. The invention further concerns the polymer
hydrogel obtainable by the method of the invention and the use
thereof in a number of different applications.
Inventors: |
Sannino; Alessandro; (Lecce,
IT) ; Ambrosio; Luigi; (Ottaviano (Naples), IT)
; Nicolais; Luigi; (Ercolano (Naples), IT) ;
Demitri; Christian; (San Pietro In Lama, IT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GELESIS LLC |
Boston |
MA |
US |
|
|
Assignee: |
GELESIS LLC
Boston
MA
|
Family ID: |
39312966 |
Appl. No.: |
14/150430 |
Filed: |
January 8, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12703286 |
Feb 10, 2010 |
8658147 |
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14150430 |
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PCT/EP2008/006582 |
Aug 8, 2008 |
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12703286 |
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PCT/IT2007/000584 |
Aug 10, 2007 |
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PCT/EP2008/006582 |
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Current U.S.
Class: |
536/63 |
Current CPC
Class: |
A61K 47/38 20130101;
A23L 29/262 20160801; A61K 31/765 20130101; A61L 15/28 20130101;
Y02W 30/40 20150501; A61L 15/60 20130101; A61P 3/04 20180101; Y02W
30/47 20150501; C08B 11/20 20130101; C08B 15/005 20130101; C08J
3/246 20130101; C08J 2301/28 20130101; A61K 9/06 20130101; A61L
15/225 20130101; C08J 3/24 20130101; Y02E 50/30 20130101; Y02E
50/343 20130101; A61L 15/225 20130101; C08L 1/26 20130101; A61L
15/28 20130101; C08L 1/26 20130101 |
Class at
Publication: |
536/63 |
International
Class: |
C08B 15/00 20060101
C08B015/00 |
Claims
1-35. (canceled)
36. A polymer hydrogel comprising an ionic polymer and a
polycarboxylic acid selected from C.sub.4-C.sub.12-dicarboxylic
acids, tricarboxylic acids and tetracarboxylic acids, wherein said
polycarboxylic acid cross-links the ionic polymer, said polymer
hydrogel having a swelling ratio in distilled water of at least
about 50.
37. The polymer hydrogel of claim 36, wherein the ionic polymer is
carboxymethylcellulose and the polycarboxylic acid is citric
acid.
38. The polymer hydrogel of claim 37 wherein the weight ratio of
citric acid to carboxymethylcellulose is about 1% to about 5%.
39. (canceled)
40. The polymer hydrogel of claim 36 having a swelling ratio in
distilled water of at least 70.
41. The polymer hydrogel of claim 40 having a swelling ratio in
distilled water of at least about 100.
42-51. (canceled)
52. The polymer hydrogel of claim 40 having a swelling ratio in
distilled water of at least 80.
53. The polymer hydrogel of claim 40 having a swelling ratio in
distilled water of about 50 to about 250.
54. The polymer hydrogel of claim 40 having a swelling ratio in
distilled water of about 50 to about 350.
55. A pharmaceutical composition comprising the polymer hydrogel of
claim 36.
56. The pharmaceutical composition of claim 55 wherein the ionic
polymer is carboxymethylcellulose and the polycarboxylic acid is
citric acid.
57. The pharmaceutical composition of claim 56 wherein the weight
ratio of citric acid to carboxymethylcellulose is about 1% to about
5%.
58. The pharmaceutical composition of claim 55 wherein the polymer
hydrogel has a swelling ratio in distilled water of at least about
70.
59. The pharmaceutical composition of claim 55 wherein polymer
hydrogel has a swelling ratio in distilled water of at least about
100.
60. The pharmaceutical composition of claim 55 wherein the polymer
hydrogel has a swelling ratio in distilled water of at least about
80.
61. The pharmaceutical composition of claim 55 wherein the polymer
hydrogel has a swelling ratio in distilled water of about 50 to
about 250.
62. The pharmaceutical composition of claim 55 wherein the polymer
hydrogel has a swelling ratio in distilled water of about 50 to
about 350.
Description
RELATED APPLICATION(S)
[0001] This application is a continuation of U.S. application Ser.
No. 12/703,286, filed Feb. 10, 2010, which is a continuation of
International Application No. PCT/EP2008/006582, which designated
the United States and was filed on Aug. 8, 2008, published in
English, which is a continuation-in-part of International
Application No. PCT/IT2007/000584, which designated the United
States and was filed on Aug. 10, 2007, published in English. The
entire teachings of the above applications are incorporated herein
by reference.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to polymer hydrogels and
methods of preparation thereof.
[0003] Polymer hydrogels are cross-linked hydrophilic polymers
which are capable of absorbing high amounts of water. In
particular, cross-linked polymer hydrogels capable of absorbing an
amount of water in excess of 10 times their dry weight are defined
as "superabsorbent". Some of these materials are even capable of
absorbing over 1 litre of water per gram of dry polymer.
[0004] The cross-links or cross-linking knots, i.e. the physical or
chemical bonds between the macromolecular chains forming the
polymer hydrogel network, guarantee the structural integrity of the
polymer-liquid system, on the one hand preventing the complete
solubilisation of the polymer, and on the other hand allowing the
retention of the aqueous phase within the molecular mesh.
[0005] The superabsorbent polymer hydrogels which are currently
available on the market are characterised not only by their marked
absorbent properties, but also by their biocompatibility, which is
probably due to the high water content, and, above all, by the
possibility of adjusting their absorption properties according to
the external stimuli. Consequently, such polymer hydrogels may be
used as intelligent materials, for example for the manufacture of
sensors or actuators for a number of industrial applications.
Besides the usual applications as absorbent cores in the field of
personal hygiene absorbent products, there are more recent and
innovative applications such as for example in the biomedical
field, for the development of controlled release drug formulations,
artificial muscles, sensors, etc., and in agriculture and
horticulture, for example in devices for the controlled release of
water and nutrients in arid soils.
[0006] However, the superabsorbent polymer hydrogels currently
available are almost exclusively acrylic-based products, and hence
not biodegradable.
[0007] Given the growing interest in environmental protection
issues, over recent years a vast amount of interest has been
focussed on the development of superabsorbent materials based on
biodegradable polymers, having properties which are similar to
those of the traditional superabsorbent polyacrylics.
[0008] Examples of biodegradable polymers used to obtain
superabsorbent polymer hydrogels are starch and cellulose
derivatives.
[0009] In 1990 Anbergen and Oppermann [1] proposed a method for the
synthesis of a superabsorbent material made entirely from cellulose
derivatives. In particular, they used hydroxyethylcellulose (HEC)
and a carboxymethylcellulose sodium salt (CMCNa), chemically
cross-linked in a basic solution with divinylsulphone. However, the
absorption properties of such materials are not high compared to
those of the acrylic-based superabsorbent materials.
[0010] In 1996 Esposito and co-workers [2], studying the synthetic
process proposed by Anbergen and Opperman, developed a method for
increasing the absorption properties of the gel, acting mainly on
the physical properties of the material. The basic idea was the
induction of microporosity into the polymer structure, so as to
promote absorption and retention of water by capillarity. Said
microporosity was induced during the drying step, which was carried
out by phase inversion in a nonsolvent for the polymer, and the
absorption properties of the material thus obtained were markedly
superior to those of the air-dried gel.
[0011] CMCNa may be chemically cross-linked with any reagent which
is bifunctional with respect to cellulose. Besides the
divinylsulphone used in the synthetic process according to Anbergen
and Opperman, epichlorohydrin, formaldehyde and various diepoxides
have also been used as cross-linking agents. However, such
compounds are highly toxic in their unreacted states [3]. Some
carbodiimides are known amongst the unconventional cross-linking
agents. Particularly, the use of carbodiimides in order to
cross-link salified or non-salified carboxymethylcellulose (CMC)
was described in [4]. Carbodiimides induce the formation of ester
bonds between cellulose macromolecules without participating in the
bonds themselves, instead giving rise to a urea derivative having
very low toxicity [5]. A superabsorbent polymer hydrogel obtained
by cross-linking carboxymethylcellulose sodium salt and
hydroxyethylcellulose with carbodiimide as the cross-linking agent
is disclosed in the international patent application WO 2006/070337
[6].
[0012] However, the carbodiimide used as a cross-linking agent in
WO 2006/070337 has the disadvantage of being extremely expensive.
Moreover, during the cross-linking reaction with CMCNa, this
substance turns into a slightly toxic urea derivative, which must
be removed during the washing step, thereby further increasing the
costs and the complexity of the production process. These drawbacks
are extremely unfavourable, particularly in connection with those
applications which require large scale production of the polymer
hydrogels and which, consequently, involve high costs both with
respect to the purchase of the starting materials and with respect
to the disposal of the toxic substances which are produced during
synthesis.
