Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Rod – strand – filament or fiber
Reexamination Certificate
2000-06-14
2001-07-03
Acquah, Samuel A. (Department: 1711)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Rod, strand, filament or fiber
C528S486000, C528S487000, C525S054110, C525S054400, C428S357000, C428S364000, C530S342000, C530S345000, C530S353000, C530S356000, C530S357000
Reexamination Certificate
active
06254986
ABSTRACT:
FIELD OF INVENTION
This invention pertains to surface and bulk modified proteins and synthetic polypeptides with improved properties over their unmodified counterparts. Specifically, this invention describes proteins and synthetic polypeptides acylated with alkyl- and/or alkenyl-succinic and other similarly substituted cyclic anhydrides under practically unhydrous conditions. The peracylated proteins and polypeptides, subject of this invention, may be used as (a) biodegradable film or fiber-formers made by tradition melt-processing; (b) carriers for the controlled delivery of drugs; (c) a prodrug for prolonged bioavailability of the active drug; and (d) water-repellent wool fabric and leather goods.
DESCRIPTION OF PRIOR ART
Modification of proteins have long been practiced mostly in the leather, pharmaceutical, and textile industries to achieve certain desirable properties (Carter, 1971; Moncrief, 1975). However, with the exception of a disclosure made by one of the inventors on the acylation of isolated soy protein (ISP) using substituted cyclic anhydrides, all pertinent modifications of the prior art to this invention have been limited to acylation with fatty acids and unsubstituted succinic acid. Typical examples of the pertinent prior art include (a) the acylation of insulin with fatty acid derivatives based on up to 7 carbon atoms and higher acids (Asada et al, 1994; Lindsay et al, U.S. Pat. No. 3,950,517) to increase its stability in the biological environment; (b) acylation of insulin with C
2
to C
18
fatty acid to prolong its biological activity and increase its transcutaneous mobility under iontophoretic conditions (Njieha & Shalaby, 1992a); (c) acylation of insulin with succinic anhydride to increase its transcutaneous mobility under iontophoretic conditions (Corbett et al, 1996); (f) acylation of epidermal growth factor (EGF) with long-chain fatty acids to improve its enzymatic stability (Njieha & Shalaby, 1991, 1992b).
SUMMARY OF THE INVENTION
This invention deals with useful derivatives of proteins and synthetic polypeptides, which can be formed by solution, microdispersion, or surface peracylation with alkyl- and alkenyl-substituted anhydrides, such as those of succinic anhydride. Typical examples of derivatives formed by peracylation include those of (a) isolated soy protein (ISP), which are thermoplastic material capable of melt-processing to biodegradable films, rods, and fibers; (b) albumin, which are water insoluble materials for use as drug carriers; (c) casein and zein, which are water insoluble, biodegradable material for use as drug carriers and film formations; and (d) insulin for prolonged control of hyperglycemia. Examples of surface acylated proteins include: (a) surface-treated collagen-based substrates such as sutures for improved in vivo strength retention; (b) leather goods for improved water repellency; and (c) wool and silk fabrics for improved water repellency. Typically, the peracylation is conducted using one or more type of alkyl and/or alkenyl-anhydride in practically non-aqueous medium and, preferably, in the presence of an acidic catalyst. Bioactive proteins and synthetic polypeptides can similarly be modified to prolong their in vivo biological activities.
DETAILS OF THE INVENTION
This invention deals with solution microdispersion or surface peracylation of proteins such as isolated soy protein, ricin A-chain, albumin, casein, zein, &agr;-keratin, silk, insulin, epidermal growth factor and collagen as well as synthetic polypeptides, such as somatostatin and LHRH, where each of the acylated heterochain molecules carries at least two alkyl- or alkenyl-succinamide or glutaramide or their corresponding imido species. Sufficient amounts of anhydrides are used to achieve more than two acylations per heterochain molecule (e.g., a protein or synthetic polypeptide chain, peracylated denotes having at least two acyl moieties per heterochain). The acylation results primarily in amide-acid side or terminal groups and can be further cyclized to imide groups upon thermal treatment. Depending on the type of heterochain to be acylated and whether the substrate is fully or partially subjected to the acylation process, outcomes of the acylation can vary. In one instance, the substrate is an ISP and the acylated product differs from the parent molecule in being less hydrophilic, practically water insoluble, and melt-processable. Subsequent melt-extrusion and compression molding of the modified ISP result in fibers and films, respectively. The fibers can be oriented by unidirectional drawing to improve their tensile properties. Similarly, the resulting films can be oriented by constrained, unidirectional or biaxial solid state compression (as described by Shalaby et al, 1996). Both the resulting films and fibers made from acylation ISP are degradable by microorganisms. A typical acylation scheme of ISP is described in Example 1. Molding of typical samples of acylated ISP and properties of the resulting films are given in Example 2.
In a second embodiment of this invention, zein is peracylated with substituted cyclic anhydrides to produce water-insoluble, melt-processable materials for use in the production of biodegradable fibers and films as well as controlled delivery systems of pharmaceuticals and pesticides.
In a third embodiment of this invention, casein is peracylated with substituted cyclic anhydrides to produce melt-processable thermoplastic materials for use in the production of biodegradable fibers, films or carriers for controlled delivery of pharmaceuticals and pesticides.
In a fourth embodiment of this invention, bovine albumin is peracylated to produce practically water insoluble film-forming derivatives, which are biodegradable and can be used as: (a) carriers for the controlled release of traditional organic drugs, pesticides, synthetic peptides, and bioactive proteins; and (b) capsules for oral administration of drugs.
In a fifth embodiment of this invention, insulin molecules are peracylated to (a) reduce their solubility and tendency to dimerize or polymerize; (b) regulate their bioavailability for being in the form of a prodrug; and (c) increase their enzyme stability and, hence, prolong their activity. Growth factors with similar functionalities to insulin can also be acylated to increase their stability against enzymatic degradation and, hence prolong their biological effects. These include fibroblast-derived growth factor (PdGF) and epidermal growth factor (EGF).
In a sixth embodiment of this invention, surface peracylation of silk collagen sutures and fabric or wool fabrics is performed to increase their water repellency and minimize reduction of their tensile strength in a moist environment. Similarly, surface acylation can be used to (a) increase the water repellency of leather goods and improve its frictional properties, and (b) decrease swelling of collagen suture and, hence, maintain its wet strength and improve its tie-down characteristics.
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patent: 4045239 (1977-08-01), Hammer et al.
patent: 5070188 (1991-12-01), Njieha et al.
patent: 5216125 (1993-06-01), Kouge
patent: 5260396 (1993-11-01), Kroner et al.
patent: 5405766 (1995-04-01), Kallury et al.
patent: 5468843 (1995-11-01), Boyd et al.
patent: 5523293 (1996-06-01), Jane et al.
patent: 5677422 (1997-10-01), Safarian et al.
patent: 5700904 (1997-12-01), Baker et al.
Allan Jacqueline M.
Corbett Joel T.
Shalaby Shalaby W.
Acquah Samuel A.
Gregory Leigh P.
Poly-Med, Inc.
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