Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Processes of preparing a desired or intentional composition...
Reexamination Certificate
1998-05-15
2002-07-09
Szekely, Peter (Department: 1714)
Synthetic resins or natural rubbers -- part of the class 520 ser
Synthetic resins
Processes of preparing a desired or intentional composition...
C424S423000, C424S426000, C523S113000, C523S114000, C523S218000, C524S055000, C524S555000, C524S556000, C524S916000, C524S027000, C536S020000, C536S114000
Reexamination Certificate
active
06417247
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for constructing an implant by placement of a paste comprising a stimuli sensitive polymer solution carrying a biocompatible ceramic component which hardens under physiological conditions to form a solid implant. The implant may also include a therapeutic agent or a radioisotope.
BACKGROUND OF THE INVENTION
Many researchers have experimented with drug delivery vehicles based on the use of controlled release implant materials. Others have sought to provide improved implants for filling in tissue losses from age or trauma, to hard or soft tissues. Calcium phosphate pastes have been suggested as bone and dental fillers. Gels have been used as control release devices and as fillers. Representative studies are discussed below.
In U.S. Pat. No. 4,188,373, certain polyols are used in aqueous compositions to provide thermally gelling aqueous systems. In these systems, the sol-gel transition temperature can be changed by manipulating the concentration of polymer. In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822 drug delivery systems are described which utilize thermosetting gels. In these systems, both the gel transition temperature and/or the rigidity of the gel can be modified by adjustment of the pH and/or the ionic strength, as well as by the concentration of the polymer. U.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760, and 4,911,926 also disclose gels that deliver pharmaceutical compositions.
In U.S. Pat. No. 4,895,724, compositions are disclosed for the controlled release of pharmacological macromolecular compounds contained in a matrix of chitosan. Chitosan can be cross-linked utilizing aldehydes, epichlorohydrin, benzoquinone, etc. In U.S. Pat. No. 4,795,642, discloses gelatin-encapsulated, controlled-release pharmaceutical compositions, wherein the gelatin encloses a solid matrix formed by the cation-assisted gelation of a liquid filling composition incorporating a vegetable gum together with a pharmaceutically-active compound. The vegetable gums are disclosed as polysaccharide gums such as alginates which can be gelled utilizing a cationic gelling agent such as an alkaline earth metal cation.
Osmotic drug delivery systems are disclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chamber compartment for holding osmotic agents, adjuvants, enzymes, drugs, pro-drugs, pesticides, and the like. These materials are enclosed by semipermeable membranes so as to allow the fluids within the chambers to diffuse into the environment into which the osmotic drug delivery system is in contact. U.S. Pat. No. 5,587,175 teaches a process for forming a protective corneal shield or an ablatable corneal shield or mask in situ comprising administering to the eye of a mammal an aqueous composition capable of being gelled in situ to produce an hyper osmotic, hypo osmotic, or iso osmotic aqueous gel having a controlled pH, said aqueous composition, including at least one film forming polymer; and gelling said film forming polymer in situ to form said protective corneal shield or ablatable corneal shield or mask.
U.S. Pat. No. 3,949,073 discloses injectable atelocollagen solutions which precipitate at body temperature, thus leading to the formation of fibers which remain at the injection site whereas the excipient is progressively resorbed. U.S. Pat. No. 5,658,593 in one embodiment provides micro capsules based on atelocollagen optionally mixed with a glycosaminoglycan such as chondroitin-4-sulfate, the micro capsules containing granules of hydroxyapatite in suspension in a viscous bio compatible carrier solution of a gel of atelocollagen optionally mixed with a glycosaminoglycan, in particular chondroitin-4-sulfate, for use as a filler material in forming injectable implants.
U.S. Pat. No. 5,626,861 teaches a method for the fabrication of three-dimensional macro porous polymer matrices for use as bone graft or implant material was developed. The composites are formed from a mixture of biodegradable, bio compatible polymer and hydroxyapatite (HA), a particulate calcium phosphate ceramic. The method leaves irregular pores in the composite between 100 and 250 microns in size by formation of a solid gel comprising a soluble material and dissolving the material to form voids in the gel. In a preferred embodiment, implants are composed of a 50:50 poly(lactide-co-glycolide) (PLGA) polymer and reinforced by hydroxyapatite. Mechanical and histological analysis showed the matrix fabricated by this method to be structurally and mechanically similar to cancellous bone. Prior to degradation, pure polymer specimens exhibited an elastic modulus of 293 MPa and specimens which were 50% HA by weight exhibited a modulus of 1459 MPa. After six weeks of degradation under physiological conditions, the reinforcing effect of ceramic loading had diminished. Modulus of polymer matrices at all HA load levels had decreased sharply to approximately 10 MPa. Mean macro- and micro pore diameters of the polymer specimens were 100 mu m and 20 mu m respectively and remained constant throughout degradation. The implants are hardened, leached and then implanted into the subject where they are slowly degraded by natural bodily action over a period of time. The implant size and shape must be predetermined and thus may not perfectly fit the site to be repaired.
B. R. Constantz, et als, 1995, Skeletal Repair by in Situ Formation of the Mineral Phase of Bone,
Science,
267:1796-1799. Discloses a process for the surgical implantation of a paste that hardens in minutes under physiological conditions. The mixture comprises a mixture of calcium phosphates and sodium phosphate, and hardens due to the crystallization of dahlite, not mediated by a stimulus setting gel. The mixture hardens regardless of whether it is placed in the body. The paste is a hydroxyapatite precursor and does not include gel components.
B. Flautre, et als, 1996, Evaluation of Hydroxyapatite Powder Coated with Collagen as an Injectable Bone Substitute: Microscopic Study in Rabbit,
J. Materials Science:Materials in Medicine,
7:63-67, discloses an injectable mix of hydroxyapatite and collagen but there is no disclosure of providing a stimulus response setting material. The group uses HA and atecollegen and chondrotin-4-sulfate formulated as micro spheres, similar to the patents discussed above. There is no provision for a gel which forms in response to a stimulus provided by exposure to the environment of the body, and there is no provision for differential loss of materials to provide a porous matrix. A further study by the same group, G. Pasquier, et als, 1996, Injectable Percutaneous Bone Biomaterials: an Experimental Study in a Rabbit Model,
J. Materials Science:Materials in Medicine,
7:683-690, discloses mixtures comprising an orthopaedic acrylic cement (polymethylmethacrylate (“PMMA”)) and HA as well as HA and collagen. The PMMA was used as a reference bio-inert material. There is no disclosure of a stimulus setting gel for producing a composite which only hardens in response to a stimulus supplied by the body.
M. Ito, et als, 1994, Experimental Development of a Chitosan-bonded &bgr;-Tricalcium Phosphate Bone Filling Paste,
Bio
-
Medical Materials and Eng.,
4:439-499, discloses a composite of chitosan and tricalcium phosphate containing alkaline oxides of calcium, magnesium or zinc, which provided the conditions to produce setting. Again the material hardens without regard to stimulus supplied from the body. A similar study is reported by M. Takechi, et als, 1996, Non-decay Type Fast-setting Calcium Phosphate Cement Using Chitosan,
J. Materials Science:Materials in Medicine,
7:317-322. Takechi uses sodium alginate or chitosan as a water insoluble gel to protect calcium phosphate cements from decay during setting under physiological conditions. In these materials the cements set as they normally do and the gel forms in response to the calcium provided by the cement. Again there is no gel formation in response to a physiological stimulus for the composite material.
There is a
Armstrong Beth L.
Campbell Allison A.
Gutowska Anna
Song Lin
May Stephen R.
Szekely Peter
Zimmerman Paul W.
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