[0013] Furthermore, the formation of substances having a certain
degree of toxicity, although very low, is a key factor for ruling
out the possibility of using such polymers in biomedical and
pharmaceutical applications.
SUMMARY OF THE INVENTION
[0014] The object of the present invention is to provide polymer
hydrogels which overcome the above-mentioned disadvantages
associated with the use of carbodiimide as a cross-linking
agent.
[0015] These and other objects are achieved by the polymer
hydrogels of the invention and the method of preparation thereof as
defined herein. The polymer hydrogels of the invention are based on
the use of a polycarboxylic acid, such as citric acid, as the
cross-linking agent, and in preferred embodiments, also include the
use of a molecular spacer.
[0016] The invention relates, in part, to the discovery that the
cross-linking of soluble cellulose derivatives with citric acid
(3-carboxy-3-hydroxy-1,5-pentanedioic acid; hereinafter designated
"CA") results in the formation of polymer hydrogels and
superabsorbent polymer hydrogels. CA is naturally occurring,
non-toxic and available on the market at low cost. Although CA has
been reported as a cross-linking agent for polymers such as
cellulose, hydroxypropylmethylcellulose and starch, in textile and
food applications [7-11], in these applications CA is used to
cross-link and further stabilize insoluble fibers, to provide a
fabric with enhanced resiliency and mechanical properties. However,
the use of CA to cross-link carboxymethylcellulose or other soluble
hydrophilic polymers for preparing polymer hydrogels and
superabsorbent polymer hydrogels has not been previously
disclosed.
[0017] The method of preparing a polymer hydrogel according to the
present invention comprises the step of cross-linking an aqueous
solution comprising a hydrophilic polymer with a polycarboxylic
acid, optionally in the presence of a compound which functions as a
molecular spacer.
[0018] In one embodiment, the aqueous solution comprises two or
more hydrophilic polymers, such as, for example, hydroxylated
polymers. For example, the aqueous solution can comprise a first
hydrophilic polymer and a second hydrophilic polymer, which can be
present in the same or different amounts on a weight basis. In one
embodiment, the first hydrophilic polymer is an ionic polymer and
the second polymer is a nonionic polymer.
[0019] In one preferred embodiment, the invention provides a method
for preparing a polymer hydrogel, comprising the steps of (a)
providing an aqueous solution of carboxymethylcellulose,
hydroxyethylcellulose, citric acid and a molecular spacer; (b)
heating the aqueous solution, thereby evaporating the water and
cross-linking the carboxymethylcellulose and hydroxyethylcellulose
to form a polymer hydrogel material; (c) washing the polymer
hydrogel material with water or a polar organic solvent to form a
washed polymer hydrogel; (d) immersing the washed polymer hydrogel
in a cellulose nonsolvent, thereby producing a dried polymer
hydrogel.
[0020] In yet another embodiment, the present invention provides
polymer hydrogels, such as superabsorbent polymer hydrogels, which
can be prepared using the methods of the invention. Such polymer
hydrogels comprise at least one hydrophilic polymer cross-linked
with a polycarboxylic acid. Further, the invention includes
articles of manufacture which comprise such polymer hydrogels.
BRIEF SUMMARY OF THE DRAWINGS
[0021] FIG. 1 illustrates the proposed mechanism of polymer
cross-linking by citric acid.
[0022] FIG. 2 is a graph of cumulative food intake as a function of
time for rats administered a polymer hydrogel of the invention
orally and rats administered vehicle only.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The present invention provides polymer hydrogels, methods of
preparing the polymer hydrogels, methods of use of the polymer
hydrogels and articles of manufacture comprising the polymer
hydrogels.
[0024] The method of preparing a polymer hydrogel of the present
invention comprises the step of cross-linking an aqueous solution
comprising a hydrophilic polymer with a polycarboxylic acid,
thereby producing the polymer hydrogel. In some embodiments, the
aqueous solution comprises two or more hydrophilic polymers. For
example, the aqueous solution can comprise a first hydrophilic
polymer and a second hydrophilic polymer, which can be present in
the same or different amounts on a weight basis. In preferred
embodiments, the first hydrophilic polymer is an ionic polymer and
the second polymer is a nonionic polymer.
[0025] The cross-linking reaction is preferably conducted at
elevated temperature, for example, at a temperature greater than
room temperature (25.degree. C.). For example, the reaction can be
conducted at a temperature from about 30.degree. C. to about
150.degree. C., preferably from about 50.degree. C. to about
120.degree. C. In one embodiment, while the cross-linking reaction
is conducted at elevated temperature, the reaction solution is
concentrated by removal of water. The removal of water can be
accomplished, for example, by evaporation. In one embodiment, a
fraction of the water is removed. In another embodiment,
substantially all of the water is removed, thereby producing a dry
residue. Optionally, the reaction mixture is maintained at elevated
temperature for a period of time following removal of water to
dryness.
[0026] As used herein, the term "hydrophilic polymer" refers to a
polymer which is substantially water-soluble and, preferably,
includes monomeric units which are hydroxylated. A hydrophilic
polymer can be a homopolymer, which includes only one repeating
monomeric unit, or a copolymer, comprising two or more different
repeating monomeric units. In a preferred embodiment, the
hydrophilic polymer is hydroxylated, such as polyallyl alcohol,
polyvinyl alcohol or a polysaccharide. Examples of suitable
polysaccharides include substituted celluloses, substituted
dextrans, starches and substituted starches, glycosaminoglycans,
chitosan and alginates.
[0027] Polysaccharides which can be used include alkylcelluloses,
such as C.sub.1-C.sub.6-alkylcelluloses, including methylcellulose,
ethylcellulose and n-propylcellulose; substituted alkylcelluloses,
including hydroxy-C.sub.1-C.sub.6-alkylcelluloses and
hydroxy-C.sub.1-C.sub.6-alkyl-C.sub.1-C.sub.6-alkylcelluloses, such
as hydroxyethylcellulose, hydroxy-n-propylcellulose,
hydroxy-n-butylcellulose, hydroxypropylmethylcellulose,
ethylhydroxyethylcellulose and carboxymethylcellulose; starches,
such as corn starch, hydroxypropylstarch and carboxymethylstarch;
substituted dextrans, such as dextran sulfate, dextran phosphate
and diethylaminodextran; glycosaminoglycans, including heparin,
hyaluronan, chondroitin, chondroitin sulfate and heparan sulfate;
and polyuronic acids, such as polyglucuronic acid, polymanuronic
acid, polygalacturonic acid and polyarabinic acid.
[0028] As used herein, the term "ionic polymer" refers to a polymer
comprising monomeric units having an acidic functional group, such
as a carboxyl, sulfate, sulfonate, phosphate or phosphonate group,
or a basic functional group, such as an amino, substituted amino or
guanidyl group. When in aqueous solution at a suitable pH range, an
ionic polymer comprising acidic functional groups will be a
polyanion, and such a polymer is referred to herein as an "anionic
polymer". Likewise, in aqueous solution at a suitable pH range, an
ionic polymer comprising basic functional groups will be a
polycation. Such a polymer is referred to herein as a "cationic
polymer". As used herein, the terms ionic polymer, anionic polymer
and cationic polymer refer to hydrophilic polymers in which the
acidic or basic functional groups are not charged, as well as
polymers in which some or all of the acidic or basic functional
groups are charged, in combination with a suitable counterion.
Suitable anionic polymers include alginate, dextran sulfate,
carboxymethylcellulose, hyaluronic acid, polyglucuronic acid,
polymanuronic acid, polygalacturonic acid, polyarabinic acid;
chrondroitin sulfate and dextran phosphate. Suitable cationic
polymers include chitosan and dimethylaminodextran. A preferred
ionic polymer is carboxymethylcellulose, which can be used in the
acid form, or as a salt with a suitable cation, such as sodium or
potassium.
[0029] The term "nonionic polymer", as used herein, refers to a
hydrophilic polymer which does not comprise monomeric units having
ionizable functional groups, such as acidic or basic groups. Such a
polymer will be uncharged in aqueous solution. Examples of suitable
nonionic polymers for use in the present method are
polyallylalcohol, polyvinylalcohol, starches, such as corn starch
and hydroxypropylstarch, alkylcelluloses, such as
C.sub.1-C.sub.6-alkylcelluloses, including methylcellulose,
ethylcellulose and n-propylcellulose; substituted alkylcelluloses,
including hydroxy-C.sub.1-C.sub.6-alkylcelluloses and
hydroxy-C.sub.1-C.sub.6-alkyl-C.sub.1-C.sub.6-alkylcelluloses, such
as hydroxyethylcellulose, hydroxy-n-propylcellulose,
hydroxy-n-butylcellulose, hydroxypropylmethylcellulose, and
ethylhydroxyethylcellulose.
