Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2001-05-10
2003-10-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S423000, C424S426000, C424S484000, C424S485000, C424S078080, C424S078170, C514S054000
Reexamination Certificate
active
06635267
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel hyaluronic acid gel with fluidity or with fluidity and transparency and a method of its production, and further, to a biomedical material with good biocompatibility.
BACKGROUND ART
Hyaluronic acid (hereinafter referred to simply as HA) is a linear macromolecular polysaccharide consisting of alternately bonded &bgr;-D-N-acetylglucosamine and &bgr;-D-glucuronic acid. HA is found not only in connective tissues of mammals but also in cockscombs and the capsules of Streptococci. HA is obtainable not only by extraction from cockscombs and umbilical cords, but also as purified products from the culture broth of streptococci.
Natural HA is polydisperse in respect of molecular weight and is known to show excellent biocompatibility even when implanted or injected into the body by virtue of the absence of species and organ specificity. However, because of the relatively short in vivo residence time of HA solution in biological application, improvement of the persistency of HA by chemical crosslinking with various chemical modifiers has been attempted to broaden its use for medical materials.
(I) Concerning the joints, synovial fluid supplies nutrition to the articular cartilage and has incomparable functions as a lubricant and a shock absorber. It is clarified that its excellent viscoelastisity heavily owes to one of the main components, HA.
Concentration and molecular weight analyses of HA demonstrated the concentration and molecular weight of HA in the synovial fluid from patients with arthritis such as osteoarthritis and chronic articular rheumatism generally tended to lower than in normal synovial fluid, and the lower concentration and molecular weight of HA were closely associated with development of locomotor dysfunction and pain attributable to the weaker lubricating action and the weaker protecting action on the surface of the articular cartilage of synovial fluid.
Injection of high molecular weight HA solution (Artz: from Seikagaku Corporation, average molecular weight 900000; Hyalgan: from Fidia, average molecular weight <500000) into diseased joints has been widely adopted as an effective measure for osteoarthritis among those articular diseases, and the source of high purity HA preparations for this purpose is cockscombs. Such HA preparations from cockscombs are biologically inherent and quite safe but usually have to be administered as frequently as several to 10 times to show significant therapeutic effect.
Persistency tests on rabbits revealed that HA with a molecular weight of less than 1000000 administered into the knee joint cavities disappeared from the knee joint cavities in 1 to 3 days and suggested the need of frequent administrations (Blood Coagulation and Fibrinolysis, vol 12, 173, 1992).
On the other hand, the molecular weight of HA found in the living body is reported to be as high as millions to 10000000, and a crosslinked HA derivative [Hylan: from Biomatrix] obtained by treatment with a chemical crosslinker has been developed as a therapeutic agent for knee joints with the idea that high molecular weight HA closer to the biologically intact one is likely to have higher effect.
Reportedly, the crosslinked HA persisted for a period as long as 20 to 30 days after administration into rabbit knee joint cavities in the above-mentioned persistency tests and produced sufficient effect when administered three times in clinical tests, and is practically used as a therapeutic agent for arthritis (Journal of Theumatology vol.20, 16, 1993).
(II) Next, concerning emboli, treatments through embolization are known to effective for various diseases such as angiopathy, paraplastic aneurysm and varix. Obstruction of arteries as the nourishing channels for tumours is also effective in tumour treatment.
Some proposals have been made for embolization. For example, a balloon embolization method using a balloon-tip catheter has been developed (W. Taki et al., Surg. Neurol, Vol.12, 363, 1979). In addition, a method in which 2-hydroxyethyl methacrylate (HEMA) is introduced into a balloon together with a polymerization catalyst through a catheter is also known (W. Taki et al., Surg. Neurol, Vol.13, 140, 1980).
For cancer treatment through embolization, use of cisplatin-containing chitin (Tahara et al., Cancer and Chemotherapy, vol.21(13), 2225, 1994), use of poly(benzyl 1-glutamate) microspheres carrying cisplatin (Li C et al., Parm, Res., Vol.11(12), 1792, 1994) and use of SMANCS and Lipiodol suspension together with gelatin sponge as a embolizing material (Nakamura et al., Cancer and Chemotherapy, vol.22(11), 1390, 1996) have been reported. In addition, Poly(DL-lactate) microspheres are reported as a suitable material for use in embolismic chemotherapy in combination with continuous injection of a chemotherapeutic agent (Flandroy P et al., J Control Release, Vol.44(2/3), 153, 1997) while it is mentioned that they have to biodegrade in a couple of days so that when this therapy is practiced repeatedly.
There are a lot of problems such as the short time obstruction in the balloon embolization due to shriveling of the balloon as a bar to production of satisfactory effect and the possibility of polymerization of monomers such as HEMA inside the catheter. Most embolizing materials used in embolismic chemotherapy are synthetically available and hardly biodegradable and doubtful in respect of biocompatibility. Poly(DL-lactate) microspheres, though biodegradable, do not guarantee complete safety when repeatedly administered.
Though highly biocompatible HA has no problem with safety, HA does not embolize when merely administered in the form of solution, and is required to have improved local persistency.
(III) Concerning soft tissues, the idea of injecting various materials to repair or swell soft tissues has rapidly developed since the invention of the subcutaneous injection needle, and a number of materials have been injected into human bodies to remedy soft tissues and skins. Among them, liquid silicone has been used widely for injection but is not used as much recently as it used to be due to its side effects such as skin ulceration attributable to its long retention time. Collagen has also been injected so far in various forms such as chemically crosslinked forms and fibrous forms. Crosslinked solid collagen requires incision to be injected and has problems plasticity and flexibility. There is a disclosure about fibrous collagen in U.S. Pat. No. 3949073.
However, it shrinks in volume as its liquid components are absorbed and has to be supplemented. Injectable types of collagen like this can hardly be freed of contaminants such as immunity substances, are costly and do not necessarily have appropriate physical properties.
HA has also been attempted as an injection for soft tissues (Ann. Plast. Surg., Vol.38, 308, 1997). Because HA in solution is rapidly absorbed in vivo, various methods for chemical crosslinking of HA have been attempted to improve persistency and retention in soft tissues (U.S. Pat. No. 4582865, JP-B-6-37575, JP-A-7-97401, JP-A-60-130601).
And hylan B gel is commercially available as Hylaform in Europe (The Chemistry Biology and Medical Application of Hyaluronan and its Derivatives Vol.72, p278, PORTLAND PRESS).
(IV) Next, reference will be made to the posterior part of the eyeball, especially the retina bordered on the vitreous body. The retina marks the posterior boundary of the intraocular space, while the lens and the ciliary body mark the anterior boundary. The retina consists of two layers, the receptor layer of photosensitive cells in contact with the vitreous humor and the layer of pigment epithelial cells adjacent to the choroid. Liquid infusion into the receptor layer causes retinal detachment, separating the two layers of the retina.
For treatment of retinal detachment, the peeled retina is brought into contact with the pigmented epithelial layer and fastened by photocoagulation or cryocoagulation. The contact is achieved by pressing a inward buckle against the sclera and the choroids from
Arai Kazuhiko
Kaneko Hiroshi
Kitagawa Hironoshin
Miyoshi Teruzou
Umeda Toshihiko
Denki Kagaku Kogyo Kabushiki Kaisha
Di Nola-Baron Liliana
LandOfFree
Hyaluronic acid gel, process for the preparation thereof and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hyaluronic acid gel, process for the preparation thereof and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hyaluronic acid gel, process for the preparation thereof and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3160535