Drug – bio-affecting and body treating compositions – Extract – body fluid – or cellular material of undetermined... – Derived from musculoskeletal system – other than cardiac muscle
Reexamination Certificate
2001-09-27
2003-10-28
Page, Thurman K. (Department: 1616)
Drug, bio-affecting and body treating compositions
Extract, body fluid, or cellular material of undetermined...
Derived from musculoskeletal system, other than cardiac muscle
C424S445000, C514S781000, C524S029000
Reexamination Certificate
active
06638538
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel hardly water-soluble hyaluronic acid gel composition comprising hyaluronic acid and a polymer, which is substantially unmodified with a chemical cross-linking agent or a chemical modifying agent, and a process for its production. Further, it relates particularly to a medical material utilizing it and having good biocompatibility.
BACKGROUND ART
Hyaluronic acid is a linear macromolecular polysaccharide consisting of alternately bonded &bgr;-D-N-acetylglucosamine and &bgr;-D-glucuronic acid, and it is known to have no species or organ specificity and show excellent biocompatibility even when implanted or injected into the body.
Various chemical modifications of hyaluronic acid have been proposed in order to overcome drawbacks of hyaluronic acid in its application in vivo as a medical material, such that it is easily soluble in water and its in vivo residence time is relatively short. Further, many hyaluronic acid compositions have been studied for modification by an addition of a polymer to supplement various physical properties required for a medical material such as the strength and tissue bondability.
For example, in order to use a hyaluronic acid composition as a bone-repairing material, a higher strength is required as compared with a case where it is used for an artificial cartilage for a joint. Likewise, when a hyaluronic acid composition is used as an adhesion preventive, a higher tissue bondability is required as compared with a case where it is used as an embolizing agent.
Heretofore, a hyaluronic acid composition useful as a medical material may, for example, be a hyaluronic acid composition having sodium hyaluronate and carboxymethyl cellulose, modified with EDC (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) as a carbodiimide, as reported in e.g. JP-A-5-508161 and JP-A-6-508169. Further, W086/00912 reports on a hyaluronic acid composition having a carboxy-containing polysaccharide (such as sodium hyaluronate, carboxymethyl dextran, carboxymethyl starch or carboxymethyl cellulose) cross-linked with e.g. BDDE (1,4-butanediol glycine ether) as a di- or poly-functional epoxide. Further, JP-A-61-164558 reports on a hyaluronic acid composition having sodium hyaluronate, chondroitin sulfate, heparin or the like cross-linked with a polyfunctional epoxide, or with cyan bromide, epichlorohydrin or the like. Further, JP-A-61-138601 reports on a hyaluronic acid composition having sodium hyaluronic acid or various polymers cross-linked with divinylsulfone. Further, JP-A-6-73102 and JP-A-8-301903 report on a hyaluronic acid composition having sodium hyaluronate or various polymers cross-linked with cinnamic acid.
However, in their production, it is very difficult to completely remove the cross-linking agent, etc. for purification. Not only that, hyaluronic acid and polymers are likely to include such a cross-linking compound in the molecules, and their physiological functions, biocompatibility and safety can not hardly be said to be substantially equivalent to hyaluronic acid and the polymers.
A hyaluronic acid composition which employs no chemical cross-linking agent or no chemical modifying agent in order to maximize the excellent characteristics of biocompatibility inherent to hyaluronic acid and the polymer itself and which is useful as a biocompatible medical material and has a long in vivo residence time, has not yet been developed.
In order to accomplish the above object, the present inventors have strenuously studied the physiochemical properties of a hyaluronic acid gel (PCT/JP98/03536) itself employing no chemical cross-linking agent or no chemical modifying agent, which is composed solely of hyaluronic acid and which is excellent in biocompatibility and moldability and has an in vivo degradable nature.
Further, they have found that a hyaluronic acid gel composition comprising hyaluronic acid and a polymer, which is substantially unmodified with a chemical cross-linking agent or a chemical modifying agent, will supplement the inherent properties of a hyaluronic acid gel such as strength, adhesiveness, viscosity and elasticity and also will satisfy the physical properties required for a medical material which can hardly be satisfied by a hyaluronic acid gel alone, and it can simply be prepared and has ideal biocompatibility and retention property as a medical material, and they have arrived at the present invention.
Especially when carboxymethyl cellulose is employed as the polymer of this hyaluronic acid gel composition, the composition is particularly suitable as an adhesion preventive or a wound dressing.
DISCLOSURE OF THE INVENTION
Namely, the present invention is (1) a hyaluronic acid gel composition comprising hyaluronic acid and a polymer, which is substantially unmodified with a chemical cross-linking agent or a chemical modifying agent and which has a percentage dissolution of hyaluronic acid of 50% or lower in 12 hours in a neutral aqueous solution of 37° C., (2) the hyaluronic acid gel composition according to (1), wherein the polymer is carboxymethyl cellulose, (3) a process for producing a hyaluronic acid gel composition, which comprises freezing an aqueous solution or dispersion containing hyaluronic acid and a polymer and having a pH of 3.5 or lower, followed by unfreezing to form a hyaluronic acid gel composition, (4) a process for producing a hyaluronic acid gel composition, which comprises freezing an aqueous solution containing hyaluronic acid and having a pH of 3.5 or lower, followed by unfreezing to form a hyaluronic acid gel, and mixing the hyaluronic acid gel with a polymer or a polymer gel to form a hyaluronic acid gel composition, (5) the process for producing a hyaluronic acid gel composition according to (3) or (4), wherein the polymer is at least one member selected from the group consisting of polysaccharides, proteins, nucleic acids and synthetic polymers, (6) the process for producing a hyaluronic acid gel composition according to (3) or (4), wherein the polymer is carboxymethyl cellulose, (7) a medical material containing the hyaluronic acid gel composition as defined in (1) or (2), (8) a medical material containing a hyaluronic acid gel composition which is obtained by irradiating or injecting one member selected from the group consisting of gamma rays, electron rays, plasma or EOG to a hyaluronic acid gel composition, (9) the medical material according to (7), wherein the material is an adhesion preventive, and (10) the medical material according to (7), wherein the medical material is a wound dressing.
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the present invention will be described in detail.
In the present invention, modification means cross-linking or chemical modification to make naturally water-soluble hyaluronic acid or polymer to be hardly soluble.
The hyaluronic acid gel composition of the present invention can be obtained by freezing an aqueous solution or dispersion having a pH of 3.5 or lower containing hyaluronic acid and a polymer, followed by unfreezing and by neutralization, washing and drying.
Further, the hyaluronic acid gel composition of the present invention can be obtained by freezing an aqueous solution containing hyaluronic acid and having a pH of 3.5 or lower, followed by unfreezing to obtain a hyaluronic acid gel, which is then pulverized and put, together with a polymer gel, into an aqueous solution such as water, followed by pulverization, dispersion and drying.
With these hyaluronic acid gel compositions, the mechanical strength and the tissue bondability can simply be improved as compared with a case of the hyaluronic acid gel alone.
Any acid may be used as the acid to be employed to adjust the pH of the aqueous solution of hyaluronic acid and the polymer, so long as it is an acid capable of adjusting the pH to a level of 3.5 or lower. In order to reduce the amount of the acid, it is preferred to use a strong acid such as hydrochloric acid, nitric acid or sulfuric acid.
For freezing and unfreezing, an operation wherein a acidic aqueo
Arai Kazuhiko
Hashimoto Masamichi
Himeda Yasukazu
Miyata Yoshiaki
Umeda Toshihiko
Denki Kagaku Kogyo Kabushiki Kaisha
George Konata M.
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Page Thurman K.
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