[0030] As used herein, the term "polycarboxylic acid" refers to an
organic acid having two or more carboxylic acid functional groups,
such as dicarboxylic acids, tricarboxylic acids and tetracarboxylic
acids, and also includes the anhydride forms of such organic acids.
Dicarboxylic acids include oxalic acid, malonic acid, maleic acid,
malic acid, succinic acid, glutaric acid, adipic acid, pimelic
acid, suberic acid, azelaic acid, sebacic acid, phthalic acid,
o-phthalic acid, isophthalic acid, m-phthalic acid, and
terephthalic acid. Preferred dicarboxylic acids include
C.sub.4-C.sub.12-dicarboxylic acids. Suitable tricarboxylic acids
include citric acid, isocitric acid, aconitic acid, and
propane-1,2,3-tricarboxylic acid. Suitable tetracarboxylic acids
include pyromellitic acid, 2,3,3',4'-biphenyltetracarboxylic acid,
3,3',4,4'-tetracarboxydiphenylether,
2,3',3,4'-tetracarboxydiphenylether,
3,3',4,4'-benzophenonetetracarboxylic acid,
2,3,6,7-tetracarboxynaphthalene, 1,4,5,7-tetracarboxynaphthalene,
1,4,5,6-tetracarboxynaphthalene,
3,3',4,4'-tetracarboxydiphenylmethane,
2,2-bis(3,4-dicarboxyphenyl)propane, butanetetracarboxylic acid,
and cyclopentanetetracarboxylic acid. A particularly preferred
polycarboxylic acid is citric acid.
[0031] The method can further include the steps of purifying the
polymer hydrogel, for example, by washing the polymer hydrogel in a
polar solvent, such as water, a polar organic solvent, for example,
an alcohol, such as methanol or ethanol, or a combination thereof.
The polymer hydrogel immersed in the polar solvent swells and
releases any component, such as by-products or unreacted
polycarboxylic acid that was not incorporated into the polymer
network. Water is preferred as the polar solvent, distilled water
is still more preferred. The volume of water required during this
step to reach the maximum swelling degree of the gel, is
approximately 10- to 20-fold greater than the initial volume of the
gel itself. Taking into account the substantial amounts of water
which would be involved during this step on an industrial scale, as
well as the disposal and/or recycling of the washes, the importance
of avoiding the presence of any toxic by-products in the synthetic
process becomes evident. The polymer hydrogel washing step may be
repeated more than once, optionally changing the polar solvent
employed. For example, the polymer hydrogel can be washed with
methanol or ethanol followed by distilled water, with these two
steps optionally repeated one or more times.
[0032] The method can further include drying of the polymer
hydrogel. The drying step is carried out by immersing the fully
swollen polymer hydrogel in a cellulose nonsolvent, a process known
as phase inversion. Suitable cellulose nonsolvents include, for
example, acetone and ethanol. Drying the polymer hydrogel by phase
inversion results in a final microporous structure which improves
the absorption properties of the polymer hydrogel by capillarity.
Moreover, if the porosity is interconnected or open, i.e. the
micropores communicate with one another, the absorption/desorption
kinetics of the gel will be improved as well. When a completely or
partially swollen gel is immersed into a nonsolvent, the gel
undergoes phase inversion with the expulsion of water, until the
gel precipitates in the form of a vitreous solid as white coloured
particles. Various rinses in the nonsolvent may be necessary in
order to obtain the dried gel in a short period of time. For
example, when the swollen polymer hydrogel is immersed in acetone
as the non-solvent, a water/acetone mixture is formed which
increases in water content as the polymer hydrogel dries; at a
certain acetone/water concentration, for example, about 55% in
acetone, water is no longer able to exit from the polymer hydrogel,
and thus fresh acetone has to be added to the polymer hydrogel to
proceed with the drying process. The higher the acetone/water ratio
during drying, the faster is the drying process. Pore dimensions
are affected by the rate of the drying process and the initial
dimensions of the polymer hydrogel particles: larger particles and
a faster process tend to increase the pore dimensions; pore
dimensions in the microscale range are preferred, as pores in this
size range exhibit a strong capillary effect, resulting in the
higher sorption and water retention capacity.
[0033] The polymer hydrogels of the invention can also be dried by
another process, such as air drying, freeze drying or oven drying.
These drying methods can be used alone, in combination, or in
combination with the non-solvent drying step described above. For
example, the polymer hydrogel can be dried in a non-solvent,
followed by air drying, freeze drying, oven drying, o a combination
thereof to eliminate any residual traces of nonsolvent. Oven drying
can be carried out at a temperature of e.g. approximately
30-45.degree. C. until the residual nonsolvent is completely
removed. The washed and dried polymer hydrogel can then be used as
is, or can be milled to produce polymer hydrogel particles of a
desired size.
[0034] The cross-linking solution can optionally include a compound
which serves as a molecular spacer. A "molecular spacer", as this
term is used herein, is a polyhydroxylated compound which, although
not taking part in the reaction resulting in the formation of the
cross-linked polymer hydrogel network to a significant extent,
results in a polymer hydrogel with an increased absorption
capacity. Although in certain cases the molecular spacer may
participate in the cross-linking reaction to a small extent, it is
believed that molecular spacers function by sterically blocking
access to the polymer chains, thereby increasing the average
distance between the polymer chains. Cross-linking, therefore, can
occur at sites which are not close together, thereby enhancing the
ability of the polymer network to expand so as to greatly increase
the polymer hydrogel absorption properties. Suitable compounds for
use as molecular spacers in the methods of the present invention
include monosaccharides, disaccharides and sugar alcohols,
including sucrose, sorbitol, plant glycerol, mannitol, trehalose,
lactose, maltose, erythritol, xylitol, lactitol, maltitol,
arabitol, glycerol, isomalt and cellobiose. The molecular spacer is
preferably included in the cross-linking solution in the amount of
about 0.5% to about 10% by weight relative to the solvent, more
preferably about 2% to about 8% and more preferably about 4%.
[0035] According to a preferred embodiment of the invention, the
molecular spacer used to synthesise the polymer hydrogel is
selected from the group consisting of sorbitol, sucrose and plant
glycerol.
[0036] According to a particularly preferred embodiment of the
method of the invention, sorbitol is used as the molecular spacer,
at a concentration within the range of 0.5 to 10% by weight
referred to the weight of water, preferably within the range of 2
to 8% by weight referred to the weight of water, still more
preferably at a concentration of 4% by weight referred to the
weight of water.
[0037] In one embodiment, the aqueous solution includes an ionic
polymer, preferably an anionic polymer, and most preferably,
carboxymethylcellulose. In a particularly preferred embodiment the
anionic polymer is carboxymethylcellulose and the polycarboxylic
acid is citric acid.
[0038] In another embodiment, the aqueous solution includes an
ionic polymer and a non-ionic polymer. The ionic polymer is
preferably an anionic polymer, and most preferably,
carboxymethylcellulose. The non-ionic polymer is preferably a
substituted cellulose, more preferably a hydroxyalkylcellulose or a
hydroxyalkyl alkylcellulose, and most preferably
hydroxyethylcellulose ("HEC"). The preferred polycarboxylic acid is
citric acid.
[0039] The weight ratios of the ionic and non-ionic polymers
(ionic:non-ionic) can range from about 1:10 to about 10:1,
preferably from about 1:5 to about 5:1. In preferred embodiments,
the weight ratio is greater than 1:1, for example, from about 2 to
about 5. In a particularly preferred embodiment, the ionic polymer
is carboxymethycellulose, the non-ionic polymer is
hydroxyethylcellulose, and the weight ratio (ionic:nonionic) is
about 3:1.
[0040] In a preferred embodiment of the method of the invention,
which results in the formation of superabsorbent polymer hydrogels
having a particularly high swelling ratio (SR), the total precursor
concentration in the aqueous solution is of at least 2% by weight
referred to the weight of the water of the starting aqueous
solution, and the amount of the cross-linking agent is between
about 1% and about 5% by weight referred to the weight of the
precursor. In the present description, the term "precursor"
indicates the hydrophilic polymer(s) used as the precursors for the
formation of the polymer hydrogel polymer network, for example, in
certain embodiments the "weight of the precursor" is the weight of
CMCNa used or the combined weights of CMCNa and HEC used. The
aqueous solution preferably includes sorbitol in an amount of about
4% by weight relative to the weight of water.
