Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-01-19
2002-11-05
O'Sullivan, Peter (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S008100, C514S025000, C514S059000, C536S112000
Reexamination Certificate
active
06476204
ABSTRACT:
TECHNICAL FIELD
This invention relates to biodegradable vinyl group containing polymers which are photocrosslinkable into hydrogels.
BACKGROUND OF THE INVENTION
It is recognized that the introduction of vinyl group into water-soluble polymers provides functionality for photocrosslinking into hydrogels. For example, the water-soluble polymers are reacted with acrylates which provide vinyl groups for photocrosslinking reaction. However, the introduction of vinyl groups into the water-soluble polymers has been achieved at the expense of existing hydrophilic groups of the polymers such as hydroxyl or carboxyl groups which contribute to water solubility. As a result, the hydrophilicity of a resulting polymer and its water or solvent solubility are affected by degree of substitution so that water or solvent solubility decreases as degree of substitution increases. Moreover, the swelling ratio of the hydrogels made therefrom decreases as the degree of substitution increases. Therefore, in the prior art, a high degree of substitution is necessary for use of hydrogels for slow release of bioactive compounds and hydrogel use for slow release of bioactive compounds is inconsistent with good solubility of hydrogel forming polymers.
SUMMARY OF THE INVENTION
It is been discovered herein that vinyl-group-containing hydrogel precursors of excellent solubility that provide hydrogels that are useful for slow release of bioactive compounds are provided by monoesters of maleic acid with dextran. By monoester it is meant that the compounds have free carboxyl provided by non-esterifying carboxyl group of maleic acid. In other words, in each attached maleic acid segment, there is one ester group and one vinyl group and one free carboxyl group. The vinyl groups provide functionality for cross-linking into hydrogels. The free carboxyl groups impart hydrophilicity and enhanced solubility and are available for forming ester with and thereby linking to bioactive compound. Thus, the esterification of dextran hydroxyl results not only in addition of unsaturation for cross-linking for hydrogel formation but also in the provision of a free carboxyl group which is more hydrophilic than the dextran hydroxyl which is esterified and increases solubility while providing vinyl group for cross-linking. Contrary to what is disclosed in prior art, the hydrogel precursors have increased solubility with increasing degree of substitution and provide hydrogels with increased swelling ratio as degree of substitution increases. The hydrogel precursors herein are unique in that increase in degree of substitution does not require sacrificing solubility.
One embodiment of the invention herein is directed to dextran-maleic acid monoesters in which the average degree of substitution of each glucose unit of each &agr;-D-glucopyranosyl moiety of dextran by maleic acid ranges from 0.60 to 1.6, preferably from 0.60 to 1.30, for example, from 0.60 to 1.26, and having a weight average molecular weight ranging from 40,000 to 80,000 on a dextran basis.
These compounds are exemplified by the formula
where n has a range providing the above-described molecular weight range, for a degree of substitution of 1.0.
In a subset of this embodiment, the dextran-maleic acid monoesters have an average degree of substitution ranging from 0.85 to 0.95 and a weight average molecular weight ranging from 65,000 to 75,000 on a dextran basis.
In another subset of this embodiment, the dextran-maleic acid monoesters have an average degree of substitution ranging from 1.20 to 1.26 and a weight average molecular weight ranging from 65,000 to 75,000 on a dextran basis.
In another embodiment herein there is provided a biodegradable hydrogel formed by photocrosslinking the aforedescribed dextran-maleic acid mono ester or ester thereof (where the free carboxylic acid group of maleic acid moiety is esterified with a bioactive agent, e.g., a drug to be administered), in solution in an aqueous medium buffered to a pH ranging from 2 to 8, and drying, which at pH 7 has a maximum swelling ratio percentage ranging from 500 to 1,500 and which is characterized by increase in swelling ratio as average degree of substitution increases.
The term “on a dextran basis” is used herein to mean the weight average molecular weight referred to is that of the dextran starting material for preparing the dextran-maleic acid monoester which provides the dextran moiety of the dextran-maleic acid monoester.
The term “hydrogel” is used herein to mean a polymeric material which exhibits the ability to swell in water and to retain a significant portion of water within its structure without dissolution.
The term “biodegradable hydrogel” is used herein to mean hydrogel formed by cross-linking a polymer which is degraded by water and/or by enzymes found in nature.
The term “hydrogel precursor” is used herein to mean water soluble polymer that is photocrosslinkable in solution in a medium to form a hydrogel
The term “photocrosslinking” is used herein to mean causing vinyl bonds to break and form cross-links by the application of radiant energy.
The term “degree of substitution” is used herein to mean the number of hydroxyl groups in a glucose unit of &agr;-D-glucopyranosyl moiety of dextran that form ester group with maleic acid. Since each said glucose unit contains three hydroxyl groups, the maximum degree of substitution is 3.0. The average degree of substitution connotes the average degree of substitution based on all the glucose units in the molecules of hydrogel precursor.
The term swelling ratio is a percentage based on the following calculation
Swelling
ratio
(
%
)
=
W
s
-
W
o
W
o
×
100
where W
s
is equal to the weight of the swollen hydrogel and W
o
is the weight of a dried hydrogel. The swelling is with aqueous solution and the dried hydrogel is dried so as to be dry to the touch.
The term “maximum swelling ratio” (at pH 7) means the maximum swelling ratio obtained in the test set forth in Example VI hereinafter on soaking in pH 7 buffer solution.
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Chu Chih-Chang
Kim Sin-Hee
Won Che-Youb
Cornell Research Foundation Inc.
O'Sullivan Peter
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