Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2002-03-28
2004-01-06
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S055100, C536S001110, C536S055200, C536S055300, C536S018700, C514S053000, C514S054000
Reexamination Certificate
active
06673919
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a chemically modified hyaluronic acid and salts thereof, and a process for producing them. More specifically, the invention relates to a chemically modified hyaluronic acid and salts thereof, which are obtained by O-acylating, alkoxylating or crosslinking a complex consisting of hyaluronic acid or salts thereof and a cationic compound in a nonaqueous solvent, and a process for the production thereof.
BACKGROUND OF THE INVENTION
Hyaluronic acid is a straight-chain polysaccharide with a high molecular weight which is an alternating copolymer of N-acetyl-D-glucosamine and D-glucuronic acid. Since hyaluronic acid and a salt thereof have a large number of free carboxyl groups and free hydroxyl groups, they are hydrophilic and can be dissolved in an optional amount of water to form an aqueous solution with a high viscosity. It has been expected that hyaluronic acid derivatives having different physical properties are obtained by hindering the free carboxyl groups and/or the free hydroxyl groups.
For applications in the fields of medicine, foodstuffs, cosmetic and the like, the chemical modification of hyaluronic acid or a salt thereof has been carried out in an aqueous solvent or a hydrophilic organic solvent (see e.g. JP-A 7-309902 and JP-A 8-53501).
In the prior art, organic reactions applicable to the chemical modification of hyaluronic acid or a salt thereof has been limited, because the reactions are performed in the presence of water. In the presence of water, hyaluronic acid or a salt thereof is depolymerized by an active oxygen such as a hydroxy radical or the like generated during the reaction to reduce the molecular weight of hyaluronic acid or a salt thereof. Consequently, there is a problem that the reduction in molecular weight may adversely affect essential properties of hyaluronic acid or a salt thereof, e.g. moisturizing action, high viscosity and the like owing to high molecular weight thereof. Further, there is a problem of contamination with or production of a pyrogen and an antigenic substance arising from water and/or the hyaluronate as a raw material. For the production of modified hyaluronate, it has been necessary not only to remove the pyrogen and antigenic substance from the raw materials and/or the modified hyaluronate, but also to pay attention to the prevention of the contamination with the pyrogen and antigenic substance (JP-A 11-512778, WO97/18244).
DISCLOSURE OF THE INVENTION
An object of the invention is to provide a chemically modified hyaluronic acid or a salt thereof in the absence of water and a process for the production thereof.
We have zealously studied to solve the problems of the prior art and found that the modified hyaluronic acid or a salt thereof can be prepared by dissolving a complex of the hyaluronate and a cationic compound in a nonaqueous solvent and then O-acylating, alkoxylating or crosslinking the complex to afford the chemically modified hyaluronate in which the reduction in molecular weight is prevented and the properties of the hyaluronate such as the moisturizing action and the high viscosity are maintained. We have also found that the contamination with or the generation of a pyrogen or an antigenic substance in the final product can be considerably decreased and thus have completed the present invention.
The hyaluronic acid and salts thereof according to the invention are defined in the following items (1) to (9).
(1) A chemically modified hyaluronic acid or a salt thereof, which is prepared by O-acylating, alkoxylating or crosslinking a complex consisting of hyaluronic acid or a salt thereof and a cationic compound in a nonaqueous solvent.
(2) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), wherein the cationic compound is a quaternary ammonium salt.
(3) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), wherein the nonaqueous solvent is one or more solvents selected from the group consisting of chloroform, toluene, methylene chloride and heptane.
(4) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), in which an amount of a pyrogen and/or an antigenic substance is reduced by O-acylating, alkoxylating or crosslinking in the nonaqueous solvent.
(5) The chemically modified hyaluronic acid or a salt thereof as defined in item (4), wherein the amount of the pyrogen is not more than 0.05 endotoxin unit (EU)/mg.
(6) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), in which the O-acylating reaction is a reaction with an organic acid employing at least one acid catalyst selected from the group consisting of mineral acids, organic acids and Lewis acids, a reaction with an organic acid employing at least one dehydrating agent selected from the group consisting of N,N′-dicyclohexylcarbodiimide, 2-chloro-1-methyl pyridiniumiodide and N,N′-carbonyl diimidazole, or an O-acylation employing an acid anhydride or an acid halide in the presence of an acid binder.
(7) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), in which the alkoxylating reaction is an alkoxylation using an alkyl halide or an alkoxide in the presence of an acid binder, or an alkoxylation by the dehydration of hydroxyl groups using Brönsted acid or Lewis acid as an acid catalyst.
(8) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), in which the crosslinking reaction comprises irradiating a certain wavelength of light to the chemically modified hyaluronic acid or a salt thereof to which a photoreactive group is introduced.
(9) The chemically modified hyaluronic acid or a salt thereof as defined in item (1), in which the crosslinking reaction is a reaction using at least one crosslinking agent selected from the group consisting of polyfunctional aldehydes, polyfunctional epoxy compounds and polyhydric alcohols.
The processes for the production of hyaluronic acid and salts thereof according to the present invention are defined in the following items (10)-(18).
(10) A process for producing a chemically modified hyaluronic acid or a salt thereof, which comprises O-acylating, alkoxylating or crosslinking a complex consisting of hyaluronic acid or a salt thereof and a cationic compound in a nonaqueous solvent.
(11) The process as defined in item (10), wherein the cationic compound is a quaternary ammonium salt.
(12) The process as defined in item (10), wherein the nonaqueous solvent is one or more solvents selected from the group consisting of chloroform, toluene, methylene chloride and heptane.
(13) The process as defined in item (10), wherein an amount of a pyrogen and/or an antigenic substance in the chemically modified hyaluronic acid or salts thereof is decreased by O-acylating, alkoxylating or crosslinking the complex in the nonaqueous solvent.
(14) The process as defined in item (13), wherein the amount of the pyrogen is not more than 0.05 EU/mg.
(15) The process as defined in item (10), in which the O-acylating reaction is a reaction with an organic acid employing at least one acid catalyst selected from the group consisting of mineral acids, organic acids and Lewis acids, a reaction with an organic acid employing at least one dehydrating agent selected from the group consisting of N,N′-dicyclohexylcarbodiimide, 2-chloro-1-methyl pyridiniumiodide and N,N′-carbonyl diimidazole, or an O-acylation employing an acid anhydride or an acid halide in the presence of an acid binder.
(16) The process as defined in item (10), in which the alkoxylating reaction is an alkoxylation using an alkyl halide or an alkoxide in the presence of an acid binder, or an alkoxylation by the dehydration of hydroxyl groups using Brönsted acid or Lewis acid as an acid catalyst.
(17) The process as defined in item (10), in which the crosslinking reaction comprises irradiating a certain wavelength of light to the chemically modified hyaluronic acid or a salt thereof into which one or more photoreactive groups have been introduced.
(18) Th
Ooya Tooru
Sato Ikuo
Yui Nobuhiko
Chisso Cororation
Krishnan Ganapathy
Wilson James O.
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