[0041] The swelling ratio (SR) is a measure of the ability of the
polymer hydrogel to absorb water. SR is obtained through swelling
measurements at the equilibrium (using, for example, a Sartorius
micro scale with a sensitivity of 10.sup.-5) and it is calculated
with the following formula:
SR=(W.sub.s-W.sub.d)/W.sub.d
wherein W.sub.s is the weight of the polymer hydrogel after
immersion in distilled water for 24 hours, and W.sub.d is the
weight of the polymer hydrogel before immersion, the polymer
hydrogel having been previously dried in order to remove any
residual water.
[0042] According to the preparation method of the invention, in
this embodiment, the cross-linking reaction is preferably carried
out at a temperature between about 60.degree. C. and 120.degree. C.
Varying the temperature during this stage of the process will
enable one to increase or decrease the cross-linking degree of the
polymer network. A cross-linking temperature of about 80.degree. C.
is preferred.
[0043] One particularly preferred embodiment of the method of the
invention comprises the following steps: Step 1, the hydrophilic
polymer(s), the carboxylic acid and, optionally, the molecular
spacer are dissolved in water at room temperature; Step 2, the
water is removed from the solution at 40.degree. C. over a two-day
period; Step 3, the product of Step 2 is heated to 80.degree. C.
for 10 hours to induce the cross-linking reaction and form a
polymer hydrogel; Step 4, the polymer hydrogel is washed three
times with water over 24 hours; Step 5, the washed polymer hydrogel
is immersed in acetone for 24 hours to remove water; Step 6, the
polymer hydrogel is further dried in an oven at 45.degree. C. for 5
hours; and Step 7, the dried polymer hydrogel is milled to provide
polymer hydrogel particles.
[0044] The present invention also provides polymer hydrogels which
can be prepared using the methods of the invention. Such polymer
hydrogels comprise a hydrophilic polymer cross-linked with a
polycarboxylic acid. In other embodiments, the polymer hydrogels of
the invention include at least two hydrophilic polymers
cross-linked by a polycarboxylic acid. In one preferred embodiment,
the polymer hydrogel comprises an ionic polymer and a non-ionic
polymer and a polycarboxylic acid, preferably a C.sub.4 to
C.sub.12-dicarboxylic acid, a tricarboxylic acid or a
tetracarboxylic acid, where the polycarboxylic acid cross-links the
ionic polymer and the non-ionic polymer. The weight ratio of ionic
polymer to non-ionic polymer is preferably from about 1:5 to about
5:1, more preferably from about 2:1 to about 5:1, and most
preferably about 3:1. In one particularly preferred embodiment, the
ionic polymer is carboxymethylcellulose, the non-ionic polymer is
hydroxyethylcellulose and the polycarboxylic acid is citric acid.
In another preferred embodiment, the polymer hydrogel comprises an
ionic polymer, for example, an anionic polymer or a cationic
polymer. More preferably, the ionic polymer is
carboxymethylcellulose or a salt thereof, such as sodium
carboxymethylcellulose. In another particularly preferred
embodiment, the polymer hydrogel comprises carboxymethylcellulose
cross-linked with citric acid.
[0045] The polymer hydrogels of the invention have swelling ratios
of at least about 5. Preferably, the polymer hydrogels of the
invention are superabsorbent polymer hydrogels, for example,
polymer hydrogels having an SR of at least 10. In preferred
embodiments, the polymer hydrogels of the invention have SRs at
least about 20, about 30, about 40, about 50, about 60, about 70,
about 80, about 90 or about 100. For example, in certain
embodiments, the polymer hydrogels of the invention have SRs from
about 10 to about 100, from about 20 to about 100, from about 30 to
about 100, from about 40 to about 100, from about 50 to about 100,
from about 60 to about 100, from about 70 to about 100, from about
80 to about 100, or from about 90 to about 100. In certain
embodiments, the invention includes polymer hydrogels having SRs up
to 150, 200, 250, 300, 330 or 350.
[0046] In certain embodiments, the polymer hydrogels of the
invention can absorb an amount of one or more bodily fluids, such
as blood, blood plasma, urine, intestinal fluid or gastric fluid,
which is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times
their dry weight. The ability of the polymer hydrogel to absorb
bodily fluids can be tested using conventional means, including
testing with samples of bodily fluids obtained from one or more
subjects or with simulated bodily fluids, such as simulated urine
or gastric fluid. In certain preferred embodiments, the polymer
hydrogels can absorb significant amounts of a fluid prepared by
combining one volume of simulated gastric fluid (SGF) with eight
volumes of water. SGF can be prepared using USP Test Solutions
procedures which are known in the art. In some embodiments, the
polymer hydrogels of the invention can absorb at least about 10,
20, 30, 40, 50, 60, 70, 80, 90, 100 or more times their dry weight
of this SGF/water mixture.
[0047] The polymer hydrogels of the invention include cross-linked
polymers having varying extents of hydration. For example, the
polymer hydrogels can be provided in a state of hydration ranging
from a substantially dry or anhydrous state, such as a state in
which from about 0% to about 5% of the polymer hydrogel by weight
is water or an aqueous fluid, to states comprising a substantial
amount of water or aqueous fluid, including up to a state in which
the polymer hydrogel has absorbed a maximum amount of water or an
aqueous fluid.
[0048] The polymer hydrogels of the invention can be used in
methods for treating obesity, reducing food or calorie intake or
achieving or maintaining satiety. The methods comprise the step of
administering an effective amount of a polymer hydrogel of the
invention to the stomach of a subject, preferably by causing the
subject, such as a mammal, including a human, to ingest the polymer
hydrogel. Such polymer hydrogels can be used to take up stomach
volume, for example, by increasing the volume of a food bolus
without adding to the calorie content of the food. The polymer
hydrogel can be ingested by the subject prior to eating or in
combination with food, for example, as a mixture of the polymer
hydrogel with food. Upon ingestion and contact with gastric fluid
or a combination of gastric fluid and water, the polymer hydrogel
will swell. The polymer hydrogel can be ingested alone or in a
mixture with liquid or dry food in a dry, partially swollen or
fully swollen state, but is preferably ingested in a state of
hydration which is significantly below its fluid capacity, more
preferably the polymer hydrogel is ingested in an anhydrous state.
Thus, the volume of the stomach taken up by the polymer hydrogel
can be significantly greater than the volume of the polymer
hydrogel ingested by the subject. The polymer hydrogels of the
invention can also take up volume and/or exert pressure on the wall
of the small intestine by moving from the stomach into the small
intestine and swelling. Preferably, the polymer hydrogel will
remain swollen in the small intestine for a period of time
sufficient to inhibit the intake of food by the subject, before
shrinking sufficiently for excretion from the body. The time
sufficient to inhibit the intake of food by the subject will
generally be the time required for the subject to eat and for the
ingested food to pass through the small intestine, Such shrinking
can occur, for example, by degradation through loss of cross-links,
releasing fluid and decreasing in volume sufficiently for excretion
from the body. Preferred polymers for use in this method exhibit
pH-dependent swelling, with greater swelling observed at higher pH
than at lower pH. Thus, such a polymer will not swell significantly
in the stomach unless food and/or water is present to raise the pH
of the stomach contents and will move into the small intestine.
When ingested with food, the polymer hydrogel will initially swell
in the stomach, then shrink when the stomach is emptied of food and
the pH drops and then move from the stomach to the small intestine.
In the higher pH environment of the small intestine the polymer
hydrogel will swell, taking up volume in the small intestine and/or
exerting pressure on the wall of the small intestine.
[0049] The polymer hydrogel can optionally be administered in
combination with a pH modifying agent, which is an agent which
alters the pH of the microenvironment of the polymer hydrogel,
thereby modifying its ability to absorb fluids. For example, for
polymer hydrogels comprising an anionic polymer, agents which
increase the pH of the microenvironment can increase the
swellability of the polymer hydrogel. Suitable pH modifying agents
for use with the polymer hydrogels of the invention include
buffering agents, H.sub.2 blockers, proton pump inhibitors,
anatacids, proteins, nutritional shakes, and combinations thereof.
Suitable buffering agents and antacids include ammonium
bicarbonate, sodium bicarbonate, calcium carbonate, calcium
hydroxide, aluminium hydroxide, aluminium carbonate, magnesium
carbonate, magnesium hydroxide, potassium bicarbonate, potassium
carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide
and combinations thereof. Suitable H.sub.2 blockers include
cimetidine, ranitidine, famotidine, nizatidine and combinations
thereof. Suitable proton pump inhibitors include omeprazole,
lansoprazole, esorneprazole, pantoprazole, abeprazole, and
combinations thereof.
[0050] The present polymer hydrogels can also be used for removing
water from the gastrointestinal tract, for example, as a treatment
for subjects suffering from kidney disease, including chronic and
acute kidney disease, particularly subjects undergoing kidney
dialysis. The polymer hydrogels can further be used to modify the
fluid content in the gastrointestinal tract of a subject in need
thereof, for example, for the treatment of constipation.
[0051] The invention further includes articles of manufacture which
comprise the polymer hydrogels of the invention. Such articles of
manufacture include articles in which polyacrylic polymer hydrogels
are conventionally used, in consumer products, such as for example
absorbent products for personal care (i.e., babies' napkins,
sanitary towels, etc.) and in products for agriculture (e.g.,
devices for the controlled release of water and nutrients). The
absorption properties of the polymer hydrogels of the invention,
which in some embodiments depend on the amount of
carboxymethylcellulose employed and which can be improved by the
induction of a microporosity in the gel structure, are comparable
to those of polyacrylic gels. The polymer hydrogels obtainable by
the method of the present invention therefore possess mechanical
properties which make them suitable for use in all of the
above-mentioned fields. The present polymer hydrogels, however,
have advantages over acrylic polymer hydrogels, such as
biodegradability, the absence of any toxic by-products during the
manufacturing process and the use of fewer and readily available
reagents. Such features enable a real employment of the polymer
hydrogels of the invention in the biomedical and pharmaceutical
fields as well.
[0052] Thus, the scope of the present invention also includes the
use of the polymer hydrogels obtainable by the method of the
invention as an absorbent material in products which are capable of
absorbing water and/or aqueous solutions and/or which are capable
of swelling when brought into contact with water and/or an aqueous
solution.
[0053] The polymer hydrogels and superabsorbent polymer hydrogels
of the present invention may be used as absorbent materials in the
following fields, which are provided by way of non-limiting
example:
[0054] dietary supplements (for example, as the bulking agents in
dietary supplements for hypocaloric diets capable of conferring a
sensation of lasting satiety being retained into the stomach for a
limited period of time, or as water and low molecular weight
compounds supplements, such as mineral salts or vitamins, to be
included into drinks in a dry or swollen form);
[0055] in agricultural products (for example, in devices for the
controlled release of water and/or nutrients and/or phytochemicals,
particularly for cultivation in arid, deserted areas and in all
cases where it is not possible to carry out frequent irrigation;
such products, mixed in a dry form with the soil in the areas
surrounding the plant roots, absorb water during irrigation and are
capable of retaining it, releasing it slowly in certain cases,
together with the nutrients and phytochemicals useful for
cultivation);
[0056] in personal hygiene and household absorbent products (such
as for example, as the absorbent cores in babies'napkins, sanitary
towels and the like);
[0057] in the field of toys and gadgets (such as for example in
products which are capable of significantly changing their size
once brought into contact with water or an aqueous solution);
[0058] in the biomedical field (for example, in biomedical and/or
medical devices such as absorbent dressings for the treatment of
highly exudative wounds, such as ulcers and/or burns, or in
slow-release polymeric films suitable to slowly release liquids
adapted for use in ophthalmology); and
[0059] in the body fluid management field, i.e., for controlling
the amount of liquids into the organism, for example in products
capable of promoting the elimination of fluids from the body, such
as, for example, in the case of edema, CHF (chronic heart failure),
dialysis.
[0060] The above-mentioned products, containing a polymer hydrogel
of the present invention as the absorbent material, also fall
within the scope of the invention.
[0061] The invention further includes the use of any of the polymer
hydrogels of the invention in medicine. Such use includes the use
of a polymer hydrogel in the preparation of a medicament for the
treatment of obesity or any medical disorder or disease in which
calorie restriction has a therapeutic, palliative or prophylactic
benefit.
[0062] The following examples are provided to further illustrate
the invention and are not to be construed as limiting its
scope.
EXAMPLES
[0063] The materials and processes of the present invention will be
better understood in connection with the following examples, which
are intended as an illustration only and not limiting of the scope
of the invention. Various changes and modifications to the
disclosed embodiments will be apparent to those skilled in the art
and such changes and modifications including, without limitation,
those relating to the chemical structures, derivatives,
formulations and/or methods of the invention may be made without
departing from the spirit of the invention and the scope of the
appended claims.
Example 1
Citric Acid Cross-Linking of
Carboxymethylcellulose/Hydroxyethylcellulose Mixtures
Materials
[0064] CMCNa (MW 700 kDa, DS 0.9, food grade), HEC (MW 250 kDa,
food grade) were purchased from Eigenmann e Veronelli S.p.A. Milano
and citric acid was supplied by Dal Cin S.p.A. Sesto San Giovanni
Milano and used as received.
Polymer Hydrogel Synthesis
[0065] Polymer hydrogel samples were obtained by reacting, in
water, CMCNa and HEC with citric acid as a cross-linking agent
according the following procedure. First, a total polymer
concentration of 2% by weight of water, using a mixture of CMCNa
and HEC, with weight ratio equal to 3/1 was dissolved in distilled
water by stirring gently at room temperature until a clear solution
was obtained. Poor cross-linking efficiency has been reported if
only CMCNa is used, due both to the electrostatic repulsion between
polyelectrolyte chains and to the high degree of substitution of
hydroxyl groups at C6, the 2.5 most reactive position [13]. CMCNa
dissolution is slow at the concentration adopted; thus, first HEC
was added to water till, after 5 min, a clear solution was obtained
with a slight increase of viscosity; then, CMCNa was added, and the
stirring was kept on till a clear solution was obtained (24 h),
with a significant increase of viscosity. Finally, CA was added at
different concentrations (1.75%, 2.75%, 3.75%, 10% and 20% w/w
polymer) in order to obtain samples with various degrees of
cross-linking. This final solution was used to mold 10 mm thick
samples. All samples were first pre-dried at 30.degree. C. for 24 h
to remove absorbed water and then kept at 80.degree. C. for the
cross-linking reaction (24 h with intermediate control).
[0066] Moreover, samples containing neat HEC or neat CMCNa samples
cross-linked with CA were also prepared following exactly the same
experimental conditions used for HEC/CMCNa mixtures.
[0067] All samples were analyzed by FT IR measurements Anhydride
formation was detected by monitoring its characteristic stretching
band in the carbonyl region at 1738 cm.sup.-1 [14].
Swelling Ratio
[0068] Equilibrium swelling measurements for all the samples were
carried out in distilled water using a Sartorius microbalance
(10.sup.-5 sensitivity). The swelling ratio was measured by
weighing samples before and after their immersion in distilled
water for about 24 h. The swelling ratio (SR) is defined as
following:
SR=(W.sub.s-W.sub.d)/W.sub.d
where W.sub.s is the weight of the swollen polymer hydrogel and
W.sub.d is the weight of the dried sample [15]. Differential
Scanning calorimeter
[0069] A differential scanning calorimeter (Mettler-Toledo
822.sup.e Mettler DSC) was used for thermal analysis. The scanning
temperature range and the heating rate were 10-200.degree. C. and
5.degree. C./min, respectively.
[0070] The adopted thermal cycle was: (1) heating 10-100.degree.
C.; (2) isotherm at 100.degree. C. for 3 minutes; (3) cooling from
100.degree. C. to 10.degree. C.; (4) heating from 10.degree. C. to
200.degree. C.; (5) isotherm at 200.degree. C.; (6) cooling until
room temperature. An empty pan was used as a reference.
Fourier Transformed Infrared Spectroscopy
[0071] All FT IR spectra were recorded on a JASCO FT IR 660 plus
spectrometer equipped with an attenuated total reflectance (ATR)
crystal sampler. Film samples were used directly on a ATR crystal
sampler at a resolution of 4 cm.sup.-1, by 300 scans, at absorbance
range from 4000 cm.sup.-1 to 600 cm.sup.-1.
Results and Discussion
[0072] A DSC thermogram of neat citric acid showed a peak at about
60.degree. C., attributable to a water loss process associated with
the dehydration leading to an anhydride. A complete degradation,
starting at about 160.degree. C., is observed in the second
scan.
[0073] DSC analysis of neat CMCNa and HEC powders indicates that
some water is still absorbed in the polymers. Above 100.degree. C.
a possible degradation peak of CMCNa is detected. Both CMCNa and
HEC show a thermal stability below 100.degree. C.
[0074] A film of polymer hydrogel obtained using a 3:1 ratio of
CMCNa/HEC and 3.75% by weight of polymer of citric acid was
analyzed by DSC after drying the sample at 30.degree. C. for 24 h
and then reduced to powder. A large endothermic peak associated to
the evaporation of the water produced by the anhydrification
process is evident. A small exothermic peak, attributed to
esterification is superimposed on the first one. In the second
heating cycle the glass transition (T.sub.g=38.degree. C.) of the
cross-linked cellulose mixture is observed.
[0075] After this preliminary DSC study, different polymer hydrogel
samples were prepared according the following procedures. After
mixing reagents in water, the reaction vessel was kept at
30.degree. C. for 24 h in dry conditions to remove water. Then
temperature was raised above 60.degree. C., according with the
results of the first DSC analysis, in order to obtain the citric
acid anhydride. Above this limiting temperature citric anhydride is
available for the cross-linking reaction with cellulose OH groups.
Different reaction conditions were attempted in order to optimize
the synthetic procedure, such as temperature and CA concentration
as summarized in Table 1. Two different reaction temperatures for
the cross-linking process, 80.degree. C. and 120.degree. C., were
attempted. However, either to prevent degradation risks or to limit
the reaction rate a temperature of 80.degree. C. was chosen.
Moreover, very high concentrations (10% and 20% by weight) of CA
were initially used in order to amplify the FT IR signals
associated with each chemical reaction step. First neat CMCNa and
HEC were cross-linked with CA in order to investigate its
reactivity with each of the polymers.
TABLE-US-00001 TABLE 1 citric acid concentration Reaction label
Initial polymer (% w/w polymer) A10 CMCNa 10 A20 CMCNa 20 B10 HEC
10 B20 HEC 20 C10 CMCNa/HEC (3/1) 10 C20 CMCNa/HEC (3/1) 20
[0076] FT IR spectra were recorded of citric acid, of the A10
reaction mixture before heating and of the A10 reaction mixture
after 5 h of heating. In the CA spectrum it is possible to observe
a strong C.dbd.O band centred at 1715 cm.sup.-1 due to carboxylic
acid. The FT IR spectrum of sample A10 shows a strong absorption
band at 1590 cm.sup.-1 characteristic of cellulose [16]. After
heating, the absorbance band at about 1590 cm.sup.-1 is still
observed and additionally a new band at 1738 cm.sup.-1 appears
Anhydrides display two stretching bands in the carbonyl region
around 1758 cm.sup.-1 and 1828 cm.sup.-1. The higher frequency band
is the more intense in acyclic anhydrides whereas cyclic anhydrides
show the lower frequency C.dbd.O stretching band stronger than the
stretching band at higher frequency [14]. The new peak observed at
1738 cm.sup.-1 can be attributed to the characteristic stretching
band of the carbonyl group at lower frequency related to anhydride
formation, an intermediate reaction necessary for reaction of CA
with cellulose hydroxyl groups. In contrast, the carbonyl peak
expected at higher frequency is not detectable probably due to its
weak intensity.
[0077] FT IR spectra were recorded of citric acid, B10 reaction
mixture before heating and B10 reaction mixture after 6.5 h of
heating. The HEC spectrum again shows the band at 1590 cm.sup.-1
before and after heating while the absorbance of the carbonyl group
at 1738 cm.sup.-1 appears only after heating at 80.degree. C. as
observed for the sample A10.
[0078] Although FT IR analysis is generally considered a
qualitative technique, a literature study in literature carried out
by Coma and co-workers demonstrated that infrared spectroscopy
could be used at first approximation for the determination of the
cross-linking rate in cross-linked cellulosic derivatives [9].
Starting from this consideration, the evolution of the different
reactions finally leading to cross-linking at 80.degree. C. was
monitored by recording FT IR spectra at different reaction
times.
[0079] The area under the absorbance peak at 1738 cm.sup.-1
(A.sub.1) representative of the carbonyl group, was compared with
the area under the reference absorbance peak at 1592 cm.sup.-1
(A.sub.2) which is invariant in all spectra. The evolution of the
anhydride was evaluated as the ratio of A.sub.1/A.sub.2 as a
function of the reaction time. FTIR spectra of CMCNa polymer when
the reaction is performed at 80.degree. C. with 20% CA or 10% CA
both show a similar trend: the anhydride band, that is absent
before heating, reaches a maximum almost immediately after the
first hour, successively decreases to a minimum after 3 h, then
increasing again reaching a second maximum after 5 h. Finally a
slower process reduces the band area to zero after 24 h. It is
worth noting that in the spectrum of the 20% CA reaction, the
second maximum matches a value (A.sub.1/A.sub.2=0.10) higher than
those observed in the 10% CA reaction (A.sub.1/A.sub.2=0.04).
[0080] It is assumed that the peak at around 1738 cm.sup.-1 is due
to the anhydrification process involving free CA followed by the
first condensation of this anhydride with cellulose OH leading to a
fast disappearance of the anhydride C.dbd.O groups. Then the
carboxylate groups now linked to the polymer are able to form again
an anhydride leading to an increase of the 1738 cm.sup.-1 peak. The
second reaction of this anhydride is responsible for the
cross-linking, results in a new anhydride group consumption and
consequent reduction of the peak at 1738 cm.sup.-1. This second
reaction is slower since it involves groups linked to large
macromolecules and hence is more sterically hindered, as has also
been reported for other cellulose cross-linking processes [17].
This possible reaction mechanism is confirmed by the swelling
measurements.
[0081] FTIR spectra were also recorded for reactions of HEC polymer
when the reaction is performed at 80.degree. C. with either 20% CA
or 10% CA. In the 10% CA case, the anhydride band intensity
increases from 0 to 0.098 when the reaction time increase from 0 h
to 6.5 h, but drops to 0 when the reaction time reaches 24 h. The
20% CA reaction follows exactly the same trend providing a maximum
value of 0.079 at 5 h. Assuming that the cross-linking mechanism is
the same as described for CMCNa, the anhydrification and
esterification reactions appear superimposed in this case.
Therefore, in the FTIR spectra, the HEC polymer shows a single
peak. This latter result was in accordance with conclusion of Xie
and co-workers [18]. They studied the degree of substitution, as
evaluation of cross-linking esterification, on starch thermally
reacted with CA at different reaction time and found a maximum
after a few hours.
[0082] To explain the data observed in all FTIR spectra recorded
after 24 hours, we supposed that in all cases the polymer is
unstable when is kept in the oven for 24 hours because of
unidentified secondary reactions take place modifying polymer
structure that involve also ester functions. Xie and co-workers
[18] work guessed that the degree of substitution reached a maximum
and then decreased since dissociation of the substituents from
starch occurred when the reaction time was longer than 7 h.
[0083] Finally, to complete this study, polymer mixtures of CMCNa
and HEC were cross-linked. CMCNa has carboxylic acid functional
groups in its structure that increase the volume variation process
in solution. A preliminary attempt to follow the reaction pathway
failed. Probably the reaction systems considered are too complex
having many different reaction centers. FT IR spectra of C10
reaction registered before, after 8 h and after 13 h of heating
were compared. Reaction sample C20 shows similar spectra. Moreover,
it is worth noting that when polymer mixtures are used (C10 and
C20) a broad signal appears at about 1715 cm.sup.-1, especially
when a higher CA concentration is used in the reaction. In fact,
with 20% of CA the signal of CA at 1715 cm.sup.-1 is very broad and
overlapped to the polymer signal at 1590 cm.sup.-1 then a clear
band is not detectable. However, it should be pointed out a band
around 1715 cm.sup.-1 before heating. The C10 reaction mixture
before heating shows a band around 1715 cm.sup.-1 covering the
absorbance region monitored previously for the other reactions
(A10, A20, B10, B20); consequently a clear assignment to the
carbonyl group is difficult. However, the other two spectra
indicate that this band moves to higher wavenumbers during the
cross-linking reaction. In particular after 8 h, the FT IR spectrum
shows a broad band in the range of 1711 cm.sup.-1-1736 cm.sup.-1
and after 13 h this band appears more clearly as a narrow
absorbance band at 1737 cm.sup.-1, which is typical of carbonyl
groups. Spectra of C20 reaction provide similar results. Although a
quantitative analysis of carbonyl groups is not possible when C10
and C20 samples are cross-linked, an evaluation of the carbonyl
peak similar to those observed for the reaction of the neat
polymers can be assumed.
[0084] The cross-linking kinetics were also monitored studying the
swelling behaviour during the reaction progress. Swelling ratio was
calculated as a function of the reaction time for: (a) CMCNa with
10% or 20% of CA concentration; (b) HEC with 10% or 20% of CA
concentration; (c) the mixture of CMCNa and HEC (3/1) with 10% or
20% CA concentration; (d) the mixture of CMCNa and HEC (3/1) with
1.75%, 2.75% or 3.75% CA concentration.
[0085] The results obtained indicate that the swelling of CMCNa
cross-linked with 10% of citric acid is higher than HEC with the
same citric acid concentration after 24 h. When 20% of citric acid
was added to the celluloses, the shape of the swelling curves are
similar for HEC and CMCNa. In this case, as cross-linking proceeds
the swelling of HEC based samples decreases faster than CMCNa
samples indicating that a higher rate of reaction between CA and
HEC. This probably occurs because HEC is less sterically hindered
than CMCNa and can react more quickly than CMCNa chains. In
addition in each repeating unit, HEC has more OH groups than CMCNa
(3 vs 2).
[0086] The maximum swelling of CMCNa/CA sample is observed at the
gelation onset, after 3 h, when the second esterification reaction,
those leading to cross-linking, begins. Then as the cross-linking
process increases the corresponding equilibrium water sorption
decreases, confirming the results of FTIR analysis.
[0087] The same reaction mechanism can be assumed for neat HEC
cross-linked with CA. However in this case the overall behaviour is
slightly different as a consequence of the absence of carboxylic
groups bonded to the polymer. The results of swelling experiments
must be interpreted taking into account that the CA introduces the
high hydrophilic carboxylic groups that are responsible of the
formation of a polyelectrolyte network. Therefore the water
sorption is significantly increased as carboxylic groups are linked
first to the HEC chains and then to the gelled network. This effect
cannot be appreciated in CMCNa polymer hydrogels since a large
amount of --COOH groups, those linked to the CMCNa chains, is
already bonded to the network at the onset of gelation. A similar
trend is observed for the mixtures of HEC and CMCNa.
[0088] Polymer hydrogels of practical use presenting a high degree
of swelling were obtained with a reduced concentration of citric
acid (1.75%, 2.75%, 3.75% by weight of polymer). With a citric acid
concentration of 3.75% the swelling ratio can reach 900. This
polymer hydrogel, after swelling, is characterized by adequate
stiffness and it is able to keep the same shape of the synthesis
vat. Polymer hydrogels formerly synthesized [13] using divinyl
sulfone, a toxic reagent, as cross-linking agents and the same
ratio between CMCNa and HEC were characterized by a maximum
swelling ratio of 200. In this case a higher swelling ratio is
obtained using an environmentally friendly cross-linking agent. At
concentrations lower than 1.75% CA, a weak cross-linking associated
with insufficient mechanical property is observed.
Conclusions
[0089] This work shows for the first time that CA can be
successfully used as cross-linking agent of CMCNa/HEC mixtures. As
shown in FIG. 1, an esterification mechanism based on an anhydride
intermediate formation is proposed to explain the reaction of
cellulose polymers with CA.
[0090] The cross-linking reaction for CMCNa/HEC system was observed
either by DSC or by FTIR analysis. The evolution of the different
cross-linking reactions was monitored by means of FT IR spectra
collected at different reaction times using an excess of citric
acid. The swelling ratio, monitored at different reaction times,
confirmed the reaction path figured out from FTIR analysis. An
optimal degree of swelling (900) for practical applications was
achieved using low CA concentrations. The polymer hydrogel obtained
through the method described in this Example 1 has the great
advantage to reduce primary and production costs and avoid any
toxic intermediate during its synthetic process.
Example 2
Citric Acid Cross-Linking of Carboxymethylcellulose and
Carboxymethylcellulose/Hydroxyethylcellulose Mixtures in the
Presence of Sorbitol
Materials and Methods
[0091] All the materials employed were provided by Aldrich Italia
and were used without any further modification. The devices used in
the characterisation, in addition to the standard laboratory
glassware, cupboards and counters for standard synthesis, were a
scanning electron microscope (SEM) JEOL JSM-6500F, a precision
10.sup.-5 g Sartorius scale, an Isco mixer and an ARES
rheometer.
[0092] The polymer hydrogels were prepared by cross-linking an
aqueous solution of carboxymethylcellulose sodium salt (CMCNa) and
hydroxyethylcellulose (HEC), using citric acid (CA) as the
cross-linking agent and sorbitol as the molecular spacer. The
composition of a gel is given by the nominal amount of the reagents
in the starting solution. The parameters used to define said
composition are the following:
(i) the precursor weight concentration (%)=the total mass of
polymers in the solution (e.g. CMCNa+HEC) (g).times.100/mass of
water (g); (ii) the CMCNa to HEC weight ratio=mass of CMCNa (g) in
the solution/mass of HEC in the solution (g); (iii) the
cross-linking agent (CA) weight concentration (%)=mass of CA in the
solution (g).times.100/mass of the precursors in the solution (g);
and (iv) the molecular spacer (e.g. sorbitol) weight concentration
(%)=mass of molecular spacer (g).times.100/mass of water (g).
[0093] The laboratory tests demonstrated that a polymer
concentration lower than 2% and a CA concentration lower than 1%
either do not achieve cross-linking of the gel or led to the
synthesis of a gel having very poor mechanical properties. On the
other hand, CA concentrations higher than about 5% significantly
increase the cross-linking degree and polymer stabilization, but
excessively reduce the absorption properties of the superabsorbent
gel.
[0094] Since CMCNa is the ionic polymer species, it is possible to
achieve the desired absorption properties adjusting the weight
ratio of carboxymethylcellulose sodium salt (CMCNa) to
hydroxyethylcellulose (HEC). A CMCNa/HEC weight ratio of between
0/1 and 5/1, preferably between 1/1 and 3/1, was observed to enable
the synthesis of a polymer hydrogel having optimum absorption
properties.
[0095] Examples relating to the synthesis of different polymer
hydrogels according to the invention, differing from one another in
the weight percent (wt %) of citric acid and in the composition of
the polymeric precursor, are provided below.
[0096] Preparation of Polymer Hydrogel A:
[0097] in a beaker containing distilled water, sorbitol at a
concentration of 4% by weight referred to the weight of distilled
water was added and mixed until complete solubilisation, which
occurred within a few minutes. The CMCNa and HEC polymers are added
at a total concentration of 2% by weight referred to the weight of
distilled water, with a CMCNa/HEC weight ratio of 3/1. Mixing
proceeded until solubilisation of the whole quantity of polymer is
achieved and the solution became clear. At this stage, citric acid
at a concentration of 1% by weight referred to the weight of the
precursor was added to the solution, whose viscosity had greatly
increased. The solution thereby obtained was poured into a vessel
and dried at 48.degree. C. for 48 hours. During this process, the
macromolecules are stabilised into a polymeric network which is the
backbone of the polymer hydrogel. At the end of the cross-linking
process, the polymer hydrogel was washed with distilled water for
24 hours at room temperature. During this phase, the polymer
hydrogel swelled up thereby eliminating the impurities. In order to
obtain the maximum swelling degree and elimination of all of the
impurities, at least 3 rinses with distilled water were performed
during the 24 hours washing step. At the end of this washing step,
the polymer hydrogel was dried by phase inversion in acetone as the
nonsolvent, until a glassy white precipitate is obtained. The
precipitate is then placed into an oven at 45.degree. C. for about
3 hours, to remove any residual trace of acetone.
[0098] Preparation of Polymer Hydrogel B:
[0099] Polymer hydrogel B was prepared as polymer hydrogel A, with
the only exception that the polymer is made only of CMCNa, and that
the CMCNa concentration is 2% by weight referred to the weight of
distilled water.
[0100] Preparation of Polymer Hydrogel C:
[0101] Polymer hydrogel C was prepared as polymer hydrogel B, with
the only exception that the citric acid concentration is 2% by
weight referred to the weight of CMCNa.
[0102] Preparation of Polymer Hydrogel D:
[0103] Polymer hydrogel D was prepared as polymer hydrogel B, with
the only exception that the citric acid concentration is 0.5% by
weight referred to the weight of CMCNa.
Absorption Measurements
[0104] In order to test the absorption properties of the polymer
hydrogels prepared as described above, they were subjected to
absorption measurements in distilled water. The absorption
measurements essentially consist of placing the dry sample,
obtained from the drying step, in distilled water, so that it
swells up until an equilibrium condition is reached.
[0105] The absorption properties of the gel are assessed based on
its swelling ratio (SR), defined according to the formula
illustrated above. In order to minimise the influence of
experimental errors, each test was performed on three samples from
each gel, and then the mean value of the results of the three
measurements was taken as the effective value.
[0106] Three dry samples were taken from each of the test gels,
each having different weights and sizes. After recording the
weights, the samples were swollen in abundant quantities of
distilled water at room temperature. Upon reaching equilibrium
after 24 hours, the samples were weighed once more in order to
determine the swelling ratio.
Results
[0107] Table 2 below reports some of the results obtained, in terms
of the swelling ratio, varying the concentrations of the reagents
and the cross-linking times (6 hours, 13 hours, 18 hours, 24
hours).
TABLE-US-00002 TABLE 2 Sam- sorbi- cross-linking time/swelling
ratio ple CMCNa HEC CA tol 6 13 18 24 -- 75% 25% -- -- hours hours
hours hours g16 2% 1% 4% nr 50 30 20 g17 4% 1% 4% nr 25 10 5 nr =
not cross-linked
[0108] It is pointed out that the increase in the polymer
concentration exerts a negative effect on the swelling properties
of the final product and it is also pointed out that the
cross-linking time exerts a significant effect of the absorbing
properties.
[0109] Thus, further experiments were carried out maintaining the
polymer concentration fixed at 2% and varying the citric acid
concentration. The results are reported in Table 3.
TABLE-US-00003 TABLE 3 Sam- sorbi- cross-linking time/swelling
ratio ple CMCNa HEC CA tol 6 13 18 24 -- 75% 25% -- -- hours hours
hours hours g21 2% 2% 4% 40 25 20 10 g22 2% 1% 4% nr 50 30 20 g23
2% 0.5%.sup. 4% nr Nr 50 30 nr = not cross-linked
[0110] Table 3 shows that the sample having the best swelling ratio
is the sample designated as g22, which is characterised by a citric
acid (CA) concentration of 1%.
[0111] Thus, further experiments were performed removing completely
HEC from the solution. This should render the polymer hydrogel more
hydrophilic thereby leading to an increase of the swelling ratio.
Table 4 shows some of the results obtained.
TABLE-US-00004 TABLE 4 sorbi- cross-linking time/swelling ratio
Sam- CMCNa HEC CA tol 6 13 18 24 ple 100% 0% -- -- hours hours
hours hours g30 2% 2% 4% nr 85 55 30 g31 2% 1% 4% nr 100 75 40 g32
2% 0.5%.sup. 4% nr Nr 70 50 nr = not cross-linked
The highest swelling ratio is associated with a cross-linking time
of 13 hours and a citric acid concentration of 1%. It is also to be
noticed that higher citric acid concentrations together with
shorter cross-linking times lead to equally satisfactory swelling
ratios, although the reaction is very fast and less easy to
control.
[0112] Finally, the possibility of increasing the swelling ratio by
creating porosity into the material which could promote the
absorbing properties, was evaluated. For that purpose, the sample
g31, subjected to cross-linking for 12 hours, was swelled into
distilled water for 24 hours and then dried by phase inversion in
acetone. With this technique, a swelling ratio of 200 was
obtained.
Example 3
Swelling of a Polymer Hydrogel in Simulated Gastric Fluid (SGF) and
SGF/Water Mixtures
[0113] This example describes an evaluation of the superabsorbent
polymer hydrogel denoted polymer hydrogel B in Example 2 in in
vitro swelling and collapsing experiments in various media at
37.degree. C.
Swelling Kinetics (in 100% SGF) at 37.degree. C.
[0114] 100 mg of the dried polymer hydrogel was immersed in either
simulated gastric fluid ("SGF") or a mixture of SGF and water and
allowed to swell until an equilibrium condition was reached. SGF
was prepared according to USP Test Solutions procedures. The
swelling ratio in each fluid was determined at various time points.
The results are set forth in Tables 5 and 6.
TABLE-US-00005 TABLE 5 Swelling of dry polymer hydrogel B in 100%
SGF at 37.degree. C. The weights were recorded at 15, 30, 60 and 90
min. Swelling Time, min Swelling Ratio, g/g 15 15.4 30 15.6 60 16.2
90 15.1
TABLE-US-00006 TABLE 6 Swelling of Dry Polymer hydrogel B in a
mixture of SGF and Water (1:8) at 37.degree. C. The weights were
recorded at 15, 30, 60 and 90 min. Sweling Swelling Time, min
Ratio, g/g 15 78.8 30 84.6 60 88.6 90 79.3
Collapsing Kinetics (with Addition of SGF) at 37.degree. C.
[0115] To simulate the effect of digestion on a hydrated polymer
hydrogel, to the swollen polymer hydrogel from above (Table 6,
SGF/water) after 60 minutes, 100% SGF was slowly added to collapse
the gel particles. Swelling ratio was monitored as a function of
cumulative volume of added SGF. The results are set forth in Table
7.
TABLE-US-00007 TABLE 7 SGF added (mL) Swelling Ratio (g/g) 0 88.6 8
23.1 30 22.6 50 23.1 75 17.1
Kinetics of Swelling (in 1:8 SGF/Water), Collapsing (in SGF) and
Re-Swelling (in Simulated Intestinal Fluid)
[0116] Experiments were conducted by monitoring the swelling ratio
through a full cycle of swelling in 1:8 SGF/water, collapsing in
SGF, and re-swelling (then degradation) in simulated intestinal
fluid (SIF), all at 37.degree. C. Experiments performed and results
are provided in Table 8, for the re-swelling/degradation kinetics.
pH values are given when available.
TABLE-US-00008 TABLE 8 Kinetics of swelling in SGF/water,
collapsing in SGF, and re-swelling in SIF 60-min Collapse Swell in
in 70-mL Re-swelling/Degradation in SIF Expt. SGF/water SGF 30 45
90 120 # Swell Ratio Swell Ratio min min min min 1 95.5 20.7 71.2
87.3 pH 4.82 pH 1.76 2 95.3 19.5 72.6 80.5 pH 1.75
Conclusions:
[0117] This polymer hydrogel swells in simulated gastric fluids (pH
1.5) approximately 15 fold, and in a simulated gastric fluids/water
mixture (pH 3) approximately 85 fold. This indicates that the
polymer hydrogel has a pH/swelling correlation where at pH below 3
(pKa of CMC is .about.3.1) there will be limited swelling of the
polymer hydrogel due to absence of the Donnan effect. The polymer
can also swell in the increased pH of simulated intestinal
fluid.
Example 4
Effect of Polymer Hydrogel on Rat Feeding Behavior
[0118] A series of experiments was conducted to assess the effect
of polymer hydrogel B in laboratory animals. One objective of these
studies was to determine the effect of polymer hydrogel B on food
intake in rats. The study was conducted in male Sprague Dawley
rats, by acute administration of pre-swollen polymer hydrogel B by
oral gavage
[0119] A total of 22 male Sprague-Dawley rats were randomized into
two weight-matched groups prior to polymer hydrogel or vehicle
administration (the polymer hydrogel B was pre-swollen in water,
100 mg in 10 mL water). Food and water intake (digital balance) as
well as locomotor activity (consecutive beam brakes) were monitored
online every 5 minutes for 40 hours post dosing. Food and water
intake data were collected using MaNi FeedWin, an online
computerized feeding system using digital weighing cells. Two types
of baseline food intake (digital balance) and lick counts were
monitored. All data was entered into Excel spread-sheets and
subsequently subjected to relevant statistical analyses Results are
presented as mean.+-.SEM unless otherwise stated. Statistical
evaluation of the data is carried out using one-way or two-way
analysis of variance (ANOVA).
Results and Conclusions
[0120] FIG. 2, a graph of cumulative food intake as a function of
time, represents a typical study result. There was no difference
between the groups at base line. Gavage of 8 mL of polymer hydrogel
B induced satiety in the rats that led to a significnt decrease in
food intake. As shown in the yellow line, this polymer hydrogel
induced a marked decrease in food intake that persisted over 2
hours. These data suggest that polymer hydrogel B can induce
satiety in animals and leads to a decrease in food intake.
[0121] While this invention has been particularly shown and
described with references to preferred embodiments thereof, it will
be understood by those skilled in the art that various changes in
form and details may be made therein without departing from the
scope of the invention encompassed by the appended claims.
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